@article {pmid35595404,
year = {2022},
author = {Zúñiga Santamaría, T and Yescas Gómez, P and Fricke Galindo, I and González González, M and Ortega Vázquez, A and López López, M},
title = {Pharmacogenetic studies in Alzheimer disease.},
journal = {Neurologia (Barcelona, Spain)},
volume = {37},
number = {4},
pages = {287-303},
doi = {10.1016/j.nrleng.2018.03.022},
pmid = {35595404},
issn = {2173-5808},
abstract = {INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.<br><br>DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.<br><br>CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.},
}
@article {pmid35480186,
year = {2021},
author = {El-Hawwary, SS and Abd Almaksoud, HM and Saber, FR and Elimam, H and Sayed, AM and El Raey, MA and Abdelmohsen, UR},
title = {Green-synthesized zinc oxide nanoparticles, anti-Alzheimer potential and the metabolic profiling of Sabal blackburniana grown in Egypt supported by molecular modelling.},
journal = {RSC advances},
volume = {11},
number = {29},
pages = {18009-18025},
pmid = {35480186},
issn = {2046-2069},
abstract = {Nowadays, the biosynthesis of metal nanoparticles, particularly from plants, has been gaining interest. In the present work, the methanolic extracts of leaves, fruits, and the pollen grains of Sabal blackburniana were used for the green synthesis of ZnO nanoparticles, which were early detected by the formation of precipitate and further confirmed by UV-vis spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infra-red (FT-IR) spectroscopy and zeta potential (ZP) studies. TEM analysis has shown different shapes, predominantly irregular small spherical narrow particles included in hexagonal structures with size ranging from 2.23 to 49.56 nm. The XRD pattern confirmed that all synthesized ZnO nanoparticles have wurtzite hexagonal structure with crystalline nature. The average particle crystallite sizes were 47.21, 47.67 and 47.8 nm. The UV-visible spectra showed λ max in the range of 354-368 nm, which indicated the presence of ZnO nanoparticles. The FT-IR analysis identifies the characteristic functional groups present on the surface of ZnO nanoparticles. The ZP determination demonstrated that all representative selected synthesized ZnONPs exhibited acceptable ZP values of -30.8 to -45.9 mV, which indicated their good stability. In addition, the anti-Alzheimer potential of the selected extracts and ZnONPs was evaluated by assessing acetylcholinesterase inhibitory activity in vitro according to the improved Ellman method. The results indicated that the selected extracts have acetylcholinesterase inhibitory activity, and highlighted the promising inhibitory potential of green-synthesized ZnONPs using pollen grains, fruits and leaves extracts; they exhibited a potent inhibitory effect with IC50 values 63.78 ± 1.04651, 81.985 ± 3.075 and 117.95 ± 6.858 ng ml-1 respectively in comparison to donepezil as standard (IC50 = 50.7 ± 5.769 ng ml-1). Dereplication analysis of the selected extracts was performed using LC-MS; metabolic profiling revealed the presence of 41 compounds belonging to various chemical classes: flavonoids, steroidal saponins, terpenoids, alkaloids, lignans, sterols and fatty acids. Docking these dereplicated metabolites against the human AChE showed that the non-glycosylated flavonoid class of compounds was able to achieve interesting binding modes inside the AChE active site; they are suggested to be associated with the observed anti-AChE activity of Sabal extracts. This study is the first report to shed light on the acetylcholinesterase inhibitory activity of green-synthesized ZnO nanoparticles of S. blackburniana metabolites.},
}
@article {pmid35470341,
year = {2022},
author = {Gallacher, J and Pickering, J and Bayer, A and Heslop, L and Morgan, G and Watkins, A and Martin, R and Elwood, P},
title = {Amateur Boxing and Dementia: Cognitive Impairment Within the 35-Year Caerphilly Cohort Study.},
journal = {Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine},
volume = {32},
number = {3},
pages = {329-333},
doi = {10.1097/JSM.0000000000000976},
pmid = {35470341},
issn = {1536-3724},
mesh = {*Boxing ; *Cognition Disorders ; *Cognitive Dysfunction ; Cohort Studies ; *Dementia/diagnosis/epidemiology/psychology ; Humans ; Male ; Prospective Studies ; },
abstract = {OBJECTIVE: To examine the long-term effects of amateur boxing in a representative population sample of men.<br><br>DESIGN: The sample was examined every 5 years for 35 years. Cognition was assessed repeatedly from the third examination. Previous boxing experience and dementia were assessed at the fifth examination, and dementia assessed subsequently through medical records.<br><br>The Caerphilly Prospective Study investigates risk factors for a range of chronic diseases of diseases. These include life style and behavior, together with biological factors relevant to vascular disease.<br><br>PARTICIPANTS: 1123 adult men aged 45 to 59 years at baseline, followed for 35 years.<br><br>MAIN OUTCOME MEASURES: Cognitive impairment.<br><br>RESULTS: A report by a subject of having boxed "seriously" when younger was associated with a 2-fold increase in cognitive impairment [odds ratio (OR) = 2.27; 95% confidence intervals = 1.18-4.38]. For amnestic (Alzheimer-like) impairment, this rises to OR = 2.78 (95% confidence limits 1.37-5.65). Having boxed is associated with an "advancement" in the onset of the dementia (4.8 years; 95% confidence limits 0.9-8.8 years).<br><br>CONCLUSIONS: Amateur boxing is associated with an increased risk and an earlier onset of cognitive impairment and dementia.},
}
@article {pmid35310894,
year = {2021},
author = {Kuchta, K and Aritake, K and Urade, Y and Tung, NH and Yuan, CS and Sasaki, Y and Shimizu, K and Shoyama, Y},
title = {Preventing Dementia Using Saffron, The Kampo Medicine, Kamiuntanto, and Their Combination, Kamiuntantokabankoka.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {779821},
pmid = {35310894},
issn = {1663-9812},
abstract = {The objective of this review is to evaluate the anti-dementia activities of saffron and its combination with Kampo medicine. The Kampo formula Kamiuntanto composed of 13 crude drugs is well known for its anti-dementia activity. A significant increase in choline acetyltransferase activity and mRNA levels were observed. Polygala radix was identified as the most essential component drug in Kamiuntanto, probably due to the saponins, tenuifolin, and sinapinic acid. Ginseng was also identified as an essential Kamiuntanto component in terms of its synergistic functions with Polygala radix. Saffron, which was recommended in the Bencao Gangmu for memory and dementia, and is used as an anti-spasmodic, anti-catarrhal, and sedative herbal drug. Saffron and its major constituent, crocin were shown to enhance learning-memory, non-rapid eye movement (rem) sleep, and inhibit depression and neuronal cell death due to strong anti-oxidant and anti-inflammation activities. In addition based on the epidemiological studies such as the treatment of sleeping disorders and the clinical trials of saffron for Alzheimer patients, we demonstrated the indirect and direct anti-dementia activities of crocin and saffron.},
}
@article {pmid35295247,
year = {2021},
author = {Wolfe, MS},
title = {Targeting γ-Secretase for Familial Alzheimer's Disease.},
journal = {Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents},
volume = {30},
number = {7},
pages = {1321-1327},
pmid = {35295247},
issn = {1054-2523},
support = {R01 AG066986/AG/NIA NIH HHS/United States ; },
abstract = {Familial Alzheimer's disease (FAD) is a rare early-onset genetic form of a common dementia of old age. Striking in middle age, FAD is caused by missense mutations in three genes: APP (encoding the amyloid precursor protein) and PSEN1 and PSEN2 (encoding presenilin-1 and presenilin-2). APP is proteolytically processed successively by β-secretase and γ-secretase to produce the amyloid β-peptide (Aβ). Presenilin is the catalytic component of γ-secretase, a membrane-embedded aspartyl protease complex that cleaves APP within its single transmembrane domain to produce Aβ of varying lengths. Thus, all FAD mutations are found in the substrate and the enzyme that produce Aβ. The 42-residue variant Aβ42 has been the primary focus of Alzheimer drug discovery for over two decades, as this particular peptide is highly prone to aggregation, is the major protein deposited in the characteristic cerebral plaques of Alzheimer's disease, and is proportionately elevated in FAD. Despite extensive efforts, all agents targeting Aβ and Aβ42 have failed in the clinic, including γ-secretase inhibitors, leading to questioning of the amyloid hypothesis of Alzheimer pathogenesis. However, processing of the APP transmembrane domain by γ-secretase is complex, involving initial endoproteolysis followed by successive carboxypeptidase trimming steps to secreted Aβ peptides such as Aβ42. Recent findings reveal that FAD mutations in PSEN1 and in APP result in deficient trimming of initially formed long Aβ peptides. A logical drug discovery strategy for FAD could therefore involve the search for compounds that rescue this deficient carboxypeptidase activity. The rare early-onset FAD arguably presents a simpler path to developing effective therapeutics compared to the much more complex heterogeneous sporadic Alzheimer's disease.},
}
@article {pmid35279225,
year = {2022},
author = {Garfias, S and Tamaya Domínguez, B and Toledo Rojas, A and Arroyo, M and Rodríguez, U and Boll, C and Sosa, AL and Sciutto, E and Adalid-Peralta, L and Martinez López, Y and Fragoso, G and Fleury, A},
title = {Peripheral blood lymphocyte phenotypes in Alzheimer and Parkinson's diseases.},
journal = {Neurologia (Barcelona, Spain)},
volume = {37},
number = {2},
pages = {110-121},
doi = {10.1016/j.nrleng.2018.10.022},
pmid = {35279225},
issn = {2173-5808},
mesh = {*Alzheimer Disease ; CD4-Positive T-Lymphocytes ; Flow Cytometry ; Humans ; *Parkinson Disease ; Phenotype ; },
abstract = {INTRODUCTION: Neuroinflammation is involved in the pathophysiology of various neurological disorders, in particular Alzheimer disease (AD) and Parkinson's disease (PD). Alterations in the blood-brain barrier may allow peripheral blood lymphocytes to enter the central nervous system; these may participate in disease pathogenesis.<br><br>OBJECTIVE: To evaluate the peripheral blood lymphocyte profiles of patients with AD and PD and their association with the disease and its progression.<br><br>METHODS: The study included 20 patients with AD, 20 with PD, and a group of healthy individuals. Ten of the patients with AD and 12 of those with PD were evaluated a second time 17 to 27 months after the start of the study. Lymphocyte subpopulations and their activation status were determined by flow cytometry. All patients underwent neurological examinations using internationally validated scales.<br><br>RESULTS: Compared to healthy individuals, patients with AD and PD showed significantly higher levels of activated lymphocytes, lymphocytes susceptible to apoptosis, central memory T cells, and regulatory T and B cells. As the diseases progressed, there was a significant decrease in activated cells (CD4+ CD38+ and CD8+ CD38+ in PD and AD, CD4+ CD69+ and CD8+ CD69+ in PD), T cells susceptible to apoptosis, and some regulatory populations (CD19+ CD5+ IL10+ in PD and AD, CD19+ CD5+ IL10+ FoxP3+, CD4+ FoxP3+ CD25+ CD45RO+ in PD). In patients with AD, disease progression was associated with lower percentages of CD4+ CD38+ cells and higher percentages of effector CD4 cells at the beginning of the study. Significant differences were observed between both diseases.<br><br>CONCLUSIONS: This study provides evidence of changes in peripheral blood lymphocyte phenotypes associated with AD and PD and their severity. Considering effective blood-brain communication, our results open new avenues of research into immunomodulation therapies to treat these diseases.},
}
@article {pmid35273492,
year = {2021},
author = {Efjestad, AS and Ihle-Hansen, H and Hjellvik, V and Engedal, K and Blix, HS},
title = {Use of Drugs With Risk of Heart Rate-Related Problems is Common in Norwegian Dementia Patients Treated With Acetylcholinesterase Inhibitors: A Prevalence Study Based on the Norwegian Prescription Database.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {791578},
pmid = {35273492},
issn = {1663-9812},
abstract = {Background: Drugs commonly prescribed for heart rate control may induce adverse drug reactions in Alzheimer patients treated with acetylcholinesterase inhibitors (AChEIs). We have studied use of drugs with a known risk of Torsades de pointes (TdP) and drugs used to treat behavioral and psychological symptoms of dementia, as well as a combination of drugs with a known risk of TdP and drugs with a known heart rate-lowering effect, before and after initiating treatment with AChEIs. Methods: The study applied data from the Norwegian Prescription Database for the period 2004-2016. Prescriptions of concomitant use of drugs in persistent users of AChEIs was studied in a follow-up period from 4 years before to 2 years after AChEI initiation in men and women of two age groups: 37-80 and 81-88 years. Results: A small number of patients were prescribed haloperidol (∼1.5% The second year after AChEI initiation), digoxin/digitoxin (∼3%), and verapamil (∼1.3%), while a substantial proportion of the patients were prescribed betablockers (∼28%) and citalopram/escitalopram (∼17%). During follow-up, up to 6% of the study population were prescribed both betablockers and citalopram/citalopram in addition to AChEIs, a combination that increased over the follow-up period and was observed most frequently in women in the oldest age group. Conclusions: A large proportion (∼44%) of patients treated with AChEIs were prescribed drugs that could cause bradycardic and prolonged time from the start of the Q wave to the end of the T wave (QT interval). Thus, action should be taken to reduce the combination of drugs with risk of bradycardia and prolonged QT interval. Medication review on a regular basis could be an option as an important risk-reducing intervention.},
}
@article {pmid35199552,
year = {2021},
author = {Rauchová, H},
title = {Coenzyme Q10 effects in neurological diseases.},
journal = {Physiological research},
volume = {70},
number = {Suppl4},
pages = {S683-S714},
pmid = {35199552},
issn = {1802-9973},
mesh = {Animals ; Antioxidants/pharmacology ; Electron Transport ; Humans ; Mitochondria/metabolism ; *Mitochondrial Diseases/metabolism ; *Nervous System Diseases/drug therapy/metabolism ; Ubiquinone/analogs &amp; derivatives/therapeutic use ; },
abstract = {Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).},
}
@article {pmid35194452,
year = {2021},
author = {Rahimpour, Y and Delazar, A and Asnaashari, S and Asgharian, P},
title = {The Genus Ferulago: A Review on Ethnopharmacology, Phytochemistry, and Pharmacology.},
journal = {Iranian journal of pharmaceutical research : IJPR},
volume = {20},
number = {4},
pages = {352-377},
pmid = {35194452},
issn = {1735-0328},
abstract = {The Ferulago genus appertains to the Umbelliferae family comprises 49 species which are mainly distributed in Asia, Europe, and Africa. This paper aims to review the morphological properties of Ferulago species, herbal components, and their pharmacological properties. The information of this review paper has been collected from journals available in databases including Science Direct, Web of Science, Scopus, PubMed, EBSCO, Google Scholar, and Hindawi up to March 2020. In traditional medicine, the genus of Ferulago has been used to treat intestinal worms, snake bites, wound skin infections, diseases of the spleen and gastrointestinal tract, and headaches. It not only has been used traditionally as a preservative agent to dairy, oil ghee, and meat but also has given them a pleasant taste. The main components of Ferulago spp. are monoterpenes, sesquiterpenes, coumarin, furanocoumarin, flavonoids, and terpenoids have been the reason for the antimicrobial, antioxidant, anticoagulant, antidiabetic, Alzheimer, and larvicidal properties of this plant. This review confirms that many traditional uses of some Ferulago species have now been validated by modern pharmacology research. Rigorous investigations of all the species of Ferulago concerning phytochemical and pharmacological properties, mainly their mechanism of action, efficacy, and safety might offer a context for researchers to prosper plant-derived medications like anti-diabetes, antibiotics, and sedatives treating drugs, and the key to directing clinical trials.},
}
@article {pmid35186260,
year = {2021},
author = {Bishop, MM and Fixen, DR and Linnebur, SA and Pearson, SM},
title = {Cognitive effects of vortioxetine in older adults: a systematic review.},
journal = {Therapeutic advances in psychopharmacology},
volume = {11},
number = {},
pages = {20451253211026796},
pmid = {35186260},
issn = {2045-1253},
abstract = {Many older adults experience a deterioration in cognitive function with aging, and this can have a negative impact on quality of life. Late-life depression has been linked to mild cognitive impairment and dementia, and treating depression with an agent that has procognitive effects could be beneficial. Vortioxetine is a novel antidepressant with a multimodal mechanism of action that works primarily via serotonin transporter inhibition, 5-HT1A receptor agonism and 5-HT3 receptor antagonism. A recent systematic review demonstrated procognitive effects of vortioxetine when indirectly compared with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors in adults aged 18-65 years with major depressive disorder. While this systematic review demonstrated promising procognitive effects from vortioxetine, the included studies did not enroll older adults, who are at the highest risk of cognitive impairment. Therefore, our systematic review sought to investigate the effects of vortioxetine on cognitive functioning in patients over the age of 65 years. Three studies met the prespecified search criteria and were evaluated. Overall, these preliminary data suggest that vortioxetine has promising effects in improving cognition in older adults with depressive symptoms and may have a place in therapy in older adults with depression and/or cognitive impairment, including Alzheimer's disease. Additional long-term studies that include more diverse populations with comorbidities and direct comparisons with other antidepressants are needed to fully understand the potential cognitive benefits in older adults.},
}
@article {pmid35179048,
year = {2021},
author = {Eratne, D and Janelidze, S and Malpas, CB and Loi, S and Walterfang, M and Merritt, A and Diouf, I and Blennow, K and Zetterberg, H and Cilia, B and Wannan, C and Bousman, C and Everall, I and Zalesky, A and Jayaram, M and Thomas, N and Berkovic, SF and Hansson, O and Velakoulis, D and Pantelis, C and Santillo, A and , },
title = {Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives.},
journal = {The Australian and New Zealand journal of psychiatry},
volume = {},
number = {},
pages = {48674211058684},
doi = {10.1177/00048674211058684},
pmid = {35179048},
issn = {1440-1614},
abstract = {OBJECTIVE: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias.<br><br>METHODS: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59).<br><br>RESULTS: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]).<br><br>CONCLUSION: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.},
}
@article {pmid35154336,
year = {2022},
author = {Park, HG and Perumean-Chaney, SE and Bartolucci, AA},
title = {Exploring Factors Associated With Successful Nonpharmacological Interventions for People With Dementia.},
journal = {Dementia and neurocognitive disorders},
volume = {21},
number = {1},
pages = {1-16},
pmid = {35154336},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: We investigated existing nonpharmacological programs for people with dementia (PWD) to explore critical factors related to the effectiveness of these types of programs.<br><br>METHODS: We conducted a qualitative systematic literature review to identify nonpharmacological intervention programs developed for PWD and reviewed 36 randomized controlled trials. Among several outcomes reported in each study, we focused on the most common outcomes including quality of life (QoL), neuropsychiatric symptoms, depression, agitation, and cognition for further review.<br><br>RESULTS: Several factors were identified that might affect the outcomes of nonpharmacological interventions for PWD including study design, characteristics of the intervention, maintaining research participants, heterogeneity issues, and implementation fidelity. About half of studies in this review reported positive program effects on their targeted outcomes such as Well-being and Health for PWD on improving quality of life, neuropsychiatric symptoms and agitation; cognitive stimulation therapy on QoL, neuropsychiatric symptoms and cognition; and a stepwise multicomponent intervention on neuropsychiatric symptoms, depression and agitation.<br><br>CONCLUSIONS: We found some programs even with a rigorous study design did not produce expected outcomes while other programs with poor designs reported positive outcomes, which necessitates further investigation on the validity of the assessments. Factors such as individual tailored and customized interventions, promoting social interactions, ease of administration and compatibility of interventions, and developing program theory need to be considered when developing nonpharmacological intervention programs.},
}
@article {pmid35145394,
year = {2021},
author = {Becker, S and Sharma, MJ and Callahan, BL},
title = {ADHD and Neurodegenerative Disease Risk: A Critical Examination of the Evidence.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {826213},
pmid = {35145394},
issn = {1663-4365},
abstract = {In this review, we undertake a critical appraisal of eight published studies providing first evidence that a history of attention-deficit/hyperactivity disorder (ADHD) may increase risk for the later-life development of a neurodegenerative disease, in particular Lewy body diseases (LBD), by up to five-fold. Most of these studies have used data linked to health records in large population registers and include impressive sample sizes and adequate follow-up periods. We identify a number of methodological limitations as well, including potential diagnostic inaccuracies arising from the use of electronic health records, biases in the measurement of ADHD status and symptoms, and concerns surrounding the representativeness of ADHD and LBD cohorts. Consequently, previously reported risk associations may have been underestimated due to the high likelihood of potentially missed ADHD cases in groups used as "controls", or alternatively previous estimates may be inflated due to the inclusion of confounding comorbidities or non-ADHD cases within "exposed" groups that may have better accounted for dementia risk. Prospective longitudinal studies involving well-characterized cases and controls are recommended to provide some reassurance about the validity of neurodegenerative risk estimates in ADHD.},
}
@article {pmid35133330,
year = {2021},
author = {Río, AÁ and Marván, ML},
title = {Ethical dilemmas in the face of the possibility of suffering from Alzheimer's disease or other dementias. An exploratory study.},
journal = {Gaceta medica de Mexico},
volume = {157},
number = {4},
pages = {404-410},
doi = {10.24875/GMM.M21000582},
pmid = {35133330},
issn = {0016-3813},
mesh = {Adult ; Advance Directives ; *Alzheimer Disease/diagnosis ; Cross-Sectional Studies ; Decision Making ; Humans ; Surveys and Questionnaires ; },
abstract = {INTRODUCTION: In Mexico, efforts have been made to increase understanding of Alzheimer's disease (AD) and other dementias, as well as to improve the care of patients with these diseases and that of their caregivers. However, people's interest in making decisions and facing the ethical dilemmas regarding the possibility of living with mental diseases has not been investigated.<br><br>OBJECTIVE: To know the opinions of mature adults on some ethical dilemmas related to the possibility of living with AD or other dementias.<br><br>METHODS: Observational, cross-sectional, correlational study. Participants answered a self-administered questionnaire.<br><br>RESULTS: 134 mature adults answered the questionnaire; 70.9% had thought about the possibility of suffering from some dementia and the vast majority would like to know their diagnosis; approximately, half the participants had informed their families of their wishes about medical treatment in the future; 39.6% did not approve artificially feeding a patient who can no longer eat or decide; 37.3% did approve this.<br><br>CONCLUSIONS: There is interest in advance decisions in the face of the possibility of suffering from dementia. To answer unanswered questions in this regard, it is important for research on the subject to continue, as well as to solve some ethical dilemmas and promote the use of advance directives.},
}
@article {pmid35111193,
year = {2021},
author = {Piamonte, BLC and Anlacan, VMM and Jamora, RDG and Espiritu, AI},
title = {Googling Alzheimer Disease: An Infodemiological and Ecological Study.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {11},
number = {3},
pages = {333-339},
pmid = {35111193},
issn = {1664-5464},
abstract = {INTRODUCTION: Understanding the emergent role of the internet on the health-seeking behavior of people is critical not only in the areas of medicine and public health but also in the field of infodemiology.<br><br>METHODS: Using Google Trends, data on global search queries for Alzheimer disease (AD) between January 2004 and April 2021 were analyzed. The relationship between online interest, as reflected by search volume index (SVI), and measures of disease burden, namely prevalence, deaths, and disability-adjusted life years, was evaluated.<br><br>RESULTS: There was a reduction in the tendency to search for AD during the past two decades. SVI peaks corresponded to news of famous people with AD and awareness months. Symptoms, causes, and differences with the term dementia were central queries for persons interested in AD. No notable overall correlation between SVI and measures of disease burden was found due to competing results. Sub-group analyses, however, showed that these correlations may be influenced by socioeconomic development, with strong negative significant associations observed in lower middle-income countries.<br><br>CONCLUSION: Online interest in AD may represent a more complex metric influenced by socioeconomic factors. Awareness of the impact of celebrity diagnosis and awareness months on online search behavior may prove useful in the planning of public health campaigns for AD.},
}
@article {pmid35100131,
year = {2021},
author = {Garnier-Crussard, A and Krolak-Salmon, P},
title = {Reader Response: Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment.},
journal = {Neurology},
volume = {97},
number = {12},
pages = {608},
doi = {10.1212/WNL.0000000000012585},
pmid = {35100131},
issn = {1526-632X},
mesh = {*Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; *Cognitive Dysfunction/genetics ; Humans ; tau Proteins ; },
}
@article {pmid35100130,
year = {2021},
author = {Therriault, J and Pascoal, T and Gauthier, S and Rosa-Neto, P},
title = {Author Response: Frequency of Biologically Defined Alzheimer Disease in Relation to Age, Sex, APOE ε4, and Cognitive Impairment.},
journal = {Neurology},
volume = {97},
number = {12},
pages = {609},
doi = {10.1212/WNL.0000000000012586},
pmid = {35100130},
issn = {1526-632X},
mesh = {*Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; *Cognitive Dysfunction/genetics ; Humans ; tau Proteins ; },
}
@article {pmid35077620,
year = {2021},
author = {Vakilian, A and Ahmadi, AM and Heidari, M and Jalali, N and Nazer, M and Bidaki, MZ and Hashemi, SM and Mirabzadeh, M and Rezaei, A and Amirteimoury, M and Najmaddini, P},
title = {Vitamin B12 Administration Facilitates The Antipsychotic And Pain-Relieving Effects Of Quetiapine, In The Alzheimer Patients With Psychotic Symptoms.},
journal = {Journal of Ayub Medical College, Abbottabad : JAMC},
volume = {33(Suppl 1)},
number = {4},
pages = {S744-S751},
pmid = {35077620},
issn = {1819-2718},
mesh = {*Alzheimer Disease/drug therapy ; *Antipsychotic Agents/therapeutic use ; Humans ; Pain/drug therapy ; Quetiapine Fumarate/therapeutic use ; Treatment Outcome ; Vitamin B 12 ; },
abstract = {BACKGROUND: Psychotic symptoms in Alzheimer's disease (AD) patients are a problem in medicine. The efficacy of the vitamin B12 on the treatment of the psychotic symptoms of the AD patients in the association with antipsychotic drugs Quetiapine and Risperidone, was evaluated in this Study.<br><br>METHODS: The effects of vitamin B12 along with two other drugs were studied on the Mini-Mental State Examination (MMSE), Clinical Global Impression (CGI), Brief Psychiatric Rating Scale (BPRS) and pain Visual Analogue Scale (VAS) in 47 AD patients with psychotic symptoms, including 4 groups, psychotic AD patients treated with Risperidone, Risperidone plus vitamin B12, Quetiapine and Quetiapine plus vitamin B12 .<br><br>RESULTS: The results showed that Quetiapine improved all of the psychotic criteria, while Quetiapine plus vitamin B12 had better results on BPRS after 2 weeks, VAS score and MMSE. Risperidone also improves all of the criteria except MMSE and drug efficacy index, while, vitamin B12 neutralize the effects of the Risperidone on the BPRS, VAS, and severity of illness.<br><br>CONCLUSION: Due to these results, Quetiapine is the preferred antipsychotics drug and Vitamin B12 plays an effective role in treatment as an adjunct therapy.},
}
@article {pmid35058015,
year = {2022},
author = {Souza, ID and Anderson, JL and Queiroz, MEC},
title = {Crosslinked zwitterionic polymeric ionic liquid-functionalized nitinol wires for fiber-in-tube solid-phase microextraction and UHPLC-MS/MS as an amyloid beta peptide binding protein assay in biological fluids.},
journal = {Analytica chimica acta},
volume = {1193},
number = {},
pages = {339394},
doi = {10.1016/j.aca.2021.339394},
pmid = {35058015},
issn = {1873-4324},
mesh = {Alloys ; *Amyloid beta-Peptides ; Carrier Proteins ; Chromatography, High Pressure Liquid ; Humans ; *Ionic Liquids ; Solid Phase Microextraction ; Tandem Mass Spectrometry ; },
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder characterized by extracellular accumulation of amyloid-β peptide (Aβ) in the brain interstitium. Human serum albumin (HSA) highly binds to Aβ in blood plasma and is thought to inhibit plaque formation in peripheral tissue. Thus, the evaluation of albumin binding to Aβ is an important key to understand the dynamics of these molecules in the biological system of patients with AD. In this work, a fiber-in-tube solid-phase microextraction (fiber-in-tube SPME) and ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to estimate Aβ fraction binding to HSA in cerebrospinal fluid (CSF) and plasma samples. Crosslinked zwitterionic polymeric ionic liquid (zwitterionic PIL)-coated nitinol wires were developed and packed into a polyether ether ketone (PEEK) capillary for a fiber-in-tube SPME and UHPLC-MS/MS method. Zwitterionic PIL sorbent was synthetized from 1-vinyl-3-(butanesulfonate)imidazolium ([VIm+C4SO3-]) and 1,12-di(3-vinylimidazolium)dodecane dibromide ([(VIm)2C12]2[Br]) monomers by in-situ thermally-initiated polymerization. Morphological characterization by scanning electron microscopy (SEM) and atomic force microscopy (AFM) revealed a decrease in the surface roughness of the nitinol wires from ∼17 nm to 1 nm after the in-situ polymerization. The zwitterionic PIL sorbent selectively preconcentrates Aβ through a two-pronged interaction mechanism. The fiber-in-tube SPME and UHPLC-MS/MS method presented lower limits of quantification (LLOQ) of 0.4 ng mL-1 for Aβ38 and 0.3 ng mL-1 for Aβ40 and Aβ42, a linear range from LLOQ values to 15 ng mL-1 with coefficients of determination higher than 0.99, precision with coefficient of variation (CV) values ranging from 2.1 to 7.3% and accuracy with relative standard deviation (RSD) values from -0.3 to 7.4. This method was successfully applied to evaluate the binding of HSA to Aβ in cerebrospinal fluid (CSF) and plasma samples.},
}
@article {pmid35057967,
year = {2022},
author = {Emran, MY and Shenashen, MA and Elmarakbi, A and Selim, MM and El-Safty, SA},
title = {Nitrogen-doped carbon hollow trunk-like structure as a portable electrochemical sensor for noradrenaline detection in neuronal cells.},
journal = {Analytica chimica acta},
volume = {1192},
number = {},
pages = {339380},
doi = {10.1016/j.aca.2021.339380},
pmid = {35057967},
issn = {1873-4324},
mesh = {Animals ; *Carbon ; Electrodes ; *Nitrogen ; Norepinephrine ; Rats ; Reproducibility of Results ; },
abstract = {To date, the production and development of portable analytical devices for environmental and healthcare applications are rapidly growing. Herein, a portable electrochemical sensor for monitoring of noradrenaline (NA) secreted from living cells using mesoporous carbon-based materials was fabricated. The modification of the interdigitated electrode array (IDA) by nitrogen-doped mesoporous carbon spheres (N-doped MCS) and nitrogen-doped carbon hollow trunk-like structure (N-doped CHT) was used to fabricate the NA sensor. The N-doped CHT surface shows multiple holes distributed with micrometer-sized open holes (1-2 μm) and nanometer-sized thin walls (∼98 nm). The N-doped CHT surface heterogeneity of wrinkled and twisted hollow trunk structures improve the diffusion pathway and the NA molecules loading. The N-doped CHT/IDA showed a highly selective assay for monitoring of NA with high sensitivity (1770 μA/μM × cm2), a low detection limit (0.005 μM), and a wide linear range (0.01-0.3 μM). The N-doped CHT/IDA monitored the NA secreted from PC12 cells under various concentrations of simulation agents (KCl). The designed N-doped CHT/IDA provides a portable NA-sensor assay with facile signaling, good stability, high biocompatibility, in-vitro assay compatibility, and good reproducibility. Therefore, the designed sensor can be used as a portable sensor for NA detection in live cells and can be matched with portable smartphones after further developments.},
}
@article {pmid35037593,
year = {2021},
author = {Wilks, H and Aschenbrenner, AJ and Gordon, BA and Balota, DA and Fagan, AM and Musiek, E and Balls-Berry, J and Benzinger, TLS and Cruchaga, C and Morris, JC and Hassenstab, J},
title = {Sharper in the morning: Cognitive time of day effects revealed with high-frequency smartphone testing.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {43},
number = {8},
pages = {825-837},
doi = {10.1080/13803395.2021.2009447},
pmid = {35037593},
issn = {1744-411X},
support = {P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cognition ; *Cognitive Dysfunction/diagnosis ; Humans ; Memory, Short-Term ; Middle Aged ; Smartphone ; },
abstract = {Decades of research has established a shift from an "eveningness" preference to a "morningness" preference with increasing age. Accordingly, older adults typically have better cognition in morning hours compared to evening hours. We present the first known attempt to capture circadian fluctuations in cognition in individuals at risk for Alzheimer disease (AD) using a remotely administered smartphone assessment that samples cognition rapidly and repeatedly over several days. Older adults (N = 169, aged 61-94 years; 93% cognitively normal) completed four brief smartphone-based testing sessions per day for 7 consecutive days at quasi-random time intervals, assessing associate memory, processing speed, and visual working memory. Scores completed during early hours were averaged for comparison with averaged scores completed during later hours. Mixed effects models evaluated time of day effects on cognition. Additional models included clinical status and cerebrospinal fluid (CSF) biomarkers for beta amyloid (Aβ42) and phosphorylated tau181 (pTau). Models with terms for age, gender, education, APOE ε4 status, and clinical status revealed significantly worse performance on associate memory in evening hours compared to morning hours. Contemporaneously reported mood and fatigue levels did not moderate relationships. Using CSF data to classify individuals with and without significant AD pathology, there were no group differences in performance in morning hours, but subtle impairment emerged in associate memory in evening hours in those with CSF-confirmed AD pathology. These findings indicate that memory is worse in evening hours in older adults, that this pattern is consistent across several days, and is independent of measures of mood and fatigue. Further, they provide preliminary evidence of a "cognitive sundowning" in the very earliest stages of AD. Time of day may be an important consideration for assessments in observational studies and clinical trials in AD populations.},
}
@article {pmid35034721,
year = {2022},
author = {Azzaz, F and Yahi, N and Di Scala, C and Chahinian, H and Fantini, J},
title = {Ganglioside binding domains in proteins: Physiological and pathological mechanisms.},
journal = {Advances in protein chemistry and structural biology},
volume = {128},
number = {},
pages = {289-324},
doi = {10.1016/bs.apcsb.2021.08.003},
pmid = {35034721},
issn = {1876-1631},
mesh = {Amyloid beta-Peptides ; *COVID-19 ; Gangliosides ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; },
abstract = {Gangliosides are anionic lipids that form condensed membrane clusters (lipid rafts) and exert major regulatory functions on a wide range of proteins. In this review, we propose a new view of the structural features of gangliosides with special emphasis on emerging properties associated with protein binding modes. We analyze the different possibilities of molecular associations of gangliosides in lipid rafts and the role of cholesterol in this organization. We are particularly interested in amide groups of N-acetylated sugars which make it possible to neutralize the negative charge of the carboxylate group of sialic acids. We refer to this effect as "NH trick" and we demonstrate that it is operative in GM1, GD1a, GD1b and GT1b gangliosides. The NH trick is key to understand the different topologies adopted by gangliosides (chalice-like at the edge of lipid rafts, condensed clusters in central areas) and their impact on protein binding. We define three major types of ganglioside-binding domains (GBDs): α-helical, loop shaped, and large flat surface. We describe the mode of interaction of each GBD with typical reference proteins: synaptotagmin, 5HT1A receptor, cholera and botulinum toxins, HIV-1 surface envelope glycoprotein gp120, SARS-CoV-2 spike protein, cellular prion protein, Alzheimer's β-amyloid peptide and Parkinson's disease associated α-synuclein. We discuss the common mechanisms and peculiarities of protein binding to gangliosides in the light of physiological and pathological conditions. We anticipate that innovative ganglioside-based therapies will soon show an exponential growth for the treatment of cancer, microbial infections, and neurodegenerative diseases.},
}
@article {pmid35023134,
year = {2021},
author = {Ikeda, T and Hori, Y and Sohma, Y and Kanai, M and Tomita, T},
title = {Photo-Oxygenation: An Innovative New Therapeutic Approach Against Amyloidoses.},
journal = {Advances in experimental medicine and biology},
volume = {1339},
number = {},
pages = {415-422},
pmid = {35023134},
issn = {0065-2598},
mesh = {*Alzheimer Disease ; Amyloid ; *Amyloidosis/therapy ; *Frontotemporal Dementia ; Humans ; *Parkinson Disease ; },
abstract = {Many types of amyloidoses are pathologically characterized by the deposition of amyloid, which is comprised of fibrils formed by abnormally aggregated proteins, in various peripheral tissues and the central nervous system (CNS). Neurodegenerative disorders, such as Alzheimer disease (AD), Parkinson disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are well-known CNS amyloidoses that are characterized by amyloid deposition both inside and outside of cells. The amyloidogenic proteins of each disease have distinct primary sequences, and they normally function as soluble proteins. However, these proteins all aggregate and form amyloid with a common intermolecular tertiary structure, namely, a cross-β-sheet structure, finally leading to the onset of each disease. Therefore, inhibition of the aggregation of amyloid proteins or efficient clearance of the already formed amyloids are thought to be promising therapeutic strategies against amyloidoses.},
}
@article {pmid35023084,
year = {2021},
author = {Athanasiadou, E and Tsaloglidou, A and Koukourikos, K and Papathanasiou, IV and Iliadis, CH and Frantzana, A and Fradelos, E and Kourkouta, L},
title = {Care of Patients with Alzheimer's Disease.},
journal = {Advances in experimental medicine and biology},
volume = {1339},
number = {},
pages = {9-20},
pmid = {35023084},
issn = {0065-2598},
mesh = {*Alzheimer Disease ; Anxiety ; Caregivers ; Emotions ; Female ; Humans ; Surveys and Questionnaires ; },
abstract = {INTRODUCTION: Alzheimer's disease is one of the irreversible dementias and leads to death. About 10% of people over 60 years and 20% of people over 80 will have Alzheimer's sometime in their lives. In the case of Alzheimer's disease, care can turn into an extremely large and unevenly distributed burden. The burden that caregivers are called upon to lift is particularly high at the physical, psychological, and social levels.<br><br>PURPOSE: The purpose of this study was to describe the characteristics and needs of caregivers and even informal ones, that is, patients in the patient's family or friendly environment who voluntarily or unintentionally offer unpaid care to patients with Alzheimer's disease.<br><br>MATERIAL AND METHODS: The present study was conducted using the Carer Well-Being and Support Questionnaire (CWSv2) at Thessaloniki Psychiatric Hospital between October and December 2019. For the statistical analysis, the SPSS package 23 was used.<br><br>RESULTS: Alzheimer-type dementia is a condition with gradual, inevitable, and uncontrollable deterioration. So, it was expected that those involved in the care of these patients would be afraid of what their patient future care would be. Consequently, there is a high correlation coefficient between the two relevant variables (Fisher's Exact Test: 31,426; Sig: 0.007). Caregivers need to be alert at all times in order to fulfill their role and care for their loved one. There is a strong correlation index between the two variables (Fisher's Exact Test: 32,761; Sig: 0.003). The situation of a lack or distorted form of communication between patients and caregivers may also create or exacerbate caregivers' anxiety, causing them feelings of depression and deadlock that is also reflected in the relevant correlation index (Fisher's Exact Test: 30,053; Sig: 0.001). Women were more in need for additional help, with the two variables being marginally statistically significant (Fisher's Exact Test: 5.373; Sig: 0.05).<br><br>CONCLUSIONS: Taking into account the results, as reflected through the elaboration of the closed and open questions of this tool, new structures and services should be created in order to facilitate caregivers' job.},
}
@article {pmid35010895,
year = {2021},
author = {Naomi, R and Embong, H and Othman, F and Ghazi, HF and Maruthey, N and Bahari, H},
title = {Probiotics for Alzheimer's Disease: A Systematic Review.},
journal = {Nutrients},
volume = {14},
number = {1},
pages = {},
pmid = {35010895},
issn = {2072-6643},
support = {Fundamental Research Grant (FRGS/1/2020/SKK0/UPM/02/4)//Ministry of Higher Education/ ; },
mesh = {Alzheimer Disease/*diet therapy ; Brain-Gut Axis/*drug effects/physiology ; Gastrointestinal Microbiome/*drug effects ; Humans ; Probiotics/*administration &amp; dosage/*therapeutic use ; },
abstract = {Alzheimer's disease (AD) is the most common form of neurodegenerative disorders affecting mostly the elderly. It is characterized by the presence of Aβ and neurofibrillary tangles (NFT), resulting in cognitive and memory impairment. Research shows that alteration in gut microbial diversity and defects in gut brain axis are linked to AD. Probiotics are known to be one of the best preventative measures against cognitive decline in AD. Numerous in vivo trials and recent clinical trials have proven the effectiveness of selected bacterial strains in slowing down the progression of AD. It is proven that probiotics modulate the inflammatory process, counteract with oxidative stress, and modify gut microbiota. Thus, this review summarizes the current evidence, diversity of bacterial strains, defects of gut brain axis in AD, harmful bacterial for AD, and the mechanism of action of probiotics in preventing AD. A literature search on selected databases such as PubMed, Semantic Scholar, Nature, and Springer link have identified potentially relevant articles to this topic. However, upon consideration of inclusion criteria and the limitation of publication year, only 22 articles have been selected to be further reviewed. The search query includes few sets of keywords as follows. (1) Probiotics OR gut microbiome OR microbes AND (2) Alzheimer OR cognitive OR aging OR dementia AND (3) clinical trial OR in vivo OR animal study. The results evidenced in this study help to clearly illustrate the relationship between probiotic supplementation and AD. Thus, this systematic review will help identify novel therapeutic strategies in the future as probiotics are free from triggering any adverse effects in human body.},
}
@article {pmid35008528,
year = {2021},
author = {Sierri, G and Dal Magro, R and Vergani, B and Leone, BE and Formicola, B and Taiarol, L and Fagioli, S and Kravicz, M and Tremolizzo, L and Calabresi, L and Re, F},
title = {Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs.},
journal = {International journal of molecular sciences},
volume = {23},
number = {1},
pages = {},
pmid = {35008528},
issn = {1422-0067},
support = {2017PFYK27//PRIN Research Italy/ ; },
mesh = {ATP Binding Cassette Transporter 1/*metabolism ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/*metabolism ; Apolipoprotein A-I/metabolism ; Astrocytes/*metabolism ; Biological Transport/physiology ; Biomimetics/methods ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Cell Line ; Cholesterol/*metabolism ; Humans ; Lipoproteins, HDL/*metabolism ; },
abstract = {The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins' synthesis and lipoproteins' assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins' levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood-brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.},
}
@article {pmid35005289,
year = {2021},
author = {Adhikari, UK and Sakiz, E and Habiba, U and Mikhael, M and Senesi, M and David, MA and Guillemin, GJ and Ooi, L and Karl, T and Collins, S and Tayebi, M},
title = {Treatment of microglia with Anti-PrP monoclonal antibodies induces neuronal apoptosis in vitro.},
journal = {Heliyon},
volume = {7},
number = {12},
pages = {e08644},
pmid = {35005289},
issn = {2405-8440},
abstract = {Previous reports highlighted the neurotoxic effects caused by some motif-specific anti-PrPC antibodies in vivo and in vitro. In the current study, we investigated the detailed alterations of the proteome with liquid chromatography-mass spectrometry following direct application of anti-PrPC antibodies on mouse neuroblastoma cells (N2a) and mouse primary neuronal (MPN) cells or by cross-linking microglial PrPC with anti-PrPC antibodies prior to co-culture with the N2a/MPN cells. Here, we identified 4 (3 upregulated and 1 downregulated) and 17 (11 upregulated and 6 downregulated) neuronal apoptosis-related proteins following treatment of the N2a and N11 cell lines respectively when compared with untreated cells. In contrast, we identified 1 (upregulated) and 4 (2 upregulated and 2 downregulated) neuronal apoptosis-related proteins following treatment of MPN cells and N11 when compared with untreated cells. Furthermore, we also identified 3 (2 upregulated and 1 downregulated) and 2 (1 upregulated and 1 downregulated) neuronal apoptosis-related related proteins following treatment of MPN cells and N11 when compared to treatment with an anti-PrP antibody that lacks binding specificity for mouse PrP. The apoptotic effect of the anti-PrP antibodies was confirmed with flow cytometry following labelling of Annexin V-FITC. The toxic effects of the anti-PrP antibodies was more intense when antibody-treated N11 were co-cultured with the N2a and the identified apoptosis proteome was shown to be part of the PrPC-interactome. Our observations provide a new insight into the prominent role played by microglia in causing neurotoxic effects following treatment with anti-PrPC antibodies and might be relevant to explain the antibody mediated toxicity observed in other related neurodegenerative diseases such as Alzheimer.},
}
@article {pmid35002917,
year = {2021},
author = {Chang, TY and Yang, CP and Chen, YH and Lin, CH and Chang, MH},
title = {Age-Stratified Risk of Dementia in Parkinson's Disease: A Nationwide, Population-Based, Retrospective Cohort Study in Taiwan.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {748096},
pmid = {35002917},
issn = {1664-2295},
abstract = {Introduction: Parkinson's disease (PD) manifests with dominant motor symptoms and a wide range of non-motor symptoms (NMS). Dementia is one of the most disabling and exhausting NMS throughout the clinical course. We conducted a population-based, age-stratified, retrospective cohort study to investigate the incidence rate and risk of dementia of patients with newly diagnosed PD, and linked to the clinicopathological PD subtypes. Methods: Patients with newly diagnosed PD (PD group, n = 760) and control subjects (non-PD group, n = 3,034) were selected from the Taiwan's National Health Insurance Research Database from January 2001 to December 2005. The dementia incidence rate and dementia-free survival rate were calculated. Results: The overall dementia incidence rate was 17.5 and 5.7 per 1,000 person-years in PD and non-PD groups, respectively. The PD group had a significantly higher overall risk of dementia than controls (p < 0.001). The younger PD patients had a lower dementia incidence rate than the older PD patients, but a higher dementia risk compared to the same age of controls (<60 years, adjusted HR 6.55, 95% CI 1.56-27.48, p = 0.010). The dementia-free survival rate was significantly lower in the PD group compared to the non-PD group during follow-up (p < 0.001). Conclusion: In our study, the older age of onset in PD patients resulted in a higher incidence rate of dementia. In the young age of PD patients, the incidence rate of dementia was lower than the older PD patients, but the dementia risk was higher than controls of the same age. These findings possibly implied that there were different pathogenesis and pathologies causing dementia in younger and older PD patients.},
}
@article {pmid35002376,
year = {2021},
author = {Abanmy, N and Alsabhan, J and Gard, P and Scutt, G},
title = {Association between the Val66Met polymorphism (rs6265/G196A) of the BDNF gene and cognitive performance with SSRI use in Arab Alzheimer's disease patients.},
journal = {Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society},
volume = {29},
number = {12},
pages = {1392-1398},
pmid = {35002376},
issn = {1319-0164},
abstract = {Brain derived neutrophic factor (BDNF) is a protein and a member of the neurotrophin family of growth factors, supports the survival of existing neurons and encourages the growth and differentiation of new neurons and synapses. The BDNF gene Val66Met polymorphism (rs6265/G196A) is responsible for BDNF synthesis that impact BDNF function that includes memory and cognition. This study investigated whether the BDNF gene Val66Met polymorphism (rs6265/G196A) is associated with cognitive function changes in both Alzheimer disease (AD) patients and elderly participants. In addition the impact of SSRI use on cognition improvement will be assessed. Healthy young, middle ages (25-59 years old) and elderly (more than 60 years old) participants (140) as well as 40 AD patients of whom are both of Saudi Arabian origin were recruited. The genotyping for the association study was performed by real-time PCR using Taqman chemistry in the ABI Prism 7900HT Sequence Detection System. Both Mini-Mental Status Examination (MMSE) and Clinical Dementia Rating (CDR) were used to assess cognitive function of healthy and AD participants, respectively. The findings showed that the BDNF Val66Met genotype distributions and allele frequencies have significant association with cognitive performance in both elderly control group and AD patients. The main findings showed that carriers of GG homozygotes (Val/Val) have superior cognitive performance among AD patients and elderly control subjects. In addition the use of SSRIs in 13 AD patients and 17 elderly participants positively improved cognitive function in elderly (p > 0.001) but not in AD patients (p = 0.1).},
}
@article {pmid35002135,
year = {2021},
author = {Patel, I and Patel, J and Jindal, SV and Desai, D and Desai, S},
title = {Knowledge, Awareness, and Attitude Towards Dementia Amongst Medical Undergraduate Students: Can a Sensitization Program Help?.},
journal = {Annals of Indian Academy of Neurology},
volume = {24},
number = {5},
pages = {754-758},
pmid = {35002135},
issn = {0972-2327},
abstract = {BACKGROUND: Current undergraduate medical academic curriculum does not emphasize on evaluation and management of dementia. The knowledge and attitude of medical students towards patients with dementia in India has not been ascertained previously.<br><br>OBJECTIVE: We aimed to assess the knowledge and attitude of final year medical students about dementia and Alzheimer's disease. We also aimed to assess if a dedicated sensitization cum teaching session by a group of interns doctors guided by a neurologist could help improve students' knowledge and awareness towards dementia or not.<br><br>METHODS AND MATERIALS: 82 consenting final year medical students answered questionnaires of Alzheimer Disease Knowledge Scale (ADKS) and Dementia Attitude Scale (DAS) at a baseline level. A sensitization cum teaching session by intern doctors was conducted to enhance students' knowledge about dementia. A post sensitization reassessment of students was done to assess impact of the session.<br><br>RESULTS: The ADKS score was 57% at baseline which was increased to 71% post sensitization program. The mean DAS score was 3.2 at baseline which was reported to be 3.4 after sensitization program. Students reported significant improvement in their knowledge level but did not show the same improvement in their attitude and comfort level in caring for dementia after the sensitization program. Students were still not comfortable dealing with patients with dementia.<br><br>CONCLUSION: Medical students lack significant knowledge and training about dementia. Patient contact and practical training for basic assessment and care of dementia needs to be incorporated in the current academic curriculum. Dedicated sensitization sessions on dementia care can help improve the gap. Practical exposure to management of patients with dementia would be required to enhance the comfort level and attitude of students towards dementia.},
}
@article {pmid34992853,
year = {2021},
author = {N'Go, PK and Ahami, OTA and El Hessni, A and Azzaoui, FZ and Aboussaleh, Y and Tako, AN},
title = {Neuroprotective effects of the Chrysophyllum perpulchrum extract against an Alzheimer-like rat model of β amyloid1-40 intrahippocampal injection.},
journal = {Translational neuroscience},
volume = {12},
number = {1},
pages = {545-560},
pmid = {34992853},
issn = {2081-3856},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a threatening disease for African populations in the upcoming years because of the increase in their expectancy of life. Here, we investigated whether natural products from Chrysophyllum perpulchrum as catechin and two dimeric procyanidins (catechin + hexose) could prevent progression of oxidative stress and cognitive changes using an AD-like rat model induced by Aβ1-40 injection into the hippocampal CA1 subfield.<br><br>METHODOLOGY: Adult male Wistar rats were either microinjected with 1% ammonia as a vehicle (10 µL) or aggregated Aβ1-40 at 10 µg bilateral hippocampus. On the 14th day of post-surgery, some Aβ rats were treated with melatonin (10 mg/kg i.p.) or with the Chrysophyllum perpulchrum extract (300 mg/kg p.o.), and some sham-operated rats received the extract alone. Cognitive abilities were tested with Y-maze, object recognition test and Morris Water Maze. Oxidative stress markers as well as the level of activated microglial cells were assayed in the brain.<br><br>RESULTS: Aβ rats exhibited significant deficits of recognition memory and spatial learning. This was associated with an increase of microglia Iba 1 immunoreactivity as well as nitric oxide (NO), malondialdehyde and superoxide dismutase levels but not to the thiol content in the hippocampus, prefrontal cortex and septum of AD-like rats. The Chrysophyllum perpulchrum extract treatment mitigated Aβ-induced cognitive impairments and reversed microglia overactivation and subsequent generation of oxidative stress markers. Interestingly, the neuroprotective actions of the Chrysophyllum perpulchrum extract seem to be comparable to the control drug melatonin used albeit with some more beneficial effects.<br><br>CONCLUSION: These findings are preliminary and should be strengthened by more pharmacological studies of bioactive compounds of Chrysophyllum perpulchrum before being proposed as a promising drug against AD.},
}
@article {pmid34992713,
year = {2021},
author = {Mohieldin, AM and Alachkar, A and Yates, J and Nauli, SM},
title = {Novel biomarkers of ciliary extracellular vesicles interact with ciliopathy and Alzheimer's associated proteins.},
journal = {Communicative &amp; integrative biology},
volume = {14},
number = {1},
pages = {264-269},
pmid = {34992713},
issn = {1942-0889},
support = {R01 HL147311/HL/NHLBI NIH HHS/United States ; R56 HL131577/HL/NHLBI NIH HHS/United States ; },
abstract = {Ciliary extracellular vesicles (ciEVs), released from primary cilia, contain functional proteins that play an important role in cilia structure and functions. We have recently shown that ciEVs and cytosolic extracellular vesicles (cyEVs) have unique and distinct biomarkers. While ciEV biomarkers have shown some interactions with known ciliary proteins, little is known about the interaction of ciEV proteins with proteins involved in ciliopathy and neurodegenerative disorders. Here, we reveal for the first time the protein-protein interaction (PPI) between the top five ciEVs biomarkers with ciliopathy and Alzheimer disease (AD) proteins. These results support the growing evidence of the critical physiological roles of cilia in neurodegenerative disorders.},
}
@article {pmid34983883,
year = {2021},
author = {Yang, H and Jeong, Y},
title = {Correlation between Alteration of Sharp-wave Ripple Coupled Cortical Oscillation and Long-term Memory Deficit in Alzheimer Disease Model Mice.},
journal = {Experimental neurobiology},
volume = {30},
number = {6},
pages = {430-440},
pmid = {34983883},
issn = {1226-2560},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by prominent episodic memory dysfunction. Recent studies have suggested that there is a sequential mechanism in the memory deficit, with long-term ones preceding short-term ones. However, there is lack of explanation for these symptoms. Interaction between the hippocampus and retrosplenial cortex (RSC) during slow-wave sleep (SWS) is a crucial step for successful long-term memory formation. In particular, sharp-wave ripple (SWR) is a principal hippocampus oscillation that coordinates with RSC activity. To determine the relationship between memory dysfunction and SWR-related oscillation changes in AD, we implanted local field potential electrodes in the hippocampus and RSC of AD model mice (APP/PS1). We found that the SWR-coupled ripple wave increased in the RSC, while the amplitude of the SWR was preserved. In addition, the corresponding delta power in hippocampus and RSC was elevated, together with altered delta synchrony in AD mice. All these findings showed a significant correlation with long-term memory deficits measured in contextual fear conditions. Our study suggests that altered SWR-coupled oscillations are a possible underlying mechanism of episodic memory dysfunction in AD mice.},
}
@article {pmid34981477,
year = {2021},
author = {Hedayati-Moghadam, M and Hosseinian, S and Paseban, M and Shabgah, AG and Gholizadeh, J and Jamialahmadi, T and Sathyapalan, T and Sahebkar, A},
title = {The Role of Chemokines in Cardiovascular Diseases and the Therapeutic Effect of Curcumin on CXCL8 and CCL2 as Pathological Chemokines in Atherosclerosis.},
journal = {Advances in experimental medicine and biology},
volume = {1328},
number = {},
pages = {155-170},
pmid = {34981477},
issn = {0065-2598},
mesh = {*Atherosclerosis/drug therapy ; *Cardiovascular Diseases/drug therapy ; Chemokine CCL2 ; Chemokines ; *Curcumin/pharmacology/therapeutic use ; Humans ; Interleukin-8 ; },
abstract = {Curcumin, as a vegetative flavonoid, has a protective and therapeutic role in various adverse states such as oxidative stress and inflammation. Remedial properties of this component have been reported in the different chronic diseases including cancers (myeloma, pancreatic, breast, colorectal), vitiligo, psoriasis, neuropathic pains, inflammatory disorders (osteoarthritis, uveitis, ulcerative colitis, Alzheimer), cardiovascular conditions, and diabetes.Cardiovascular disorders include atherosclerosis and various manifestations of atherosclerosis such as stroke, and myocardial infarction (MI) is the leading cause of mortality globally. Studies have shown varying expressions of inflammatory and non-inflammatory chemokines and chemokine receptors in cardiovascular disease, which have been highlighted first in this review. The alteration in chemokines secretion and chemokine receptors has an essential role in the pathophysiology of cardiovascular disease. Chemokines as cytokines with low molecular weight (8-12 kDa) mediate white blood cell (WBC) chemotactic reactions, vascular cell migration, and proliferation that induce endothelial dysfunction, atherogenesis, and cardiac hypertrophy.Several studies reported that curcumin could be advantageous in the attenuation of cardiovascular diseases via anti-inflammatory effects and redress of chemokine secretion and chemokine receptors. We present these studies with a focus on two chemokines: CXCL8 (IL-8) and CCL2 (chemoattractant protein 1 or MCP-1). Future research will further elucidate the precise potential of curcumin on chemokines in the adjustment of cardiovascular system activity or curcumin chemokine-based therapies.},
}
@article {pmid34975502,
year = {2021},
author = {Zeng, P and Su, HF and Ye, CY and Qiu, SW and Tian, Q},
title = {Therapeutic Mechanism and Key Alkaloids of Uncaria rhynchophylla in Alzheimer's Disease From the Perspective of Pathophysiological Processes.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {806984},
pmid = {34975502},
issn = {1663-9812},
abstract = {Presently, there is a lack of effective disease-modifying drugs for the treatment of Alzheimer's disease (AD). Uncaria rhynchophylla (UR) and its predominant active phytochemicals alkaloids have been studied to treat AD. This study used a novel network pharmacology strategy to identify UR alkaloids against AD from the perspective of AD pathophysiological processes and identified the key alkaloids for specific pathological process. The analysis identified 10 alkaloids from UR based on high-performance liquid chromatography (HPLC) that corresponded to 127 targets correlated with amyloid-β (Aβ) pathology, tau pathology and Alzheimer disease pathway. Based on the number of targets correlated with AD pathophysiological processes, angustoline, angustidine, corynoxine and isocorynoxeine are highly likely to become key phytochemicals in AD treatment. Among the 127 targets, JUN, STAT3, MAPK3, CCND1, MMP2, MAPK8, GSK3B, JAK3, LCK, CCR5, CDK5 and GRIN2B were identified as core targets. Based on the pathological process of AD, angustoline, angustidine and isocorynoxeine were identified as the key UR alkaloids regulating Aβ production and corynoxine, isocorynoxeine, dihydrocorynatheine, isorhynchophylline and hirsutine were identified as key alkaloids that regulate tau phosphorylation. The findings of this study contribute to a more comprehensive understanding of the key alkaloids and mechanisms of UR in the treatment of AD, as well as provide candidate compounds for drug research and development for specific AD pathological processes.},
}
@article {pmid34973014,
year = {2021},
author = {Ben Abdessalem, H and Ai, Y and Marulasidda Swamy, KS and Frasson, C},
title = {Virtual Reality Zoo Therapy for Alzheimer's Disease Using Real-Time Gesture Recognition.},
journal = {Advances in experimental medicine and biology},
volume = {1338},
number = {},
pages = {97-105},
pmid = {34973014},
issn = {0065-2598},
mesh = {Aged ; *Alzheimer Disease/therapy ; Anxiety Disorders ; Gestures ; Humans ; *Virtual Reality ; *Virtual Reality Exposure Therapy ; },
abstract = {Alzheimer's disease affects almost ten million people every year. Negative emotions such as frustration and anxiety can have impact on brain capability in terms of memory functions. Alzheimer's patients experience more negative emotions than healthy older adults. Non-pharmacological treatment such as animal therapy could help Alzheimer patient but has restrictions and requirements. We propose a Virtual Reality Zoo Therapy system in which the patients are immersed in a virtual environment and can interact with animals using their hands. With the immersive experience of virtual reality (VR), patients feel that they are in a real therapy room and can freely interact with animals. This system is controlled by an intelligent agent which tracks the patients' emotions using electroencephalography and commands the animals according to their hand gesture and emotions. Experiments have been done and preliminary results show that it is possible to predict patients' hand gesture and interpret them in order to interact with virtual animals and the Zoo Therapy system can reduce the negative emotions.},
}
@article {pmid34971747,
year = {2022},
author = {Cecerska-Heryć, E and Polikowska, A and Serwin, N and Roszak, M and Grygorcewicz, B and Heryć, R and Michalczyk, A and Dołęgowska, B},
title = {Importance of oxidative stress in the pathogenesis, diagnosis, and monitoring of patients with neuropsychiatric disorders, a review.},
journal = {Neurochemistry international},
volume = {153},
number = {},
pages = {105269},
doi = {10.1016/j.neuint.2021.105269},
pmid = {34971747},
issn = {1872-9754},
mesh = {*Alzheimer Disease/diagnosis/metabolism ; Antioxidants/metabolism ; Humans ; Lipid Peroxidation ; Oxidation-Reduction ; *Oxidative Stress ; },
abstract = {Oxidative stress is defined as the persistent imbalance between the activity of toxic reactive forms of both oxygen and nitrogen and the antioxidant defense. In low concentrations, they are essential for the proper functioning of the body. Still, their excessive amount contributes to the damage of the biomolecules, consequently leading to various pathologies of the organism. Due to the lipid-rich brain structure, enormous oxygen consumption, and the lack of a sufficient antioxidant barrier make it highly susceptible to oxidative imbalance. Hence, oxidative stress has been linked to various psychiatric disorders. These diseases include all behavioral, emotional, and cognitive abnormalities associated with a significant impediment to social life. Each of the diseases in question: Alzheimer's disease, schizophrenia, depression, and bipolar disorder, is characterized by excessive oxidative stress. Considerable damages to DNA, RNA, proteins, lipids, and mitochondrial dysfunction, are observed. All conditions show increased lipid peroxidation, which appears to be typical of psychiatric disorders because the brain contains large amounts of these types of molecules. In addition, numerous abnormalities in the antioxidant defense are noted, but the results of studies on the activity of antioxidant enzymes differ significantly. The most promising biomarkers seem to be GSH in Alzheimer's disease as an early-stage marker of the disease and thioredoxin in schizophrenia as a marker for therapy monitoring. Data from the literature are consistent with the decrease in antioxidants such as vitamin C, E, uric acid, albumin, etc. Despite these numerous inconsistencies, it seems that oxidative stress is present in the course of psychiatric diseases. Still, it cannot be conclusively determined whether it is the direct cause of development, a consequence of other abnormalities at the biochemical or molecular level, or the result of the disease itself.},
}
@article {pmid34971258,
year = {2021},
author = {Sanchez, CP},
title = {Efficacy of cognitive stimulation therapy virtual program for older adults with dementia in COVID-19 isolation.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {17 Suppl 8},
number = {},
pages = {e056213},
doi = {10.1002/alz.056213},
pmid = {34971258},
issn = {1552-5279},
abstract = {BACKGROUND: Cognitive stimulation virtual therapy (CSVT) is an evidence-based psychosocial intervention for people with mild-to-moderate dementia due to various etiological factors.<br><br>OBJECTIVE: The aim of the present study was to assess the efficacy of a cognitive stimulation virtual therapy CSVT program, in individuals who have vascular or Alzheimer dementia in COVID-19 isolation.<br><br>METHODS: Older adults with mild vascular or Alzheimer dementia (N = 20) were assigned to one of two programs: one group (N = 10) attended during six months, two sessions per week program of the cognitive stimulation virtual therapy CSVT program, while the other, active control group (N = 10) took part in alternative activities. The following tests were applied to their primary caregivers. A short form of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and quality of life (Quality of Life (QoL) RESULTS: Compared with the active controls, the cognitive stimulation virtual therapy CSVT program showed a greater improvement in general cognitive functioning after the intervention (i.e. score increase on the IQCODE test). A trend towards improvement was also identified in short term/working memory and perceived quality of life (Quality of life (QoL) of elderly with dementia). The primary caregivers also perceived an improvement in mood, stress, anxiety and quality of sleep after the start of the virtual therapy during COVID-19 isolation.<br><br>CONCLUSION: The present results support the efficacy of cognitive stimulation virtual therapy CSVT program in people with dementia during COVID-19 isolation.},
}
@article {pmid34970718,
year = {2022},
author = {Vecchio, F and Quaranta, D and Miraglia, F and Pappalettera, C and Di Iorio, R and L'Abbate, F and Cotelli, M and Marra, C and Rossini, PM},
title = {Neuronavigated Magnetic Stimulation combined with cognitive training for Alzheimer's patients: an EEG graph study.},
journal = {GeroScience},
volume = {44},
number = {1},
pages = {159-172},
pmid = {34970718},
issn = {2509-2723},
mesh = {Aged ; *Alzheimer Disease/diagnosis ; Cognition/physiology ; *Cognition Disorders ; Electroencephalography ; Humans ; Transcranial Magnetic Stimulation/methods ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in elderly subjects. Recent studies verified the effects of cognitive training combined with repetitive transcranial magnetic stimulation (rTMS-COG) in AD patients. Here, we analyzed neuropsychological and neurophysiological data, derived from electroencephalography (EEG), to evaluate the effects of a 6-week protocol of rTMS-COG in 72 AD. We designed a randomized, double-blind, sham-controlled trial to evaluate efficacy of rTMS on 6 brain regions obtained by an individual MRI combined with COG related to brain areas to stimulate (i.e., syntax and grammar tasks, comprehension of lexical meaning and categorization tasks, action naming, object naming, spatial memory, spatial attention). Patients underwent neuropsychological and EEG examination before (T0), after treatment (T1), and after 40 weeks (T2), to evaluate the effects of rehabilitation therapy. "Small World" (SW) graph approach was introduced allowing us to model the architecture of brain connectivity in order to correlate it with cognitive improvements. We found that following 6 weeks of intensive daily treatment the immediate results showed an improvement in cognitive scales among AD patients. SW present no differences before and after the treatment, whereas a crucial SW modulation emerges at 40-week follow-up, emphasizing the importance of rTMS-COG rehabilitation treatment for AD. Additional results demonstrated that the delta and alpha1 SW seem to be diagnostic biomarkers of AD, whereas alpha2 SW might represent a prognostic biomarker of cognitive recovery. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression, and rTMS-COG can be regarded as a potentially useful treatment for AD.},
}
@article {pmid34969939,
year = {2022},
author = {Yoo, HS and Jeon, S and Cavedo, E and Ko, M and Yun, M and Lee, PH and Sohn, YH and Grothe, MJ and Teipel, S and Hampel, H and Evans, AC and Ye, BS},
title = {Association of β-Amyloid and Basal Forebrain With Cortical Thickness and Cognition in Alzheimer and Lewy Body Disease Spectra.},
journal = {Neurology},
volume = {98},
number = {9},
pages = {e947-e957},
pmid = {34969939},
issn = {1526-632X},
mesh = {*Alzheimer Disease/complications/diagnostic imaging ; Amyloid beta-Peptides/metabolism ; *Basal Forebrain/metabolism ; Brain/metabolism ; Cognition ; *Cognitive Dysfunction ; Cross-Sectional Studies ; Humans ; *Lewy Body Disease/complications/diagnostic imaging ; Positron-Emission Tomography ; },
abstract = {OBJECTIVE: Cholinergic degeneration and β-amyloid contribute to brain atrophy and cognitive dysfunction in Alzheimer disease (AD) and Lewy body disease (LBD), but their relationship has not been comparatively evaluated.<br><br>METHODS: In this cross-sectional study, we recruited 28 normal controls (NC), 55 patients with AD mild cognitive impairment (MCI), 34 patients with AD dementia, 28 patients with LBD MCI, and 51 patients with LBD dementia. Participants underwent cognitive evaluation, brain MRI to measure the basal forebrain (BF) volume and global cortical thickness (CTh), and 18F-florbetaben (FBB) PET to measure the standardized uptake value ratio (SUVR). Using general linear models and path analyses, we evaluated the association of FBB-SUVR and BF volume with CTh or cognitive dysfunction in the AD spectrum (AD and NC) and LBD spectrum (LBD and NC), respectively. Covariates included age, sex, education, deep and periventricular white matter hyperintensities, intracranial volume, hypertension, diabetes, and hyperlipidemia.<br><br>RESULTS: BF volume mediated the association between FBB-SUVR and CTh in both the AD and LBD spectra, while FBB-SUVR was associated with CTh independently of BF volume only in the LBD spectrum. Significant correlation between voxel-wise FBB-SUVR and CTh was observed only in the LBD group. FBB-SUVR was independently associated with widespread cognitive dysfunction in both the AD and LBD spectra, especially in the memory domain (standardized beta [B] for AD spectrum = -0.60, B for LBD spectrum = -0.33). In the AD spectrum, BF volume was associated with memory dysfunction (B = 0.18), and CTh was associated with language (B = 0.21) and executive (B = 0.23) dysfunction. In the LBD spectrum, however, BF volume and CTh were independently associated with widespread cognitive dysfunction.<br><br>CONCLUSIONS: There is a common β-amyloid-related degenerative mechanism with or without the mediation of BF in the AD and LBD spectra, while the association of BF atrophy with cognitive dysfunction is more profound and there is localized β-amyloid-cortical atrophy interaction in the LBD spectrum.},
}
@article {pmid34968250,
year = {2021},
author = {Casciaro, F and Persico, G and Rusin, M and Amatori, S and Montgomery, C and Rutkowsky, JR and Ramsey, JJ and Cortopassi, G and Fanelli, M and Giorgio, M},
title = {The Histone H3 K4me3, K27me3, and K27ac Genome-Wide Distributions Are Differently Influenced by Sex in Brain Cortexes and Gastrocnemius of the Alzheimer's Disease PSAPP Mouse Model.},
journal = {Epigenomes},
volume = {5},
number = {4},
pages = {},
pmid = {34968250},
issn = {2075-4655},
support = {1R56AG057163-01A1/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Women represent the majority of Alzheimer's disease patients and show typical symptoms. Genetic, hormonal, and behavioral mechanisms have been proposed to explain sex differences in dementia prevalence. However, whether sex differences exist in the epigenetic landscape of neuronal tissue during the progression of the disease is still unknown.<br><br>METHODS: To investigate the differences of histone H3 modifications involved in transcription, we determined the genome-wide profiles of H3K4me3, H3K27ac, and H3K27me3 in brain cortexes of an Alzheimer mouse model (PSAPP). Gastrocnemius muscles were also tested since they are known to be different in the two sexes and are affected during the disease progression.<br><br>RESULTS: Correlation analysis distinguished the samples based on sex for H3K4me3 and H3K27me3 but not for H3K27ac. The analysis of transcription starting sites (TSS) signal distribution, and analysis of bounding sites revealed that gastrocnemius is more influenced than brain by sex for the three histone modifications considered, exception made for H3K27me3 distribution on the X chromosome which showed sex-related differences in promoters belonging to behavior and cellular or neuronal spheres in mice cortexes.<br><br>CONCLUSIONS: H3K4me3, H3K27ac, and H3K27me3 signals are slightly affected by sex in brain, with the exception of H3K27me3, while a higher number of differences can be found in gastrocnemius.},
}
@article {pmid34967389,
year = {2021},
author = {Cheng, X and Wang, H and Zheng, Z and Feng, K and Tang, S and Liu, Y and Chen, K and Bi, C and Gao, M and Ji, L},
title = {Alzheimer disease effects of different stages on intestinal flora: A protocol for systematic review and meta-analysis.},
journal = {Medicine},
volume = {100},
number = {52},
pages = {e28462},
pmid = {34967389},
issn = {1536-5964},
support = {81373528//Innovative Research Group Project of the National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease ; *Cognitive Dysfunction ; *Gastrointestinal Microbiome ; Humans ; Meta-Analysis as Topic ; Research Design ; Systematic Reviews as Topic ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is a common degenerative disease of the central nervous system that can be divided into 3 stages, according to the degree of cognitive impairment. The clinical manifestations are cognitive dysfunction and memory loss, impacting the daily activities of the affected individuals. In recent years, studies have demonstrated a relationship between intestinal flora and AD. However, no meta-analysis has documented the correlation between AD and intestinal flora, to the best of our knowledge. Herein, we sought to assess the correlation between different stages of AD and intestinal flora. A systematic and comprehensive understanding of this relationship is of great significance for developing prevention and treatment strategies against AD.<br><br>METHODS: A comprehensive search of the medical literature in Chinese and English language was performed in databases, such as PubMed, EBSCO, CNKI, web of science, WanFang, Cochrane Library, and CBM databases. Pre-defined search strategies were used to retrieve clinical studies of Alzheimer disease and gut microbiota. The included studies were independently analyzed by the 2 researchers who extracted the data. The quality of the data was evaluated according to the "Cochrane system evaluator manual." Finally, Endnote and RevMan software were used for systematic regression and meta-analysis of evidence.<br><br>RESULTS: We documented the intestinal flora changes in the 3 stages of Alzheimer disease, according to currently available clinical evidence, and revealed the correlation between the abundance and diversity of flora and treatment efficacy. These findings are essential for developing new strategies for the prevention and treatment of Alzheimer disease.<br><br>INPLASY REGISTRATION NUMBER: INPLASY2021100093.<br><br>ETHICS AND DISSEMINATION: Since all data utilized in this systematic review and meta-analysis are published, ethical approval was not needed.},
}
@article {pmid34967222,
year = {2022},
author = {Sible, IJ and Nation, DA and , },
title = {Visit-to-Visit Blood Pressure Variability and Longitudinal Tau Accumulation in Older Adults.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {79},
number = {3},
pages = {629-637},
pmid = {34967222},
issn = {1524-4563},
support = {R01 AG064228/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 AG060049/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P01 AG052350/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Blood Pressure/*physiology ; Blood Pressure Determination ; Brain/*diagnostic imaging/metabolism ; Cognitive Dysfunction/diagnostic imaging/metabolism/*physiopathology ; Dementia/diagnostic imaging/metabolism/*physiopathology ; Female ; Humans ; Male ; Middle Aged ; Neuroimaging ; Positron-Emission Tomography ; tau Proteins/*metabolism ; },
abstract = {BACKGROUND: Elevated blood pressure variability (BPV) is predictive of dementia, independent of average blood pressure levels, but neuropathological mechanisms remain unclear. We examined whether BPV in older adults is related to tau accumulation in brain regions vulnerable to Alzheimer disease and whether relationships are modified by apoϵ4 carrier status.<br><br>METHODS: Two hundred eighty-six Alzheimer's Disease Neuroimaging Initiative participants without history of dementia underwent 3 to 4 blood pressure measurements over 12 months and ≥1 tau positron emission tomography thereafter. BPV was calculated as variability independent of mean. Each scan determined tau burden (standardized uptake value ratio) for a temporal meta-region of interest, including burden from entorhinal cortex, amygdala, parahippocampus, fusiform, inferior temporal, and middle temporal. Bayesian linear growth modeling examined the role of BPV, apolipoprotein ϵ4 carrier status, and time on regional tau accumulation after controlling for several variables, including baseline hypertension.<br><br>RESULTS: Elevated BPV was related to tau accumulation at follow-up in a temporal meta-region, independent of average blood pressure levels (ß, 0.89 [95% credible interval, 0.86-0.92]) and especially in entorhinal cortex (ß, 2.57 [95% credible interval, 2.15-2.99]). Apoϵ4 carriers with elevated BPV had the fastest tau accumulation at follow-up (ß, 1.73 [95% credible interval, 0.47-3.03]).<br><br>CONCLUSIONS: BPV is related to tau accumulation in brain regions vulnerable to Alzheimer disease, independent of average blood pressure. APOEϵ4 modified this relationship. Bidirectionality of findings is possible. BPV may represent a marker of vascular dysfunction related to early-stage tau pathology contributing to Alzheimer disease.},
}
@article {pmid34966281,
year = {2021},
author = {Khanal, P and Zargari, F and Far, BF and Kumar, D and R, M and Mahdi, YK and Jubair, NK and Saraf, SK and Bansal, P and Singh, R and Selvaraja, M and Dey, YN},
title = {Integration of System Biology Tools to Investigate Huperzine A as an Anti-Alzheimer Agent.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {785964},
pmid = {34966281},
issn = {1663-9812},
abstract = {Aim: The present study aimed to investigate huperzine A as an anti-Alzheimer agent based on the principle that a single compound can regulate multiple proteins and associated pathways, using system biology tools. Methodology: The simplified molecular-input line-entry system of huperzine A was retrieved from the PubChem database, and its targets were predicted using SwissTargetPrediction. These targets were matched with the proteins deposited in DisGeNET for Alzheimer disease and enriched in STRING to identify the probably regulated pathways, cellular components, biological processes, and molecular function. Furthermore, huperzine A was docked against acetylcholinesterase using AutoDock Vina, and simulations were performed with the Gromacs package to take into account the dynamics of the system and its effect on the stability and function of the ligands. Results: A total of 100 targets were predicted to be targeted by huperzine A, of which 42 were regulated at a minimum probability of 0.05. Similarly, 101 Kyoto Encyclopedia of Genes and Genomes pathways were triggered, in which neuroactive ligand-receptor interactions scored the least false discovery rate. Also, huperzine A was predicted to modulate 54 cellular components, 120 molecular functions, and 873 biological processes. Furthermore, huperzine A possessed a binding affinity of -8.7 kcal/mol with AChE and interacted within the active site of AChE via H-bonds and hydrophobic interactions.},
}
@article {pmid34966025,
year = {2021},
author = {de Guise, E and Soucy, B and Joubert, S and Correa, JA and Dagher, JH},
title = {Risk Factors for Alzheimer Disease Development After Traumatic Brain Injury: A Preliminary Study.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000481},
pmid = {34966025},
issn = {1546-4156},
abstract = {Traumatic brain injury (TBI) is increasingly recognized as a major risk factor for developing neurocognitive disorders, though this association remains controversial. Determination of risk factors for post-traumatic neurodegeneration in patients with TBI is critical given the high incidence of TBI. We hypothesized that cardiovascular and metabolic comorbidities, in addition to TBI severity, are associated with the risk of post-traumatic development of Alzheimer disease dementia (ADD). A case-controlled retrospective study was conducted using medical records and medical insurance data of 5642 patients with TBI admitted to a tertiary trauma center over a 12-year period, to assess risk factors of developing ADD after TBI. Logistic regression shows that presence of post-traumatic amnesia (P=0.03) and chronic vascular lesions (P=0.04) are significantly associated with development of ADD after TBI. This innovative preliminary study is the first to explore risk factors for post-traumatic ADD. Further association studies are essential to optimize care following TBI.},
}
@article {pmid34965504,
year = {2022},
author = {Qurrat-Ul-Ain, and Abid, A and Lateef, M and Rafiq, N and Eijaz, S and Tauseef, S},
title = {Multi-activity tetracoordinated pallado-oxadiazole thiones as anti-inflammatory, anti-Alzheimer, and anti-microbial agents: Structure, stability and bioactivity comparison with pallado-hydrazides.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {146},
number = {},
pages = {112561},
doi = {10.1016/j.biopha.2021.112561},
pmid = {34965504},
issn = {1950-6007},
mesh = {Alzheimer Disease/pathology ; Anti-Infective Agents/chemistry/*pharmacology ; Anti-Inflammatory Agents/chemistry/*pharmacology ; Bacteria/drug effects ; Cholinesterase Inhibitors ; Fungi/drug effects ; Hydrazines/pharmacology ; Lipoxygenase Inhibitors/metabolism ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Oxadiazoles/chemistry ; Palladium/chemistry ; Structure-Activity Relationship ; Thiones/chemistry/*pharmacology ; },
abstract = {Herein, we report a comparative study based on structure, thermal and solution stability, and biopotency against lipoxygenase (LOX), butyrylcholinesterase (BChE) and microbes for Pd(II) compounds of N,O,S bearing 5-(C5H4XR)-1,3,4-oxadiazole-2-thiones (L') of type [PdL'Cl2] (P'n) and N,O bearing respective hydrazides (L) of type trans-[PdL2Cl2] (Pn) {X = C, R = 4-I, 2-Br, 4-NO2, 3-NO2, 2-Cl, 3-Cl (n = 1-6, serially); X = N (n = 7)}
. Spectral techniques (IR, EI-MS, NMR) and physicochemical evaluations successfully characterized the new compounds. The L' behaved as bidentate S-N donors bonded through exocyclic sulfur and N-3' nitrogen, while L acted as amino N donors. UV-vis (solution speciation) and thermal degradation profiles consistently confirmed the greater stability for P'n than Pn compounds. These compounds manifested varying degree in vitro potential to inhibit LOX, BChE and several bacteria and fungi, affected mainly by Pd(II) presence, M-L binding mode, nature and position of R, or halo groups electronegativity. Molecular docking with human 5-LOX and BChE further validated the respective experimental inhibition findings and explored several putative mechanistic interactions (H-bonding, π-stacking, π-alkyl, π-S, etc.) at the enzyme active sites. Pn generally offered superior antimicrobial and anti-LOX (anti-inflammatory) potential than respective P'n compounds, with P3/P'5, P(2,3,7)/P'3, and P6 being comparable, better and equivalent to ampicillin, nystatin and baicalein, the reference antibacterial, antifungal and anti-LOX drugs, respectively. Contrarily, the anti-BChE activity of P'n was found better than Pn compounds, showing P'2/P1 as the most promising anti-Alzheimer drug candidates. This study bares important structural and mechanistic aspects in optimizing antimicrobial, anti-inflammatory and anti-Alzheimer activities, highlighting some potential future pallado-drug candidates.},
}
@article {pmid34965428,
year = {2021},
author = {Lee, SH and Rezzonico, MG and Friedman, BA and Huntley, MH and Meilandt, WJ and Pandey, S and Chen, YJ and Easton, A and Modrusan, Z and Hansen, DV and Sheng, M and Bohlen, CJ},
title = {TREM2-independent oligodendrocyte, astrocyte, and T cell responses to tau and amyloid pathology in mouse models of Alzheimer disease.},
journal = {Cell reports},
volume = {37},
number = {13},
pages = {110158},
doi = {10.1016/j.celrep.2021.110158},
pmid = {34965428},
issn = {2211-1247},
mesh = {Alzheimer Disease/immunology/metabolism/*pathology ; Amyloid/*chemistry ; Animals ; Astrocytes/immunology/metabolism/*pathology ; Female ; Male ; Membrane Glycoproteins/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Oligodendroglia/immunology/metabolism/*pathology ; Receptors, Immunologic/*physiology ; T-Lymphocytes/*immunology ; tau Proteins/*metabolism ; },
abstract = {Non-neuronal responses in neurodegenerative disease have received increasing attention as important contributors to disease pathogenesis and progression. Here we utilize single-cell RNA sequencing to broadly profile 13 cell types in three different mouse models of Alzheimer disease (AD), capturing the effects of tau-only, amyloid-only, or combined tau-amyloid pathology. We highlight microglia, oligodendrocyte, astrocyte, and T cell responses and compare them across these models. Notably, we identify two distinct transcriptional states for oligodendrocytes emerging differentially across disease models, and we determine their spatial distribution. Furthermore, we explore the impact of Trem2 deletion in the context of combined pathology. Trem2 knockout mice exhibit severely blunted microglial responses to combined tau and amyloid pathology, but responses from non-microglial cell types (oligodendrocytes, astrocytes, and T cells) are relatively unchanged. These results delineate core transcriptional states that are engaged in response to AD pathology, and how they are influenced by a key AD risk gene, Trem2.},
}
@article {pmid34964690,
year = {2021},
author = {Klein, M and Kaleem, A and Oetjen, S and Wünkhaus, D and Binkle, L and Schilling, S and Gjorgjieva, M and Scholz, R and Gruber-Schoffnegger, D and Storch, S and Kins, S and Drewes, G and Hoffmeister-Ullerich, S and Kuhl, D and Hermey, G},
title = {Converging roles of PSENEN/PEN2 and CLN3 in the autophagy-lysosome system.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/15548627.2021.2016232},
pmid = {34964690},
issn = {1554-8635},
abstract = {PSENEN/PEN2 is the smallest subunit of the γ-secretase complex, an intramembrane protease that cleaves proteins within their transmembrane domains. Mutations in components of the γ-secretase underlie familial Alzheimer disease. In addition to its proteolytic activity, supplementary, γ-secretase independent, functions in the macroautophagy/autophagy-lysosome system have been proposed. Here, we screened for PSENEN-interacting proteins and identified CLN3. Mutations in CLN3 are causative for juvenile neuronal ceroid lipofuscinosis, a rare lysosomal storage disorder considered the most common neurodegenerative disease in children. As mutations in the PSENEN and CLN3 genes cause different neurodegenerative diseases, understanding shared cellular functions of both proteins might be pertinent for understanding general cellular mechanisms underlying neurodegeneration. We hypothesized that CLN3 modulates γ-secretase activity and that PSENEN and CLN3 play associated roles in the autophagy-lysosome system. We applied CRISPR gene-editing and obtained independent isogenic HeLa knockout cell lines for PSENEN and CLN3. Following previous studies, we demonstrate that PSENEN is essential for forming a functional γ-secretase complex and is indispensable for γ-secretase activity. In contrast, CLN3 does not modulate γ-secretase activity to a significant degree. We observed in PSENEN- and CLN3-knockout cells corresponding alterations in the autophagy-lysosome system. These include reduced activity of lysosomal enzymes and lysosome number, an increased number of autophagosomes, increased lysosome-autophagosome fusion, and elevated levels of TFEB (transcription factor EB). Our study strongly suggests converging roles of PSENEN and CLN3 in the autophagy-lysosome system in a γ-secretase activity-independent manner, supporting the idea of common cytopathological processes underlying different neurodegenerative diseases.},
}
@article {pmid34964515,
year = {2022},
author = {Alizadeh, SR and Ebrahimzadeh, MA},
title = {O-Glycoside quercetin derivatives: Biological activities, mechanisms of action, and structure-activity relationship for drug design, a review.},
journal = {Phytotherapy research : PTR},
volume = {36},
number = {2},
pages = {778-807},
doi = {10.1002/ptr.7352},
pmid = {34964515},
issn = {1099-1573},
mesh = {Drug Design ; Flavonoids ; *Glycosides/pharmacology ; *Quercetin/pharmacology ; Structure-Activity Relationship ; },
abstract = {Quercetin as a valuable natural flavonoid has shown extensive biological activities, including anticancer, antioxidant, antibacterial, antiinflammatory, anti-Alzheimer, antifungal, antiviral, antithalassemia, iron chelation, antiobesity, antidiabetic, antihypertension, and antiphospholipase A2 (PLA2) activities, by the modulation of various targets and signaling pathways that have attracted much attention. However, the low solubility and poor bioavailability of quercetin have limited its applications; therefore, the researchers have tried to design and synthesize many new derivatives of quercetin through different strategies to modify quercetin restrictions and improve its biological activities. This review categorized the O-glycoside derivatives of Quercetin into two main classes, 3-O-glycoside and other O-glycoside derivatives. Also, it studied biological activities, structure-activity relationship (SAR), and the action mechanism of O-glycoside quercetin derivatives. Overall, we summarized past and present research for discovering new potent lead compounds. HIGHLIGHTS: Quercetin is a natural flavonoid with a valuable scaffold. O-Glycoside quercetin derivatives represents broad-spectrum biological activities. The structure-activity relationship investigation is discussed after modifying the scaffold of quercetin. This review can help researchers to rationally design/develop various drugs.},
}
@article {pmid34963433,
year = {2021},
author = {Turkez, H and Arslan, ME and Barboza, JN and Kahraman, CY and de Sousa, DP and Mardinoğlu, A},
title = {Therapeutic Potential of Ferulic Acid in Alzheimer's Disease.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/1567201819666211228153801},
pmid = {34963433},
issn = {1875-5704},
abstract = {Alzheimer's Disease (AD) is one of the most important neurodegenerative diseases and it covers 60% of whole dementia cases. AD is a constantly progressing neurodegenerative disease as a result of the production of β-amyloid (Aβ) protein and the accumulation of hyper-phosphorylated Tau protein; it causes breakages in the synaptic bonds and neuronal deaths to a large extent. Millions of people worldwide suffer from AD because there is no definitive drug for disease prevention, treatment or slowdown. Over the last decade, multiple target applications have been developed for AD treatments. These targets include Aβ accumulations, hyper-phosphorylated Tau proteins, mitochondrial dysfunction, and oxidative stress resulting in toxicity. Various natural or semisynthetic antioxidant formulations have been shown to protect brain cells from Aβ induced toxicity and provide promising potentials for AD treatment. Ferulic acid (FA), a high-capacity antioxidant molecule, is naturally synthesized from certain plants. FA has been shown to have different substantial biological properties, such as anticancer, antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and cardioprotective actions, etc. Furthermore, FA exerted neuroprotection via preventing Aβ-fibril formation, acting as an anti-inflammatory agent, and inhibiting free radical generation and acetylcholinesterase (AChE) enzyme activity. In this review, we present key biological roles of FA and several FA derivatives in Aβ-induced neurotoxicity, protection against free radical attacks, and enzyme inhibitions and describe them as possible therapeutic agents for the treatment of AD.},
}
@article {pmid34961464,
year = {2021},
author = {Chandarana, CV and Roy, S},
title = {Comprehensive Review on Neuro-Degenerative Type 3DM.},
journal = {Current diabetes reviews},
volume = {},
number = {},
pages = {},
doi = {10.2174/1573399818666211213103624},
pmid = {34961464},
issn = {1875-6417},
abstract = {Alzheimer disease (AD) is thought to be the metabolic illness raised by defective insulin signaling, insulin resistance, and low insulin levels in the brain, according to a growing body of research. The "Type 3 diabetes" has been postulated for AD because reduced insulin signalling has molecular and physiological consequences that are comparable to Type I and Type 2 diabetes mellitus (Type 1 DM and Type 2 DM, respectively). The similarities between type 2 diabetes and Alzheimer's disease suggest that these clinical trials might yield therapeutic benefits. However, it's important to note that lowering your risk of Alzheimer's dementia, whether you have diabetes or not, is still a multidimensional process involving factors like exercise, smoking, alcohol, food, and mental challenge. The current aim is to show the relationship between T3D and AD being based on both the processing of amyloid-β (Aβ) precursor protein toxicity and the clearance of Aβ are the result of an impaired insulin signaling. The brain's metabolism with its high lipid content and energy needs, places excess demands on mitochondria and appears more susceptible to oxidative damage than the rest of the body. Current data suggests that increased oxidative stress relates to amyloid-β (Aβ) pathology and onset of AD.},
}
@article {pmid34959619,
year = {2021},
author = {Viel, C and Brandtner, AT and Weißhaar, A and Lehto, A and Fuchs, M and Klein, J},
title = {Effects of Magnesium Orotate, Benfotiamine and a Combination of Vitamins on Mitochondrial and Cholinergic Function in the TgF344-AD Rat Model of Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {14},
number = {12},
pages = {},
pmid = {34959619},
issn = {1424-8247},
support = {0815//Wörwag Pharma (Germany)/ ; },
abstract = {Glucose hypometabolism, mitochondrial dysfunction, and cholinergic deficits have been reported in early stages of Alzheimer's disease (AD). Here, we examine these parameters in TgF344-AD rats, an Alzheimer model that carries amyloid precursor protein and presenilin-1 mutations, and of wild type F344 rats. In mitochondria isolated from rat hippocampi, we found reductions of complex I and oxidative phosphorylation in transgenic rats. Further impairments, also of complex II, were observed in aged (wild-type and transgenic) rats. Treatment with a "cocktail" containing magnesium orotate, benfotiamine, folic acid, cyanocobalamin, and cholecalciferol did not affect mitochondrial activities in wild-type rats but restored diminished activities in transgenic rats to wild-type levels. Glucose, lactate, and pyruvate levels were unchanged by age, genetic background, or treatment. Using microdialysis, we also investigated extracellular concentrations of acetylcholine that were strongly reduced in transgenic animals. Again, ACh levels in wild-type rats did not change upon treatment with nutrients, whereas the cocktail increased hippocampal acetylcholine levels under physiological stimulation. We conclude that TgF344-AD rats display a distinct mitochondrial and cholinergic dysfunction not unlike the findings in patients suffering from AD. This dysfunction can be partially corrected by the application of the "cocktail" which is particularly active in aged rats. We suggest that the TgF344-AD rat is a promising model to further investigate mitochondrial and cholinergic dysfunction and potential treatment approaches for AD.},
}
@article {pmid34959070,
year = {2022},
author = {Ruganzu, JB and Peng, X and He, Y and Wu, X and Zheng, Q and Ding, B and Lin, C and Guo, H and Yang, Z and Zhang, X and Yang, W},
title = {Downregulation of TREM2 expression exacerbates neuroinflammatory responses through TLR4-mediated MAPK signaling pathway in a transgenic mouse model of Alzheimer's disease.},
journal = {Molecular immunology},
volume = {142},
number = {},
pages = {22-36},
doi = {10.1016/j.molimm.2021.12.018},
pmid = {34959070},
issn = {1872-9142},
mesh = {Alzheimer Disease/genetics/*pathology ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Brain/cytology/metabolism ; Cell Line ; Cytokines/metabolism ; Disease Models, Animal ; Down-Regulation/genetics ; Female ; Gliosis/pathology ; MAP Kinase Signaling System/genetics ; Male ; Maze Learning/physiology ; Membrane Glycoproteins/*biosynthesis ; Memory, Short-Term/physiology ; Mice ; Mice, Transgenic ; Microglia/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Neuroglia/cytology/pathology ; Neuroinflammatory Diseases/genetics/immunology/*pathology ; Plaque, Amyloid/pathology ; Receptors, Immunologic/*biosynthesis ; Toll-Like Receptor 4/*metabolism ; },
abstract = {Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that downregulation of TREM2 significantly aggravated AD-related neuropathology including Aβ accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by Aβ1-42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation-related diseases.},
}
@article {pmid34957899,
year = {2021},
author = {Salehi, S and Nourbakhsh, MS and Yousefpour, M and Rajabzadeh, G and Sahab-Negah, S},
title = {Chitosan-coated niosome as an efficient curcumin carrier to cross the blood-brain barrier: an animal study.},
journal = {Journal of liposome research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/08982104.2021.2019763},
pmid = {34957899},
issn = {1532-2394},
abstract = {This study aims to improve the curcumin bio-stability and brain permeability by loading in bare niosome (BN) and chitosan-coated niosome (ChN). Span 60, tween 60, and cholesterol were optimized as niosome shell components to attain the highest encapsulation efficiency (EE), besides the lowest particle size, using the mixture design method. The resulting optimized BN had a mean diameter of 80 ± 0.2 nm and surface charge of -31 ± 0.1 mv, which changed to 85 ± 0.15 nm and 35 ± 0.12 mv, respectively, after applying the chitosan layer. The EE% in bare niosome were about 80 ± 0.2, which changed to 82 ± 0.21 in ChN. The optimized formulation displayed sustained release, following the Hixson-Crowell model.Wistar rats were subjected to intraperitoneal injection (i.p.) of BN and ChN to evaluate the blood-brain barrier permeability of the curcumin. In this regard, ChN significantly increased curcumin concentration in different parts of the liver, plasma, and central nervous system (cerebral cortex, cerebellum, and stratum), compared with BN. Altogether, our results showed that ChN could be used as a promising delivery system for the treatment of some neurological diseases such as Alzheimer's.},
}
@article {pmid34957735,
year = {2021},
author = {Ehrlich, D and Dunzinger, A and Malsiner-Walli, G and Grün, B and Topakian, R and Hodolic, M and Kainz, E and Pichler, R},
title = {Lack of association between cortical amyloid deposition and glucose metabolism in early stage Alzheimer´s disease patients.},
journal = {Radiology and oncology},
volume = {56},
number = {1},
pages = {23-31},
pmid = {34957735},
issn = {1581-3207},
mesh = {*Alzheimer Disease/diagnostic imaging/metabolism ; Amyloid beta-Peptides/metabolism ; Fluorodeoxyglucose F18 ; Glucose/metabolism ; Humans ; Positron Emission Tomography Computed Tomography ; },
abstract = {BACKGROUND: Beta amyloid (Aβ) causes synaptic dysfunction leading to neuronal death. It is still controversial if the magnitude of Aβ deposition correlates with the degree of cognitive impairment. Diagnostic imaging may lead to a better understanding the role of Aβ in development of cognitive deficits. The aim of the present study was to investigate if Aβ deposition in the corresponding brain region of early stage Alzheimer´s disease (AD) patients, directly correlates to neuronal dysfunction and cognitive impairment indicated by reduced glucose metabolism.<br><br>PATIENTS AND METHODS: In 30 patients with a clinical phenotype of AD and amyloid positive brain imaging, 2-[18F] fluoro-2-deoxy-d-glucose (FDG) PET/CT was performed. We extracted the average [18F] flutemetamol (Vizamyl) uptake for each of the 16 regions of interest in both hemispheres and computed the standardized uptake value ratio (SUVR) by dividing the Vimazyl intensities by the mean signal of positive and negative control regions. Data were analysed using the R environment for statistical computing and graphics.<br><br>RESULTS: Any negative correlation between Aβ deposition and glucose metabolism in 32 dementia related and corresponding brain regions in AD patients was not found. None of the correlation coefficient values were statistically significant different from zero based on two-sided p- value.<br><br>CONCLUSIONS: Regional Aβ deposition did not correlate negatively with local glucose metabolism in early stage AD patients. Our findings support the role of Aβ as a valid biomarker, but does not permit to conclude that Aβ is a direct cause for an aberrant brain glucose metabolism and neuronal dysfunction.},
}
@article {pmid34957486,
year = {2021},
author = {Jackson, RJ and Meltzer, JC and Nguyen, H and Commins, C and Bennett, RE and Hudry, E and Hyman, BT},
title = {APOE4 derived from astrocytes leads to blood-brain barrier impairment.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awab478},
pmid = {34957486},
issn = {1460-2156},
abstract = {Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood brain barrier.},
}
@article {pmid34954669,
year = {2022},
author = {Zeilinger, EL and Zrnic Novakovic, I and Komenda, S and Franken, F and Sobisch, M and Mayer, AM and Neumann, LC and Loosli, SV and Hoare, S and Pietschnig, J},
title = {Informant-based assessment instruments for dementia in people with intellectual disability: A systematic review and standardised evaluation.},
journal = {Research in developmental disabilities},
volume = {121},
number = {},
pages = {104148},
doi = {10.1016/j.ridd.2021.104148},
pmid = {34954669},
issn = {1873-3379},
mesh = {Aged ; Bias ; *Dementia/diagnosis ; *Down Syndrome/diagnosis ; Humans ; *Intellectual Disability/diagnosis/epidemiology ; Mass Screening ; },
abstract = {BACKGROUND: Dementia in people with intellectual disability (ID) is frequent but hard to recognise. Evidence-based recommendations for suitable instruments are lacking.<br><br>AIMS: The present study set out to evaluate informant-based dementia assessment instruments and to provide evidence-based recommendations for instruments most suitable in clinical practice and research.<br><br>METHOD AND PROCEDURES: A systematic review was conducted across ten international electronic databases. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines, including a risk of bias assessment, was applied to extract information and to evaluate measurement properties and the quality of available evidence.<br><br>OUTCOMES AND RESULTS: In total, 42 studies evaluating 18 informant-based assessment instruments were analysed. For screening purposes, we recommend the Behavioral and Psychological Symptoms of Dementia in Down Syndrome Scale (BPSD-DS), the Cognitive Scale for Down Syndrome (CS-DS), and the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID). For a more thorough dementia assessment, we recommend the Cambridge Examination for Mental Disorders of Older People with Down's Syndrome and Others with Intellectual Disabilities (CAMDEX-DS).<br><br>CONCLUSIONS AND IMPLICATIONS: Our study informs clinicians and researchers about adequate, well-evaluated dementia assessment instruments for people with ID, and highlights the need for high quality studies, especially regarding content validity.},
}
@article {pmid34952254,
year = {2022},
author = {Lithgow, BJ and Dastgheib, Z and Moussavi, Z},
title = {Baseline Prediction of rTMS efficacy in Alzheimer patients.},
journal = {Psychiatry research},
volume = {308},
number = {},
pages = {114348},
doi = {10.1016/j.psychres.2021.114348},
pmid = {34952254},
issn = {1872-7123},
mesh = {*Alzheimer Disease/psychology/therapy ; Cognition ; Discriminant Analysis ; Humans ; *Transcranial Magnetic Stimulation/methods ; Treatment Outcome ; },
abstract = {Repetitive transcranial magnetic stimulation (rTMS) with extensive 2-6-week protocols are applied to improve cognition and/or slow the cognitive decline seen in Alzheimer's Disease (AD). To date, there are no means to predict the response of a patient to rTMS treatment at baseline. Electrovestibulography (EVestG) biomarkers can be used to predict, at baseline, the efficacy of rTMS when applied to AD individuals. In a population of 27 AD patients (8 with significant cerebrovascular symptomatology, labelled ADcvd) EVestG signals were measured before and after rTMS treatment, and then compared with 16 age-matched healthy controls. MoCA was measured at baseline, whilst ADAS-Cog was the primary outcome measure. AD severity and comorbid cerebrovascular disease were treated as covariates. Using ADAS-Cog total score change, 13/27 AD/ADcvd patients improved with rTMS and 14/27 showed no-improvement. Leave-one-out-cross-validated linear-discriminant-analysis using two EVestG features yielded a blind accuracy of 75% for separating the improved and non-improved populations. Three-way separation of improved/non-improved/control accuracy was 91.9% using MoCA (67% alone) and one EVestG feature (66% alone). AD severity affects the rTMS treatment efficacy. The effect of existing significant cerebrovascular symptomatology on the efficacy of rTMS treatment remains unresolved. Baseline EVestG features can be predictive of the efficacy of rTMS treatment.},
}
@article {pmid34951386,
year = {2021},
author = {Todri, J and Lena, O and Todri, A and Fuentes, JM},
title = {Does the Global Postural Re-Education Affect the Psychological and Postural Aspects of Alzheimer Disease Patients? A Six Months Quasi-Experimental Study.},
journal = {Current Alzheimer research},
volume = {18},
number = {13},
pages = {1057-1065},
doi = {10.2174/1567205019666211223094811},
pmid = {34951386},
issn = {1875-5828},
mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/therapy ; Cognition ; Female ; Humans ; Male ; Mental Status and Dementia Tests ; Quality of Life ; Treatment Outcome ; },
abstract = {OBJECTIVE: To study the implementation of Global Postural Re-education as a rehabilitative alternative in residence facilities for seniors with Alzheimer, and to verify its effect on psychological and cognitive symptoms.<br><br>METHODS: A quasi-experimental design was employed using month-follow-up assessments at 1,3, and 6 months respectively. Ninety elderly people participated in the composition of the study sample: 69 women and 21 men aged from 67 to 89 years (80.2 ±5.5), grouped in two phases: mild and moderate, according to Alzheimer severity. Patients in both groups received the same treatment twice a week for consecutively 24 weeks. Three follow-up medium-long term assessments were performed at intervals of 1, 3, and 6 months. Outcome measures included Mini-Mental State Examination, Geriatric Depression Scale, Quality of Life in Alzheimer Disease, Barthel Index, and Tinetti Scale.<br><br>RESULTS: The severity of groups therapy interaction showed significant changes in four outcome measures as cognition [F(1,88)=60.26; p=.000; partial η2= 0.406], depression [F(1,88)=8.24; p=.005; partial η2= 0.086], life quality [F(1,88)= 10.45; p=.002; partial η2= 0.106] and equilibrium [F(1,88)= 6.96; p=.010; partial η2= 0.073]. No changes were found for autonomy [F(1,88)= 1.10; p=.297; partial η2= 0.012]. These changes between the two groups were observed at the sixth month follow-up assessment.<br><br>CONCLUSION: Global postural reeducation could be useful as a complementary rehabilitation treatment in Alzheimer patients.},
}
@article {pmid34951383,
year = {2021},
author = {Peña-Bautista, C and Álvarez-Sánchez, L and García, L and Baquero, M and Cháfer-Pericás, C},
title = {Assessment of apolipoprotein E genotype for β-amyloid status prediction.},
journal = {Current Alzheimer research},
volume = {18},
number = {13},
pages = {1032-1040},
doi = {10.2174/1567205019666211223141524},
pmid = {34951383},
issn = {1875-5828},
support = {CP16/00082//Instituto de Salud Carlos III , Miguel Servet I Project/ ; PI19/00570//Spanish Ministry of Economy and Competitiveness/ ; },
mesh = {*Alzheimer Disease/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction/diagnosis ; Genotype ; Humans ; Peptide Fragments/cerebrospinal fluid ; tau Proteins/genetics ; },
abstract = {BACKGROUND: Apolipoprotein E (ApoE) is the major genetic risk factor for sporadic Alzheimer's Disease (AD). Some studies showed a relationship between ApoE4 genotype and the cerebrospinal fluid (CSF) biomarkers (β-amyloid42, p-Tau, t-Tau), as well as with cognitive status. In this sense, it could be interesting to develop an approach to establish amyloid status in a minimally invasive way.<br><br>METHODS: The present study assessed the ApoE genotype in different participant groups (mild cognitive impairment due to AD (MCI-AD), mild/moderate dementia due to AD, MCI not due to AD (MCI not AD), other neurological diseases, healthy participants) (n = 342).<br><br>RESULTS: As expected, the ApoE4 allele was more prevalent in AD patients, characterized by impairment in CSF β-amyloid42 levels (Aβ +), than in the other groups (Aβ -). In this sense, ApoE4-carrier subjects showed lower CSF levels for β-amyloid42 and higher CSF levels for t-Tau and p-Tau. From this, a multivariate model to predict Aβ status was developed by means of partial least square analysis (PLS) and predictive variables (ApoE genotype, cognitive score, sex, age). This model showed suitable AUC-ROC 0.792 (95% CI, 0.744-0.840) and predictive negative value (81.6%).<br><br>CONCLUSION: ApoE genotype could be useful in detecting CSF β-amyloid42 impairment associated with early AD development.},
}
@article {pmid34950896,
year = {2021},
author = {Hainsworth, AH and Elahi, FM and Corriveau, RA},
title = {An introduction to therapeutic approaches to vascular cognitive impairment.},
journal = {Cerebral circulation - cognition and behavior},
volume = {2},
number = {},
pages = {100033},
pmid = {34950896},
issn = {2666-2450},
support = {MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/R005567/1/MRC_/Medical Research Council/United Kingdom ; MR/T033371/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Vascular cognitive impairment (VCI), encompassing vascular dementia, has been claimed as the "second-most common dementia" after Alzheimer Disease. Whether or not this is true, the clinical picture of most dementia in older people includes vascular disease. There are no validated pharmacological targets for prevention or treatment of VCI. This has inspired a multitude of potential treatment approaches, reflected by the articles in this Special Issue. These include in vitro testing of the novel oral anticoagulant dabigatran for protection against β-amyloid neurotoxicity, and an overview of neuroinflammation in VCI and the role of circulating markers (PIGF, VEGF-D) identified by the MarkVCID study. There are reviews of potential therapeutics, including adrenomedullin and nootropic preparations (exemplified by cerebrolysin). The role of sleep is reviewed, with possible therapeutic targets (5HT2A receptors). There is a clinical study protocol (INVESTIGATE-SVD) and a feasibility analysis for a secondary prevention trial in small vessel disease. Clinical data include secondary analyses of blood pressure and cerebral blood flow from a longitudinal clinical trial (NILVAD), differences between methylphenidate and galantamine responders and non-responders (STREAM-VCI), appraisal of treatment approaches in India, and primary outcomes from a randomised trial of Argentine tango dancing to preserve cognition in African American women (ACT). Treating vascular disease has great potential to improve global cognitive health, with public health impacts alongside individual benefit. Vascular disease burden varies across populations, offering the possibility of proactively addressing health inequity in dementia using vascular interventions. The next 5-10 years will witness cost-effective lifestyle interventions, repurposed drugs and novel therapeutics.},
}
@article {pmid34950895,
year = {2021},
author = {Ruchoux, MM and Kalaria, RN and Román, GC},
title = {The pericyte: A critical cell in the pathogenesis of CADASIL.},
journal = {Cerebral circulation - cognition and behavior},
volume = {2},
number = {},
pages = {100031},
pmid = {34950895},
issn = {2666-2450},
support = {G0400074/MRC_/Medical Research Council/United Kingdom ; G0502157/MRC_/Medical Research Council/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; G1100540/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease presenting with migraine, mood and cognitive disorders, focal neurological deficits, recurrent ischemic attacks, lacunar infarcts and brain white matter changes. As they age, CADASIL patients invariably develop cognitive impairment and subcortical dementia. CADASIL is caused by missense mutations in the NOTCH3 gene resulting in a profound cerebral vasculopathy affecting primarily arterial vascular smooth muscle cells, which target the microcirculation and perfusion. Based on a thorough review of morphological lesions in arteries, veins, and capillaries in CADASIL, we surmise that arteriolar and capillary pericyte damage or deficiency appears a key feature in the pathogenesis of the disease. This may affect critical pericyte-endothelial interactions causing stroke injury and vasomotor disturbances. Changes in microvascular permeability due to perhaps localized blood-brain barrier alterations and pericyte secretory dysfunction likely contribute to delayed neuronal as well as glial cell death. Moreover, pericyte-mediated cerebral venous insufficiency may explain white matter lesions and the dilatation of Virchow-Robin perivascular spaces typical of CADASIL. The postulated central role of the pericyte offers some novel approaches to the study and treatment of CADASIL and enable elucidation of other forms of cerebral small vessel diseases and subcortical vascular dementia.},
}
@article {pmid34949203,
year = {2021},
author = {Vandenbark, AA and Offner, H and Matejuk, S and Matejuk, A},
title = {Microglia and astrocyte involvement in neurodegeneration and brain cancer.},
journal = {Journal of neuroinflammation},
volume = {18},
number = {1},
pages = {298},
pmid = {34949203},
issn = {1742-2094},
support = {1IK6BX004209//senior research career scientist award/ ; R21 AI148409/AI/NIAID NIH HHS/United States ; 2R42AI122574//national institute of allergy and infectious diseases awards/ ; I01 BX005112/BX/BLRD VA/United States ; 2I01 BX000226//biomedical laboratory research and development, va office of research and development/ ; 5I01 BX005112//blr&amp;d merit review for pre-ind studies of drugs and biologics award/ ; IK6 BX004209/BX/BLRD VA/United States ; I01 BX000226/BX/BLRD VA/United States ; },
mesh = {Animals ; Astrocytes/*pathology ; Brain Neoplasms/*complications/*pathology ; Humans ; Microglia/*pathology ; Neurodegenerative Diseases/*etiology/*pathology ; },
abstract = {The brain is unique and the most complex organ of the body, containing neurons and several types of glial cells of different origins and properties that protect and ensure normal brain structure and function. Neurological disorders are the result of a failure of the nervous system multifaceted cellular networks. Although great progress has been made in the understanding of glia involvement in neuropathology, therapeutic outcomes are still not satisfactory. Here, we discuss recent perspectives on the role of microglia and astrocytes in neurological disorders, including the two most common neurodegenerative conditions, Alzheimer disease and progranulin-related frontotemporal lobar dementia, as well as astrocytoma brain tumors. We emphasize key factors of microglia and astrocytic biology such as the highly heterogeneic glial nature strongly dependent on the environment, genetic factors that predispose to certain pathologies and glia senescence that inevitably changes the CNS landscape. Our understanding of diverse glial contributions to neurological diseases can lead advances in glial biology and their functional recovery after CNS malfunction.},
}
@article {pmid34949153,
year = {2021},
author = {Shimada, T and Uehara, T and Nagasawa, T and Hasegawa, M and Maeda, Y and Kawasaki, Y},
title = {A case report of late-onset schizophrenia differentiated from a dementing disorder.},
journal = {Neurocase},
volume = {27},
number = {6},
pages = {467-473},
doi = {10.1080/13554794.2021.2016858},
pmid = {34949153},
issn = {1465-3656},
mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/diagnosis/pathology ; Amyloid beta-Peptides ; Biomarkers ; Female ; Hallucinations ; Humans ; *Schizophrenia/diagnosis/pathology ; tau Proteins ; },
abstract = {We report a case of late-onset schizophrenia that required differentiation from a dementing disorder. The patient was an 83-year-old woman who had experienced auditory hallucinations since she was 67 years old. The patient had slightly elevated total tau and slightly decreased amyloid β1-42, cerebrospinal fluid biomarkers. This case was identified as late-onset schizophrenia. However, the results of cerebrospinal fluid biomarkers indicated that neurofibrillary tangles and neuronal death, which are characteristic of Alzheimer 's disease, may also have been present. Late-onset schizophrenia should be treated based on an appropriate differential diagnosis, including neuropathological consideration of dementing disorders.},
}
@article {pmid34948180,
year = {2021},
author = {Kowalczyk, P and Sulejczak, D and Kleczkowska, P and Bukowska-Ośko, I and Kucia, M and Popiel, M and Wietrak, E and Kramkowski, K and Wrzosek, K and Kaczyńska, K},
title = {Mitochondrial Oxidative Stress-A Causative Factor and Therapeutic Target in Many Diseases.},
journal = {International journal of molecular sciences},
volume = {22},
number = {24},
pages = {},
pmid = {34948180},
issn = {1422-0067},
mesh = {Animals ; Antioxidants/pharmacology ; Disease/etiology ; Free Radicals/metabolism ; Humans ; Mitochondria/*metabolism ; Mitochondrial Diseases/*physiopathology ; Oxidative Stress/*physiology ; Reactive Oxygen Species/adverse effects/metabolism ; },
abstract = {The excessive formation of reactive oxygen species (ROS) and impairment of defensive antioxidant systems leads to a condition known as oxidative stress. The main source of free radicals responsible for oxidative stress is mitochondrial respiration. The deleterious effects of ROS on cellular biomolecules, including DNA, is a well-known phenomenon that can disrupt mitochondrial function and contribute to cellular damage and death, and the subsequent development of various disease processes. In this review, we summarize the most important findings that implicated mitochondrial oxidative stress in a wide variety of pathologies from Alzheimer disease (AD) to autoimmune type 1 diabetes. This review also discusses attempts to affect oxidative stress as a therapeutic avenue.},
}
@article {pmid34947975,
year = {2021},
author = {Le, D and Brown, L and Malik, K and Murakami, S},
title = {Two Opposing Functions of Angiotensin-Converting Enzyme (ACE) That Links Hypertension, Dementia, and Aging.},
journal = {International journal of molecular sciences},
volume = {22},
number = {24},
pages = {},
pmid = {34947975},
issn = {1422-0067},
mesh = {Aging/genetics/*metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Dementia/genetics/*metabolism ; Disease Models, Animal ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Hypertension/genetics/*metabolism ; Peptidyl-Dipeptidase A/genetics/*metabolism ; },
abstract = {A 2018 report from the American Heart Association shows that over 103 million American adults have hypertension. The angiotensin-converting enzyme (ACE) (EC 3.4.15.1) is a dipeptidyl carboxylase that, when inhibited, can reduce blood pressure through the renin-angiotensin system. ACE inhibitors are used as a first-line medication to be prescribed to treat hypertension, chronic kidney disease, and heart failure, among others. It has been suggested that ACE inhibitors can alleviate the symptoms in mouse models. Despite the benefits of ACE inhibitors, previous studies also have suggested that genetic variants of the ACE gene are risk factors for Alzheimer's disease (AD) and other neurological diseases, while other variants are associated with reduced risk of AD. In mice, ACE overexpression in the brain reduces symptoms of the AD model systems. Thus, we find two opposing effects of ACE on health. To clarify the effects, we dissect the functions of ACE as follows: (1) angiotensin-converting enzyme that hydrolyzes angiotensin I to make angiotensin II in the renin-angiotensin system; (2) amyloid-degrading enzyme that hydrolyzes beta-amyloid, reducing amyloid toxicity. The efficacy of the ACE inhibitors is well established in humans, while the knowledge specific to AD remains to be open for further research. We provide an overview of ACE and inhibitors that link a wide variety of age-related comorbidities from hypertension to AD to aging. ACE also serves as an example of the middle-life crisis theory that assumes deleterious events during midlife, leading to age-related later events.},
}
@article {pmid34947257,
year = {2021},
author = {Azmat, A and Tufail, M and Chandio, AD},
title = {Synthesis and Characterization of Ti-Sn Alloy for Orthopedic Application.},
journal = {Materials (Basel, Switzerland)},
volume = {14},
number = {24},
pages = {},
pmid = {34947257},
issn = {1996-1944},
support = {Acad /50(48)/2165//NED University of Engineering and Technology/ ; },
abstract = {Titanium (Ti)-based alloys (e.g., Ti6Al4V) are widely used in orthopedic implant applications owing to their excellent mechanical properties and biocompatibility. However, their corrosion resistance needs to be optimized. In addition, the presence of aluminum and vanadium cause alzheimer and cancer, respectively. Therefore, in this study, titanium-based alloys were developed via powder metallurgy route. In these alloys, the Al and V were replaced with tin (Sn) which was the main aim of this study. Four sets of samples were prepared by varying Sn contents, i.e., 5 to 20 wt. %. This was followed by characterization techniques including laser particle analyzer (LPA), X-ray diffractometer (XRD), scanning electron microscope (SEM), computerized potentiostate, vicker hardness tester, and nanoindenter. Results demonstrate the powder sizes between 50 and 55 µm exhibiting very good densification after sintering. The alloy contained alpha at all concentrations of Sn. However, as Sn content in the alloy exceeded from 10 wt. %, the formation of intermetallic compounds was significant. Thus, the presence of such intermetallic phases are attributed to enhanced elastic modulus. In particular, when Sn content was between 15 and 20 wt. % a drastic increase in elastic modulus was observed thereby surpassing the standard/reference alloy (Ti6Al4V). However, at 10 wt. % of Sn, the elastic modulus is more or less comparable to reference counterpart. Similarly, hardness was also increased in an ascending order upon Sn addition, i.e., 250 to 310 HV. Specifically, at 10 wt. % Sn, the hardness was observed to be 250 HV which is quite near to reference alloy, i.e., 210 HV. Moreover, tensile strength (TS) of the alloys were calculated using hardness values since it was very difficult to prepare the test coupons using powders. The TS values were in the range of 975 to 1524 MPa at all concentrations of Sn. In particular, the TS at 10 wt. % Sn is 1149 MPa which is comparable to reference counterpart (1168 MPa). The corrosion rate of Titanium-Sn alloys (as of this study) and reference alloy, i.e., Ti6Al4V were also compared. Incorporation of Sn reduced the corrosion rate at large than that of reference counterpart. In particular, the trend was in decreasing order as Sn content increased from 5 to 20 wt. %. The minimum corrosion rate of 3.65 × 10-9 mm/year was noticed at 20 wt. % than that of 0.03 mm/year of reference alloy. This shows the excellent corrosion resistance upon addition of Sn at all concentrations.},
}
@article {pmid34944628,
year = {2021},
author = {Peña-Bautista, C and Álvarez-Sánchez, L and Cañada-Martínez, AJ and Baquero, M and Cháfer-Pericás, C},
title = {Epigenomics and Lipidomics Integration in Alzheimer Disease: Pathways Involved in Early Stages.},
journal = {Biomedicines},
volume = {9},
number = {12},
pages = {},
pmid = {34944628},
issn = {2227-9059},
support = {PI19/00570//Instituto de Salud Carlos III/ ; },
abstract = {BACKGROUND: Alzheimer Disease (AD) is the most prevalent dementia. However, the physiopathological mechanisms involved in its development are unclear. In this sense, a multi-omics approach could provide some progress.<br><br>METHODS: Epigenomic and lipidomic analysis were carried out in plasma samples from patients with mild cognitive impairment (MCI) due to AD (n = 22), and healthy controls (n = 5). Then, omics integration between microRNAs (miRNAs) and lipids was performed by Sparse Partial Least Squares (s-PLS) regression and target genes for the selected miRNAs were identified.<br><br>RESULTS: 25 miRNAs and 25 lipids with higher loadings in the sPLS regression were selected. Lipids from phosphatidylethanolamines (PE), lysophosphatidylcholines (LPC), ceramides, phosphatidylcholines (PC), triglycerides (TG) and several long chain fatty acids families were identified as differentially expressed in AD. Among them, several fatty acids showed strong positive correlations with miRNAs studied. In fact, these miRNAs regulated genes implied in fatty acids metabolism, as elongation of very long-chain fatty acids (ELOVL), and fatty acid desaturases (FADs).<br><br>CONCLUSIONS: The lipidomic-epigenomic integration showed that several lipids and miRNAs were differentially expressed in AD, being the fatty acids mechanisms potentially involved in the disease development. However, further work about targeted analysis should be carried out in a larger cohort, in order to validate these preliminary results and study the proposed pathways in detail.},
}
@article {pmid34944489,
year = {2021},
author = {Soto-Mercado, V and Mendivil-Perez, M and Velez-Pardo, C and Jimenez-Del-Rio, M},
title = {(-)-Epigallocatechin-3-Gallate Diminishes Intra-and Extracellular Amyloid-Induced Cytotoxic Effects on Cholinergic-like Neurons from Familial Alzheimer's Disease PSEN1 E280A.},
journal = {Biomolecules},
volume = {11},
number = {12},
pages = {},
pmid = {34944489},
issn = {2218-273X},
mesh = {Alzheimer Disease/drug therapy/*genetics/metabolism ; Amyloid beta-Peptides/*chemistry/drug effects/toxicity ; Catechin/*analogs &amp; derivatives/pharmacology ; Cells, Cultured ; Cholinergic Neurons/*cytology/drug effects/metabolism ; Female ; Gene Regulatory Networks/drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Microscopy, Fluorescence ; Models, Biological ; Mutation ; Presenilin-1/*genetics ; Protein Aggregates/drug effects ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by functional disruption, death of cholinergic neurons (ChNs) because of intracellular and extracellular Aβ aggregates, and hyperphosphorylation of protein TAU (p-TAU). To date, there are no efficient therapies against AD. Therefore, new therapies for its treatment are in need. The goal of this investigation was to evaluate the effect of the polyphenol epigallocatechin-3-gallate (EGCG) on cholinergic-like neurons (ChLNs) bearing the mutation E280A in PRESENILIN 1 (PSEN1 E280A). To this aim, wild-type (WT) and PSEN1 E280A ChLNs were exposed to EGCG (5-50 μM) for 4 days. Untreated or treated neurons were assessed for biochemical and functional analysis. We found that EGCG (50 μM) significantly inhibited the aggregation of (i)sAPPβf, blocked p-TAU, increased ∆Ψm, decreased oxidation of DJ-1 at residue Cys106-SH, and inhibited the activation of transcription factor c-JUN and P53, PUMA, and CASPASE-3 in mutant ChLNs compared to WT. Although EGCG did not reduce (e)Aβ42, the polyphenol reversed Ca2+ influx dysregulation as a response to acetylcholine (ACh) stimuli in PSEN1 E280A ChLNs, inhibited the activation of transcription factor NF-κB, and reduced the secretion of pro-inflammatory IL-6 in wild-type astrocyte-like cells (ALCs) when exposed to mutant ChLNs culture supernatant. Taken together, our findings suggest that the EGCG might be a promising therapeutic approach for the treatment of FAD.},
}
@article {pmid34943096,
year = {2021},
author = {Mostafa, NM and Mostafa, AM and Ashour, ML and Elhady, SS},
title = {Neuroprotective Effects of Black Pepper Cold-Pressed Oil on Scopolamine-Induced Oxidative Stress and Memory Impairment in Rats.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {12},
pages = {},
pmid = {34943096},
issn = {2076-3921},
support = {IFPIP-714-166-1442//The Deputyship for Research &amp; Innovation, Ministry of Education in Saudi Arabia/ ; },
abstract = {Oxidative stress is usually associated with many neurodegenerative diseases. In this study, the gas chromatography-mass spectrometry (GC-MS) analysis of cold-pressed oil (CPO) from black pepper (Piper nigrum) fruits was performed and its neuroprotective effects were evaluated for the first time. The analysis of CPO revealed the presence of the lignan sesamin (39.78%), the alkaloid piperine (33.79%), the monoterpene hydrocarbons 3-carene (9.53%) and limonene (6.23%), and the sesquiterpene β-caryophyllene (10.67%). Black pepper hydrodistilled oil (HDO) was also comparatively analyzed by GC-MS to show the impact of oil isolation by two different methodologies on their components and class of compounds identified. HDO analysis revealed 35 compounds (99.64% of the total peak areas) mainly composed of monoterpene hydrocarbons (77.28%), such as limonene (26.50%), sabinene (21.36%), and β-pinene (15.53%), and sesquiterpene hydrocarbons (20.59%) represented mainly by β-caryophyllene (19.12%). Due to the low yield obtained for HDO (0.01% v/w), only CPO was chosen for the evaluation of its neuroprotective potential. Alzheimer-type dementia was induced in rats by scopolamine intraperitoneal injection (1.5 mg/kg/day) for seven days. CPO was administered orally (100 mg/kg) for a week before scopolamine administration and then concomitantly for another week. Donepezil (1 mg/kg, orally) was used as a reference drug. CPO administration significantly improved the rat behaviors as evaluated by the Morris water maze test, evident from prolongation in time spent in the platform quadrant (262.9%, compared to scopolamine) and increasing in the crossing time by 18.18% compared to the control group. The rat behavior tested by passive avoidance, showed prolongation in the step-through latency compared to control. Moreover, CPO significantly (p < 0.05) ameliorated the activities of antioxidant enzymes such as catalase, superoxide dismutase (SOD) and reduced malondialdehyde (MDA) equivalents by 22.48%, 45.41%, and 86.61%, respectively, compared to scopolamine. Furthermore, CPO administration decreased scopolamine-induced elevated acetylcholinesterase levels in rats' hippocampi by 51.30%. These results were supported by histopathological and in silico molecular docking studies. Black pepper oil may be a potential antioxidant and neuroprotective supplement.},
}
@article {pmid34939734,
year = {2022},
author = {Yu, ZY and Chen, DW and Tan, CR and Zeng, GH and He, CY and Wang, J and Bu, XL and Wang, YJ},
title = {Physiological clearance of Aβ by spleen and splenectomy aggravates Alzheimer-type pathogenesis.},
journal = {Aging cell},
volume = {21},
number = {1},
pages = {e13533},
pmid = {34939734},
issn = {1474-9726},
mesh = {Alzheimer Disease/*pathology ; Amyloid beta-Peptides/*adverse effects ; Animals ; Disease Models, Animal ; Female ; Humans ; Mice ; Mice, Transgenic ; Spleen/*pathology ; Splenectomy/*methods ; },
abstract = {BACKGROUND: A previous study demonstrated that nearly 40%-60% of brain Aβ flows out into the peripheral system for clearance. However, where and how circulating Aβ is cleared in the periphery remains unclear. The spleen acts as a blood filter and an immune organ. The aim of the present study was to investigate the role of the spleen in the clearance of Aβ in the periphery.<br><br>METHODS: We investigated the physiological clearance of Aβ by the spleen and established a mouse model of AD and spleen excision by removing the spleens of APP/PS1 mice to investigate the effect of splenectomy on AD mice.<br><br>RESULTS: We found that Aβ levels in the splenic artery were higher than those in the splenic vein, suggesting that circulating Aβ is cleared when blood flows through the spleen. Next, we found that splenic monocytes/macrophages could take up Aβ directly in vivo and in vitro. Splenectomy aggravated behaviour deficits, brain Aβ burden and AD-related pathologies in AD mice.<br><br>CONCLUSION: Our study reveals for the first time that the spleen exerts a physiological function of clearing circulating Aβ in the periphery. Our study also suggests that splenectomy, which is a routine treatment for splenic rupture and hypersplenism, might accelerate the development of AD.},
}
@article {pmid34939537,
year = {2021},
author = {Marotta, G and Basagni, F and Rosini, M and Minarini, A},
title = {Role of Fyn Kinase Inhibitors in Switching Neuroinflammatory Pathways.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0929867329666211221153719},
pmid = {34939537},
issn = {1875-533X},
abstract = {Fyn kinase is a member of the Src non-receptor tyrosine kinase family. Fyn is involved in multiple signaling pathways extending from cell proliferation and differentiation to cell adhesion and cell motility, and it has been found to be overexpressed in various types of cancers. In the central nervous system, Fyn exerts several different functions such as axon-glial signal transduction, oligodendrocyte maturation and myelination, and it is implicated in neuroinflammatory processes. Based on these premises, Fyn emerges as an attractive target in cancer and neurodegenerative disease therapy, particularly Alzheimer disease (AD), based on its activation by Aβ via cellular prion protein and its interaction with tau protein. However, Fyn is also a challenging target since the Fyn inhibitors discovered so far, due to the relevant homology of Fyn with other kinases, suffer from off-target effects. This review covers the efforts performed in the last decade to identify and optimize small molecules that effectively inhibit Fyn, both in enzymatic and in cell assays, including drug repositioning practices, as an opportunity of therapeutic intervention in neurodegeneration.},
}
@article {pmid34937781,
year = {2022},
author = {Cullen, N and Janelidze, S and Palmqvist, S and Stomrud, E and Mattsson-Carlgren, N and Hansson, O and , },
title = {Association of CSF Aβ38 Levels With Risk of Alzheimer Disease-Related Decline.},
journal = {Neurology},
volume = {98},
number = {9},
pages = {e958-e967},
pmid = {34937781},
issn = {1526-632X},
mesh = {*Alzheimer Disease/complications ; Amyloid beta-Peptides ; Biomarkers ; *Cognitive Dysfunction/diagnosis ; Humans ; Peptide Fragments ; tau Proteins ; },
abstract = {BACKGROUND AND OBJECTIVE: Experimental studies suggest that the balance between short and long β-amyloid (Aβ) species might modulate the toxic effects of Aβ in Alzheimer disease (AD), but clinical evidence is lacking. We studied whether Aβ38 levels in CSF relate to risk of AD dementia and cognitive decline.<br><br>METHODS: CSF Aβ38 levels were measured in 656 individuals across 2 clinical cohorts: the Swedish BioFINDER study and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cox regression models were used to evaluate the association between baseline Aβ38 levels and risk of AD dementia in AD biomarker-positive individuals (AD+; determined by CSF phosphorylated tau [P-tau]/Aβ42 ratio) with subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Linear mixed-effects models were used to evaluate the association between baseline Aβ38 levels and cognitive decline as measured by the Mini-Mental State Examination (MMSE) in AD+ participants with SCD, MCI, or AD dementia.<br><br>RESULTS: In the BioFINDER cohort, high Aβ38 levels were associated with slower decline in MMSE score (β = 0.30 points per SD, p = 0.001) and with lower risk of conversion to AD dementia (hazard ratio 0.83 per SD, p = 0.03). In the ADNI cohort, higher Aβ38 levels were associated with less decline in MMSE score (β = 0.27, p = 0.01) but not risk of conversion to AD dementia (p = 0.66). Aβ38 levels in both cohorts were significantly associated with both cognitive and clinical outcomes when further adjusted for CSF P-tau or CSF Aβ42 levels.<br><br>DISCUSSION: Higher CSF Aβ38 levels are associated with lower risk of AD-related changes in 2 independent clinical cohorts. These findings suggest that γ-secretase modulators could be effective as disease-altering therapy.<br><br>ClinicalTrials.gov Identifier: NCT03174938.},
}
@article {pmid34937778,
year = {2022},
author = {Yu, L and Boyle, PA and Wingo, AP and Yang, J and Wang, T and Buchman, AS and Wingo, TS and Seyfried, NT and Levey, AI and De Jager, PL and Schneider, JA and Bennett, DA},
title = {Neuropathologic Correlates of Human Cortical Proteins in Alzheimer Disease and Related Dementias.},
journal = {Neurology},
volume = {98},
number = {10},
pages = {e1031-e1039},
pmid = {34937778},
issn = {1526-632X},
support = {P30 AG072975/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG056533/AG/NIA NIH HHS/United States ; R56 AG062633/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease/pathology ; Brain/pathology ; *Cerebral Amyloid Angiopathy/complications ; Humans ; Lewy Bodies/pathology ; Membrane Proteins/metabolism ; Mitochondrial Proteins/metabolism ; *Neurodegenerative Diseases/pathology ; beta-Lactamases/metabolism ; },
abstract = {BACKGROUND AND OBJECTIVES: Alzheimer dementia is a complex clinical syndrome that can be defined broadly as an amnestic multidomain dementia. We previously reported human cortical proteins that are implicated in Alzheimer dementia. To understand the pathologic correlates of these proteins for underlying disease mechanisms, we investigated cortical protein associations with common age-related neuropathologies.<br><br>METHODS: Participants were community-dwelling older adults from 2 cohort studies of aging and dementia. All underwent detailed annual clinical evaluations, and brain autopsies were performed after death. We use Alzheimer disease (AD) to refer to pathologically defined disease and Alzheimer dementia to refer to the clinical syndrome. Indices for AD, cortical Lewy bodies, limbic predominant age-related TAR DNA binding protein 43 encephalopathy neuropathologic changes (LATE-NC), hippocampal sclerosis, macroscopic infarcts, microinfarcts, cerebral amyloid angiopathy, atherosclerosis, and arteriolosclerosis were quantified during uniform structured neuropathologic evaluations. High-throughput protein abundances from frozen dorsolateral prefrontal cortex were quantified with mass spectrometry-based tandem mass tag proteomics analysis. Eleven human cortical proteins implicated in Alzheimer dementia, including angiotensin-converting enzyme, calcium-regulated heat-stable protein 1 (CHSP1), procathepsin H (CATH), double C2-like domain-containing protein α, islet cell autoantigen 1-like protein, serine β-lactamase-like protein LACTB, mitochondrial, pleckstrin homology domain-containing family A member 1, replication termination factor 2, sorting nexin-32, syntaxin-4, and syntaxin-6 (STX6), were previously identified with an integrative approach. Logistic regression analysis examined the association of protein expression with each of the neuropathologic indices.<br><br>RESULTS: A total of 391 older adults were included. We did not observe associations of these protein targets with pathologic diagnosis of AD. In contrast, multiple proteins were associated with non-AD neurodegenerative and cerebrovascular conditions. In particular, higher CHSP1 expression was associated with cortical Lewy bodies and macroscopic infarcts, and higher CATH expression was associated with LATE-NC and arteriolosclerosis. Furthermore, while higher STX6 expression increased the risk of Alzheimer dementia, the protein was not associated with any of the neuropathologic indices investigated.<br><br>DISCUSSION: Cortical proteins implicated in Alzheimer dementia do not necessarily work through AD pathogenesis; rather, non-AD neurodegenerative and vascular diseases and other pathways are at play. Furthermore, some proteins are pleiotrophic and associated with both neurodegenerative and cerebrovascular pathologies.},
}
@article {pmid34933129,
year = {2022},
author = {Mahaman, YAR and Embaye, KS and Huang, F and Li, L and Zhu, F and Wang, JZ and Liu, R and Feng, J and Wang, X},
title = {Biomarkers used in Alzheimer's disease diagnosis, treatment, and prevention.},
journal = {Ageing research reviews},
volume = {74},
number = {},
pages = {101544},
doi = {10.1016/j.arr.2021.101544},
pmid = {34933129},
issn = {1872-9649},
mesh = {*Alzheimer Disease/diagnosis/therapy ; Amyloid beta-Peptides ; Biomarkers ; Humans ; *Neurodegenerative Diseases ; Neurofibrillary Tangles ; Plaque, Amyloid ; tau Proteins ; },
abstract = {Alzheimer's disease (AD), being the number one in terms of dementia burden, is an insidious age-related neurodegenerative disease and is presently considered a global public health threat. Its main histological hallmarks are the Aβ senile plaques and the P-tau neurofibrillary tangles, while clinically it is marked by a progressive cognitive decline that reflects the underlying synaptic loss and neurodegeneration. Many of the drug therapies targeting the two pathological hallmarks namely Aβ and P-tau have been proven futile. This is probably attributed to the initiation of therapy at a stage where cognitive alterations are already obvious. In other words, the underlying neuropathological changes are at a stage where these drugs lack any therapeutic value in reversing the damage. Therefore, there is an urgent need to start treatment in the very early stage where these changes can be reversed, and hence, early diagnosis is of primordial importance. To this aim, the use of robust and informative biomarkers that could provide accurate diagnosis preferably at an earlier phase of the disease is of the essence. To date, several biomarkers have been established that, to a different extent, allow researchers and clinicians to evaluate, diagnose, and more specially exclude other related pathologies. In this study, we extensively reviewed data on the currently explored biomarkers in terms of AD pathology-specific and non-specific biomarkers and highlighted the recent developments in the diagnostic and theragnostic domains. In the end, we have presented a separate elaboration on aspects of future perspectives and concluding remarks.},
}
@article {pmid34930444,
year = {2021},
author = {Schneider, LS and Qiu, Y and Thomas, RG and Evans, C and Jacobs, DM and Jin, S and Kaye, JA and LaCroix, AZ and Messer, K and Salmon, DP and Sano, M and Schafer, K and Feldman, HH},
title = {Impact of potential modifications to Alzheimer's disease clinical trials in response to disruption by COVID-19: a simulation study.},
journal = {Alzheimer's research &amp; therapy},
volume = {13},
number = {1},
pages = {201},
pmid = {34930444},
issn = {1758-9193},
support = {R01 AG057684/NH/NIH HHS/United States ; R01 AG051346/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/drug therapy ; *COVID-19 ; Computer Simulation ; Humans ; Pandemics ; SARS-CoV-2 ; },
abstract = {BACKGROUND: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made.<br><br>METHODS: We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.<br><br>RESULTS: Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.<br><br>DISCUSSION: These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials' validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.},
}
@article {pmid34929532,
year = {2022},
author = {Arévalo, B and Blázquez, M and Serafín, V and Montero-Calle, A and Calero, M and Valverde, A and Barderas, R and Campuzano, S and Yáñez-Sedeño, P and Pingarrón, JM},
title = {Unraveling autoimmune and neurodegenerative diseases by amperometric serological detection of antibodies against aquaporin-4.},
journal = {Bioelectrochemistry (Amsterdam, Netherlands)},
volume = {144},
number = {},
pages = {108041},
doi = {10.1016/j.bioelechem.2021.108041},
pmid = {34929532},
issn = {1878-562X},
mesh = {*Hydrogen Peroxide ; },
abstract = {This work reports the first electroanalytical bioplatform to date for the determination of antibodies against aquaporin-4 (AQP4-Abs), whose serum level is considered as relevant biomarker for certain autoimmune diseases. The bioplatform relies on the use of magnetic microparticles modified with the biotinylated protein for the capture of specific antibodies. The captured IgGs are enzymatically labelled with a secondary antibody conjugated to the horseradish peroxidase (HRP) enzyme. Amperometric transduction is performed using the H2O2/hydroquinone (HQ) system, which results in a cathodic current variation directly proportional to the concentration of the target antibodies. The evaluation of the analytical and operational characteristics of the developed bioplatform shows that it is competitive in terms of sensitivity with the only biosensor reported to date as well as with the commercially available ELISA kits. The achieved limit of detection value is 8.8 pg mL-1. In addition, compared to ELISA kits, the developed bioplatform is advantageous in terms of cost and point of care operation ability. The bioplatform was applied to the analysis of control serum samples with known AQP4-Abs contents as well as of sera from healthy individuals and patients diagnosed with Systemic Lupus Erythematosus (SLE) and Alzheimer (AD) diseases, providing results in agreement with the ELISA methodology.},
}
@article {pmid34929173,
year = {2022},
author = {Ahmed, R and Huang, J and Lifshitz, R and Martinez Pomier, K and Melacini, G},
title = {Structural determinants of the interactions of catechins with Aβ oligomers and lipid membranes.},
journal = {The Journal of biological chemistry},
volume = {298},
number = {2},
pages = {101502},
doi = {10.1016/j.jbc.2021.101502},
pmid = {34929173},
issn = {1083-351X},
support = {201710GSD-402345-288638//CIHR/Canada ; },
mesh = {*Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; *Catechin/chemistry ; Humans ; *Inosine Diphosphate ; Lipids ; },
abstract = {The aberrant self-assembly of intrinsically disordered proteins (IDPs) into soluble oligomers and their interactions with biological membranes underlie the pathogenesis of numerous neurodegenerative diseases, including Alzheimer's disease. Catechins have emerged as useful tools to reduce the toxicity of IDP oligomers by modulating their interactions with membranes. However, the structural determinants of catechin binding to IDP oligomers and membranes remain largely elusive. Here, we assemble a catechin library by combining several naturally occurring chemical modifications and, using a coupled NMR-statistical approach, we map at atomic resolution the interactions of such library with the Alzheimer's-associated amyloid-beta (Aβ) oligomers and model membranes. Our results reveal multiple catechin affinity drivers and show that the combination of affinity-reducing covalent changes may lead to unexpected net gains in affinity. Interestingly, we find that the positive cooperativity is more prevalent for Aβ oligomers than membrane binding, and that the determinants underlying catechin recognition by membranes are markedly different from those dissected for Aβ oligomers. Notably, we find that the unanticipated positive cooperativity arises from the critical regulatory role of the gallate catechin moiety, which recruits previously disengaged substituents into the binding interface and leads to an overall greater compaction of the receptor-bound conformation. Overall, the previously elusive structural attributes mapped here provide an unprecedented foundation to establish structure-activity relationships of catechins.},
}
@article {pmid34929074,
year = {2021},
author = {Kuo, PH},
title = {Cleaning the brain through turbulent glymphatic flow: The washing machine hypothesis.},
journal = {Lymphology},
volume = {54},
number = {3},
pages = {133-139},
pmid = {34929074},
issn = {2522-7963},
mesh = {Brain ; *Glymphatic System ; Humans ; },
abstract = {In a thought experiment, a "washing machine" model is proposed based on turbulent flow from complex multi-dimensional forces to characterize fluid dynamics in the brain. The glymphatic system's hypothetical role in this system is illustrated in a series of diagrams. Implications of this model are discussed in terms of normal physiology and a variety of pathologic conditions such as brain atrophy and Alzheimer disease.},
}
@article {pmid34925029,
year = {2021},
author = {Pérez, MF and Saravia, F and Castro, MG and Bregonzio, C},
title = {Editorial: Targeting Neuroinflammation in Central Nervous System Disorders: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {771610},
pmid = {34925029},
issn = {1663-9812},
}
@article {pmid34922638,
year = {2021},
author = {Rovelet-Lecrux, A and Feuillette, S and Miguel, L and Schramm, C and Pernet, S and Quenez, O and Ségalas-Milazzo, I and Guilhaudis, L and Rousseau, S and Riou, G and Frébourg, T and Campion, D and Nicolas, G and Lecourtois, M},
title = {Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease.},
journal = {Acta neuropathologica communications},
volume = {9},
number = {1},
pages = {196},
pmid = {34922638},
issn = {2051-5960},
mesh = {Alzheimer Disease/*genetics/*metabolism ; HEK293 Cells ; Humans ; LDL-Receptor Related Proteins/*genetics/*metabolism ; Membrane Transport Proteins/*genetics/*metabolism ; Mutation, Missense ; },
abstract = {The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer's disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.},
}
@article {pmid34921933,
year = {2022},
author = {Verheijen, MCT and Krauskopf, J and Caiment, F and Nazaruk, M and Wen, QF and van Herwijnen, MHM and Hauser, DA and Gajjar, M and Verfaillie, C and Vermeiren, Y and De Deyn, PP and Wittens, MMJ and Sieben, A and Engelborghs, S and Dejonckheere, W and Princen, K and Griffioen, G and Roggen, EL and Briedé, JJ},
title = {iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain samples.},
journal = {Toxicology letters},
volume = {356},
number = {},
pages = {89-99},
doi = {10.1016/j.toxlet.2021.12.009},
pmid = {34921933},
issn = {1879-3169},
mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease ; Amyloid beta-Peptides/genetics/*metabolism ; Cell Differentiation ; Cerebral Cortex/*cytology ; Copper/toxicity ; Environmental Pollutants/toxicity ; Gene Expression Regulation ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Male ; Metals, Heavy/toxicity ; Neurons/drug effects/*physiology ; Pesticides/toxicity ; Transcriptome ; tau Proteins/genetics/*metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by the progressive impairment of cognition and memory loss. Sporadic AD (sAD) represents approximately 95 % of the AD cases and is induced by a complex interplay between genetic and environmental factors called "Alzheimerogens". Heavy metals (e.g. copper) and pesticides (e.g. fipronil) can affect many AD-related processes, including neuroinflammation (considered as AD-inducing factor). Research would benefit from in vitro models to investigate effects of Alzheimerogens. We compared transcriptomics changes in sAD induced pluripotent stem cell (iPSC) derived cortical neurons to differentially expressed genes (DEGs) identified in post-mortem AD brain tissue. These analyses showed that many AD-related processes could be identified in the sAD iPSC-derived neurons, and furthermore, could even identify more DEGs functioning in these processes than post-mortem AD-brain tissue. Thereafter, we exposed the iPSCs to AD-inducing factors (copper(II)chloride, fipronil sulfone and an inflammatory cytokine cocktail). Cytokine exposure induced expression of immune related genes while copper-exposure affected genes involved in lipid and cholesterol metabolism, which are known AD-related processes. Fipronil-exposure did not result in significant transcriptomic changes, although prolonged exposures or higher doses may be necessary. Overall, we show that iPSC-derived cortical neurons can be beneficial in vitro models to identify Alzheimerogens and AD-related molecular mechanisms.},
}
@article {pmid34919811,
year = {2022},
author = {de Leeuw, SM and Kirschner, AWT and Lindner, K and Rust, R and Budny, V and Wolski, WE and Gavin, AC and Nitsch, RM and Tackenberg, C},
title = {APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes.},
journal = {Stem cell reports},
volume = {17},
number = {1},
pages = {110-126},
pmid = {34919811},
issn = {2213-6711},
mesh = {Alleles ; Apolipoprotein E2/*genetics/metabolism ; Apolipoprotein E3/*genetics/metabolism ; Apolipoprotein E4/*genetics/metabolism ; Astrocytes/*metabolism ; Cell Cycle/genetics ; Cell Differentiation/*genetics ; Cholesterol/metabolism ; Genotype ; *Homeostasis ; Humans ; Immunohistochemistry ; Induced Pluripotent Stem Cells/*cytology/metabolism ; Inflammation/genetics/metabolism ; Lipid Metabolism ; Neural Stem Cells/cytology/metabolism ; },
abstract = {The apolipoprotein E4 (APOE4) variant is the strongest genetic risk factor for Alzheimer disease (AD), while the APOE2 allele is protective. A major question is how different APOE genotypes affect the physiology of astrocytes, the main APOE-producing brain cells. Here, we differentiated human APOE-isogenic induced pluripotent stem cells (iPSCs) (APOE4, E3, E2, and APOE knockout [APOE-KO]) to functional "iAstrocytes". Mass-spectrometry-based proteomic analysis showed genotype-dependent reductions of cholesterol and lipid metabolic and biosynthetic pathways (reduction: APOE4 >E3 >E2). Cholesterol efflux and biosynthesis were reduced in APOE4 iAstrocytes, while subcellular localization of cholesterol in lysosomes was elevated. An increase in immunoregulatory proteomic pathways (APOE4 >E3 >E2) was accompanied by elevated cytokine release in APOE4 cells (APOE4 >E3 >E2 >KO). Activation of iAstrocytes exacerbated proteomic changes and cytokine secretion mostly in APOE4 iAstrocytes, while APOE2 and APOE-KO iAstrocytes were least affected. Taken together, APOE4 iAstrocytes reveal a disease-relevant phenotype, causing dysregulated cholesterol/lipid homeostasis, increased inflammatory signaling, and reduced β-amyloid uptake, while APOE2 iAstrocytes show opposing effects.},
}
@article {pmid34919689,
year = {2021},
author = {Kandimalla, R and Manczak, M and Pradeepkiran, JA and Morton, H and Reddy, PH},
title = {A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddab360},
pmid = {34919689},
issn = {1460-2083},
support = {AG066347/NH/NIH HHS/United States ; },
abstract = {The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy, and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (ad). Our lab reported increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau, and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in ad. These abnormal interactions, result in the proliferation of dysfunctional mitochondria in ad neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in ad. To determine the impact of reduced Drp1 in ad, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology &amp; mitochondrial function, dendritic spines in Tau mice relative to double mutant mice. When compared to Tau mice, double mutant mice did better on Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA and proteins levels autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared to Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number is reduced and length is increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.},
}
@article {pmid34919633,
year = {2021},
author = {Xhima, K and Markham-Coultes, K and Kofoed, RH and Saragovi, HU and Hynynen, K and Aubert, I},
title = {Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awab460},
pmid = {34919633},
issn = {1460-2156},
abstract = {Early degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive decline in Alzheimer's disease (AD). Evidence from preclinical models of neuronal injury and aging support a pivotal role for nerve growth factor (NGF) in neuroprotection, resilience, and cognitive function. However, whether NGF can provide therapeutic benefit in the presence of AD-related pathologies remains unresolved. Perturbations in the NGF signaling system in AD may render neurons unable to benefit from NGF administration. Additionally, challenges related to brain delivery remain for clinical translation of NGF-based therapies in AD. To be safe and efficient, NGF-related agents should stimulate the NGF receptor, tropomyosin receptor kinase A (TrkA), avoid activation through the p75 neurotrophin receptor (p75NTR), and be delivered non-invasively to targeted brain areas using real-time monitoring. We addressed these limitations using MRI-guided focused ultrasound (MRIgFUS) to increase blood-brain barrier (BBB) permeability locally and transiently, allowing an intravenously administered TrkA agonist that does not activate p75NTR, termed D3, to enter targeted brain areas. Here, we report the therapeutic potential of selective TrkA activation in a transgenic mouse model that recapitulates numerous AD-associated pathologies. Repeated MRIgFUS-mediated delivery of D3 (D3/FUS) improved cognitive function in the TgCRND8 model of AD. Mechanistically, D3/FUS treatment effectively attenuated cholinergic degeneration and promoted functional recovery. D3/FUS treatment also resulted in widespread reduction of brain amyloid pathology and dystrophic neurites surrounding amyloid plaques. Furthermore, D3/FUS markedly enhanced hippocampal neurogenesis in TgCRND8 mice, implicating TrkA agonism as a novel therapeutic target to promote neurogenesis in the context of AD-related pathology. Thus, this study provides evidence that selective TrkA agonism confers neuroprotection to effectively counteract AD-related vulnerability. Recent clinical trials demonstrate that non-invasive BBB modulation using MRIgFUS is safe, feasible and reversible in AD patients. TrkA receptor agonists coupled with MRIgFUS delivery constitute a promising disease-modifying strategy to foster brain health and counteract cognitive decline in AD.},
}
@article {pmid34919190,
year = {2022},
author = {Jellinger, KA},
title = {Recent update on the heterogeneity of the Alzheimer's disease spectrum.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {129},
number = {1},
pages = {1-24},
pmid = {34919190},
issn = {1435-1463},
mesh = {*Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; *Cognitive Dysfunction/metabolism ; Humans ; Neurofibrillary Tangles/pathology ; Plaque, Amyloid/metabolism ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD), the most common form of dementia worldwide, is a mixed proteinopathy (β-amyloid, tau and other proteins). Classically defined as a clinicopathological entity, AD is a heterogeneous, multifactorial disorder with various pathobiological subtypes showing different forms of cognitive presentation, currently referred to as the Alzheimer spectrum or continuum. Its morphological hallmarks are extracellular β-amyloid (amyloid plaques) and intraneuronal tau aggregates forming neurofibrillary tangles and neurites, vascular amyloid deposits (cerebral amyloid angiopathy), synapse and neuronal loss as well as neuroinflammation and reactive astrogliosis, leading to cerebral atrophy and progressive mental/cognitive impairment (dementia). In addition to "classical" AD, several subtypes with characteristic regional patterns of tau pathology have been segregated that are characterized by distinct clinical features, differences in age, sex distribution, disease duration, cognitive status, APOE genotype, and biomarker levels. In addition to four major subtypes based on the distribution of tau pathology and brain atrophy (typical, limbic predominant, hippocampal sparing, and minimal atrophy), several other clinical variants (non-amnestic, corticobasal, behavioral/dysexecutive, posterior cortical variants, etc.) have been identified. These heterogeneous AD variants are characterized by different patterns of key neuronal network destructions, in particular the default-mode network that is responsible for cognitive decline. Other frequent age-related co-pathologies, e.g., cerebrovascular lesions, Lewy and TDP-43 pathologies, hippocampal sclerosis, or argyrophilic grain disease, essentially influence the clinical picture and course of AD, and can challenge our understanding of this disorder including the threshold and causal relevance of each individual pathology. Unravelling the clinico-morphological heterogeneity among the AD spectrum entities is important for better elucidation of the pathogenic mechanisms affecting the aging brain that may enable a broader diagnostic coverage of AD as a basis for implementing precision medicine approaches and for developing preventive and ultimately disease-modifying therapies for this devastating disorder.},
}
@article {pmid34917297,
year = {2021},
author = {Jameie, SB and Pirasteh, A and Naseri, A and Jameie, MS and Farhadi, M and Babaee, JF and Elyasi, L},
title = {β-Amyloid Formation, Memory, and Learning Decline Following Long-term Ovariectomy and Its Inhibition by Systemic Administration of Apigenin and β-Estradiol.},
journal = {Basic and clinical neuroscience},
volume = {12},
number = {3},
pages = {383-394},
pmid = {34917297},
issn = {2008-126X},
abstract = {INTRODUCTION: The increasing cases of Alzheimer Disease (AD) has caused numerous problems. The risk of developing AD increases in menopausal women, too. Apigenin and β-estradiol are effective antioxidant and neuroprotective agents. We conducted the present study to explore their combined effects on β-amyloid plaque formation, memory, and learning in ovariectomized rats.<br><br>METHODS: Forty-two Wistar rats were randomly assigned into 6 groups: 1) ovariectomized (OVX), 2) OVX + apigenin, 3) OVX + β-estradiol, 4) OVX + apigenin + β-estradiol, 5 &amp;6) vehicle shams for E2 and API, and 7) surgical sham. Treatment was done with apigenin and β-estradiol. Then, we studied the formation of β-amyloid plaques, neuronal density in the hippocampus area, apoptosis, memory, and learning.<br><br>RESULTS: Findings showed the significant formation of β-amyloid plaques in the hippocampus of OVX animals and their memory impairment. Apigenin and β-estradiol significantly reduced the number of β-amyloid plaques, as well as the symptoms of memory impairment and learning, and decreased the expression of caspase-3 in treated animals.<br><br>CONCLUSION: Accordingly, β-estradiol and apigenin could have more potent therapeutic effects on AD.},
}
@article {pmid34917294,
year = {2021},
author = {Jafarzadeh, G and Shakerian, S and Farbood, Y and Ghanbarzadeh, M},
title = {Effects of Eight Weeks of Resistance Exercises on Neurotrophins and Trk Receptors in Alzheimer Model Male Wistar Rats.},
journal = {Basic and clinical neuroscience},
volume = {12},
number = {3},
pages = {349-359},
pmid = {34917294},
issn = {2008-126X},
abstract = {INTRODUCTION: This study evaluates the effects of 8 weeks of resistance exercises on the expression of neurotrophins and Trk receptors in Alzheimer model male Wistar rats.<br><br>METHODS: For this purpose, 32 mature male Wistar rats with a mean weight of 230-280 g were chosen and divided into Alzheimer and Sham groups. The rats in the sham group received normal saline, while the ones in the Alzheimer group received streptomycin via intraventricular injection. These rats were then divided into the following four subgroups: 1) resting sham, 2) exercising sham, 3) resting Alzheimer, and 4) exercising Alzheimer. The two exercising rat subgroups exercised three times a week for 8 weeks. A weight was attached to their tails, and they had to carry it on a 26-step ladder in each cycle. Resting groups were handled every day to minimize the effects of stress. At the end of the eighth week and 24 hours after the last exercise session (to avoid the effects of the last exercise session), the rats were put under deep anesthesia and beheaded. Hippocampus tissues were precisely extracted, and samples were sent to the laboratory for molecular and cellular tests. To investigate gene expression, quantitative RTPCR was used.<br><br>RESULTS: The tests for comparing the mean values of BDNF, NT3, NGF, TrkA, and TrkB in two rat groups showed that with error levels of less than 5%, there is a significant difference in the amounts of BDNF, NT3, NGF, TrkA, and TrkB between exercising rats and resting ones. These amounts were much higher in the exercising Alzheimer rats group.<br><br>CONCLUSION: Eight weeks of resistance exercises increased the expression of BDNF, NT3, and NGF genes and TrkA and TrkB receptors in Alzheimer model Wistar rats.},
}
@article {pmid34916831,
year = {2021},
author = {Wu, L and Wang, W and Tian, S and Zheng, H and Liu, P and Wu, W},
title = {Identification of Hub Genes in Patients with Alzheimer Disease and Obstructive Sleep Apnea Syndrome Using Integrated Bioinformatics Analysis.},
journal = {International journal of general medicine},
volume = {14},
number = {},
pages = {9491-9502},
pmid = {34916831},
issn = {1178-7074},
abstract = {BACKGROUND: Obstructive sleep apnea syndrome (OSA) is associated with an increased risk of Alzheimer's disease (AD). This study aimed to identify the key common genes in AD and OSA and explore molecular mechanism value in AD.<br><br>METHODS: Expression profiles GSE5281 and GSE135917 were acquired from Gene Expression Omnibus (GEO) database, respectively. Weighted gene co-expression network analysis (WGCNA) and R 4.0.2 software were used for identifying differentially expressed genes (DEGs) related to AD and OSA. Function enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and the protein-protein interaction network (PPI) using the STRING database were subsequently performed on the shared DEGs. Finally, the hub genes were screened from the PPI network using the MCC algorithm of CytoHubba plugin.<br><br>RESULTS: Seven modules and four modules were the most significant with AD and OSA by WGCNA, respectively. A total of 33 common genes were screened in AD and OSA by VENN. Functional enrichment analysis indicated that DEGs were mainly involved in cellular response to oxidative stress, neuroinflammation. Among these DEGs, the top 10 hub genes (high scores in cytoHubba) were selected in the PPI network, including AREG, SPP1, CXCL2, ITGAX, DUSP1, COL1A1, SCD, ACTA2, CCND2, ATF3.<br><br>CONCLUSION: This study presented ten target genes on the basis of common genes to AD and OSA. These candidate genes may provide a novel perspective to explore the underlying mechanism that OSA leads to an increased risk of AD at the transcriptome level.},
}
@article {pmid34915100,
year = {2022},
author = {Lai, X and Hu, J and Liu, H and Lan, L and Long, Y and Gao, X and Deng, J},
title = {A short peptide from sAPPα binding to BACE1-APP action site rescues Alzheimer-like pathology.},
journal = {Neuroscience letters},
volume = {770},
number = {},
pages = {136397},
doi = {10.1016/j.neulet.2021.136397},
pmid = {34915100},
issn = {1872-7972},
mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyloid Precursor Protein Secretases/antagonists &amp; inhibitors/*metabolism ; Amyloid beta-Peptides/chemistry/*metabolism ; Animals ; Aspartic Acid Endopeptidases/antagonists &amp; inhibitors/*metabolism ; Binding Sites ; Blood-Brain Barrier/metabolism ; Cell Line, Tumor ; Humans ; Male ; Mice ; Neuroprotective Agents/pharmacology/*therapeutic use ; Peptide Fragments/chemistry/pharmacology/*therapeutic use ; Protease Inhibitors/pharmacology/*therapeutic use ; Protein Binding ; Proteolysis/drug effects ; },
abstract = {Amyloid β-peptide (Aβ) is the driven force of Alzheimer's disease (AD), and reducing Aβ production could be a potential therapeutic strategy for AD. sAPPα appears to have the ability to specifically inhibit β-cleavage of APP without inhibiting BACE1 completely, direct administration of sAPPα may not be clinically applicable due to the low permeability of blood-brain barrier (BBB). In this study, we investigated the neuroprotective effects of a short peptide generated from sAPPα, which could specifically bind to BACE1 at the BACE1-APP action site. We found that this peptide significantly reduced Aβ production both in vivo and in vitro, thus further attenuated Aβ deposition, Tau hyperphosphorylation, neuroinflammation et al. and rescued behavioral deficits. Therefore, this short peptide may hold promise for the treatment of AD due to its neuroprotective effects, low molecular weight to cross BBB, and less safety concerns. The anti-neurodegenerative capacity of sAPPα may not result solely from direct inhibition of BACE1.},
}
@article {pmid34915044,
year = {2022},
author = {Badrikoohi, M and Esmaeili-Bandboni, A and Babaei, P},
title = {Simultaneous administration of bromodomain and histone deacetylase I inhibitors alleviates cognition deficit in Alzheimer's model of rats.},
journal = {Brain research bulletin},
volume = {179},
number = {},
pages = {49-56},
doi = {10.1016/j.brainresbull.2021.12.004},
pmid = {34915044},
issn = {1873-2747},
mesh = {Alzheimer Disease/*drug therapy ; Animals ; Azepines/pharmacology ; Behavior, Animal/drug effects ; Benzamides/pharmacology ; CREB-Binding Protein/*drug effects ; Disease Models, Animal ; Drug Therapy, Combination ; Epigenesis, Genetic/drug effects ; Histone Deacetylase Inhibitors/administration &amp; dosage/*pharmacology ; Male ; Memory Disorders/*drug therapy ; Nuclear Proteins/*antagonists &amp; inhibitors ; Pyridines/pharmacology ; Random Allocation ; Rats ; Rats, Wistar ; Transcription Factors/*antagonists &amp; inhibitors ; Triazoles/pharmacology ; Tumor Necrosis Factor-alpha/*drug effects ; },
abstract = {BACKGROUND: Histone deacetylases (HDACs) target various genes responsible for cognitive functions. However, chromatin readers, particularly bromodomain-containing protein 4 (BRD4), are capable to change the final products of genes. The objective of this study was to evaluate the simultaneous effects of inhibition of HDACs and BRD4 on spatial and aversive memories impaired by amyloid β (Aβ) in a rat model of Alzheimer's disease (AD) considering CREB and TNF-α signaling.<br><br>METHODS: Forty male Wistar rats aged 3 months were randomly divided into five groups: saline +DMSO, Aβ+saline+DMSO, Aβ+JQ1, Aβ+MS-275, Aβ+JQ1+MS-275, and received the related treatments. MS-275, is the second generation of HDACs inhibitor, and JQ1 is a potent inhibitor of the BET family of bromodomain proteins in mammals. After the treatments, cognitive function was assessed by Morris water maze (MWM) and passive avoidance learning (PAL). The hippocampal level of mRNA for CREB and TNF-α, and also phosphorylated CREB were measured using real-time PCR and western blotting respectively.<br><br>RESULTS: Administration of JQ1 and MS-275, either separately or simultaneously, improved acquisition and retrieval of spatial and aversive memories as it was evident by decreased escape latency and increased time spent in the target quadrant (TTS) in Morris water maze (MWM), together with increase in step-through latency, but reduced time spent in the dark zone time in passive avoidance learning (PAL) compared with Aβ+saline+DMSO. Furthermore, there was a significant rise in the hippocampal level of CREB mRNA and phosphorylated CREB, but a reduction in TNF-α expression in comparison with Aβ + Saline.<br><br>CONCLUSION: Simultaneous administration of JQ1 and MS-275 improves acquisition and retrieval of both spatial and aversive memories partly via CREB and TNF-α signaling with no superiority to monotherapy.},
}
@article {pmid34914971,
year = {2022},
author = {Abdel-Aal, RA and Hussein, OA and Elsaady, RG and Abdelzaher, LA},
title = {Naproxen as a potential candidate for promoting rivastigmine anti-Alzheimer activity against aluminum chloride-prompted Alzheimer's-like disease in rats; neurogenesis and apoptosis modulation as a possible underlying mechanism.},
journal = {European journal of pharmacology},
volume = {915},
number = {},
pages = {174695},
doi = {10.1016/j.ejphar.2021.174695},
pmid = {34914971},
issn = {1879-0712},
mesh = {*Rivastigmine ; },
abstract = {BACKGROUND AND AIM: Alzheimer's disease (AD) is one of the leading causes of dependence and disability among the elderly worldwide. The traditional anti-Alzheimer medication, rivastigmine, one of the cholinesterase inhibitors (ChEIs), fails to achieve a definitive cure. We tested the hypothesis that naproxen administration to the rivastigmine-treated aluminum chloride (AlCl3) Alzheimer's rat model could provide an additive neuroprotective effect compared to rivastigmine alone.<br><br>MATERIALS AND METHODS: The studied groups were control (Cont), AlCl3 treated (Al), rivastigmine treated (RIVA), naproxen treated (Napro), and combined rivastigmine and naproxen treated (RIVA + Napro). Rats' memory, spatial learning, and cognitive behavior were assessed followed by evaluation of hippocampal acetylcholinesterase (AChE) activity. Hippocampal and cerebellar histopathology were thoroughly examined. Activated caspase-3 and the neuroepithelial stem cells marker; nestin expressions were immunohistochemically assayed.<br><br>RESULTS: AD rats displayed significantly impaired memory and cognitive function, augmented hippocampal AChE activity; massive neurodegeneration associated with enhanced astrogliosis, apoptosis, and impaired neurogenesis. Except for the enhancement of neurogenesis and suppression of apoptosis, the combination therapy had no additional neuroprotective benefit over rivastigmine-only therapy.<br><br>CONCLUSION: Naproxen's efficacy was established by its ability to function at the cellular level, improved neurogenesis, and decreased, apoptosis without having an additional mitigating impact on cognitive impairment in rivastigmine-treated AD rats.},
}
@article {pmid34913981,
year = {2021},
author = {James, C and Ranson, JM and Everson, R and Llewellyn, DJ},
title = {Performance of Machine Learning Algorithms for Predicting Progression to Dementia in Memory Clinic Patients.},
journal = {JAMA network open},
volume = {4},
number = {12},
pages = {e2136553},
pmid = {34913981},
issn = {2574-3805},
mesh = {Aged ; Area Under Curve ; Cognitive Dysfunction/*diagnosis ; Dementia/*diagnosis/epidemiology ; Disease Progression ; Female ; Humans ; Incidence ; Machine Learning/*statistics &amp; numerical data ; Male ; Predictive Value of Tests ; Prognosis ; Prospective Studies ; Risk Assessment/*methods ; Risk Factors ; Sensitivity and Specificity ; United States ; },
abstract = {Importance: Machine learning algorithms could be used as the basis for clinical decision-making aids to enhance clinical practice.<br><br>Objective: To assess the ability of machine learning algorithms to predict dementia incidence within 2 years compared with existing models and determine the optimal analytic approach and number of variables required.<br><br>This prognostic study used data from a prospective cohort of 15 307 participants without dementia at baseline to perform a secondary analysis of factors that could be used to predict dementia incidence. Participants attended National Alzheimer Coordinating Center memory clinics across the United States between 2005 and 2015. Analyses were conducted from March to May 2021.<br><br>Exposures: 258 variables spanning domains of dementia-related clinical measures and risk factors.<br><br>Main Outcomes and Measures: The main outcome was incident all-cause dementia diagnosed within 2 years of baseline assessment.<br><br>Results: In a sample of 15 307 participants (mean [SD] age, 72.3 [9.8] years; 9129 [60%] women and 6178 [40%] men) without dementia at baseline, 1568 (10%) received a diagnosis of dementia within 2 years of their initial assessment. Compared with 2 existing models for dementia risk prediction (ie, Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score, and the Brief Dementia Screening Indicator), machine learning algorithms were superior in predicting incident all-cause dementia within 2 years. The gradient-boosted trees algorithm had a mean (SD) overall accuracy of 92% (1%), sensitivity of 0.45 (0.05), specificity of 0.97 (0.01), and area under the curve of 0.92 (0.01) using all 258 variables. Analysis of variable importance showed that only 6 variables were required for machine learning algorithms to achieve an accuracy of 91% and area under the curve of at least 0.89. Machine learning algorithms also identified up to 84% of participants who received an initial dementia diagnosis that was subsequently reversed to mild cognitive impairment or cognitively unimpaired, suggesting possible misdiagnosis.<br><br>Conclusions and Relevance: These findings suggest that machine learning algorithms could accurately predict incident dementia within 2 years in patients receiving care at memory clinics using only 6 variables. These findings could be used to inform the development and validation of decision-making aids in memory clinics.},
}
@article {pmid34913091,
year = {2021},
author = {Stazi, M and Lehmann, S and Sakib, MS and Pena-Centeno, T and Büschgens, L and Fischer, A and Weggen, S and Wirths, O},
title = {Long-term caffeine treatment of Alzheimer mouse models ameliorates behavioural deficits and neuron loss and promotes cellular and molecular markers of neurogenesis.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {79},
number = {1},
pages = {55},
pmid = {34913091},
issn = {1420-9071},
support = {20021//Alzheimer Forschung Initiative/ ; WI 3472/10-1//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Alzheimer Disease/*drug therapy ; Amyloid beta-Peptides/metabolism ; Animals ; Biomarkers/metabolism ; Caffeine/*pharmacology ; Cells, Cultured ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Neurogenesis/*drug effects ; Neurons/*drug effects/pathology ; Plaque, Amyloid/*drug therapy ; },
abstract = {Epidemiological studies indicate that the consumption of caffeine, the most commonly ingested psychoactive substance found in coffee, tea or soft drinks, reduces the risk of developing Alzheimer's disease (AD). Previous treatment studies with transgenic AD mouse models reported a reduced amyloid plaque load and an amelioration of behavioral deficits. It has been further shown that moderate doses of caffeine have the potential to attenuate the health burden in preclinical mouse models of a variety of brain disorders (reviewed in Cunha in J Neurochem 139:1019-1055, 2016). In the current study, we assessed whether long-term caffeine consumption affected hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4-month period reduced hippocampal neuron loss, rescued learning and memory deficits, and ameliorated impaired neurogenesis. Neuron-specific RNA sequencing analysis in the hippocampus revealed an altered expression profile distinguished by the up-regulation of genes linked to synaptic function and processes, and to neural progenitor proliferation. Treatment of 5xFAD mice, which develop prominent amyloid pathology, with the same paradigm also rescued behavioral deficits but did not affect extracellular amyloid-β (Aβ) levels or amyloid precursor protein (APP) processing. These findings challenge previous assumptions that caffeine is anti-amyloidogenic and indicate that the promotion of neurogenesis might play a role in its beneficial effects.},
}
@article {pmid34910735,
year = {2021},
author = {Farfel, JM and Leurgans, SE and Capuano, AW and de Moraes Sampaio, MC and Wilson, RS and Schneider, JA and Bennett, DA},
title = {Dementia and autopsy-verified causes of death in racially-diverse older Brazilians.},
journal = {PloS one},
volume = {16},
number = {12},
pages = {e0261036},
pmid = {34910735},
issn = {1932-6203},
support = {R01 AG054058/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Autopsy ; Brazil ; *Cause of Death ; Dementia/*complications/ethnology ; Educational Status ; Female ; Humans ; Male ; },
abstract = {BACKGROUND: While dementia has been associated with specific causes of death, previous studies were relatively small autopsy series or population-based studies lacking autopsy confirmation and were restricted to Non-Latinx Whites. Here, we examine the association of dementia with autopsy-verified causes of death in racially-diverse older Brazilians.<br><br>METHODS: As part of the Pathology, Alzheimer´s and Related Dementias Study (PARDoS), a community-based study in Brazil, we included 1941 racially-diverse deceased, 65 years or older at death. We conducted a structured interview with legal informants including the Clinical Dementia Rating (CDR) Scale for dementia proximate to death. Causes of death were assessed after full-body autopsy and macroscopic examination of the brain, thoracic and abdominal/pelvic organs. Up to four causes of death were reported for each decedent. Causes of death were classified as circulatory, infectious, cancer and other. Logistic regression was used to determine associations of dementia with cause of death, controlling for age, sex, race, and education.<br><br>RESULTS: Dementia was associated with a higher odds of an infectious cause of death (OR = 1.81, 95%CI:1.45-2.25), and with a lower odds of a circulatory disease as cause of death (OR = 0.69, 95%CI:0.54-0.86) and cancer as cause of death (OR = 0.41, 95%CI:0.24-0.71). Dementia was associated with a higher odds of pneumonia (OR = 1.92, 95%CI:1.53-2.40) and pulmonary embolism (OR = 2.31, 95%CI:1.75-3.05) as causes of death and with a lower odds of acute myocardial infarction (OR = 0.42, 95%CI:0.31-0.56) and arterial disease (OR = 0.76, 95%CI:0.61-0.94) as causes of death.<br><br>CONCLUSION: Racially-diverse older Brazilians with dementia had a higher odds of an infectious cause of death and a lower odds of cancer and circulatory disease as causes of death than those without dementia.},
}
@article {pmid34909647,
year = {2021},
author = {Bhat, A and Dalvi, H and Jain, H and Rangaraj, N and Singh, SB and Srivastava, S},
title = {Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal.},
journal = {Current research in pharmacology and drug discovery},
volume = {2},
number = {},
pages = {100012},
pmid = {34909647},
issn = {2590-2571},
abstract = {Neurodegenerative disorders which affects a larger population pose a great clinical challenge. These disorders impact the quality of life of an individual by damaging the neurons, which are the unit cells of the brain. Clinicians are faced with the grave challenge of inhibiting the progression of these diseases as available treatment options fail to meet the clinical demand. Thus, treating the disease/disorder symptomatically is the Hobson's choice. The goal of the researchers is to introduce newer therapies in this segment and introducing a new molecule will take long years of development. Hence, drug repurposing/repositioning can be a better substitute in comparison to time consuming and expensive drug discovery and development cycle. Presently, a paradigm shift towards the re-purposing of drugs can be witnessed. Statins which have been previously approved as anti-hyperlipidemic agents are in the limelight of research for re-purposed drugs. Owing to their anti-inflammatory and antioxidant nature, statins act as neuroprotective in several brain disorders. Further they attenuate the amyloid plaques and protein aggregation which are the triggering factors in the Alzheimer's and Parkinson's respectively. In case of Huntington disease and Multiple sclerosis they help in improving the psychomotor symptoms and stimulate remyelination thus acting as neuroprotective. This article reviews the potential of statins in treating neurodegenerative disorders along with a brief discussion on the safety concerns associated with use of statins and human clinical trial data linked with re-tasking statins for neurodegenerative disorders along with the regulatory perspectives involved with the drug repositioning.},
}
@article {pmid34908159,
year = {2022},
author = {Lu, WH and Giudici, KV and Guyonnet, S and Aggarwal, G and Nguyen, AD and Morley, JE and Vellas, B and de Souto Barreto, P and , },
title = {Associations of plasma neurofilament light chain and progranulin with frailty in older adults.},
journal = {Journal of the American Geriatrics Society},
volume = {70},
number = {4},
pages = {1236-1243},
doi = {10.1111/jgs.17604},
pmid = {34908159},
issn = {1532-5415},
support = {//Institutional startup funds/ ; //Alzheimer Prevention in Occitania and Catalonia (APOC Chair of Excellence - Inspire Program)/ ; //Association Monegasque pour la Recherche sur la maladie d'Alzheimer (AMPA)/ ; //Avid Radiopharmaceuticals Inc./ ; MP0022856//European Regional Development Fund (ERDF)/ ; //ExonHit Therapeutics SA/ ; //French Ministry of Health (PHRC 2008, 2009)/ ; //Gérontopôle of Toulouse/ ; //INSERM-University of Toulouse III UMR 1295 Unit/ ; //Pierre Fabre Research Institute/ ; 1901175//Region Occitanie/Pyrénées-Méditerranée/ ; //University Hospital Center of Toulouse/ ; },
mesh = {Aged ; *Alzheimer Disease ; Cross-Sectional Studies ; Frail Elderly ; *Frailty/diagnosis ; Humans ; Independent Living ; Intermediate Filaments ; Progranulins ; },
abstract = {BACKGROUND: In previous studies, plasma neurofilament light chain (NfL) and progranulin (PGRN) levels are associated with cognitive and physical impairment in older individuals. However, evidence of their relationships with frailty is lacking. This study aims to explore the associations of plasma NfL and PGRN levels with frailty in community-dwelling older adults.<br><br>METHODS: We included 507 older adults (mean [standard deviation] age, 76.7 [4.5] years) with plasma NfL and PGRN measurements from the Multidomain Alzheimer Preventive Trial (MAPT). The timepoint of biomarker measurements, either 12 or 24 months after study enrollment, was defined as the baseline for each participant. Frailty phenotype (robust, pre-frail, and frail) was assessed at 12, 24, 36, 48, and 60 months by Fried's frailty criteria. The cross-sectional associations between plasma neurodegenerative biomarkers and frailty severity were examined using logistic regressions. We further used Cox proportional hazard models to evaluate the associations between plasma biomarkers and incident frailty among robust or pre-frail participants at baseline (n = 403).<br><br>RESULTS: At baseline, participants with high plasma NfL levels (>93.11 pg/ml [the upper quartile]) had a higher likelihood of pre-frailty or frailty compared to their normal NfL counterparts (odds ratio = 1.68; 95% confidence interval = 1.10-2.57); however, this association did not remain significant after controlling for covariates. Neither NfL nor PGRN levels showed prospective associations with incident frailty over 4 years.<br><br>CONCLUSIONS: This study failed to find associations of circulating NfL and PGRN levels with frailty among community-dwelling older adults in adjusted analyses. Whether plasma neurodegenerative markers serve as potential biomarkers of frailty requires further investigation.},
}
@article {pmid34906980,
year = {2022},
author = {Chu, WT and Wang, WE and Zaborszky, L and Golde, TE and DeKosky, S and Duara, R and Loewenstein, DA and Adjouadi, M and Coombes, SA and Vaillancourt, DE},
title = {Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract.},
journal = {Neurology},
volume = {98},
number = {7},
pages = {e700-e710},
pmid = {34906980},
issn = {1526-632X},
support = {R01 NS023945/NS/NINDS NIH HHS/United States ; RF1 NS023945/NS/NINDS NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; R01 NS052318/NS/NINDS NIH HHS/United States ; },
mesh = {*Alzheimer Disease/psychology ; *Basal Forebrain ; Basal Nucleus of Meynert ; *Cognitive Dysfunction/diagnostic imaging ; Humans ; Locus Coeruleus/diagnostic imaging ; Water ; },
abstract = {BACKGROUND AND OBJECTIVES: The goal of this work was to determine the relationship between diffusion microstructure and early changes in Alzheimer disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain.<br><br>METHODS: Diffusion MRI scans were collected on cognitively normal participants (CN) and patients with early mild cognitive impairment (EMCI), late mild cognitive impairment, and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, 4 magnocellular regions of the basal forebrain (e.g., nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples.<br><br>RESULTS: FW was significantly higher in patients with EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; p fdr < 0.05). FW was significantly higher in those with AD compared to CN in all the examined regions (mean Cohen d = 1.41; p fdr < 0.01). In addition, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all 5 cognitive impairment metrics and neurofilament light chain levels (mean r 2 = 0.10; p fdr < 0.05).<br><br>DISCUSSION: These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and noninvasive early marker of structural changes related to cognitive impairment.},
}
@article {pmid34906975,
year = {2022},
author = {Li, Y and Schindler, SE and Bollinger, JG and Ovod, V and Mawuenyega, KG and Weiner, MW and Shaw, LM and Masters, CL and Fowler, CJ and Trojanowski, JQ and Korecka, M and Martins, RN and Janelidze, S and Hansson, O and Bateman, RJ},
title = {Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques.},
journal = {Neurology},
volume = {98},
number = {7},
pages = {e688-e699},
pmid = {34906975},
issn = {1526-632X},
support = {P30 AG072979/AG/NIA NIH HHS/United States ; R56 AG061900/AG/NIA NIH HHS/United States ; K23 AG053426/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides ; Biomarkers ; Humans ; Peptide Fragments ; Plaque, Amyloid ; Positron-Emission Tomography ; },
abstract = {BACKGROUND AND OBJECTIVES: To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols.<br><br>METHODS: Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40.<br><br>RESULTS: In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals.<br><br>DISCUSSION: Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants.},
}
@article {pmid34906893,
year = {2022},
author = {Chauhan, BS and Kumar, R and Kumar, P and Kumar, P and Sinha, S and Mishra, SK and Kumar, P and Tiwari, KN and Critchley, AT and Prithiviraj, B and Srikrishna, S},
title = {Neuroprotective potential of flavonoid rich Ascophyllum nodosum (FRAN) fraction from the brown seaweed on an Aβ42 induced Alzheimer's model of Drosophila.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {95},
number = {},
pages = {153872},
doi = {10.1016/j.phymed.2021.153872},
pmid = {34906893},
issn = {1618-095X},
mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; Animals ; *Ascophyllum ; Disease Models, Animal ; Drosophila ; Drosophila melanogaster ; Flavonoids/pharmacology ; Neuroprotection ; Peptide Fragments ; *Seaweed ; },
abstract = {BACKGROUND: In Alzheimer Disease (AD) pathogenesis, aggregation of Aβ42 fibrils strongly correlates with memory dysfunction and neurotoxicity. Till date, no promising cures for AD. Report shows that flavonoids contributed anti-oxidant, anti-cancer and neuroprotection activity by regulating the mitochondrial machinery. Here, we first report the identification of flavonoids from Ascophyllum nodosum as having the ability to dissolve Aβ42 fibrils in an AD model of Drosophila. FRAN could be superior anti-AD agents for neuroprotection, their underlying mechanism and how they collectively halted amyloidogenesis is currently being investigated.<br><br>PURPOSE: This study aimed to investigate the neuroprotective role of FRAN in the Aβ42 expressing AD model of Drosophila.<br><br>METHODS: Drosophila stocks: OregonR+, ey-GAL4/CyO, elavc155-GAL4, UAS-mitoGFP, UAS-mcherry.mito.OMM, UAS-Aβ42/CyO were used, cultured at 28±1 °C in a BOD incubator. Ascophyllum extract rich in flavonoids as revealed by LC-MS study and employed against the AD flies. The validation of Aβ42 expression was done by immunostaining and q-RT PCR. The eye roughness of AD flies was scored in a dose-dependent manner. Further, In vivo and in silico studies of FRAN extract was executed against Aβ42 induced neurotoxicity.<br><br>RESULTS: In order to determine the most effective lethal dose of FRAN extract concentration 1, 2, 5, 10 mg/ml were screened using OregonR+flies. Extract 1 and 2 mg/ml did not show any lethality. Hence, extract 2 mg/ml was employed on AD flies and a ≥ 50% rescue in the eye phenotype was observed using SEM images. This dose had a strong effect on cell apoptosis, viability, longevity, mitochondrial dysfunction and oxidative stress by regulating mitochondrial dynamic markers in comparable to control. Extract also scavenging free radicals in order to maintain in situ cellular ROS and prevent Aβ42-induced neurotoxicity in vivo and in silico. Hence, we suggest its great potential as a future therapeutic agent for AD treatment.<br><br>CONCLUSION: In conclusion, FRAN extract rich in flavonoids as having largest neuroprotective activity against Aβ42 aggregation in eye tissue of Drosophila. Extract shows strong effect against Aβ42-induced neurotoxicity by altering the various cellular and molecular events. So, it could be considered as strong anti-AD agents for neuroprotection.},
}
@article {pmid34905943,
year = {2022},
author = {Sveikata, L and Charidimou, A and Viswanathan, A},
title = {Vessels Sing Their ARIAs: The Role of Vascular Amyloid in the Age of Aducanumab.},
journal = {Stroke},
volume = {53},
number = {1},
pages = {298-302},
doi = {10.1161/STROKEAHA.121.036873},
pmid = {34905943},
issn = {1524-4628},
support = {R01 AG047975/AG/NIA NIH HHS/United States ; R01 NS104130/NS/NINDS NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/complications/*drug therapy ; Amyloid/*drug effects ; Amyloid beta-Peptides/metabolism ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Cerebral Amyloid Angiopathy/complications/*drug therapy ; Humans ; Time Factors ; },
abstract = {We review the implications of the recently approved aducanumab amyloid-β immunotherapy for treating Alzheimer disease with comorbid cerebral amyloid angiopathy. In clinical trials, amyloid-β immunotherapy has been associated with a high rate of amyloid-related imaging abnormalities, potentially driven by coexisting cerebral amyloid angiopathy. Therefore, immunotherapy's efficacy in patients may be modified by coexisting cerebrovascular pathology. We discuss the contributions of cerebral amyloid angiopathy on the development of amyloid-related imaging abnormalities and propose strategies to identify cerebral amyloid angiopathy in patients considered for immunotherapy.},
}
@article {pmid34901961,
year = {2021},
author = {Yoshimura, M and Arizono, E and Takase, K and Okubo, M and Takahashi, Y and Saito, K and Shimizu, S},
title = {Usefulness of texture analysis in 123I-FP-CIT for the differentiation of AD and DLB subtypes.},
journal = {Hellenic journal of nuclear medicine},
volume = {24},
number = {3},
pages = {206-213},
doi = {10.1967/s002449912404},
pmid = {34901961},
issn = {1790-5427},
mesh = {*Alzheimer Disease/diagnostic imaging ; Diagnosis, Differential ; Humans ; Iodine Radioisotopes ; *Lewy Body Disease/diagnostic imaging ; Tomography, Emission-Computed, Single-Photon ; Tropanes ; },
abstract = {OBJECTIVE: I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) is well known to be a useful tracer for differentiating dementia with Lewy bodies (DLB) and Alzheimer disease (AD). However, clinically, there are some cases in which these diseases cannot be differentiated by ordinary quantitative methods. Therefore, in this study, we established an index that reflects not only the total count but also the distribution and heterogeneity of tracer uptake. We investigated whether assessment of the heterogeneous depletion of 123I-FP-CIT is useful for the differentiation of various types of dementia, i.e., probable DLB, possible DLB, and AD, using texture analysis.<br><br>MATERIALS AND METHODS: A total of 122 patients with either probable DLB (n=35), possible DLB (n=23), AD (n=44), and normal controls (n=20) were analyzed. Summated single photon emission computed tomography (SPECT) images (7 to 10 slices) of the patients, including the bilateral striatum, were analyzed using the gray-level histogram method (GLHM) of texture analysis. Mean, variance, skewness, and kurtosis of GLHM were compared with the specific binding ratio by Livia Tossici-Bolt's method (SBR).<br><br>RESULTS: The sensitivity and specificity for differentiating probable DLB from possible DLB, AD, and normal controls were 97.1% and 77.0%, respectively, for skewness, using a cut-off point of 6.8%, and 97.1% and 81.6%, respectively, for kurtosis, using a cut-off point of 53.4%. The sensitivity and specificity for differentiating probable and possible DLB from AD and normal controls was 65.5% and 98.4%, respectively, for skewness, using a cut-off point of 6.4%, and 79.3% and 93.8%, respectively, for kurtosis, using a cut-off point of 53.4%.<br><br>CONCLUSION: In the assessment of the efficacy of 123I-FP-CIT to differentiate AD and DLB subtypes, mean, variance, skewness, and kurtosis by GLHM was as useful as the SBR method. Moreover, possible DLB and probable DLB could be differentiated by skewness and kurtosis. Our results demonstrate that texture analysis is more useful than conventional quantitative methods for obtaining valuable information of the brain. Textural features as such may have considerable potential as imaging biomarkers of DLB progression.},
}
@article {pmid34901437,
year = {2022},
author = {Eger, SJ and Le Guen, Y and Khan, RR and Hall, JN and Kennedy, G and Zaharchuk, G and Couthouis, J and Brooks, WS and Velakoulis, D and Napolioni, V and Belloy, ME and Dalgard, CL and Mormino, EC and Gitler, AD and Greicius, MD},
title = {Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease.},
journal = {Neurology. Genetics},
volume = {8},
number = {1},
pages = {e647},
pmid = {34901437},
issn = {2376-7839},
support = {R01 AG060747/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVES: The F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).<br><br>METHODS: Eight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.<br><br>RESULTS: The female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers.<br><br>DISCUSSION: The results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.},
}
@article {pmid34901060,
year = {2021},
author = {Bouter, C and Irwin, C and Franke, TN and Beindorff, N and Bouter, Y},
title = {Quantitative Brain Positron Emission Tomography in Female 5XFAD Alzheimer Mice: Pathological Features and Sex-Specific Alterations.},
journal = {Frontiers in medicine},
volume = {8},
number = {},
pages = {745064},
pmid = {34901060},
issn = {2296-858X},
abstract = {Successful back-translating clinical biomarkers and molecular imaging methods of Alzheimer's disease (AD), including positron emission tomography (PET), are very valuable for the evaluation of new therapeutic strategies and increase the quality of preclinical studies. 18F-Fluorodeoxyglucose (FDG)-PET and 18F-Florbetaben-PET are clinically established biomarkers capturing two key pathological features of AD. However, the suitability of 18F-FDG- and amyloid-PET in the widely used 5XFAD mouse model of AD is still unclear. Furthermore, only data on male 5XFAD mice have been published so far, whereas studies in female mice and possible sex differences in 18F-FDG and 18F-Florbetaben uptake are missing. The aim of this study was to evaluate the suitability of 18F-FDG- and 18F-Florbetaben-PET in 7-month-old female 5XFAD and to assess possible sex differences between male and female 5XFAD mice. We could demonstrate that female 5XFAD mice showed a significant reduction in brain glucose metabolism and increased cerebral amyloid deposition compared with wild type animals, in accordance with the pathology seen in AD patients. Furthermore, we showed for the first time that the hypometabolism in 5XFAD mice is gender-dependent and more pronounced in female mice. Therefore, these results support the feasibility of small animal PET imaging with 18F-FDG- and 18F-Florbetaben in 5XFAD mice in both, male and female animals. Moreover, our findings highlight the need to account for sex differences in studies working with 5XFAD mice.},
}
@article {pmid34900838,
year = {2021},
author = {Ghazbani, A and Mansourzadeh, MJ and Mehdizadeh, G and Ghobadi, M and Arzaghi, SM and Ostovar, A},
title = {Contribution of Iranian researchers in Alzheimer's disease research: A 10 years scientometric analysis.},
journal = {Journal of diabetes and metabolic disorders},
volume = {20},
number = {2},
pages = {2025-2036},
pmid = {34900838},
issn = {2251-6581},
abstract = {BACKGROUND: Alzheimer's disease is the most common form of dementia and is a rising issue for global health. Iran is struggling with a growing number of the elderly population and also a decrease in fertility rate. The goal of this study was to review and evaluate Alzheimer's disease publications by Iranian researchers.<br><br>METHODS: We searched for Alzheimer and all its related keywords in the Web of Science to find related documents published by Iranian researchers from 2010 until 2019. Bibliometric parameters at the level of documents, authors, and organizations were assessed. The co-authorship matrix was computed using Bibexcel, and visualizations were performed by VOSviewer.<br><br>RESULTS: Totally, 1042 documents from 4949 researchers (8.6 authors per document) were retrieved from Web of Science. Original articles (77.06%) and reviews (16.21%) were the most common document types for Iranian publications and also one article was retracted. As results, the average citation per document was 20.68. Iranian researchers mainly collaborated with researchers from the United States, Italy, Australia, and Canada, respectively. The co-occurrence networks for keywords represented five publication clusters in the collection. The largest cluster was related to studies on oxidative stress in Alzheimer's Disease, followed by in-vivo studies in the field of brain neurons destruction.<br><br>CONCLUSION: We found that Iranian researchers made significant impacts in the field of Alzheimer's disease and covered a wide range of related areas over the last 10 years.},
}
@article {pmid34900527,
year = {2021},
author = {Sun, J and Zhong, H and Wang, K and Li, N and Chen, L},
title = {Gains from no real PAINS: Where 'Fair Trial Strategy' stands in the development of multi-target ligands.},
journal = {Acta pharmaceutica Sinica. B},
volume = {11},
number = {11},
pages = {3417-3432},
pmid = {34900527},
issn = {2211-3835},
abstract = {Compounds that selectively modulate multiple targets can provide clinical benefits and are an alternative to traditional highly selective agents for unique targets. High-throughput screening (HTS) for multitarget-directed ligands (MTDLs) using approved drugs, and fragment-based drug design has become a regular strategy to achieve an ideal multitarget combination. However, the unexpected presence of pan-assay interference compounds (PAINS) suspects in the development of MTDLs frequently results in nonspecific interactions or other undesirable effects leading to artefacts or false-positive data of biological assays. Publicly available filters can help to identify PAINS suspects; however, these filters cannot comprehensively conclude whether these suspects are "bad" or innocent. Additionally, these in silico approaches may inappropriately label a ligand as PAINS. More than 80% of the initial hits can be identified as PAINS by the filters if appropriate biochemical tests are not used resulting in false positive data that are unacceptable for medicinal chemists in manuscript peer review and future studies. Therefore, extensive offline experiments should be used after online filtering to discriminate "bad" PAINS and avoid incorrect evaluation of good scaffolds. We suggest that the use of "Fair Trial Strategy" to identify interesting molecules in PAINS suspects to provide certain structure‒function insight in MTDL development.},
}
@article {pmid34900398,
year = {2021},
author = {He, C and Zhao, X and Lei, Y and Nie, J and Lu, X and Song, J and Wang, L and Li, H and Liu, F and Zhang, Y and Niu, Q},
title = {Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al.},
journal = {Molecular therapy. Nucleic acids},
volume = {26},
number = {},
pages = {1401-1417},
pmid = {34900398},
issn = {2162-2531},
abstract = {Aluminum is a known neurotoxin that can induce Aβ deposition and abnormal phosphorylation of tau protein, leading to Alzheimer disease (AD)-like damages such as neuronal damage and decreased learning and memory functions. In this study, we constructed a rat model of subchronic aluminum maltol exposure, and the whole-transcriptome sequencing was performed on the hippocampus of the control group and the middle-dose group. A total of 167 miRNAs, 37 lncRNAs, 256 mRNAs, and 64 circRNAs expression changed. The Kyoto Encyclopedia of Genes and Genomes showed that PI3K/AKT pathway was the most enriched pathway of DEGs, and IRS1 was the core molecule in the PPI network. circRNA/lncRNA-miRNA-mRNA networks of all DEGs, DEGs in the PI3K/AKT pathway, and IRS1 were constructed by Cytoscape. Molecular experiment results showed that aluminum inhibited the IRS1/PI3K/AKT pathway and increased the content of Aβ and tau. In addition, we also constructed an AAV intervention rat model, proving that inhibition of miR-96-5p expression might resist aluminum-induced injury by upregulating expression of IRS1. In general, these results suggest that the ceRNA networks are involved in the neurotoxic process of aluminum, providing a new strategy for studying the toxicity mechanism of aluminum and finding biological targets for the prevention and treatment of AD.},
}
@article {pmid34896396,
year = {2022},
author = {Shobo, A and James, N and Dai, D and Röntgen, A and Black, C and Kwizera, JR and Hancock, MA and Huy Bui, K and Multhaup, G},
title = {The amyloid-β1-42-oligomer interacting peptide D-AIP possesses favorable biostability, pharmacokinetics, and brain region distribution.},
journal = {The Journal of biological chemistry},
volume = {298},
number = {1},
pages = {101483},
doi = {10.1016/j.jbc.2021.101483},
pmid = {34896396},
issn = {1083-351X},
mesh = {*Alzheimer Disease/metabolism/pathology ; *Amyloid beta-Peptides/pharmacokinetics/pharmacology ; Animals ; *Brain/metabolism ; Female ; Male ; Mice ; Mice, Transgenic ; *Peptide Fragments/pharmacokinetics/pharmacology ; },
abstract = {We have previously developed a unique 8-amino acid Aβ42 oligomer-Interacting Peptide (AIP) as a novel anti-amyloid strategy for the treatment of Alzheimer's disease. Our lead candidate has successfully progressed from test tubes (i.e., in vitro characterization of protease-resistant D-AIP) to transgenic flies (i.e., in vivo rescue of human Aβ42-mediated toxicity via D-AIP-supplemented food). In the present study, we examined D-AIP in terms of its stability in multiple biological matrices (i.e., ex-vivo mouse plasma, whole blood, and liver S9 fractions) using MALDI mass spectrometry, pharmacokinetics using a rapid and sensitive LC-MS method, and blood brain barrier (BBB) penetrance in WT C57LB/6 mice. D-AIP was found to be relatively stable over 3 h at 37 °C in all matrices tested. Finally, label-free MALDI imaging showed that orally administered D-AIP can readily penetrate the intact BBB in both male and female WT mice. Based upon the favorable stability, pharmacokinetics, and BBB penetration outcomes for orally administered D-AIP in WT mice, we then examined the effect of D-AIP on amyloid "seeding" in vitro (i.e., freshly monomerized versus preaggregated Aβ42). Complementary biophysical assays (ThT, TEM, and MALDI-TOF MS) showed that D-AIP can directly interact with synthetic Aβ42 aggregates to disrupt primary and/or secondary seeding events. Taken together, the unique mechanistic and desired therapeutic potential of our lead D-AIP candidate warrants further investigation, that is, testing of D-AIP efficacy on the altered amyloid/tau pathology in transgenic mouse models of Alzheimer's disease.},
}
@article {pmid34896071,
year = {2022},
author = {Schrader, JM and Xu, F and Lee, H and Barlock, B and Benveniste, H and Van Nostrand, WE},
title = {Emergent White Matter Degeneration in the rTg-DI Rat Model of Cerebral Amyloid Angiopathy Exhibits Unique Proteomic Changes.},
journal = {The American journal of pathology},
volume = {192},
number = {3},
pages = {426-440},
pmid = {34896071},
issn = {1525-2191},
support = {R01 NS094201/NS/NINDS NIH HHS/United States ; RF1 AG053991/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Annexin A3/metabolism ; Brain/metabolism ; *Cerebral Amyloid Angiopathy/metabolism ; Cystatin C/metabolism ; Proteomics ; Rats ; *White Matter/metabolism ; },
abstract = {Cerebral amyloid angiopathy (CAA), characterized by cerebral vascular amyloid accumulation, neuroinflammation, microbleeds, and white matter (WM) degeneration, is a common comorbidity in Alzheimer disease and a prominent contributor to vascular cognitive impairment and dementia. WM loss was recently reported in the corpus callosum (CC) in the rTg-DI rat model of CAA. The current study shows that the CC exhibits a much lower CAA burden compared with the adjacent cortex. Sequential Window Acquisition of All Theoretical Mass Spectra tandem mass spectrometry was used to show specific proteomic changes in the CC with emerging WM loss and compare them with the proteome of adjacent cortical tissue in rTg-DI rats. In the CC, annexin A3, heat shock protein β1, and cystatin C were elevated at 4 months (M) before WM loss and at 12M with evident WM loss. Although annexin A3 and cystatin C were also enhanced in the cortex at 12M, annexin A5 and the leukodystrophy-associated astrocyte proteins megalencephalic leukoencephalopathy with subcortical cysts 1 and GlialCAM were distinctly elevated in the CC. Pathway analysis indicated neurodegeneration of axons, reflected by reduced expression of myelin and neurofilament proteins, was common to the CC and cortex; activation of Tgf-β1 and F2/thrombin was restricted to the CC. This study provides new insights into the proteomic changes that accompany WM loss in the CC of rTg-DI rats.},
}
@article {pmid34895363,
year = {2021},
author = {Silva, P and Rodríguez-Pérez, M and Gómez-Torres, Ó and Burgos-Ramos, E},
title = {Olive oil and wine as source of multi-target agents in the prevention of Alzheimer disease.},
journal = {Nutrition research reviews},
volume = {},
number = {},
pages = {1-15},
doi = {10.1017/S095442242100041X},
pmid = {34895363},
issn = {1475-2700},
abstract = {Olive oil and wine are consumed daily worldwide, and they constitute the fundamental pillars of the healthy Mediterranean diet. Polyphenolic compounds, naturally present in both olive oil and wine, are responsible for their beneficial properties. Current studies have shown the neuroprotective effects of polyphenols independently of their well-known antioxidant action. In this work, we have focused on reviewing the protective effect of polyphenols from extra virgin olive oil and wine in Alzheimer´s disease (AD), to emphasise that both foods could be a possible therapeutic tool. Beneficial effects have been described in β-aggregation, neurofibrillary tangles, autophagy and mitochondrial function, as well as in cerebral insulin resistance. Furthermore, to date, a harmful dose has not been described. Both pre-clinical and clinical works demonstrate that polyphenols act on neuropathological and cognitive disorders of AD, preventing or stopping the onset of this devastating disease. However, there are certain limitations in these studies, since it is very difficult to research diseases that lead to cognitive impairment. Although all the findings obtained are very encouraging, more studies should be carried out investigating the use of the polyphenols from olive oil and wine as therapeutic agents in the progression of AD. Therefore, more longitudinal studies in humans with a homogeneous cohort of patients are necessary to corroborate the efficacy of these nutraceuticals, as well as determine the most appropriate dose for this purpose.},
}
@article {pmid34892212,
year = {2021},
author = {Matsuda, N and Nakari, I and Takadama, K},
title = {Alzheimer Dementia Detection Based on Unstable Circadian Rhythm Waves Extracted from Heartrate.},
journal = {Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference},
volume = {2021},
number = {},
pages = {4473-4476},
doi = {10.1109/EMBC46164.2021.9630606},
pmid = {34892212},
issn = {2694-0604},
mesh = {Aged ; *Alzheimer Disease/diagnosis ; Child, Preschool ; Circadian Rhythm ; Heart Rate ; Humans ; Middle Aged ; },
abstract = {This paper proposes the novel Alzheimer dementia (AD) detection method based on unstable circadian rhythm of heartrate acquired from mattress sensor. Concretely, the pro-posed method, UCRADD (Unstable Circadian Rhythm based Alzheimer Dementia Detection), estimates the circadian rhythm of heartrate by calculating the regression of the trigonometric functions with the maximum likelihood estimation, and judges instability of the circadian rhythm by the coefficients of the equation estimated trigonometric functions. Through the human subject experiment with one elderly AD subject in two months (i.e., August and December), three elderly (age from 60-70) non-AD subjects, the ten middle-aged non-AD subjects and eight young non-AD subjects, the following implications have been revealed: (1) UCRADD succeeds to detect the AD patients in the high rate and keeps it in two months (78.9% in August and 82.4% in December), while our previous method cannot keep the rate at the same level in two months (57.9% in August and 82.4% in December). (2) the instability of circadian rhythm of heartrate has the potential of being new symptom of AD.},
}
@article {pmid34890262,
year = {2021},
author = {Imbimbo, BP and Watling, M},
title = {What have we learned from past failures of investigational drugs for Alzheimer's disease?.},
journal = {Expert opinion on investigational drugs},
volume = {30},
number = {12},
pages = {1175-1182},
doi = {10.1080/13543784.2021.2017881},
pmid = {34890262},
issn = {1744-7658},
mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; Drugs, Investigational ; Humans ; tau Proteins ; },
abstract = {INTRODUCTION: In the last 15 years, huge efforts against Alzheimer's disease (AD) with drugs targeting β-amyloid (Aβ) and tau have produced poor clinical results. Aducanumab, a recently FDA-approved anti-Aβ monoclonal antibody has been greeted with distrust by most experts, hospitals and insurance companies for its level of efficacy and poor tolerability.<br><br>AREA COVERED: We reviewed literature on Alzheimer trials using PubMed, meeting abstracts and ClnicalTrials.gov and discuss what we can learn from past failures of investigational drugs for Alzheimer's disease, especially anti-Aβ and anti-tau drugs.<br><br>EXPERT OPINION: It is our opinion that previous failures of anti-AD drugs suggest that soluble Aβ and tau are not appropriate drug targets. In addition, pivotal clinical trials of future clinical candidates should avoid major protocol amendments and futility analyses. Study protocols should adopt better measures to protect study blinding and minimize the potential introduction of major biases in the evaluation of clinical results. Finally, alternative biological targets should be pursued as well as more multimodal approaches to addressing neurodegeneration in AD.},
}
@article {pmid34888171,
year = {2021},
author = {Falter, A and Van Den Bossche, MJA},
title = {How non-rapid eye movement sleep and Alzheimer pathology are linked.},
journal = {World journal of psychiatry},
volume = {11},
number = {11},
pages = {1027-1038},
pmid = {34888171},
issn = {2220-3206},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by the presence of senile plaques and neurofibrillary tangles. Research attempts to identify characteristic factors that are associated with the presence of the AD pathology on the one hand and that increase the risk of developing AD on the other. Changes in non-rapid eye movement (NREM) sleep may meet both requirements for various reasons. First, NREM-sleep is important for optimal memory function. In addition, studies report that the presence of AD pathology is associated with NREM-sleep changes. Finally, more and more results appear to suggest that sleep problems are not only a symptom of AD but can also increase the risk of AD. Several of these studies suggest that it is primarily a lack of NREM-sleep that is responsible for this increased risk. However, the majority investigated sleep only through subjective reporting, as a result of which NREM-sleep could not be analyzed separately. The aim of this literature study is therefore to present the results of the studies that relate the AD pathology and NREM-sleep (registered by electroencephalography). Furthermore, we try to evaluate whether NREM-sleep analysis could be used to support the diagnosis of AD and whether NREM-sleep deficiency could be a causal factor in the development of AD.},
}
@article {pmid34881727,
year = {2021},
author = {Jones, DT and Graff-Radford, J},
title = {Executive Dysfunction and the Prefrontal Cortex.},
journal = {Continuum (Minneapolis, Minn.)},
volume = {27},
number = {6},
pages = {1586-1601},
pmid = {34881727},
issn = {1538-6899},
mesh = {*Cognitive Dysfunction ; *Dorsolateral Prefrontal Cortex ; Executive Function ; Humans ; Neuropsychological Tests ; Prefrontal Cortex ; },
abstract = {PURPOSE OF REVIEW: This article summarizes the cognitive and behavioral functions of the prefrontal cortex with an emphasis on executive cognitive functions and the clinical consequences associated with executive dysfunction. The clinical manifestations of lesions to the lateral prefrontal, orbitofrontal, medial prefrontal, and frontopolar cortex are reviewed.<br><br>RECENT FINDINGS: Traditional lesion studies have emphasized the role of a brain region in controlling a cognitive function. With advances in neurology, neuropsychology, and neuroimaging, the participation of the prefrontal cortex in large-scale networks has been established with recognition that cognitive dysfunction can arise not only from a lesion within a network but also from degenerative disease targeting these large-scale, dynamic neural networks. Although executive dysfunction can result from frontal lobe injury, this article highlights the role of distributed processes subserving executive functions. An atypical phenotype of Alzheimer disease has been described that selectively targets parietal-temporal-frontal networks important for core executive functions.<br><br>SUMMARY: Executive function comprises working memory, cognitive flexibility, and inhibition and depends on top-down (ie, goal-driven) control of distributed processes occurring throughout the brain. The exact behavioral output (ie, function) depends on the content of the processes being controlled. Prefrontal cortex regions serve key cognitive functions related to social, emotional, and motivational aspects of behavior. The dorsal lateral prefrontal cortex plays a role in working memory, goal-driven attention, task switching, planning, problem-solving, and novelty-seeking. The ventral lateral prefrontal cortex plays a role in inhibition, response selection, and monitoring; the medial prefrontal cortex in self-knowledge, motivation, emotional regulation, and updating goal-directed behavior; the orbitofrontal cortex in personality, inhibition, and emotional and social reasoning. Although dysexecutive syndromes have been traditionally associated with dorsolateral prefrontal cortex injury, it is now recognized that they can also result from an impaired parietal-temporal-frontal system, which is targeted in a distinct form of atypical Alzheimer disease. This dysexecutive Alzheimer phenotype is characterized by impaired task performance on a wide battery of neuropsychological tests and simple daily tasks that require executive control. In contrast, dysexecutive syndromes more localized to the frontal lobe involve impaired executive control of social, emotional, and motivational aspects of behavior.},
}
@article {pmid34880687,
year = {2021},
author = {Al-Naami, B and Abu Owida, H and Abu Mallouh, M and Al-Naimat, F and Agha, M and Al-Hinnawi, AR},
title = {A New Prototype of Smart Wearable Monitoring System Solution for Alzheimer's Patients.},
journal = {Medical devices (Auckland, N.Z.)},
volume = {14},
number = {},
pages = {423-433},
pmid = {34880687},
issn = {1179-1470},
abstract = {PURPOSE: The daily life management of patients with Alzheimer's disease (AD) constitutes a significant and rapidly expanding health-care responsibility. In this study, an innovative prototype of a wireless-sensing smart wearable medical device (SWMD) is proposed as a multi-functions solution for Alzheimer patients. The SWMD is aimed to assemble three main biomedical engineering advances: 1) use of a Wi-Fi microcontroller, 2) simultaneous monitoring of a set of vital biomarkers, and 3) cautions of fall down conditions, in addition to GPS location indicator.<br><br>METHODS: The SWMD employs a Wi-Fi controller that is incorporated with electronic circuits to monitor three vital signals (temperature, heart rate, and oxygen saturation), fall down conditions in three directions (X, Y, and Z axis), and GPS location. The SWMD was connected to the Firebase Service (database hosted on the Internet Cloud). The proposed device was tested on 13 normal volunteers. The left side, right side, forward, and backward fall down conditions were assessed. The prototype's functions during daily activity such as rising hand, sitting down or standing up, and walking conditions were also assessed.<br><br>RESULTS: The three assembled functions were all successfully incorporated to build the SWDM device as a suggested solution offering real-time alerts during daily activity to AD patients. The Bland-Altman statistical test showed no significant difference (p-value >0.05) between the SWMD biomarkers' acquisition and the reference methods. The gyro/accelerator sensor yielded 93% sensitivity in fall down detection and 95% specificity during daily activities. The GPS yielded correct positioning of the SWDM holder, while the internet cloud allowed saving and managing all vital biomarkers daily.<br><br>CONCLUSION: The SWMD is a possible solution for daily life support for AD patients. It incorporates three functions in one single device, GPS location indicator, monitoring set of biomarkers, and fall down alert, which are all controlled via a Wi-Fi micro controller on-line connected to Internet Cloud. It successfully would allow the management of the daily records as well as the real-time alerts to remote persons.},
}
@article {pmid34879376,
year = {2021},
author = {Tao, X and Che, Y and Li, C and Ruan, W and Xu, J and Yu, Y and Yang, F and Wang, J and Li, H},
title = {Novel SNX13 Frameshift Variant in an Individual with Developmental Delay.},
journal = {Cytogenetic and genome research},
volume = {161},
number = {10-11},
pages = {514-519},
doi = {10.1159/000520296},
pmid = {34879376},
issn = {1424-859X},
mesh = {Child, Preschool ; Developmental Disabilities/*genetics ; Frameshift Mutation/*genetics ; Homozygote ; Humans ; Intellectual Disability/*genetics ; Male ; Sorting Nexins/*genetics ; },
abstract = {Recently, an increasing number of genes have been associated with global developmental delay (GDD) and intellectual disability (ID). The sorting nexin (SNX) protein family plays multiple roles in protein trafficking and intracellular signaling. SNXs have been reported to be associated with several disorders, including Alzheimer disease and Down syndrome. Despite the growing evidence of an association of SNXs with neurodegeneration, SNX13 deficiency has not been associated with GDD or ID. In this study, we present the case of a 4-year-old boy with brain dysplasia and GDD, including language delay, cognitive delay, and dyskinesia. Exome sequencing revealed a 1-bp homozygous deletion in SNX13 (NM_015132.5: exon8: c.742_743del; p.Tyr248Leufs*20), which caused a frameshift and predicted early termination. Sanger sequencing confirmed that the variant was inherited from his parents respectively. Our findings associate SNX13 variation with GDD for the first time and provide a new GDD candidate gene.},
}
@article {pmid34879329,
year = {2022},
author = {Ko, K and Yi, D and Byun, MS and Lee, JH and Jeon, SY and Kim, WJ and Byeon, G and Sung, K and Han, D and Lee, Y and Joung, H and Jung, G and Lee, JY and Kim, H and Kim, YK and Kang, KM and Sohn, CH and Lee, DY and , },
title = {Cognitive reserve proxies, Alzheimer pathologies, and cognition.},
journal = {Neurobiology of aging},
volume = {110},
number = {},
pages = {88-95},
doi = {10.1016/j.neurobiolaging.2021.10.005},
pmid = {34879329},
issn = {1558-1497},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/metabolism/*pathology/*psychology ; Amyloid beta-Peptides/metabolism ; Atrophy ; Brain/diagnostic imaging/metabolism/physiopathology ; Cerebral Cortex/pathology ; *Cognition ; *Cognitive Reserve ; Female ; Humans ; Male ; Middle Aged ; Multimodal Imaging/methods ; },
abstract = {This study aimed to explore the moderating effects of the frequently used cognitive reserve (CR) proxies [i.e., education, premorbid intelligence quotient (pIQ), occupational complexity (OC), and lifetime cognitive activity (LCA)] on the relationships between various in vivo Alzheimer's disease (AD) pathologies and cognition. In total, 351 [268 cognitively unimpaired (CU), 83 cognitive impaired (CI)] older adults underwent multi-modal brain imaging to measure AD pathologies and cognitive assessments, and information on CR proxies was obtained. For overall participants, only education moderated the relationship between Aβ deposition and cognition. Education, pIQ, and LCA, but not OC, showed moderating effect on the relationship between AD-signature cerebral hypometabolism and cognition. In contrast, only OC had a moderating effect on the relationship between cortical atrophy of the AD-signature regions and cognition. Such moderation effects of the CR proxies were similarly observed in CI individuals, but most of them were not in CU individuals. The findings suggest that the proposed CR proxies have different moderating effects on the relationships between specific AD pathologies and cognition.},
}
@article {pmid34879014,
year = {2021},
author = {Fesharaki-Zadeh, A},
title = {A Case of Possible Chronic Traumatic Encephalopathy and Alzheimer's Disease in an Ex-Football Player.},
journal = {The neurologist},
volume = {},
number = {},
pages = {},
doi = {10.1097/NRL.0000000000000391},
pmid = {34879014},
issn = {2331-2637},
abstract = {INTRODUCTION: Chronic traumatic encephalopathy (CTE) is a debilitating neurodegenerative disease, which is often the sequelae of repetitive head trauma. Although the definitive diagnosis of CTE is made postmortem, there are proposed clinical algorithms aimed at identifying characteristic features of CTE, based on a combination of clinical history, serum, cerebrospinal fluid and neuroimaging biomarkers. There are promising new advances in positron emission tomography neuroimaging, including tau specific ligands, which will potentially provide a robust assessment as well as an exploratory tool of the disease semiology and progression.<br><br>CASE REPORT: Here is a unique case of an ex-football player, who suffered multiple prior traumatic brain injuries throughout his career, and presented to our clinic with significant episodic memory, visuospatial and executive functioning deficits, as well as comorbid mood and behavioral changes in the absence of prior psychiatric history or substance use. His clinical presentation and biomarkers were consistent with a suspected diagnosis of CTE comorbid with Alzheimer disease, which comprises a significant portion of overall CTE cases.<br><br>CONCLUSION: This case report presents a patient with a subtle case of dementia, which could be easily mistaken for behavioral variant frontotemporal dementia or primary progressive aphasia. This in turn highlights the importance of detailed longitudinal history taking, as well as rigorous biomarker studies.},
}
@article {pmid34878960,
year = {2021},
author = {Shaikh, S and Dhavan, P and Singh, P and Uparkar, J and Vaidya, SP and Jadhav, BL and Ramana, MMV},
title = {Design, synthesis and biological evaluation of novel antipyrine based α-aminophosphonates as anti-Alzheimer and anti-inflammatory agent.},
journal = {Journal of biomolecular structure &amp; dynamics},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/07391102.2021.2006088},
pmid = {34878960},
issn = {1538-0254},
abstract = {Herein, a series of novel antipyrine based α-aminophosphonates derivatives were synthesized and characterized. The synthesized derivatives were subjected for in vitro cholinesterase inhibition, enzyme kinetic studies, protein denaturation assay, proteinase inhibitory assay and cell viability assay. For cholinesterase inhibition, the results inferred that the test compounds possess better AChE activity (0.46 to 6.67 µM) than BuChE (2.395 to 12.47 µM). Compound 4j inhibited both AChE and BuChE (IC50 = 0.475 ± 0.12 µM and 2.95 ± 0.16 µM, respectively), implying that it serves as a dual AChE/BuChE inhibitor. Also, kinetic studies revealed that compound 4j exhibits mixed-type inhibition against both AChE and BuChE, with Ki values of 3.003 µM and 5.750 µM, respectively. Further, protein denaturation and proteinase inhibitory assays were used to test in vitro anti-inflammatory potential. It was found that compound 4o exhibited highest activity against protein denaturation (IC50 = 42.64 ± 0.19 µM) and proteinase inhibition (IC50 = 37.57 ± 0.19 µM) when compared to diclofenac. In addition, cell viability assay revealed that active compounds possess no cytotoxicity against N2a cell and RAW 264.7 macrophages. Finally, molecular docking experiments for AChE, BuChE, and COX-2 were conducted to better understand the binding modes of active compounds.Communicated by Ramaswamy H. Sarma.},
}
@article {pmid34878820,
year = {2021},
author = {Morawska, MM and Moreira, CG and Ginde, VR and Valko, PO and Weiss, T and Büchele, F and Imbach, LL and Masneuf, S and Kollarik, S and Prymaczok, N and Gerez, JA and Riek, R and Baumann, CR and Noain, D},
title = {Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson's disease.},
journal = {Science translational medicine},
volume = {13},
number = {623},
pages = {eabe7099},
doi = {10.1126/scitranslmed.abe7099},
pmid = {34878820},
issn = {1946-6242},
mesh = {*Alzheimer Disease ; Animals ; Disease Models, Animal ; Humans ; Mice ; *Parkinson Disease/metabolism ; *Sleep, Slow-Wave ; *Synucleinopathies ; alpha-Synuclein/metabolism ; },
abstract = {Slow-wave sleep (SWS) modulation in rodent models of Alzheimer’s disease alters extracellular amyloid burden. In Parkinson’s disease (PD), SWS appears to be closely linked with disease symptoms and progression. PD is characterized by damaging intracellular α-synuclein (αSyn) deposition that propagates extracellularly, contributing to disease spread. Intracellular αSyn is sensitive to degradation, whereas extracellular αSyn may be eliminated by glymphatic clearance, a process increased during SWS. Here, we explored whether long-term slow-wave modulation in murine models of PD presenting αSyn aggregation alters pathological protein burden and, thus, might constitute a valuable therapeutic target. Sleep-modulating treatments showed that enhancing slow waves in both VMAT2-deficient and A53T mouse models of PD reduced pathological αSyn accumulation compared to control animals. Nonpharmacological sleep deprivation had the opposite effect in VMAT2-deficient mice, severely increasing the pathological burden. We also found that SWS enhancement was associated with increased recruitment of aquaporin-4 to perivascular sites, suggesting a possible increase of glymphatic function. Furthermore, mass spectrometry data revealed differential and specific up-regulation of functional protein clusters linked to proteostasis upon slow wave–enhancing interventions. Overall, the beneficial effect of SWS enhancement on neuropathological outcome in murine synucleinopathy models mirrors findings in models of Alzheimer. Modulating SWS might constitute an effective strategy for modulating PD pathology in patients.},
}
@article {pmid34877187,
year = {2021},
author = {Alkasabera, A and Onyali, CB and Anim-Koranteng, C and Shah, HE and Ethirajulu, A and Bhawnani, N and Mostafa, JA},
title = {The Effect of Type-2 Diabetes on Cognitive Status and the Role of Anti-diabetes Medications.},
journal = {Cureus},
volume = {13},
number = {11},
pages = {e19176},
pmid = {34877187},
issn = {2168-8184},
abstract = {Type-2 diabetes mellitus prevalence is constantly increasing; this is explained by the increase of its risk factors and the amelioration of its management. Therefore, people are living longer with diabetes mellitus, which, in turn, has revealed new complications of the disease. Dementia is represented mainly by Alzheimer's disease and is an interesting topic of study. Accordingly, statistics have shown that dementia incidence is doubled in diabetic patients. The establishment of a relation between type-2 diabetes mellitus was studied on several levels in both humans and animal subjects. First, insulin receptors were found in the brain, especially the hippocampus, and insulin transport to the brain is mainly accomplished through the blood-brain barrier. Secondly, several studies showed that insulin affects multiple neurotransmitters in favor of promoting memory and cognition status. Thirdly, multiple pathological studies showed that insulin and Alzheimer's disease share many common lesions in the brain, such as beta-amyloid plaques, amylin-Aβ plaques, hyper-phosphorylated tau protein, and brain atrophy, especially in the hippocampus. After recognizing the positive effect of insulin on cognitive status, and the harmful effect of insulin resistance on cognitive status, multiple studies were focused on the role of anti-diabetes medications in fighting dementia. Consequently, these studies showed a positive impact of oral anti-diabetes medication, as well as insulin in limiting the progression of dementia and promoting cognitive status. Moreover, their effects were also noticed on limiting the pathological lesions of Alzheimer's disease. Accordingly, we can consider type-2 diabetes mellitus as a risk factor for dementia and Alzheimer's disease. Therefore, this can be used on the pharmaceutical level by the promising implication of antidiabetics as a treatment of dementia and Alzheimer's disease or at least to limit its progression. However, multiple clinical studies should be dedicated to proving the true benefits of anti-diabetes medications in treating dementia before they can be used in reality.},
}
@article {pmid34874463,
year = {2022},
author = {Bowles, KR and Pugh, DA and Oja, LM and Jadow, BM and Farrell, K and Whitney, K and Sharma, A and Cherry, JD and Raj, T and Pereira, AC and Crary, JF and Goate, AM},
title = {Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD.},
journal = {Acta neuropathologica},
volume = {143},
number = {2},
pages = {225-243},
pmid = {34874463},
issn = {1432-0533},
support = {P30 AG066514/AG/NIA NIH HHS/United States ; U54 NS123746/NS/NINDS NIH HHS/United States ; },
mesh = {Alternative Splicing/genetics ; Alzheimer Disease/*genetics/*pathology ; Brain/pathology ; Exons/genetics ; Humans ; Neurons/pathology ; Protein Isoforms ; Supranuclear Palsy, Progressive/*genetics/*pathology ; Tauopathies/genetics/pathology ; tau Proteins/*genetics ; },
abstract = {Understanding regulation of MAPT splicing is important to the etiology of many nerurodegenerative diseases, including Alzheimer disease (AD) and progressive supranuclear palsy (PSP), in which different tau isoforms accumulate in pathologic inclusions. MAPT, the gene encoding the tau protein, undergoes complex alternative pre-mRNA splicing to generate six isoforms. Tauopathies can be categorized by the presence of tau aggregates containing either 3 (3R) or 4 (4R) microtubule-binding domain repeats (determined by inclusion/exclusion of exon 10), but the role of the N-terminal domain of the protein, determined by inclusion/exclusion of exons 2 and 3 has been less well studied. Using a correlational screen in human brain tissue, we observed coordination of MAPT exons 2 and 10 splicing. Expressions of exon 2 splicing regulators and subsequently exon 2 inclusion are differentially disrupted in PSP and AD brain, resulting in the accumulation of 1N4R isoforms in PSP and 0N isoforms in AD temporal cortex. Furthermore, we identified different N-terminal isoforms of tau present in neurofibrillary tangles, dystrophic neurites and tufted astrocytes, indicating a role for differential N-terminal splicing in the development of disparate tau neuropathologies. We conclude that N-terminal splicing and combinatorial regulation with exon 10 inclusion/exclusion is likely to be important to our understanding of tauopathies.},
}
@article {pmid34874434,
year = {2021},
author = {Slomski, A},
title = {Methylphenidate Treats Apathy in Alzheimer Disease.},
journal = {JAMA},
volume = {326},
number = {21},
pages = {2120},
doi = {10.1001/jama.2021.20775},
pmid = {34874434},
issn = {1538-3598},
mesh = {*Alzheimer Disease/drug therapy ; *Apathy ; *Central Nervous System Stimulants/therapeutic use ; Double-Blind Method ; Humans ; *Methylphenidate/therapeutic use ; },
}
@article {pmid34873310,
year = {2022},
author = {Barnes, LL},
title = {Alzheimer disease in African American individuals: increased incidence or not enough data?.},
journal = {Nature reviews. Neurology},
volume = {18},
number = {1},
pages = {56-62},
pmid = {34873310},
issn = {1759-4766},
mesh = {African Americans/*statistics &amp; numerical data ; Aged ; Alzheimer Disease/*epidemiology ; Data Collection ; Ethnicity ; Humans ; Incidence ; Middle Aged ; United States/epidemiology ; },
abstract = {Research on racial differences in Alzheimer disease (AD) dementia has increased in recent years. Older African American individuals bear a disproportionate burden of AD and cognitive impairment compared with non-Latino white individuals. Tremendous progress has been made over the past two decades in our understanding of the neurobiological substrates of AD. However, owing to well-documented challenges of study participant recruitment and a persistent lack of biological data in the African American population, knowledge of the drivers of these racial disparities has lagged behind. Therapeutic targets and effective interventions for AD are increasingly sought, but without a better understanding of the disease in African American individuals, any identified treatments and/or cures will evade this rapidly growing at-risk population. In this Perspective, I introduce three key obstacles to progress in understanding racial differences in AD: uncertainty about diagnostic criteria, disparate cross-sectional and longitudinal findings; and a dearth of neuropathological data. I also highlight evidence-informed strategies to move the field forward.},
}
@article {pmid34873149,
year = {2021},
author = {Chen, HH and Petty, LE and Sha, J and Zhao, Y and Kuzma, A and Valladares, O and , and Bush, W and Naj, AC and Gamazon, ER and Below, JE},
title = {Genetically regulated expression in late-onset Alzheimer's disease implicates risk genes within known and novel loci.},
journal = {Translational psychiatry},
volume = {11},
number = {1},
pages = {618},
pmid = {34873149},
issn = {2158-3188},
support = {R01 GM140287/GM/NIGMS NIH HHS/United States ; R01 HG011138/HG/NHGRI NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; RF1 AG061351/AG/NIA NIH HHS/United States ; R56 AG068026/AG/NIA NIH HHS/United States ; R35 HG010718/HG/NHGRI NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; },
abstract = {Late-onset Alzheimer disease (LOAD) is highly polygenic, with a heritability estimated between 40 and 80%, yet risk variants identified in genome-wide studies explain only ~8% of phenotypic variance. Due to its increased power and interpretability, genetically regulated expression (GReX) analysis is an emerging approach to investigate the genetic mechanisms of complex diseases. Here, we conducted GReX analysis within and across 51 tissues on 39 LOAD GWAS data sets comprising 58,713 cases and controls from the Alzheimer's Disease Genetics Consortium (ADGC) and the International Genomics of Alzheimer's Project (IGAP). Meta-analysis across studies identified 216 unique significant genes, including 72 with no previously reported LOAD GWAS associations. Cross-brain-tissue and cross-GTEx models revealed eight additional genes significantly associated with LOAD. Conditional analysis of previously reported loci using established LOAD-risk variants identified eight genes reaching genome-wide significance independent of known signals. Moreover, the proportion of SNP-based heritability is highly enriched in genes identified by GReX analysis. In summary, GReX-based meta-analysis in LOAD identifies 216 genes (including 72 novel genes), illuminating the role of gene regulatory models in LOAD.},
}
@article {pmid34871668,
year = {2022},
author = {Hadrich, F and Chamkha, M and Sayadi, S},
title = {Protective effect of olive leaves phenolic compounds against neurodegenerative disorders: Promising alternative for Alzheimer and Parkinson diseases modulation.},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {159},
number = {},
pages = {112752},
doi = {10.1016/j.fct.2021.112752},
pmid = {34871668},
issn = {1873-6351},
mesh = {Animals ; Female ; Flavonoids/*pharmacology ; Humans ; Male ; Metabolic Syndrome ; Mice ; *Neurodegenerative Diseases ; Olea/*chemistry ; Phenols/*pharmacology ; Plant Leaves/chemistry ; Protective Agents/*pharmacology ; Signal Transduction/drug effects ; },
abstract = {The main objective of this work was to review literature on compounds extracted from olive tree leaves, such as simple phenols (hydroxytyrosol) and flavonoids (Apigenin, apigenin-7-O-glucoside, luteolin.) and their diverse pharmacological activities as antioxidant, antimicrobial, anti-viral, anti-obesity, anti-inflammatory and neuroprotective properties. In addition, the study discussed the key mechanisms underlying their neuroprotective effects. This study adopted an approach of collecting data through the databases provided by ScienceDirect, SCOPUS, MEDLINE, PubMed and Google Scholar. This review revealed that there was an agreement on the great impact of olive tree leaves phenolic compounds on many metabolic syndromes as well as on the most prevalent neurodegenerative diseases such as Alzheimer and Parkinson. These findings would be of great importance for the use of olive tree leaves extracts as a food supplement and/or a source of drugs for many diseases. In addition, this review would of great help to beginning researchers in the field since it would offer them a general overview of the studies undertaken in the last two decades on the topic.},
}
@article {pmid34870910,
year = {2021},
author = {Teplyshova, AM and Datieva, VK},
title = {[Alzheimer disease and epilepsy].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {121},
number = {10. Vyp. 2},
pages = {23-29},
doi = {10.17116/jnevro202112110223},
pmid = {34870910},
issn = {1997-7298},
mesh = {*Alzheimer Disease/diagnosis/drug therapy/epidemiology ; Animals ; Anticonvulsants/therapeutic use ; *Cognitive Dysfunction/diagnosis/epidemiology/etiology ; *Epilepsy/drug therapy/epidemiology ; Humans ; Seizures/drug therapy ; },
abstract = {Alzheimer Disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory, difficulty in thinking, changes in behavior and personality disorders. The risk of developing epileptic seizures (ES) in patients with AD increases significantly. Animal and human studies have shown a close relationship between the pathogenesis of ES and AD. The exact prevalence of ES in AD remains unclear due to methodological difficulties, in particular, detection of ES in patients with cognitive impairment. EP types differ in sporadic and hereditary forms of AD. Antiepileptic therapy in AD has its own characteristics. Certain antiepileptic drugs can have a positive effect on cognitive function.},
}
@article {pmid34870909,
year = {2021},
author = {Ponomareva, EV and Krinsky, SA and Gavrilova, SI},
title = {[Prognosis of amnestic mild cognitive impairment: clinical and immunological correlations].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {121},
number = {10. Vyp. 2},
pages = {16-22},
doi = {10.17116/jnevro202112110216},
pmid = {34870909},
issn = {1997-7298},
mesh = {Aged ; *Alzheimer Disease ; *Cognitive Dysfunction/diagnosis ; Follow-Up Studies ; Humans ; Neuropsychological Tests ; Prognosis ; },
abstract = {OBJECTIVE: To determine the long-term (three-year) prognosis of the cognitive deficits progression in elderly people with amnestic mild cognitive impairment (aMCI) based on the analysis of the initial clinical and immunological parameters.<br><br>MATERIAL AND METHODS: This study is based on a clinical and follow-up study of 252 outpatients with aMCI, who were observed in the Federal State Budgetary Scientific Institution «Mental Health Research Center» from 2018 to 2020. The psychometric assessment complex included the following scales and tests: MMSE, MoCA, The 10 words test, BNT, David Wechsler's Scale, subtest 6, CDT, Memory test of 5 geometric shapes, BVRT Test, DRS - Mattis Dementia Rating Scale: Verbal fluency, DRS - Mattis Dementia Rating Scale, The Munsterberg Test. As part of the study, the level of cytokines (TNF-a, IL-1, IL-6, IL-8, IL-10) in the blood serum was determined in all patients by enzyme immunoassay (ELISA), using diagnostic kits manufactured by Cytokine LLC.<br><br>RESULTS: In patients with a progression of aMCI syndrome, an increase in proinflammatory cytokines IL-1, IL-6, IL-8, TNF-α is initially detected, which may reflect the level of systemic inflammation or functional insufficiency of anti-inflammatory mechanisms. In turn, the group with a subsequent improvement in cognitive functioning, on the contrary, is distinguished by an initially increased level of the anti-inflammatory interleukin system (IL-10).<br><br>CONCLUSION: We provide new data on the presence of systemic inflammation and immune disturbances and their association with clinical course of disease in the majority of elderly patients with aMCI.<br><br>CONCLUSION: Signs of a chronic low-level systemic inflammatory response in patients with aMCI is the unfavorable prognosis criterion: in such patients, cognitive deficit significantly progresses or dementia due to Alzheimer disease develops within three years.},
}
@article {pmid34870612,
year = {2021},
author = {van Gils, AM and Visser, LN and Hendriksen, HM and Georges, J and Muller, M and Bouwman, FH and van der Flier, WM and Rhodius-Meester, HF},
title = {Assessing the Views of Professionals, Patients, and Care Partners Concerning the Use of Computer Tools in Memory Clinics: International Survey Study.},
journal = {JMIR formative research},
volume = {5},
number = {12},
pages = {e31053},
pmid = {34870612},
issn = {2561-326X},
abstract = {BACKGROUND: Computer tools based on artificial intelligence could aid clinicians in memory clinics in several ways, such as by supporting diagnostic decision-making, web-based cognitive testing, and the communication of diagnosis and prognosis.<br><br>OBJECTIVE: This study aims to identify the preferences as well as the main barriers and facilitators related to using computer tools in memory clinics for all end users, that is, clinicians, patients, and care partners.<br><br>METHODS: Between July and October 2020, we sent out invitations to a web-based survey to clinicians using the European Alzheimer's Disease Centers network and the Dutch Memory Clinic network, and 109 clinicians participated (mean age 45 years, SD 10; 53/109, 48.6% female). A second survey was created for patients and care partners. They were invited via Alzheimer Europe, Alzheimer's Society United Kingdom, Amsterdam Dementia Cohort, and Amsterdam Aging Cohort. A total of 50 patients with subjective cognitive decline, mild cognitive impairment, or dementia (mean age 73 years, SD 8; 17/34, 34% female) and 46 care partners (mean age 65 years, SD 12; 25/54, 54% female) participated in this survey.<br><br>RESULTS: Most clinicians reported a willingness to use diagnostic (88/109, 80.7%) and prognostic (83/109, 76.1%) computer tools. User-friendliness (71/109, 65.1%); Likert scale mean 4.5, SD 0.7), and increasing diagnostic accuracy (76/109, 69.7%; mean 4.3, SD 0.7) were reported as the main factors stimulating the adoption of a tool. Tools should also save time and provide clear information on reliability and validity. Inadequate integration with electronic patient records (46/109, 42.2%; mean 3.8, SD 1.0) and fear of losing important clinical information (48/109, 44%; mean 3.7, SD 1.2) were most frequently indicated as barriers. Patients and care partners were equally positive about the use of computer tools by clinicians, both for diagnosis (69/96, 72%) and prognosis (73/96, 76%). In addition, most of them thought favorably regarding the possibility of using the tools themselves.<br><br>CONCLUSIONS: This study showed that computer tools in memory clinics are positively valued by most end users. For further development and implementation, it is essential to overcome the technical and practical barriers of a tool while paying utmost attention to its reliability and validity.},
}
@article {pmid34867298,
year = {2021},
author = {Lemon, N and Canepa, E and Ilies, MA and Fossati, S},
title = {Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {772278},
pmid = {34867298},
issn = {1663-4365},
support = {R01 AG062572/AG/NIA NIH HHS/United States ; R01 NS104127/NS/NINDS NIH HHS/United States ; },
abstract = {The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.},
}
@article {pmid34867272,
year = {2021},
author = {Sandebring-Matton, A and Axenhus, M and Bogdanovic, N and Winblad, B and Schedin-Weiss, S and Nilsson, P and Tjernberg, LO},
title = {Microdissected Pyramidal Cell Proteomics of Alzheimer Brain Reveals Alterations in Creatine Kinase B-Type, 14-3-3-γ, and Heat Shock Cognate 71.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {735334},
pmid = {34867272},
issn = {1663-4365},
abstract = {Novel insights on proteins involved in Alzheimer's disease (AD) are needed. Since multiple cell types and matrix components are altered in AD, bulk analysis of brain tissue maybe difficult to interpret. In the current study, we isolated pyramidal cells from the cornu ammonis 1 (CA1) region of the hippocampus from five AD and five neurologically healthy donors using laser capture microdissection (LCM). The samples were analyzed by proteomics using 18O-labeled internal standard and nano-high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for relative quantification. Fold change between AD and control was calculated for the proteins that were identified in at least two individual proteomes from each group. From the 10 cases analyzed, 62 proteins were identified in at least two AD cases and two control cases. Creatine kinase B-type (CKB), 14-3-3-γ, and heat shock cognate 71 (Hsc71), which have not been extensively studied in the context of the human AD brain previously, were selected for further studies by immunohistochemistry (IHC). In hippocampus, semi-quantitative measures of IHC staining of the three proteins confirmed the findings from our proteomic analysis. Studies of the same proteins in the frontal cortex revealed that the alterations remained for CKB and 14-3-3-γ but not for Hsc71. Protein upregulation in CA1 neurons of final stage AD is either a result of detrimental, pathological effects, or from cell-specific protective response mechanisms in surviving neurons. Based on previous findings from experimental studies, CKB and Hsc71 likely exhibit protective effects, whereas 14-3-3-γ may represent a detrimental pathway. These new players could reflect pathways of importance for the development of new therapeutic strategies.},
}
@article {pmid34867156,
year = {2021},
author = {Dobryakova, YV and Spivak, YS and Zaichenko, MI and Koryagina, AA and Markevich, VA and Stepanichev, MY and Bolshakov, AP},
title = {Intrahippocampal Adeno-Associated Virus-Mediated Overexpression of Nerve Growth Factor Reverses 192IgG-Saporin-Induced Impairments of Hippocampal Plasticity and Behavior.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {745050},
pmid = {34867156},
issn = {1662-4548},
abstract = {One of the aspects of Alzheimer disease is loss of cholinergic neurons in the basal forebrain, which leads to development of cognitive impairment. Here, we used a model of cholinergic deficit caused by immunotoxin 192IgG-saporin to study possible beneficial effects of adeno-associated virus (AAV)-mediated overexpression of nerve growth factor (NGF) in the hippocampus of rats with cholinergic deficit. Suspension of recombinant AAV carrying control cassette or cassette with NGF was injected into both hippocampi of control rats or rats with cholinergic deficit induced by intraseptal injection of 192IgG-saporin. Analysis of choline acetyltransferase (ChAT) immunostaining showed that NGF overexpression in the hippocampus did not prevent strong loss of ChAT-positive neurons in the septal area caused by the immunotoxin. Induction of cholinergic deficit in the hippocampus led to impairments in Y-maze and beam-walking test but did not affect behavioral indices in the T-maze, open field test, and inhibitory avoidance training. NGF overexpression in the rats with cholinergic deficit restored normal animal behavior in Y-maze and beam-walking test. Recording of field excitatory postsynaptic potentials in vivo in the hippocampal CA1 area showed that induction of cholinergic deficit decreased magnitude of long-term potentiation (LTP) and prevented a decrease in paired-pulse ratio after LTP induction, and NGF overexpression reversed these negative changes in hippocampal synaptic characteristics. The beneficial effect of NGF was not associated with compensatory changes in the number of cells that express NGF receptors TrkA and NGFR in the hippocampus and medial septal area. NGF overexpression also did not prevent a 192IgG-saporin-induced decrease in the activity of acetylcholine esterase in the hippocampus. We conclude that NGF overexpression in the hippocampus under conditions of cholinergic deficit induces beneficial effects which are not related to maintenance of cholinergic function.},
}
@article {pmid34867098,
year = {2021},
author = {Faught, E},
title = {Restoring EEG to its Rightful Place in Alzheimer Disease Care.},
journal = {Epilepsy currents},
volume = {21},
number = {3},
pages = {175-176},
pmid = {34867098},
issn = {1535-7597},
}
@article {pmid34866970,
year = {2021},
author = {Ranneh, Y and Abu Bakar, MF and Ismail, NA and Kormin, F and Mohamed, M and Md Akim, A and Isha, A},
title = {Anti-aging and antioxidant of four traditional malaysian plants using simplex centroid mixture design approach.},
journal = {Saudi journal of biological sciences},
volume = {28},
number = {12},
pages = {6711-6720},
pmid = {34866970},
issn = {1319-562X},
abstract = {Aging is a naturally biological process with adverse effects. The continuous accumulation of reactive oxygen species (ROS) trigger cellular and tissue damage by activating several aging enzymes. The antioxidant properties of traditional medicinal plants used by Jakun aborigine's community are a promising approach to alleviate aging process and prevent Alzheimer. The aim of the current investigation was to optimize a novel anti-aging formulation from traditional plants (Cnestis palala stem, Urceola micrantha stem, Marantodes pumilum stem and Microporus xanthopus fruiting bodies) using simplex centroid mixture design (SCMD). After selecting the optimal formulations based on desirability function of antioxidant activity (DPPḢ, ABTS ˙ + and FRAP), they were further examined against the activity of aging-related-enzymes (collagenase, tyrosinase, acetyl- and butyrylcholinesterase). The single extracts of C. palala, U. micrantha and the binary mixture of C. palala and U. micrantha were the optimal formulations with high antioxidant activities. Single extract of U. micrantha showed the highest inhibition towards matrix metalloproteinase-1 (49.44 ± 4.11 %), while C. palala water extract showed highest inhibitions towards tyrosinase (14.06 ± 0.31%), acetylcholinesterase (32.92 ± 2.13%) and butyrylcholinesterase (34.89 ± 2.84%) enzymes. The single extracts of C. palala and U. micrantha displayed better activity as compared to the binary mixture formulation. In conclusion, these findings could be a baseline for further exploration of novel anti-aging agents from natural resources.},
}
@article {pmid34864127,
year = {2022},
author = {Li, F and Li, Y and Deng, ZP and Zhu, XJ and Zhang, ZG and Zhang, XD and Tian, JL and Li, W and Zhao, P},
title = {Traditional uses, phytochemistry, pharmacology and clinical applications of Cortex Juglandis Mandshuricae: A comprehensive review.},
journal = {Journal of ethnopharmacology},
volume = {285},
number = {},
pages = {114887},
doi = {10.1016/j.jep.2021.114887},
pmid = {34864127},
issn = {1872-7573},
mesh = {Animals ; Drugs, Chinese Herbal/chemistry/*pharmacology ; Humans ; Juglans/*chemistry ; Phytochemicals ; *Phytotherapy ; Plant Extracts/chemistry/*pharmacology ; },
abstract = {ETHNOPHARMALOGICAL RELEVANCE: Cortex Juglandis Mandshuricae (CJM) is the dry branch or stem bark of the Juglans mandshurica Maxim. and is widely used as a traditional Chinese medicine in Asia and Africa. Its use was first recorded in Kaibao Bencao.<br><br>AIM OF THE STUDY: The present review provides a deeper insight, better awareness and detailed knowledge of phytochemistry, pharmacology, quality control, along with clinical applications of Cortex Juglandis Mandshuricae.<br><br>METHODS: The relevant information of Cortex Juglandis Mandshuricae was obtained from several databases including Web of Science, PubMed, and CNKI. The medical books, PhD and MSc dissertations in Chinese were also used to perform this work.<br><br>RESULTS: CJM has been traditionally used against a wide range of diseases, including dysentery, acute conjunctivitis, bacterial infections, and cancer. A total of 249 compounds have been isolated from CJM; they mainly include quinones and their derivatives, flavonoids, tannins, diarylheptanoids, triterpenoids, coumarins, phenylpropanoids, and volatile oils. These compounds exert anti-tumor, anti-oxidant, anti-inflammatory, bacteriostatic, anti-complement, immunomodulatory, anti-parasitic activities. Specifically, the effects of juglone, alkaloids and unsaturated fatty acid CJM components against hepatic cancer occur through exertion of apoptosis through a mitochondria-dependent pathway. In addition, taxifolin and several tannins have been found to have anti-HIV activity, and (±)-juglanaloid A and (±)-juglanaloid B target Alzheimer disease. Quality control is monitored through identification of juglone, quercetin, and volatile oils. A clinical preparation of CJM, Compound Muji Granules, is used in the treatment of various liver diseases with good therapeutic effect.<br><br>CONCLUSION: While CJM has been used extensively as a folk medicine, the relationships between structure and activity remain unclear. More in vivo models are needed to study the pharmacological mechanisms of action and to assess potential toxic components, in addition to which the evidence used to demonstrate the quality standards of medicinal materials is clearly inadequate. Therefore, more in-depth research is needed to provide a reasonable scientific basis improve its clinical utilization.},
}
@article {pmid34862388,
year = {2021},
author = {Haytural, H and Benfeitas, R and Schedin-Weiss, S and Bereczki, E and Rezeli, M and Unwin, RD and Wang, X and Dammer, EB and Johnson, ECB and Seyfried, NT and Winblad, B and Tijms, BM and Visser, PJ and Frykman, S and Tjernberg, LO},
title = {Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis.},
journal = {Scientific data},
volume = {8},
number = {1},
pages = {312},
pmid = {34862388},
issn = {2052-4463},
support = {R01 AG053960/AG/NIA NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; U01 AG046161/AG/NIA NIH HHS/United States ; RF1 AG057470/AG/NIA NIH HHS/United States ; R01 AG057339/AG/NIA NIH HHS/United States ; RF1 AG057471/AG/NIA NIH HHS/United States ; R01 AG061800/AG/NIA NIH HHS/United States ; RF1 AG062181/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/*metabolism ; Extracellular Matrix ; Humans ; Immunity ; Oxidative Phosphorylation ; Proteome/*metabolism ; Proteomics/methods ; Synaptic Transmission ; },
abstract = {Mass spectrometry (MS)-based proteomics is a powerful tool to explore pathogenic changes of a disease in an unbiased manner and has been used extensively in Alzheimer disease (AD) research. Here, by performing a meta-analysis of high-quality proteomic studies, we address which pathological changes are observed consistently and therefore most likely are of great importance for AD pathogenesis. We retrieved datasets, comprising a total of 21,588 distinct proteins identified across 857 postmortem human samples, from ten studies using labeled or label-free MS approaches. Our meta-analysis findings showed significant alterations of 757 and 1,195 proteins in AD in the labeled and label-free datasets, respectively. Only 33 proteins, some of which were associated with synaptic signaling, had the same directional change across the individual studies. However, despite alterations in individual proteins being different between the labeled and the label-free datasets, several pathways related to synaptic signaling, oxidative phosphorylation, immune response and extracellular matrix were commonly dysregulated in AD. These pathways represent robust changes in the human AD brain and warrant further investigation.},
}
@article {pmid34862322,
year = {2022},
author = {Ferro, DA and Kuijf, HJ and Hilal, S and van Veluw, SJ and van Veldhuizen, D and Venketasubramanian, N and Tan, BY and Biessels, GJ and Chen, C},
title = {Association Between Cerebral Cortical Microinfarcts and Perilesional Cortical Atrophy on 3T MRI.},
journal = {Neurology},
volume = {98},
number = {6},
pages = {e612-e622},
doi = {10.1212/WNL.0000000000013140},
pmid = {34862322},
issn = {1526-632X},
mesh = {Aged ; Atrophy/pathology ; Cerebral Cortex/diagnostic imaging/pathology ; *Dementia, Vascular/pathology ; Humans ; *Magnetic Resonance Imaging ; Neuropsychological Tests ; },
abstract = {BACKGROUND AND OBJECTIVES: Cerebral cortical microinfarcts (CMIs) are a novel MRI marker of cerebrovascular disease (CeVD) that predicts accelerated cognitive decline. Presence of CMIs is known to be associated with global cortical atrophy, although the mechanism linking the two is unclear. Our primary objective was to examine the relation between CMIs and cortical atrophy and to establish possible perilesional atrophy surrounding CMIs. Our secondary objective was to examine the role of cortical atrophy in CMI-associated cognitive impairment.<br><br>METHODS: Patients were recruited from 2 Singapore memory clinics between December 2010 and September 2013 and included if they received the diagnosis no objective cognitive impairment, cognitive impairment (with or without a history of stroke), or Alzheimer or vascular dementia. Cortical thickness, chronic CMIs, and MRI markers of CeVD were assessed on 3T MRI. Patients underwent cognitive testing. Cortical thickness was compared globally between patients with and without CMIs, regionally within individual patients with CMIs comparing brain regions with CMIs to the corresponding contralateral region without CMIs, and locally within individuals patients in a 50-mm radius of CMIs. Global cortical thickness was analyzed as mediator in the relation between CMI and cognitive performance.<br><br>RESULTS: Of the 238 patients (mean age 72.5 years, SD 9.1 years) enrolled, 75 had ≥1 CMIs. Patient with CMIs had a 2.1% lower global cortical thickness (B = -0.049 mm, 95% confidence interval [CI] 0.091 to -0.007, p = 0.022) compared to patients without CMIs, after correction for age, sex, education, and intracranial volume. In patients with CMIs, cortical thickness in brain regions with CMIs was 2.2% lower than in contralateral regions without CMIs (B = -0.048 mm [95% CI -0.071 to -0.026], p < 0.001). In a 20-mm radius area surrounding the CMI core, cortical thickness was lower than in the area 20 to 50 mm from the CMI core (mean difference -0.06 mm [-0.10 to -0.02], p = 0.002). Global cortical thickness was a significant mediator in the relationship between CMI presence and cognitive performance as measure with the Mini-Mental State Examination (B = -0.12 [-0.22 to -0.01], p = 0.025).<br><br>DISCUSSION: We found cortical atrophy surrounding CMIs, suggesting a perilesional effect in a cortical area many times larger than the CMI core. Our findings support the notion that CMIs affect brain structure beyond the actual lesion site.},
}
@article {pmid34859598,
year = {2022},
author = {Leuzy, A and Mattsson-Carlgren, N and Palmqvist, S and Janelidze, S and Dage, JL and Hansson, O},
title = {Blood-based biomarkers for Alzheimer's disease.},
journal = {EMBO molecular medicine},
volume = {14},
number = {1},
pages = {e14408},
pmid = {34859598},
issn = {1757-4684},
support = {P30 AG062422/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Biomarkers ; Humans ; Peptide Fragments/metabolism ; tau Proteins/metabolism ; },
abstract = {Neurodegenerative disorders such as Alzheimer's disease (AD) represent a mounting public health challenge. As these diseases are difficult to diagnose clinically, biomarkers of underlying pathophysiology are playing an ever-increasing role in research, clinical trials, and in the clinical work-up of patients. Though cerebrospinal fluid (CSF) and positron emission tomography (PET)-based measures are available, their use is not widespread due to limitations, including high costs and perceived invasiveness. As a result of rapid advances in the development of ultra-sensitive assays, the levels of pathological brain- and AD-related proteins can now be measured in blood, with recent work showing promising results. Plasma P-tau appears to be the best candidate marker during symptomatic AD (i.e., prodromal AD and AD dementia) and preclinical AD when combined with Aβ42/Aβ40. Though not AD-specific, blood NfL appears promising for the detection of neurodegeneration and could potentially be used to detect the effects of disease-modifying therapies. This review provides an overview of the progress achieved thus far using AD blood-based biomarkers, highlighting key areas of application and unmet challenges.},
}
@article {pmid34859035,
year = {2021},
author = {Lu, WH and Giudici, KV and Rolland, Y and Guyonnet, S and Mangin, JF and Vellas, B and de Souto Barreto, P},
title = {Associations Between Nutritional Deficits and Physical Performance in Community-Dwelling Older Adults.},
journal = {Frontiers in nutrition},
volume = {8},
number = {},
pages = {771470},
pmid = {34859035},
issn = {2296-861X},
abstract = {Background: Whether multiple nutritional deficiencies have a synergic effect on mobility loss remains unknown. This study aims to evaluate associations between multi-nutritional deficits and physical performance evolution among community-dwelling older adults. Methods: We included 386 participants from the Multidomain Alzheimer Preventive Trial (MAPT) (75.6 ± 4.5 years) not receiving omega-3 polyunsaturated fatty acid (PUFA) supplementation and who had available data on nutritional deficits. Baseline nutritional deficits were defined as plasma 25 hydroxyvitamin D <20 ng/ml, plasma homocysteine >14 μmol/L, or erythrocyte omega-3 PUFA index ≤ 4.87% (lower quartile). The Short Physical Performance Battery (SPPB), gait speed, and chair rise time were used to assess physical performance at baseline and after 6, 12, 24, 36, 48, and 60 months. We explored if nutrition-physical performance associations varied according to the presence of low-grade inflammation (LGI) and brain imaging indicators. Results: Within-group comparisons showed that physical function (decreased SPPB and gait speed, increased chair rise time) worsened over time, particularly in participants with ≥2 nutritional deficits; however, no between-group differences were observed when individuals without deficit and those with either 1 or ≥2 deficits were compared. Our exploratory analysis on nutritional deficit-LGI interactions showed that, among people with ≥2 deficits, chair rise time was increased over time in participants with LGI (adjusted mean difference: 3.47; 95% CI: 1.03, 5.91; p = 0.017), compared with individuals with no LGI. Conclusions: Accumulated deficits on vitamin D, homocysteine, and omega-3 PUFA were not associated with physical performance evolution in older adults, but they determined declined chair rise performance in subjects with low-grade inflammation. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT00672685], identifier [NCT00672685].},
}
@article {pmid34856835,
year = {2021},
author = {Tan, WJ and Lim, XYH and Lee, T and Wong, SC and Koh, HJ and Yeo, D},
title = {Enhancing the caregiving experience of family care partners in Singapore through an arts programme for persons with dementia: an exploratory study.},
journal = {Aging &amp; mental health},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/13607863.2021.2008306},
pmid = {34856835},
issn = {1364-6915},
abstract = {Objectives: Arts-based programmes for persons with dementia have shown promise in alleviating some of the caregiving challenges for family care partners. The present study sought to broaden the sociocultural perspectives of arts-based programmes by investigating the impact of a locally developed Arts &amp; Dementia programme for persons with dementia on their family care partners in Singapore.Methods: Thirty-two family care partners of persons with dementia who participated in the Arts &amp; Dementia programme were recruited. A mixed-methodological study was employed utilising quantitative pre- and post-programme data from the Zarit Burden Interview and Gain in Alzheimer care Instrument, and qualitative data from semi-structured group interviews.Results: Although there were no self-reported short-term changes in perceived caregiving difficulties and gains, semi-structured group interviews revealed potential caregiving benefits. Six overarching themes were identified: (1) contentment and social engagement, (2) re-connecting and developing new interests, (3) positive influence on caregiving, (4) enhancements to the programme, (5) more arts programmes, and (6) more support for families living with dementia.Conclusion: The present study highlights potential benefits of community-based arts activities in enabling caregiving to be a more positive experience for care partners.Supplemental data for this article is available online at http://dx.doi.org/10.1080/13607863.2021.2008306'I kept blaming myself for not spending enough time with him. Communication with him is different now. Watching him on the stage, he is happy and with a purpose'. (Gary, male).},
}
@article {pmid34856171,
year = {2022},
author = {Chen, CLH and Lu, Q and Moorakonda, RB and Kandiah, N and Tan, BY and Villaraza, SG and Cano, J and Venketasubramanian, N},
title = {Alzheimer's Disease THErapy With NEuroaid (ATHENE): A Randomized Double-Blind Delayed-Start Trial.},
journal = {Journal of the American Medical Directors Association},
volume = {23},
number = {3},
pages = {379-386.e3},
doi = {10.1016/j.jamda.2021.10.018},
pmid = {34856171},
issn = {1538-9375},
mesh = {Acetylcholinesterase/therapeutic use ; *Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/therapeutic use ; Double-Blind Method ; Drugs, Chinese Herbal/*therapeutic use ; Humans ; *Time-to-Treatment ; Treatment Outcome ; },
abstract = {OBJECTIVES: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression.<br><br>DESIGN: Randomized double-blind placebo-controlled delayed-start study.<br><br>SETTING AND PARTICIPANT: Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n = 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035).<br><br>METHODS: The primary outcome measure was occurrence of serious adverse events (SAEs) at 6 months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales.<br><br>RESULTS: There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference -4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD) -1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences.<br><br>CONCLUSIONS AND IMPLICATIONS: This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.},
}
@article {pmid34856086,
year = {2021},
author = {Balázs, N and Bereczki, D and Kovács, T},
title = {Cholinesterase inhibitors and memantine for the treatment of Alzheimer and non-Alzheimer dementias.},
journal = {Ideggyogyaszati szemle},
volume = {74},
number = {11-12},
pages = {379-387},
doi = {10.18071/isz.74.0379},
pmid = {34856086},
issn = {0019-1442},
mesh = {*Alzheimer Disease/drug therapy ; Caregivers ; Cholinesterase Inhibitors/therapeutic use ; Humans ; *Memantine/therapeutic use ; Quality of Life ; },
abstract = {In aging societies, the morbidity and mortality of dementia is increasing at a significant rate, thereby imposing burden on healthcare, economy and the society as well. Patients' and caregivers' quality of life and life expectancy are greatly determined by the early diagnosis and the initiation of available symptomatic treatments. Cholinesterase inhibitors and memantine have been the cornerstones of Alzheimer's therapy for approximately two decades and over the years, more and more experience has been gained on their use in non-Alzheimer's dementias too. The aim of our work was to provide a comprehensive summary about the use of cholinesterase inhibitors and memantine for the treatment of Alzheimer's and non-Alzheimers's dementias.},
}
@article {pmid34855291,
year = {2022},
author = {Chen, SX and Xiang, JY and Han, JX and Yang-Feng, and Li, HZ and Chen, H and Xu, M},
title = {Essential Oils from Spices Inhibit Cholinesterase Activity and Improve Behavioral Disorder in AlCl3 Induced Dementia.},
journal = {Chemistry &amp; biodiversity},
volume = {19},
number = {1},
pages = {e202100443},
doi = {10.1002/cbdv.202100443},
pmid = {34855291},
issn = {1612-1880},
support = {//Faculty of Life Science and Technology/ ; //Kunming University of Science and Technology/ ; 2016BC013//Science and Technology Planning Project of Yunnan Province/ ; //Program for Innovative Research Team/ ; 2019IC003//University of Yunnan Province and Ronald J Quinn AM Academician Workstation/ ; },
mesh = {Acetylcholinesterase/chemistry/metabolism ; Aluminum Chloride/toxicity ; Amomum/*chemistry/metabolism ; Animals ; Behavior, Animal/drug effects ; Binding Sites ; Cholinesterase Inhibitors/*chemistry/metabolism/pharmacology/therapeutic use ; Dementia/chemically induced/drug therapy ; Disease Models, Animal ; Elettaria/*chemistry/metabolism ; Gas Chromatography-Mass Spectrometry ; Molecular Docking Simulation ; Oils, Volatile/*chemistry/metabolism/pharmacology/therapeutic use ; Piper nigrum/*chemistry/metabolism ; Zebrafish ; },
abstract = {The chemical compositions of essential oils (EOs) prepared from six spices including cinnamon, amomum tsao-ko, cardamom, amomum, black pepper and white pepper were analyzed by gas chromatography-mass spectrometry (GC/MS), which led to identify almost 200 volatile compounds. All EOs of spices showed cholinesterase inhibitory activity. Among them, pepper EO showed most potent acetylcholinesterase (AChE) inhibitory activity with IC50 values of 8.54 μg/mL (black pepper EO) and 5.02 μg/mL (white pepper EO). Molecular docking and in vitro validation suggested that 3-carene, α-pinene and β-pinene with IC50 value of 1.73, 2.66, and 14.75 μg/mL, respectively, might be active constituents of spices oil in inhibiting AChE. Furthermore, amomum tsao-ko EO and amomum EO can improve behavioral disorder in dementia zebrafish induced by aluminum trichloride (AlCl3).},
}
@article {pmid34854749,
year = {2022},
author = {Lonergan, PE and Washington, SL and Cowan, JE and Zhao, S and Broering, JM and Cooperberg, MR and Carroll, PR},
title = {Androgen Deprivation Therapy and the Risk of Dementia after Treatment for Prostate Cancer.},
journal = {The Journal of urology},
volume = {207},
number = {4},
pages = {832-840},
doi = {10.1097/JU.0000000000002335},
pmid = {34854749},
issn = {1527-3792},
mesh = {Aged ; Androgen Antagonists/*therapeutic use ; Antineoplastic Agents, Hormonal/*therapeutic use ; Dementia/diagnosis/*etiology ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Propensity Score ; Proportional Hazards Models ; Prostatic Neoplasms/*drug therapy/*psychology ; Retrospective Studies ; Risk Factors ; Sensitivity and Specificity ; },
abstract = {PURPOSE: The association between androgen deprivation therapy (ADT) and dementia in men with prostate cancer remains inconclusive. We assessed the association between cumulative ADT exposure and the onset of dementia in a nationwide longitudinal registry of men with prostate cancer.<br><br>MATERIALS AND METHODS: A retrospective analysis of men aged ≥50 years from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry was performed. The primary outcome was onset of dementia after primary treatment. ADT exposure was expressed as a time-varying independent variable of total ADT exposure. The probability of receiving ADT was estimated using a propensity score. Cox proportional hazards regression was performed to determine the association between ADT exposure and dementia with competing risk of death, adjusted for propensity score and clinical covariates among men receiving various treatments.<br><br>RESULTS: Of 13,570 men 317 (2.3%) were diagnosed with dementia after a median of 7.0 years (IQR 3.0-12.0) of followup. Cumulative ADT use was significantly associated with dementia (HR 2.02; 95% CI 1.40-2.91; p <0.01) after adjustment. In a subset of 8,506 men, where propensity score matched by whether or not they received ADT, there was also an association between ADT use and dementia (HR 1.59; 95% CI 1.03-2.44; p=0.04). There was no association between primary treatment type and onset of dementia in the 8,489 men in the cohort who did not receive ADT.<br><br>CONCLUSIONS: Cumulative ADT exposure was associated with dementia. This increased risk should be accompanied by a careful discussion of the needs and benefits of ADT in those being considered for treatment.},
}
@article {pmid34854530,
year = {2021},
author = {Buckles, VD and Xiong, C and Bateman, RJ and Hassenstab, J and Allegri, R and Berman, SB and Chhatwal, JP and Danek, A and Fagan, AM and Ghetti, B and Goate, A and Graff-Radford, N and Jucker, M and Levin, J and Marcus, DS and Masters, CL and McCue, L and McDade, E and Mori, H and Moulder, KL and Noble, JM and Paumier, K and Preische, O and Ringman, JM and Fox, NC and Salloway, S and Schofield, PR and Martins, R and Vöglein, J and Morris, JC and , },
title = {Different rates of cognitive decline in autosomal dominant and late-onset Alzheimer disease.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.12505},
pmid = {34854530},
issn = {1552-5279},
support = {P50 AG005681/AG/NIA NIH HHS/United States ; },
abstract = {As prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and "sporadic" late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.},
}
@article {pmid34851866,
year = {2021},
author = {Bago Rožanković, P and Rožanković, M and Badžak, J and Stojić, M and Šušak Sporiš, I},
title = {Impact of Donepezil and Memantine on Behavioral and Psychological Symptoms of Alzheimer Disease: Six-month Open-label Study.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {34},
number = {4},
pages = {288-294},
pmid = {34851866},
issn = {1543-3641},
mesh = {*Alzheimer Disease/complications/drug therapy ; Behavioral Symptoms/drug therapy ; Donepezil/therapeutic use ; Humans ; Indans/therapeutic use ; *Memantine/therapeutic use ; Piperidines/therapeutic use ; Prospective Studies ; Treatment Outcome ; },
abstract = {BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are common in individuals with Alzheimer disease (AD). Donepezil and memantine are both widely used for the treatment of moderate AD.<br><br>OBJECTIVE: To evaluate the effects of donepezil and memantine in relieving BPSD in individuals with moderate AD.<br><br>METHOD: We conducted a prospective, randomized, 6-month clinical trial involving 85 individuals with moderate AD divided into two groups: group 1 (n = 42) was treated with donepezil; group 2 (n = 43) was treated with memantine. We used the Neuropsychiatric Inventory (NPI) to assess the prevalence and severity of BPSD at baseline and after 6 months of treatment with donepezil or memantine.<br><br>RESULTS: The two groups' baseline characteristics, including age, sex, mean length of education, and disease duration, were comparable, as were their baseline Mini-Mental State Examination scores. The NPI Total score improved from baseline to month 6 in both groups (P < 0.0001). Analyses of the NPI subdomains revealed that both donepezil treatment and memantine treatment produced statistically significant improvement in all of the NPI domains except euphoria and apathy, for which no improvement was observed after memantine treatment. Both treatments were well tolerated, with mostly mild and transient adverse effects.<br><br>CONCLUSION: Specific drugs for AD, including donepezil and memantine, may be effective in treating BPSD in individuals with moderate AD, with a favorable safety profile.},
}
@article {pmid34851865,
year = {2021},
author = {Hong, WK and Yoon, JH and Jang, H and Yoon, SJ and Moon, SY and Kim, HJ and Na, DL},
title = {Honorific Speech Impairment: A Characteristic Sign of Frontotemporal Dementia.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {34},
number = {4},
pages = {275-287},
pmid = {34851865},
issn = {1543-3641},
mesh = {*Alzheimer Disease/diagnosis ; Executive Function ; *Frontotemporal Dementia/diagnosis ; Humans ; Neuropsychological Tests ; Speech ; },
abstract = {BACKGROUND: Individuals with the behavioral variant of frontotemporal dementia (bvFTD) exhibit various levels of abulia, disinhibition, impaired judgment, and decline in executive function. Empirical evidence has shown that individuals with bvFTD also often exhibit difficulty using honorific speech, which expresses respect to another party or addressee.<br><br>OBJECTIVE: To analyze differences in the ability to use honorific speech among individuals with bvFTD, individuals with dementia of the Alzheimer type (AD dementia), and individuals with normal cognition (NC).<br><br>METHOD: A total of 53 native Korean speakers (13 bvFTD, 20 AD dementia, and 20 NC) completed an experimental honorific speech task (HST) that involved both expressive and receptive tasks. We analyzed the number of correct responses and error patterns separately for an expressive task and for a receptive task.<br><br>RESULTS: The bvFTD group had significantly fewer correct responses on the HST compared with the AD dementia and NC groups. The bvFTD group exhibited more misjudgment errors in identifying nonhonorific speech as honorific speech in the expressive task, and significantly longer response times in the receptive task, than the AD dementia and NC groups. Significant associations were identified between HST scores and cortical atrophy in the temporal and frontotemporal lobes.<br><br>CONCLUSION: A decline in the ability to use honorific speech may be a diagnosable behavioral and psychiatric symptom for bvFTD in Korean-speaking individuals. This decline in individuals with bvFTD could be attributed to multiple factors, including social manners (politeness) and impaired social language use ability (pragmatics).},
}
@article {pmid34850970,
year = {2021},
author = {Edmans, BG and Wolverson, E and Dunning, R and Slann, M and Russell, G and Crowther, G and Hall, D and Yates, R and Albert, M and Underwood, BR},
title = {Inpatient psychiatric care for patients with dementia at four sites in the United Kingdom.},
journal = {International journal of geriatric psychiatry},
volume = {37},
number = {2},
pages = {},
doi = {10.1002/gps.5658},
pmid = {34850970},
issn = {1099-1166},
}
@article {pmid34849350,
year = {2021},
author = {Benvenga, S and Antonelli, A and Fallahi, P and Bonanno, C and Rodolico, C and Guarneri, F},
title = {Amino acid sequence homology between thyroid autoantigens and central nervous system proteins: Implications for the steroid-responsive encephalopathy associated with autoimmune thyroiditis.},
journal = {Journal of clinical &amp; translational endocrinology},
volume = {26},
number = {},
pages = {100274},
pmid = {34849350},
issn = {2214-6237},
abstract = {A few patients with Hashimoto's thyroiditis or Graves' disease develop a multiform syndrome of the central nervous system (CNS) termed Hashimoto's encephalopathy or steroid-responsive encephalopathy associated with autoimmune thyroid disease (HE/SREAT). They have high levels of thyroid autoantibodies (TgAb, TPOAb and/or TSH-R-Ab) in blood and cerebrospinal fluid. Autoantibodies against alpha-enolase, aldehyde reductase-I (AKRIA) and/or dimethylargininase-I (DDAHI), proteins expressed in the CNS among other tissues, were detected in the blood and, when searched, in the cerebrospinal fluid of HE/SREAT patients. Recently, we reported that alpha-enolase, AKRIA and DDAHI share local sequence homology with each of the three autoantigens (TgAb, TPOAb, TSH-R-Ab), often in epitope-containing segments of the thyroid autoantigens. We hypothesized that there might be additional CNS-expressed proteins homologous to thyroid autoantigens, possibly overlapping known epitopes of the thyroid autoantigens. We used bioinformatic methods to address this hypothesis. Six, 27 and 47 of 46,809 CNS-expressed proteins share homology with TSH-R, Tg and TPO, respectively. The homologous regions often contain epitopes, and some match regions of thyroid autoantigens which have homology with alpha-enolase, AKRIA and/or DDAHI. Several of the aforementioned proteins are present in CNS areas that show abnormalities at neuroimaging in HE/SREAT patients. Furthermore, autoantibodies against some of the said six, 27 and 47 proteins were reported to be associated with a number of autoimmune diseases. Not only we validated our hypothesis, but we think that such a variety of potential CNS targets for thyroid Ab against epitopes contained in regions that have local homology with CNS proteins may explain the polymorphic phenotypes of HE/SREAT. Only when elevated amounts of these Ab are synthesized and trespass the blood-brain barrier, HE/SREAT appears. This might explain why HE/SREAT is so relatively rare.},
}
@article {pmid34848502,
year = {2022},
author = {Joshi, C and Sivaprakasam, K and Christley, S and Ireland, S and Rivas, J and Zhang, W and Sader, D and Logan, R and Lambracht-Washington, D and Rosenberg, R and Cullum, M and Hitt, B and Li, QZ and Barber, R and Greenberg, B and Cowell, L and Zhang, R and Stowe, A and Huebinger, R and Kelley, B and Monson, N},
title = {CSF-Derived CD4+ T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome.},
journal = {Neurology(R) neuroimmunology &amp; neuroinflammation},
volume = {9},
number = {1},
pages = {},
pmid = {34848502},
issn = {2332-7812},
support = {R01 NS102417/NS/NINDS NIH HHS/United States ; R21 NS104509/NS/NINDS NIH HHS/United States ; },
mesh = {Adaptive Immunity/*immunology ; Aged ; Alzheimer Disease/*cerebrospinal fluid/*immunology ; Autoantibodies/*cerebrospinal fluid ; CD4-Positive T-Lymphocytes/*metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Cohort Studies ; Female ; Humans ; Immunity, Innate/*immunology ; Male ; Middle Aged ; Syndrome ; },
abstract = {BACKGROUND AND OBJECTIVES: Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4+ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia.<br><br>METHODS: Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4+ and CD8+ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort.<br><br>RESULTS: Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4+ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs.<br><br>DISCUSSION: Examination of CSF indicates that CD4+ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.},
}
@article {pmid34848116,
year = {2021},
author = {Aravena, JM and Gajardo, J and Saguez, R and Hinton, L and Gitlin, LN},
title = {Nonpharmacologic Interventions for Family Caregivers of People Living With Dementia in Latin-America: A Scoping Review.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2021.10.013},
pmid = {34848116},
issn = {1545-7214},
abstract = {OBJECTIVE: Dementia prevalence in Latin America (LATAM) is rapidly increasing, contributing to significant family burden. As families are responsible for care, supportive interventions are critical. To understand the state-of-the-science, a scoping review was conducted of non-pharmacologic interventions for caregivers of people living with dementia (PLWD) in LATAM.<br><br>DESIGN: Eight databases were searched (PubMed, Embase, PsycINFO, Scopus, Scielo, Lilacs, Redalyc, Google Scholar) for nonpharmacological intervention studies published up to July, 2021 in LATAM reporting at least 1 caregiver outcome. A qualitative synthesis examined study designs, participants, and outcomes characteristics.<br><br>RESULTS: Forty-five studies were identified from 25.8% (n = 8/31) of LATAM countries (28 = Brazil, 4 = Chile, 4 = Cuba, 4 = México, 2 = Colombia, 1 = Perú, 1 = Ecuador, 1 = Argentina): 29% (n = 17) were randomized clinical trials (RCT), 7% (n = 3) nonrandomized comparison trials, 42% (n = 19) pre-post trials, 9% (n = 4) postintervention analyses, and 4% (n = 2) single case studies, comprising a total of 1,171 caregivers and 817 PLWD. For 20 RCT and nonrandomized comparison trials, 31 interventions were tested of which 48.4% (n = 15) targeted caregivers and 32.3% (n = 10) dyads. Most studies involved daughters with less than 12 years of education and tested multicomponent interventions involving disease education (90%), and cognitive behavioral coping (45%). Half of interventions (51.6%; n = 16/31) tested were adapted from other countries, and reported benefits for caregiver depression, quality of life, and burden.<br><br>CONCLUSION: Studies were conducted in a limited number of LATAM countries and few were RCTs. Results of RCTs showed benefits for socially vulnerable caregivers on psychosocial outcomes. There is an urgent need to rigorously evaluate more country/culturally specific interventions addressing unmet familial needs beyond psychosocial support.},
}
@article {pmid34848100,
year = {2022},
author = {González Hernández, A and Rodríguez Quintero, AM and Bonilla Santos, J},
title = {[Depression and its relationship with mild cognitive impairment and Alzheimer disease: A review study].},
journal = {Revista espanola de geriatria y gerontologia},
volume = {57},
number = {2},
pages = {118-128},
doi = {10.1016/j.regg.2021.10.002},
pmid = {34848100},
issn = {1578-1747},
mesh = {*Alzheimer Disease/complications/diagnosis ; Biomarkers ; *Cognitive Dysfunction/diagnosis ; Cross-Sectional Studies ; Depression/complications ; Disease Progression ; Humans ; Neuropsychological Tests ; },
abstract = {The objective of the present study was to determine whether depression precedes Mild cognitive impairment (MCI) as a risk factor or as a predictor in Alzheimer's disease (AD). A systematic review of observational studies (cross-sectional and cohort or follow-up) was carried out using the PRISMA search algorithm, for clinical markers in MCI and AD, in the Science Direct, Springer, Scopus and Proquest databases. The study eligibility criteria included inclusion criteria: of types of documents, articles of primary studies, type of source scientific journals, published in the English language, from January 2010 to April 2020, in patients with MCI and AD and in the group of age included in people with a minimum age range of 45years. Exclusion criteria were: publications older than 10years because the aim of the article was to explore recent studies, secondary research studies, type of report document, languages other than English. 3385 articles were identified, of which 30 articles were finally selected. It was found that there is an association between depression and AD, but properly as a risk factor but not, as a predictor or clinical marker of the development of AD. The degree of association is greater when they present depressive symptoms and simultaneously report subjective memory complaints or the presence of MCI.},
}
@article {pmid34847159,
year = {2021},
author = {Zangeneh, Z and Abdi-Ali, A and Khamooshian, K and Alvandi, A and Abiri, R},
title = {Bacterial variation in the oral microbiota in multiple sclerosis patients.},
journal = {PloS one},
volume = {16},
number = {11},
pages = {e0260384},
pmid = {34847159},
issn = {1932-6203},
mesh = {Adult ; Bacteria/*classification/genetics/*growth &amp; development ; Female ; Humans ; Mouth/*microbiology ; Multiple Sclerosis/*microbiology ; },
abstract = {BACKGROUND: Microorganisms in oral cavity are called oral microbiota, while microbiome consists of total genome content of microorganisms in a host. Interaction between host and microorganisms is important in nervous system development and nervous diseases such as Autism, Alzheimer, Parkinson and Multiple Sclerosis (MS). Bacterial infections, as an environmental factor in MS pathogenesis play role in T helper 17(Th17) increase and it enhancing the production of pro-inflammatory cytokines such as Interlukin-21(IL-21), IL-17 and IL -22. Oral microbiota consists diverse populations of cultivable and uncultivable bacterial species. Denaturing gradient gel electrophoresis (DGGE) is an acceptable method for identification of uncultivable bacteria. In this study, we compared the bacterial population diversity in the oral cavity between MS and healthy people.<br><br>METHODS: From October to March 2019, samples were taken at Kermanshah University of Medical Sciences' MS patients center. A total of 30 samples were taken from MS patients and another 30 samples were taken from healthy people. Phenotypic tests were used to identify bacteria after pure cultures were obtained. DNA was extracted from 1 mL of saliva, and PCR products produced with primers were electrophoresed on polyacrylamide gels.<br><br>RESULTS: The genera Staphylococcus, Actinomyces, Fusobacterium, Bacteroides, Porphyromonas, Prevotella, Veillonella, Propionibacterium and uncultivable bacteria with accession number MW880919-25, JQ477416.1, KF074888.1 and several other un-culturable strains were significantly more abundant in the MS group while Lactobacillus and Peptostreptococcus were more prevalent in the normal healthy group according to logistic regression method.<br><br>CONCLUSION: Oral micro-organisms may alleviate or exacerbate inflammatory condition which impact MS disease pathogenesis. It may be assumed that controlling oral infections may result in reduction of MS disease progression.},
}
@article {pmid34846582,
year = {2022},
author = {Cho, J and Park, M and Moon, WJ and Han, SH and Moon, Y},
title = {Sarcopenia in patients with dementia: correlation of temporalis muscle thickness with appendicular muscle mass.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {43},
number = {5},
pages = {3089-3095},
pmid = {34846582},
issn = {1590-3478},
support = {NRF-2018M3C7A1056571//National Research Foundation/ ; },
mesh = {Body Composition ; Body Mass Index ; *Dementia/complications/diagnostic imaging ; Humans ; Muscle, Skeletal ; Reproducibility of Results ; *Sarcopenia/diagnostic imaging/etiology ; Temporal Muscle ; },
abstract = {Cognitive decline is one of the most relevant signs of sarcopenia; however, it is challenging to perform tests for sarcopenia in patients with dementia. In a recent study, temporalis muscle thickness (TMT), an alternative to appendicular muscle mass (ASM), was found to be a valid index for screening sarcopenia. This study aimed to determine whether TMT correlates with ASM and evaluate the relationship between TMT and cognitive function in dementia patients. We recruited patients with a complaint of memory loss who visited the Memory Clinic of Konkuk University Medical Center between November 2014 and December 2020. Patients with probable Alzheimer's disease (AD) without weakness were included. TMT was measured on axial T1-weighted magnetic resonance (MR) images, perpendicular to the long axis of the temporal muscle, at the orbital roof level. ASM was measured using body dual-energy X-ray absorptiometry (DXA). It was calculated as the sum of lean soft tissue mass in the arms and legs, and the value by ASM divided by height squared was used. Inter-rater reliability and intra-rater reliability were good and excellent, respectively. We found a correlation between TMT and skeletal ASM, which was obtained from cranial MR images and DXA, respectively (r = 0.379, p = 0.001). TMT was negatively correlated with age (r = - 0.296, p = 0.014) and positively correlated with body mass index (BMI) (r = 0.303, p = 0.012). Additionally, TMT was correlated with MMSE (r = 0.350, p = 0.003). After adjusting for educational years, there was still a correlation between TMT and MMSE (r = 0.256, p = 0.038). This study demonstrated that TMT correlates with ASM and cognitive function in patients with dementia. Measuring TMT using cranial MR images could help diagnose sarcopenia accessibly and assess cognitive function in patients with dementia.},
}
@article {pmid34846514,
year = {2021},
author = {Goedert, M},
title = {Cryo-EM structures of τ filaments from human brain.},
journal = {Essays in biochemistry},
volume = {65},
number = {7},
pages = {949-959},
pmid = {34846514},
issn = {1744-1358},
support = {MC_U105184291/MRC_/Medical Research Council/United Kingdom ; },
mesh = {*Alzheimer Disease/metabolism ; Brain/metabolism ; Cryoelectron Microscopy ; Humans ; *Tauopathies/metabolism ; tau Proteins/chemistry/metabolism ; },
abstract = {Electron cryo-microscopy (cryo-EM) has made it possible to determine near-atomic structures of τ filaments from human brain. Previous work had shown that the cores of paired helical and straight filaments of Alzheimer's disease are made of two identical, but differently arranged C-shaped protofilaments. In recent years, cryo-EM has shown that the Alzheimer τ fold is 79 amino acids long. Five of the eight β-strands give rise to two antiparallel β-sheets, with the other three forming a β-helix. High-affinity binding sites of positron emission tomography ligand APN-1607 (PM-PBB3) are in the β-helix region. The Alzheimer fold contrasts with the 94 amino acid-long Pick fold, which is J-shaped and comprises nine β-strands that give rise to four antiparallel β-sheets, in the absence of a β-helix. Chronic traumatic encephalopathy τ fold is similar to the Alzheimer fold, but differs in the β-helix region, which is larger and contains a non-proteinaceous density that is probably hydrophobic. These folds are mostly two-layered. By contrast, the 107 amino acid τ fold of the 4R tauopathy corticobasal degeneration is four-layered and comprises 11 β-strands. It contains an internal, probably hydrophilic, density that is surrounded by τ. The τ folds described here share the presence of microtubule-binding repeats 3 and 4, as well as 10-13 amino acids after repeat 4.},
}
@article {pmid34844738,
year = {2022},
author = {Bagheri, AR and Aramesh, N and Haddad, PR},
title = {Applications of covalent organic frameworks and their composites in the extraction of pesticides from different samples.},
journal = {Journal of chromatography. A},
volume = {1661},
number = {},
pages = {462612},
doi = {10.1016/j.chroma.2021.462612},
pmid = {34844738},
issn = {1873-3778},
mesh = {Adsorption ; *Metal-Organic Frameworks ; *Pesticides/analysis ; Solid Phase Extraction ; Vegetables ; },
abstract = {Pesticides are used extensively in a wide range of applications and due to their high rate of consumption, they are ubiquitous in the different media and samples like environment, water sources, air, soil, biological materials, wastes (liquids, solids or sludges), vegetables and fruits, where they can persist for long periods. Pesticides often have hazardous side effects and can cause a range of harmful diseases like Parkinson, Alzheimer, asthma, depression and anxiety, cancer, etc, even at low concentrations. To this end, extraction, pre-concentration and determination of pesticides from various samples presents significant challenges caused by sample complexity and the low concentrations of them in many samples. Often, direct extraction and determination of pesticides are impossible due to their low concentrations and the complexity of samples. The main goals of sample preparation are removing interfering species, pre-concentrating target analyte/s and converting the analytes into more stable forms (when needed). The most popular approach is solid-phase extraction due to its simplicity, efficiency, ease of operation and low cost. This method is based on using a wide variety of materials, among which covalent organic frameworks (COFs) can be identified as an emerging class of highly versatile materials exhibiting advantageous properties, such as a porous and crystalline structure, pre-designable structure, high physical and chemical stability, ease of modification, high surface area and high adsorption capacity. The present review will cover recent developments in synthesis and applications of COFs and their composites for extraction of pesticides, different synthesis approaches of COFs, possible mechanisms for interaction of COFs-based adsorbents with pesticides and finally, future prospects and challenges in the fabrication and utilization of COFs and their composites for extraction of pesticides.},
}
@article {pmid34844529,
year = {2021},
author = {Kamal, MA and Bahbah, EI},
title = {Alzheimer Disease and Sleep Disorders: Insights into the Possible Disease Connections and the Potential Therapeutic Targets (Part II).},
journal = {CNS &amp; neurological disorders drug targets},
volume = {20},
number = {8},
pages = {674-676},
doi = {10.2174/187152732008210921121240},
pmid = {34844529},
issn = {1996-3181},
mesh = {Alzheimer Disease/*complications ; Humans ; Sleep ; Sleep Wake Disorders/*complications/drug therapy ; },
}
@article {pmid34843329,
year = {2021},
author = {Cheng, ST and Chan, WC and Fung, HH and Lam, LCW},
title = {Self-efficacy in controlling upsetting thoughts, but not positive gains, mediates the effects of benefit-finding group intervention for Alzheimer family caregivers.},
journal = {Psychology and aging},
volume = {},
number = {},
pages = {},
doi = {10.1037/pag0000654},
pmid = {34843329},
issn = {1939-1498},
support = {//Research Grants Council of Hong Kong/ ; },
abstract = {This study aimed to examine the therapeutic mechanism of the benefit-finding therapeutic (BFT) intervention that used cognitive reappraisal and alternative thinking to construct positive aspects of caregiving (PAC), in a cluster-randomized controlled trial for Alzheimer caregivers. Forty two caregivers received BFT, whereas 87 received psychoeducation as control. Depressive symptoms and global burden were outcomes measured at baseline, postintervention, and 4- and 10-month follow-up. Mediators considered included PAC (measured by benefit word count to a qualitative measure) and three self-efficacies-controlling upsetting thoughts (SE-CUT), responding to disruptive behaviors, and obtaining respite. Using mixed-effects regression, we demonstrated that benefit-finding increased caregivers' PAC and SE-CUT, but that only SE-CUT uniquely predicted depressive symptoms and global burden longitudinally. Path analyses with bootstrapped confidence intervals, using full information maximum likelihood estimation to retain the whole sample with partial missing data, showed that SE-CUT change from baseline to postintervention mediated intervention effects on depressive symptoms, but not global burden, at both follow-ups. No mediation effects were found for PAC and the other self-efficacies. The BFT effect on depressive symptoms was partly accounted for by improvement in SE-CUT. The therapeutic mechanism for the effect on burden remained unknown. The study sheds light on the importance of actively promoting positive caregiver functioning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).},
}
@article {pmid34842835,
year = {2021},
author = {Pagès, A and Rouch, L and Costa, N and Cestac, P and De Souto Barreto, P and Rolland, Y and Vellas, B and Molinier, L and Juillard-Condat, B and Mapt/Dsa Group, },
title = {Potentially Inappropriate Medication Prescribing Detected by Computer Algorithm among Older Patients: Results from the MAPT Study.},
journal = {Pharmacy (Basel, Switzerland)},
volume = {9},
number = {4},
pages = {},
pmid = {34842835},
issn = {2226-4787},
support = {1901175//Région Occitanie Pyrénées-Méditerranée/ ; MP0022856//European Regional Development Fund/ ; },
abstract = {(1) Background: Some medications may be dangerous for older patients. Potentially inappropriate medication prescribing (PIP) among older patients represents a significant cause of morbidity. The aim of this study was to create an algorithm to detect PIP in a geriatric database (Multidomain Alzheimer Preventive Trial (MAPT) study), and then to assess the algorithm construct validity by comparing the prevalence of PIP and associated factors with literature data. (2) Methods: An algorithm was constructed to detect PIP and was based on different explicit criteria among which the European list of potentially inappropriate medications (EU(7)-PIM), the STOPP and START version 2 tools. For construct validity assessment, logistic mixed-effects model repeated measures analyses were used to identify factors associated with PIP. (3) Results: Prevalence of PIP was 59.0% with the EU(7)-PIM list criteria, 43.2% with the STOPP criteria and 51.3% with the START criteria. Age, polypharmacy, and higher Charlson comorbidity index were associated with PIP. (4) Conclusions: Prevalence of PIP and associated factors are consistent with literature data, supporting the construct validity of our algorithm. This algorithm opens up interesting perspectives both in terms of analysis of very large databases and integration into e-prescribing or pharmaceutical validation software.},
}
@article {pmid34840876,
year = {2021},
author = {Calcagno, A and Celani, L and Trunfio, M and Orofino, G and Imperiale, D and Atzori, C and Arena, V and d'Ettorre, G and Guaraldi, G and Gisslen, M and Di Perri, G},
title = {Alzheimer Dementia in People Living With HIV.},
journal = {Neurology. Clinical practice},
volume = {11},
number = {5},
pages = {e627-e633},
pmid = {34840876},
issn = {2163-0402},
abstract = {OBJECTIVE: Given the aging of people living with HIV (PLWH) and the high prevalence of HIV-associated neurocognitive disorders, we aimed at describing the clinical, instrumental, and CSF features of PLWH diagnosed with Alzheimer dementia (AD).<br><br>METHODS: The databases of 3 large Italian outpatient clinics taking care of more than 9,000 PLWH were searched for the diagnosis of AD. After obtaining patients' or their next of kin's consent for publication, anonymous data were collected in an excel spreadsheet and described. Routinely collected CSF biomarkers and radiologic imaging results were recorded whether available.<br><br>RESULTS: Four patients were included in this case series who were diagnosed with AD aged between 60 and 74 years. All participants were on highly active antiretroviral therapy and showed nondetectable serum HIV RNA. Memory impairment was the most prominent cognitive feature. The diagnosis was obtained considering the exclusion of other potential causes, MRI and fluorodeoxyglucose-PET features, and, in (in 2/4), CSF AD biomarkers levels. In 1 patient, longitudinal CSF tau/p-tau increased, and beta-amyloid1-42 decreased over time despite antiretroviral therapy containing nucleotide reverse transcriptase inhibitors.<br><br>CONCLUSIONS: In older PLWH cognitive symptoms may represent the onset of AD: a multidisciplinary team may be needed for reaching a likely in vivo diagnosis.},
}
@article {pmid34840862,
year = {2021},
author = {Messinis, L and Nasios, G},
title = {Alzheimer Disease and HIV: Untangling the Gordian Knot.},
journal = {Neurology. Clinical practice},
volume = {11},
number = {5},
pages = {365-366},
pmid = {34840862},
issn = {2163-0402},
}
@article {pmid34839903,
year = {2022},
author = {Mahendran, N and P M, DRV},
title = {A deep learning framework with an embedded-based feature selection approach for the early detection of the Alzheimer's disease.},
journal = {Computers in biology and medicine},
volume = {141},
number = {},
pages = {105056},
doi = {10.1016/j.compbiomed.2021.105056},
pmid = {34839903},
issn = {1879-0534},
mesh = {*Alzheimer Disease/diagnosis ; *Deep Learning ; Early Diagnosis ; Humans ; Magnetic Resonance Imaging/methods ; Neural Networks, Computer ; },
abstract = {Ageing is associated with various ailments including Alzheimer 's disease (AD), which is a progressive form of dementia. AD symptoms develop over a period of years and, unfortunately, there is no cure. Existing AD treatments can only slow down the progression of symptoms and thus it is critical to diagnose the disease at an early stage. To help improve the early diagnosis of AD, a deep learning-based classification model with an embedded feature selection approach was used to classify AD patients. An AD DNA methylation data set (64 records with 34 cases and 34 controls) from the GEO omnibus database was used for the analysis. Before selecting the relevant features, the data were preprocessed by performing quality control, normalization and downstream analysis. As the number of associated CpG sites was huge, four embedded-based feature selection models were compared and the best method was used for the proposed classification model. An Enhanced Deep Recurrent Neural Network (EDRNN) was implemented and compared to other existing classification models, including a Convolutional Neural Network (CNN), a Recurrent Neural Network (RNN), and a Deep Recurrent Neural Network (DRNN). The results showed a significant improvement in the classification accuracy of the proposed model as compared to the other methods.},
}
@article {pmid34839794,
year = {2021},
author = {Tuerxun, M and Muhda, A and Yin, L},
title = {The molecular mechanisms of signal pathway activating effect of E2F-1/NF-κB/GSK-3β on cognitive dysfunction of Alzheimer rats.},
journal = {Bioengineered},
volume = {12},
number = {2},
pages = {10000-10008},
pmid = {34839794},
issn = {2165-5987},
mesh = {Alzheimer Disease/*complications ; Animals ; Cognitive Dysfunction/*etiology/*metabolism ; E2F1 Transcription Factor/*metabolism ; Glycogen Synthase Kinase 3 beta/*metabolism ; Hippocampus/metabolism ; Morris Water Maze Test ; NF-kappa B/*metabolism ; Phosphorylation ; Rats, Sprague-Dawley ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; tau Proteins/metabolism ; },
abstract = {Alzheimer disease (AD) seriously harms human health and its onset is insidious. Therefore, it is of great significance to find out the pathogenesis of AD disease for improving the prevention and treatment effect of the disease. The study drew attention to the influence of E2F-1/NF-κB/GSK-3β signaling pathway on cognitive dysfunction of Alzheimer rats. 60 specific pathogen-free (SPF) SD rats were selected as research subjects. The, the AD model was created by injecting Aβ1-42 into hippocampus CA1 region of AD rats using a microscopic syringe. Besides, Morris water maze test and Western blot were performed to detect the cognitive function, the levels of destination protein and active oxidation products in the brain of rats. Compared to the Sham group, the escape latency and the distance of the model group significantly increased (P < 0.05), and the number of times to pass the target quadrant was significantly reduced (P < 0.05); the expression levels of E2F-1 and NF-κB protein in the hippocampus and the phosphorylation levels of Tau231, Tau262, Tau396, Tau404 and T216-GSK-3β protein of the model group were significantly increased (P < 0.05); the ROS/RNS value in the hippocampus of the model group significantly increased (P < 0.05). AD model rats exhibit obvious cognitive dysfunction, which is associated with the activation of E2F-1/NF-κB/GSK-3β signaling pathway and the heightened Tau protein phosphorylation level.},
}
@article {pmid34836972,
year = {2021},
author = {Chang, CH and Liu, CY and Chen, SJ and Tsai, HC},
title = {Effect of N-methyl-D-aspartate receptor enhancing agents on cognition in dementia: an exploratory systematic review and meta-analysis of randomized controlled trials.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {22996},
pmid = {34836972},
issn = {2045-2322},
mesh = {Cognition Disorders/*drug therapy/etiology/pathology ; Dementia/*complications ; Humans ; Randomized Controlled Trials as Topic/*statistics &amp; numerical data ; Receptors, N-Methyl-D-Aspartate/*agonists ; },
abstract = {Multiple N-methyl-D-aspartate (NMDA) receptor enhancing agents have had promising effects on cognition among patients with dementia. However, the results remain inconsistent. This exploratory meta-analysis investigated the effectiveness of NMDA receptor enhancing agents for cognitive function. PubMed, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials (RCTs). Controlled trials assessing add-on NMDA receptor enhancing agent treatment in patients with dementia and using cognition rating scales were eligible and pooled using a random-effect model for comparisons. The standardized mean difference (SMD) was calculated in each study from the effect size; positive values indicated that NMDA receptor enhancing agent treatment improved cognitive function. Funnel plots and the I2 statistic were evaluated for statistical heterogeneity. Moderators were evaluated using meta-regression. We identified 14 RCTs with 2224 participants meeting the inclusion criteria. Add-on NMDA receptor enhancing agents had small positive significant effects on overall cognitive function among patients with dementia (SMD = 0.1002, 95% CI 0.0105-0.1900, P = 0.02860). Subgroup meta-analysis showed patients with Alzheimer's Disease and trials using the Alzheimer Disease Assessment Scale-cognitive subscale as the primary outcome had small positive significant effects (SMD = 0.1042, 95% CI 0.0076-0.2007, P = 0.03451; SMD = 0.1267, 95% CI 0.0145-0.2388, P = 0.2686). This exploratory meta-analysis showed a very small, positive, and significant effect on overall cognition function in patients with dementia. Studies with larger samples are needed to evaluate different cognitive domains and phases of dementia.},
}
@article {pmid34836480,
year = {2021},
author = {Pellegrini, F and Rosso, M and Chu, DT},
title = {Gaetano Perusini: The Forgotten Neuroscientist Behind "Alzheimer's" Disease.},
journal = {The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry},
volume = {},
number = {},
pages = {10738584211059466},
doi = {10.1177/10738584211059466},
pmid = {34836480},
issn = {1089-4098},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive and behavioral impairment with social and occupational impacts. This form of dementia is being increasingly studied, and its prevalence is expected to rise in the near future. Gaetano Perusini, a neuroscientist in the Alzheimer's laboratory, has played a major clinical and pathological role in the earlier study of Alzheimer's disease. This article summarizes his role in the discovery of the disease, which should be fairly named Alzheimer-Perusini disease.},
}
@article {pmid34836334,
year = {2021},
author = {Dominguez, LJ and Veronese, N and Vernuccio, L and Catanese, G and Inzerillo, F and Salemi, G and Barbagallo, M},
title = {Nutrition, Physical Activity, and Other Lifestyle Factors in the Prevention of Cognitive Decline and Dementia.},
journal = {Nutrients},
volume = {13},
number = {11},
pages = {},
pmid = {34836334},
issn = {2072-6643},
mesh = {Aged ; Aged, 80 and over ; Aging/psychology ; Cognitive Dysfunction/etiology/*prevention &amp; control ; Dementia/etiology/*prevention &amp; control ; Diet, Healthy/*psychology ; Dietary Supplements ; Elder Nutritional Physiological Phenomena ; Exercise/*psychology ; Female ; Humans ; *Life Style ; Male ; Nutritional Status ; Risk Factors ; },
abstract = {Multiple factors combined are currently recognized as contributors to cognitive decline. The main independent risk factor for cognitive impairment and dementia is advanced age followed by other determinants such as genetic, socioeconomic, and environmental factors, including nutrition and physical activity. In the next decades, a rise in dementia cases is expected due largely to the aging of the world population. There are no hitherto effective pharmaceutical therapies to treat age-associated cognitive impairment and dementia, which underscores the crucial role of prevention. A relationship among diet, physical activity, and other lifestyle factors with cognitive function has been intensively studied with mounting evidence supporting the role of these determinants in the development of cognitive decline and dementia, which is a chief cause of disability globally. Several dietary patterns, foods, and nutrients have been investigated in this regard, with some encouraging and other disappointing results. This review presents the current evidence for the effects of dietary patterns, dietary components, some supplements, physical activity, sleep patterns, and social engagement on the prevention or delay of the onset of age-related cognitive decline and dementia.},
}
@article {pmid34834067,
year = {2021},
author = {Dragan, ES and Dinu, MV and Ghiorghita, CA and Lazar, MM and Doroftei, F},
title = {Preparation and Characterization of Semi-IPN Cryogels Based on Polyacrylamide and Poly(N,N-dimethylaminoethyl methacrylate); Functionalization of Carrier with Monochlorotriazinyl-β-cyclodextrin and Release Kinetics of Curcumin.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {22},
pages = {},
pmid = {34834067},
issn = {1420-3049},
support = {PN-II-ID-PCE-2011-3-0300//National Council for Development and Innovation/ ; },
mesh = {Acrylic Resins/*chemistry ; Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage/chemistry ; Antineoplastic Agents/administration &amp; dosage/chemistry ; Cryogels/*chemistry ; Curcumin/*administration &amp; dosage/chemistry ; Drug Carriers/chemistry ; Drug Liberation ; Food Additives/administration &amp; dosage/chemistry ; Methacrylates/*chemistry ; Nylons/*chemistry ; beta-Cyclodextrins/*chemistry ; },
abstract = {Curcumin (CCM) is a natural hydrophobic polyphenol known for its numerous applications in the food industry as a colorant or jelly stabilizer, and in the pharmaceutical industry due to its anti-inflammatory, antibacterial, antioxidant, anti-cancer, and anti-Alzheimer properties. However, the large application of CCM is limited by its poor solubility in water and low stability. To enhance the bioavailability of CCM, and to protect it against the external degradation agents, a novel strategy, which consists in the preparation of semi-interpenetrating polymer networks, (s-IPNs) based on poly(N,N-dimethylaminoethyl methacrylate) entrapped in poly(acrylamide) networks, by a cryogelation technique, was developed in this work. All s-IPN cryogels were characterized by SEM, EDX, FTIR, and swelling at equilibrium as a function of pH. Functionalization of semi-IPN cryogel with monochlorotriazinyl-β-cyclodextrin (MCT-β-CD) led to IPN cryogel. The release profile of CCM from the composite cryogels was investigated at 37 °C, in pH 3. It was found that the cumulative release increased with the increase of the carrier hydrophobicity, as a result of increasing the cross-linking degree, the content and the molar mass of PDMAEMA. Fitting Higuchi, Korsmeyer-Peppas, and first order kinetic models on the CCM release profiles indicated the diffusion as the main driving force of drug release from the composite cryogels.},
}
@article {pmid34833381,
year = {2021},
author = {Anninos, P and Adamopoulos, A and Anninou, N and Tsagas, N},
title = {Analyzing the Effect of Weak External Transcranial Magnetic Stimulation on the Primary Dominant Frequencies of Alzheimer Patients Brain by Using MEG Recordings.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {57},
number = {11},
pages = {},
pmid = {34833381},
issn = {1648-9144},
support = {80623//General Secretariat for Research and Technology/ ; 80623//ERGO AEBE INC, GR/ ; },
mesh = {*Alzheimer Disease/therapy ; Brain/diagnostic imaging ; Humans ; *Magnetoencephalography ; Transcranial Magnetic Stimulation ; },
abstract = {Backround and Objectives: Alternative, non-invasive, and non-pharmaceutical options are gaining place in the battle of Alzheimer's Disease treatment control. Lately, the magnetic stimulation of the brain is the most prevalent technique with encouraging results. The aim of this study is to establish any possible change on the Primary Dominant Frequencies (PDF) (range 2-7 Hz) of the affected brain regions in Alzheimer Disease (AD) patients after applying extremely weak Transcranial Magnetic Stimulation. Materials and Methods: For this purpose, all AD patients were scanned with the use of MagnetoEncephaloGraphy (MEG) recordings through a whole-head 122-channel MEG system. Results: Our results exerted statistically significant PDF changes due to weak TMS accompanied by rabid attenuation of clinical symptoms. Conclusion: Thus, this is the first time that a positive therapeutic effect is being demonstrated even at pico-Tesla range magnetic fields in a small clinical group of studies for AD.},
}
@article {pmid34832918,
year = {2021},
author = {Jamshidnejad-Tosaramandani, T and Kashanian, S and Babaei, M and Al-Sabri, MH and Schiöth, HB},
title = {The Potential Effect of Insulin on AChE and Its Interactions with Rivastigmine In Vitro.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {14},
number = {11},
pages = {},
pmid = {34832918},
issn = {1424-8247},
abstract = {There is no definite cure for Alzheimer's disease (AD) due to its multifactorial origin. Drugs that inhibit acetylcholinesterase (AChE), such as rivastigmine, are promising symptomatic treatments for AD. Emerging evidence suggests that insulin therapy can hinder several aspects of AD pathology. Insulin has been shown to modify the activity of AChE, but it is still unknown how insulin and AChE interact. Combination therapy, which targets several features of the disease based on existing medications, can provide a worthy therapy option for AD management. However, to date, no studies have examined the potential interaction of insulin with AChE and/or rivastigmine in vitro. In the present study, we employed the Response Surface Methodology (RSM) as an in vitro assessment to investigate the effect of insulin on both AChE activity and rivastigmine inhibitory action using a common spectrophotometric assay for cholinesterase activity, Ellman's method. Our results showed that insulin, even at high concentrations, has an insignificant effect on both the activity of AChE and rivastigmine's inhibitory action. The variance of our data is near zero, which means that the dispersion is negligible. However, to improve our understanding of the possible interaction of insulin and rivastigmine, or its target AChE, more in silico modelling and in vivo studies are needed.},
}
@article {pmid34831288,
year = {2021},
author = {Zimmer-Bensch, G and Zempel, H},
title = {DNA Methylation in Genetic and Sporadic Forms of Neurodegeneration: Lessons from Alzheimer's, Related Tauopathies and Genetic Tauopathies.},
journal = {Cells},
volume = {10},
number = {11},
pages = {},
pmid = {34831288},
issn = {2073-4409},
support = {ZI1224/13-1//Deutsche Forschungsgemeinschaft/ ; 368482240/GRK2416DFG//Deutsche Forschungsgemeinschaft/ ; 2019_A41//Else-Kröner-Fresenius Stiftung/ ; 475/2020//Koeln Fortune Program / Faculty of Medicine, University of Cologne/ ; },
mesh = {Alzheimer Disease/*genetics ; Animals ; Biomarkers/metabolism ; DNA Methylation/*genetics ; Epigenesis, Genetic ; Humans ; Nerve Degeneration/*genetics/pathology ; Tauopathies/*genetics ; },
abstract = {Genetic and sporadic forms of tauopathies, the most prevalent of which is Alzheimer's Disease, are a scourge of the aging society, and in the case of genetic forms, can also affect children and young adults. All tauopathies share ectopic expression, mislocalization, or aggregation of the microtubule associated protein TAU, encoded by the MAPT gene. As TAU is a neuronal protein widely expressed in the CNS, the overwhelming majority of tauopathies are neurological disorders. They are characterized by cognitive dysfunction often leading to dementia, and are frequently accompanied by movement abnormalities such as parkinsonism. Tauopathies can lead to severe neurological deficits and premature death. For some tauopathies there is a clear genetic cause and/or an epigenetic contribution. However, for several others the disease etiology is unclear, with few tauopathies being environmentally triggered. Here, we review current knowledge of tauopathies listing known genetic and important sporadic forms of these disease. Further, we discuss how DNA methylation as a major epigenetic mechanism emerges to be involved in the disease pathophysiology of Alzheimer's, and related genetic and non-genetic tauopathies. Finally, we debate the application of epigenetic signatures in peripheral blood samples as diagnostic tools and usages of epigenetic therapy strategies for these diseases.},
}
@article {pmid34831163,
year = {2021},
author = {Mett, J and Lauer, AA and Janitschke, D and Griebsch, LV and Theiss, EL and Grimm, HS and Koivisto, H and Tanila, H and Hartmann, T and Grimm, MOW},
title = {Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme.},
journal = {Cells},
volume = {10},
number = {11},
pages = {},
pmid = {34831163},
issn = {2073-4409},
support = {211696//European Commission under the framework programme of the European Union/ ; 01ED1509//EU Joint Programme - Neurodegenerative Disease Research (JPND) and BMBF grants MIND-AD/ ; 01ED2003//EURO-FINGERS/ ; },
mesh = {Amyloid beta-Peptides/*metabolism ; Animals ; Biocatalysis ; Cell Line ; Fatty Acids/*metabolism ; Insulysin/*metabolism ; Mice, Inbred C57BL ; Models, Biological ; *Proteolysis ; },
abstract = {The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks of Alzheimer's disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here, we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which could not be detected in IDE knock-down cells. Further analysis of the underlying molecular mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity. The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet, revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for example in coconut oil, might be beneficial in preventing or treating Alzheimer's disease.},
}
@article {pmid34830164,
year = {2021},
author = {Cieślik, P and Siekierzycka, A and Radulska, A and Płoska, A and Burnat, G and Brański, P and Kalinowski, L and Wierońska, JM},
title = {Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies.},
journal = {International journal of molecular sciences},
volume = {22},
number = {22},
pages = {},
pmid = {34830164},
issn = {1422-0067},
support = {2019/33/B/NZ7/02699//National Science Center/ ; DIR/WK/2017/01//Ministry of Science and Higher Education/ ; },
mesh = {Animals ; Cerebral Cortex/*metabolism ; Dizocilpine Maleate/*adverse effects/pharmacology ; Excitatory Amino Acid Antagonists/*adverse effects/pharmacology ; Hippocampus/*metabolism ; Male ; Maze Learning/drug effects ; *Memory Disorders/chemically induced/metabolism ; Mice ; Nitric Oxide/*metabolism ; Scopolamine/*adverse effects/pharmacology ; },
abstract = {MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.},
}
@article {pmid34830060,
year = {2021},
author = {Santos, G and Díaz, M},
title = {Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer's Disease. Predictions from an Agent-Based Mathematical Model.},
journal = {International journal of molecular sciences},
volume = {22},
number = {22},
pages = {},
pmid = {34830060},
issn = {1422-0067},
mesh = {Alzheimer Disease/*etiology/*metabolism ; Frontal Lobe/*chemistry/*metabolism ; Humans ; Lipid Peroxidation ; Lipids/analysis/chemistry ; Membrane Microdomains/*chemistry/*metabolism ; Models, Neurological ; Molecular Dynamics Simulation ; Neurons/chemistry/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive-the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer's disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.},
}
@article {pmid34829677,
year = {2021},
author = {Frontiñán-Rubio, J and Rabanal-Ruiz, Y and Durán-Prado, M and Alcain, FJ},
title = {The Protective Effect of Ubiquinone against the Amyloid Peptide in Endothelial Cells Is Isoprenoid Chain Length-Dependent.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {11},
pages = {},
pmid = {34829677},
issn = {2076-3921},
support = {(grant number SBPLY/19/180501/000245//Consejería de Educación de la Junta de Comunidades de Castilla-La Mancha/ ; SAF2016-79311-R,//Ministry of Economy, Industry and Competitiveness/ ; 2020-GRIN-29101//University of Castilla-La Mancha/ ; },
abstract = {Vascular brain pathology constitutes a common feature in neurodegenerative diseases that could underlie their development. Indeed, vascular dysfunction acts synergistically with neurodegenerative changes to exacerbate the cognitive impairment found in Alzheimer's disease. Different injuries such as hypertension, high glucose, atherosclerosis associated with oxidized low-density lipoprotein or inflammation induce NADPH oxidase activation, overproduction of reactive oxygen species, and apoptosis in endothelial cells. Since it has been shown that pretreatment of cultured endothelial cells with the lipophilic antioxidant coenzyme Q10 (CoQ10) displays a protective effect against the deleterious injuries caused by different agents, this study explores the cytoprotective role of different CoQs homologues against Aβ25-35-induced damage and demonstrates that only pretreatment with CoQ10 protects endothelial brain cells from Aβ25-35-induced damage. Herein, we show that CoQ10 constitutes the most effective ubiquinone in preventing NADPH oxidase activity and reducing both reactive oxygen species generation and the increase in free cytosolic Ca2+ induced by Aβ25-35, ultimately preventing apoptosis and necrosis. The specific cytoprotective effect of CoQ with a side chain of 10 isoprenoid units could be explained by the fact that CoQ10 is the only ubiquinone that significantly reduces the entry of Aβ25-35 into the mitochondria.},
}
@article {pmid34827650,
year = {2021},
author = {Perrone, L and Valente, M},
title = {The Emerging Role of Metabolism in Brain-Heart Axis: New Challenge for the Therapy and Prevention of Alzheimer Disease. May Thioredoxin Interacting Protein (TXNIP) Play a Role?.},
journal = {Biomolecules},
volume = {11},
number = {11},
pages = {},
pmid = {34827650},
issn = {2218-273X},
mesh = {*Alzheimer Disease ; Brain ; Carrier Proteins ; Thioredoxins ; },
abstract = {Alzheimer disease (AD) is the most frequent cause of dementia and up to now there is not an effective therapy to cure AD. In addition, AD onset occurs decades before the diagnosis, affecting the possibility to set up appropriate therapeutic strategies. For this reason, it is necessary to investigate the effects of risk factors, such as cardiovascular diseases, in promoting AD. AD shows not only brain dysfunction, but also alterations in peripheral tissues/organs. Indeed, it exists a reciprocal connection between brain and heart, where cardiovascular alterations participate to AD as well as AD seem to promote cardiovascular dysfunction. In addition, metabolic dysfunction promotes both cardiovascular diseases and AD. In this review, we summarize the pathways involved in the regulation of the brain-heart axis and the effect of metabolism on these pathways. We also present the studies showing the role of the gut microbiota on the brain-heart axis. Herein, we propose recent evidences of the function of Thioredoxin Interacting protein (TXNIP) in mediating the role of metabolism on the brain-heart axis. TXNIP is a key regulator of metabolism at both cellular and body level and it exerts also a pathological function in several cardiovascular diseases as well as in AD.},
}
@article {pmid34825396,
year = {2022},
author = {Querol-Vilaseca, M and Sirisi, S and Molina-Porcel, L and Molina, B and Pegueroles, J and Ferrer-Raventós, P and Nuñez-Llaves, R and Dols-Icardo, O and Balasa, M and Iulita, MF and Blesa, R and Belbin, O and Clarimon, J and Fortea, J and Gelpi, E and Sánchez-Valle, R and Lleó, A},
title = {Neuropathology of a patient with Alzheimer disease treated with low doses of verubecestat.},
journal = {Neuropathology and applied neurobiology},
volume = {48},
number = {3},
pages = {e12781},
doi = {10.1111/nan.12781},
pmid = {34825396},
issn = {1365-2990},
mesh = {*Alzheimer Disease/drug therapy/pathology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Cyclic S-Oxides/therapeutic use ; Humans ; Plaque, Amyloid/drug therapy/pathology ; *Thiadiazines/therapeutic use ; },
abstract = {We report the neuropathological examination of a patient with Alzheimer's disease (AD) treated for 38 months with low doses of the BACE-1 inhibitor verubecestat. Brain examination showed small plaque size, reduced dystrophic neurites around plaques and reduced synaptic-associated Aβ compared with a group of age-matched untreated sporadic AD (SAD) cases. Our findings suggest that BACE-1 inhibition has an impact on synaptic soluble Aβ accumulation and neuritic derangement in AD.},
}
@article {pmid34825188,
year = {2021},
author = {Kim, K and Lee, JH and Kim, S and Lee, S and Lee, D and Kim, HY and Kim, I and Kim, Y},
title = {Anti-amyloidogenic indolizino[3,2-c]quinolines as imaging probes differentiating dense-core, diffuse, and coronal plaques of amyloid-β.},
journal = {RSC medicinal chemistry},
volume = {12},
number = {11},
pages = {1926-1934},
pmid = {34825188},
issn = {2632-8682},
abstract = {Abnormal deposition of amyloid-β (Aβ) is a major biomarker that is often used to diagnose Alzheimer's disease (AD). The Aβ plaque levels in the cortex and hippocampus are measured by either brain histology or positron emission tomography. Although cerebral plaques are found in several phenotypes, such as dense-core, diffuse, and coronal, imaging probes differentiating these plaques are currently unavailable. Here, we report that fluorescent indolizino[3,2-c]quinoline derivatives (YIQ) distinguish Aβ plaque phenotypes in brains of 5XFAD Alzheimer transgenic mice. We synthesized and screened 64 YIQ compounds through a series of in vitro and ex vivo Aβ staining assays. We found 20 compounds that could stain the Aβ phenotypes, 10 for dense-core plaques, eight for both dense-core and diffuse plaques, and two for solely visualizing only the coronal plaques while leaving the centric core unstained. Among the 20 imaging candidates, five YIQs displaying anti-Aβ aggregation efficacy were confirmed by thioflavin T assays and electrophoretic analyses.},
}
@article {pmid34825129,
year = {2021},
author = {Chhipa, RR and Gandbhir, O and Le, H and Sankar, S and Sundaram, P},
title = {Novel API Coated Catheter Removes Amyloid-β from Plasma of Patients with Alzheimer's Disease.},
journal = {HSOA journal of alzheimer's &amp; neurodegenerative diseases},
volume = {7},
number = {1},
pages = {},
pmid = {34825129},
issn = {2572-9608},
support = {R44 AG057327/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by the deposition of Amyloid-beta (Aβ) plaques in the brain. We have previously developed Amytrap peptide (the active pharmacological ingredient, API) and linked it to a sepharose bead matrix by click chemistry to form Amytrapper matrix, which was able to bind and remove Aβ from human sera and plasma spiked with biotinylated Aβ42 (bio-Aβ42) in vitro. To extend the logic of the previous studies, the current study investigates whether the Amytrap peptide coated inside a medically viable polycarbonate catheter (Amytrapper catheter) could bind and retain Aβ from the human sera. The Amytrapper matrix and the novel Amytrapper catheter were able to bind and retain spiked bio-Aβ42 from human sera or native Aβ from plasma of AD patients. Additional characteristics of the Amytrapper catheter are evaluated and presented in this study. The results presented here provide a proof-of-principle for the first time that extracorporeal Amytrapper device aids clearance of native Aβ (from plasma of AD patients). Thus, our device Amytrapper, either in the form of Sepharose matrix or catheter, could become a novel therapeutic strategy to remove Aβ from circulation in AD patients.},
}
@article {pmid34824332,
year = {2021},
author = {Mosaferi, B and Jand, Y and Salari, AA},
title = {Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {22941},
pmid = {34824332},
issn = {2045-2322},
support = {64.1D.1463//Maragheh University of Medical Sciences/ ; },
mesh = {Adrenocorticotropic Hormone/metabolism ; Alzheimer Disease/drug therapy/*microbiology/physiopathology/psychology ; Amyloid beta-Peptides ; Animals ; Anti-Bacterial Agents/*pharmacology ; Anxiety/microbiology/physiopathology/*prevention &amp; control/psychology ; Behavior, Animal/*drug effects ; *Brain-Gut Axis ; Depression/microbiology/physiopathology/*prevention &amp; control/psychology ; Disease Models, Animal ; Dysbiosis ; Gastrointestinal Microbiome/*drug effects ; Hypothalamo-Hypophyseal System/metabolism/*physiopathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress ; Oxytocin/metabolism ; Peptide Fragments ; },
abstract = {The gut-microbiota-brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer's disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1-42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.},
}
@article {pmid34824314,
year = {2021},
author = {Arredondo, SB and Reyes, DT and Herrera-Soto, A and Mardones, MD and Inestrosa, NC and Varela-Nallar, L},
title = {Andrographolide promotes hippocampal neurogenesis and spatial memory in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {22904},
pmid = {34824314},
issn = {2045-2322},
mesh = {Alzheimer Disease/*drug therapy/genetics/pathology/psychology ; Amyloid beta-Protein Precursor/genetics ; Animals ; Behavior, Animal/*drug effects ; Cell Proliferation/*drug effects ; Dentate Gyrus/*drug effects/pathology ; Disease Models, Animal ; Diterpenes/*pharmacology ; Female ; Genetic Predisposition to Disease ; Mice, Transgenic ; Neural Stem Cells/*drug effects/pathology ; Neurogenesis/*drug effects ; Neurons/*drug effects/pathology ; Nootropic Agents/*pharmacology ; Presenilin-1/genetics ; Spatial Memory/*drug effects ; },
abstract = {In Alzheimer´s disease (AD) there is a reduction in hippocampal neurogenesis that has been associated to cognitive deficits. Previously we showed that Andrographolide (ANDRO), the main bioactive component of Andrographis paniculate, induces proliferation in the hippocampus of the APPswe/PSEN1ΔE9 (APP/PS1) mouse model of AD as assessed by staining with the mitotic marker Ki67. Here, we further characterized the effect of ANDRO on hippocampal neurogenesis in APP/PS1 mice and evaluated the contribution of this process to the cognitive effect of ANDRO. Treatment of 8-month-old APP/PS1 mice with ANDRO for 4 weeks increased proliferation in the dentate gyrus as evaluated by BrdU incorporation. Although ANDRO had no effect on neuronal differentiation of newborn cells, it strongly increased neural progenitors, neuroblasts and newborn immature neurons, cell populations that were decreased in APP/PS1 mice compared to age-matched wild-type mice. ANDRO had no effect on migration or in total dendritic length, arborization and orientation of immature neurons, suggesting no effects on early morphological development of newborn neurons. Finally, ANDRO treatment improved the performance of APP/PS1 mice in the object location memory task. This effect was not completely prevented by co-treatment with the anti-mitotic drug TMZ, suggesting that other effects of ANDRO in addition to the increase in neurogenesis might underlie the observed cognitive improvement. Altogether, our data indicate that in APP/PS1 mice ANDRO stimulates neurogenesis in the hippocampus by inducing proliferation of neural precursor cells and improves spatial memory performance.},
}
@article {pmid34824300,
year = {2021},
author = {Zu, G and Sun, K and Li, L and Zu, X and Han, T and Huang, H},
title = {Mechanism of quercetin therapeutic targets for Alzheimer disease and type 2 diabetes mellitus.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {22959},
pmid = {34824300},
issn = {2045-2322},
support = {2016CYJS08A01-6//Tao Han/ ; },
mesh = {Alzheimer Disease/*drug therapy ; Antioxidants/chemistry/pharmacology ; Diabetes Mellitus, Type 2/*drug therapy ; Drug Delivery Systems ; Drugs, Chinese Herbal/chemistry/pharmacology ; Humans ; Hypoglycemic Agents/chemistry/pharmacology ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Protein Interaction Maps ; *Quercetin/chemistry/pharmacology ; },
abstract = {Quercetin has demonstrated antioxidant, anti-inflammatory, hypoglycemic, and hypolipidemic activities, suggesting therapeutic potential against type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). In this study, potential molecular targets of quercetin were first identified using the Swiss Target Prediction platform and pathogenic targets of T2DM and AD were identified using online Mendelian inheritance in man (OMIM), DisGeNET, TTD, DrugBank, and GeneCards databases. The 95 targets shared among quercetin, T2DM, and AD were used to establish a protein-protein interaction (PPI) network, top 25 core genes, and protein functional modules using MCODE. Metascape was then used for gene ontology and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. A protein functional module with best score was obtained from the PPI network using CytoHubba, and 6 high-probability quercetin targets (AKT1, JUN, MAPK, TNF, VEGFA, and EGFR) were confirmed by docking simulations. Molecular dynamics simulation was carried out according to the molecular docking results. KEGG pathway enrichment analysis suggested that the major shared mechanisms for T2DM and AD include "AGE-RAGE signaling pathway in diabetic complications," "pathways in cancer," and "MAPK signaling pathway" (the key pathway). We speculate that quercetin may have therapeutic applications in T2DM and AD by targeting MAPK signaling, providing a theoretical foundation for future clinical research.},
}
@article {pmid34817582,
year = {2021},
author = {Lee, G and Choi, S and Chang, J and Choi, D and Son, JS and Kim, K and Kim, SM and Jeong, S and Park, SM},
title = {Association of L-α Glycerylphosphorylcholine With Subsequent Stroke Risk After 10 Years.},
journal = {JAMA network open},
volume = {4},
number = {11},
pages = {e2136008},
pmid = {34817582},
issn = {2574-3805},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*complications/*drug therapy ; Biological Monitoring/*methods ; Cohort Studies ; Female ; Glycerylphosphorylcholine/*adverse effects/blood ; Humans ; Male ; Middle Aged ; Proportional Hazards Models ; Republic of Korea ; Retrospective Studies ; Risk Assessment/*methods ; Risk Factors ; Stroke/*chemically induced/*diagnosis ; },
abstract = {Importance: L-α glycerylphosphorylcholine (α-GPC, choline alphoscerate) is used globally by individuals older than 50 years based on its potential function as a precursor of acetylcholine. However, choline has previously been linked to a higher risk of cardiovascular disease via trimethylamine-N-oxide, a metabolite of choline by microbiota.<br><br>Objective: To investigate the association between α-GPC use and subsequent 10-year stroke risk.<br><br>A population-based, retrospective cohort study was conducted using data from the National Health Insurance Service of South Korea. Participants included men and women aged 50 years or older without underlying stroke or Alzheimer disease (N = 12 008 977).<br><br>Main Outcomes and Measures: All participants were divided into whether they were prescribed α-GPC during 2006-2008. α-GPC users were matched with nonusers for all covariates to create a matched cohort. α-GPC use was further divided into durations less than 2, 2 to 6, 6 to 12, and more than 12 months of α-GPC prescriptions. The adjusted hazard ratios (aHRs) and 95% CIs for total stroke, ischemic stroke, and hemorrhagic stroke from January 1, 2009, to January 31, 2018, were calculated by multivariate Cox proportional hazards regression.<br><br>Results: A total of 12 008 977 individuals (6 401 965 [53.3%] women) aged 50 years or older were included in the study. The mean (SD) age was 61.6 (9.4) years for nonusers and 68.3 (10.0) years for users, and that of the matching cohort was 68.2 (9.9) years for both groups. Compared with α-GPC nonusers (n = 11 900 100), users (n = 108 877) had a higher risk for total stroke (aHR, 1.46; 95% CI, 1.43-1.48), ischemic stroke (aHR 1.36; 95% CI, 1.33-1.39), and hemorrhagic stroke (aHR, 1.36; 95% CI, 1.28-1.44). After matching for all covariates, α-GPC users had a higher risk for total stroke (aHR, 1.43; 95% CI, 1.41-1.46), ischemic stroke (aHR, 1.34; 95% CI, 1.31-1.37), and hemorrhagic stroke (aHR, 1.37; 95% CI, 1.29-1.46). Increasing intake of α-GPC was associated with a higher risk for total stroke in a dose-response manner.<br><br>Conclusions and Relevance: In this cohort study, use of α-GPC was associated with a higher 10-year incident stroke risk in a dose-response manner after adjusting for traditional cerebrovascular risk factors. Future studies are needed to determine the possible mechanisms behind the potential cerebrovascular risk-elevating effects of α-GPC.},
}
@article {pmid34816125,
year = {2021},
author = {Unger, F and Konnerth, A and Zott, B},
title = {Population imaging of synaptically released glutamate in mouse hippocampal slices.},
journal = {STAR protocols},
volume = {2},
number = {4},
pages = {100877},
pmid = {34816125},
issn = {2666-1667},
mesh = {Animals ; Female ; Fluorescent Dyes/chemistry ; Glutamic Acid/*metabolism ; *Hippocampus/chemistry/cytology/diagnostic imaging/metabolism ; Male ; Mice ; Molecular Imaging ; Optical Imaging/*methods ; Pyramidal Cells/chemistry/metabolism ; Synapses/*physiology ; Synaptic Transmission/physiology ; },
abstract = {Glutamatergic neurotransmission is a widespread form of synaptic excitation in the mammalian brain. The development of genetically encoded fluorescent glutamate sensors allows monitoring synaptic signaling in living brain tissue in real time. Here, we describe single- and two-photon imaging of synaptically evoked glutamatergic population signals in acute hippocampal slices expressing the fluorescent glutamate sensor SF-iGluSnFR.A184S in CA1 or CA3 pyramidal neurons. The protocol can be readily used to study defective synaptic glutamate signaling in mouse models of neuropsychiatric disorders, such as Alzheimer disease. For complete details on the use and execution of this protocol, please refer to Zott et al. (2019).},
}
@article {pmid34815562,
year = {2022},
author = {Frisoni, GB and Altomare, D and Thal, DR and Ribaldi, F and van der Kant, R and Ossenkoppele, R and Blennow, K and Cummings, J and van Duijn, C and Nilsson, PM and Dietrich, PY and Scheltens, P and Dubois, B},
title = {The probabilistic model of Alzheimer disease: the amyloid hypothesis revised.},
journal = {Nature reviews. Neuroscience},
volume = {23},
number = {1},
pages = {53-66},
pmid = {34815562},
issn = {1471-0048},
support = {P20 AG068053/AG/NIA NIH HHS/United States ; U01 NS093334/NS/NINDS NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; R01 AG053798/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/*metabolism/*pathology/psychology ; Amyloid/*metabolism ; Amyloid Neuropathies/metabolism/pathology ; Amyloid beta-Peptides ; Animals ; Humans ; *Models, Statistical ; tau Proteins/metabolism ; },
abstract = {The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.},
}
@article {pmid34814814,
year = {2021},
author = {Bahbah, EI and Kamal, MA},
title = {Alzheimer Disease and Sleep Disorders: Insights into the Possible Disease Connections and the Potential Therapeutic Targets (Part I).},
journal = {CNS &amp; neurological disorders drug targets},
volume = {20},
number = {7},
pages = {572-573},
doi = {10.2174/187152732007210909150558},
pmid = {34814814},
issn = {1996-3181},
mesh = {Alzheimer Disease/*complications ; Humans ; Sleep ; Sleep Apnea, Obstructive/complications ; Sleep Wake Disorders/*complications ; },
}
@article {pmid34812584,
year = {2021},
author = {Perluigi, M and Picca, A and Montanari, E and Calvani, R and Marini, F and Matassa, R and Tramutola, A and Villani, A and Familiari, G and Domenico, FD and Butterfield, DA and Oh, KJ and Marzetti, E and Valentini, D and Barone, E},
title = {Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.12499},
pmid = {34812584},
issn = {1552-5279},
abstract = {INTRODUCTION: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing.<br><br>METHODS: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways.<br><br>RESULTS: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636 , a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found.<br><br>CONCLUSIONS: The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population.},
}
@article {pmid34812493,
year = {2022},
author = {Tzeng, HM and Knight, G},
title = {Could negative behaviors by patients with dementia be positive communication? Seeking ways to understand and interpret their nonverbal communication.},
journal = {Nursing forum},
volume = {57},
number = {2},
pages = {318-322},
doi = {10.1111/nuf.12674},
pmid = {34812493},
issn = {1744-6198},
mesh = {Caregivers ; *Dementia/complications ; Humans ; Nonverbal Communication ; },
abstract = {In interactions with caregivers, patients with dementia have communication challenges that are common and worrisome to families. Family and professional caregivers find it challenging to "guess" or "interpret" what their patients with dementia are trying to tell them. In this creative controversy article, we discuss how family and professional caregivers can seek to understand and correctly interpret the nonverbal communications of patients with dementia (behaviors, actions, facial expressions, and vocal sounds). Equipping family and professional caregivers with the resources to interpret the nonverbal communications of patients with dementia requires a commitment to in-service and family education in healthcare facilities. Nurses could play a critical role in raising the awareness among the public about the potential changes and declines in verbal communications of the patients with dementia.},
}
@article {pmid34810247,
year = {2022},
author = {Smirnov, DS and Salmon, DP and Galasko, D and Goodwill, VS and Hansen, LA and Zhao, Y and Edland, SD and Léger, GC and Peavy, GM and Jacobs, DM and Rissman, R and Pizzo, DP and Hiniker, A},
title = {Association of Neurofibrillary Tangle Distribution With Age at Onset-Related Clinical Heterogeneity in Alzheimer Disease: An Autopsy Study.},
journal = {Neurology},
volume = {98},
number = {5},
pages = {e506-e517},
pmid = {34810247},
issn = {1526-632X},
support = {P30 AG062429/AG/NIA NIH HHS/United States ; F30 AG063440/AG/NIA NIH HHS/United States ; },
mesh = {Age of Onset ; *Alzheimer Disease/pathology ; Autopsy ; Humans ; *Neocortex/pathology ; Neurofibrillary Tangles/pathology ; tau Proteins/metabolism ; },
abstract = {BACKGROUND AND OBJECTIVE: Patients with earlier age at onset of sporadic Alzheimer disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine whether this age-related clinical and cognitive heterogeneity is mediated by different topographic distributions of tau-aggregate neurofibrillary tangles (NFTs) or by variable amounts of concomitant non-AD neuropathology.<br><br>METHODS: The relative distribution of NFT density in hippocampus and midfrontal neocortex was calculated, and α-synuclein, TAR DNA binding protein 43 (TDP-43), and microvascular copathologies were staged, in patients with severe AD and age at onset of 51-60 (n = 40), 61-70 (n = 41), and >70 (n = 40) years. Regression, mediation, and mixed effects models examined relationships of pathologic findings with clinical features and longitudinal cognitive decline.<br><br>RESULTS: Patients with later age at onset of AD were less likely to present with nonmemory complaints (odds ratio [OR] 0.46 per decade, 95% confidence interval [CI] 0.22-0.88), psychiatric symptoms (β = -0.66, 95% CI -1.15 to -0.17), and functional impairment (β = -1.25, 95% CI -2.34 to -0.16). TDP-43 (OR 2.00, 95% CI 1.23-3.35) and microvascular copathology (OR 2.02, 95% CI 1.24-3.40) were more common in later onset AD, and α-synuclein copathology was not related to age at onset. NFT density in midfrontal cortex (β = -0.51, 95% CI -0.72 to -0.31) and midfrontal/hippocampal NFT ratio (β = -0.18, 95% CI -0.26 to -0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI 0.09-0.90) and visuospatial cognitive deficits (β = 0.97, 95% CI 0.46-1.46) were less impaired in patients with later age at onset. Mediation analyses showed that the effect of age at onset on severity of executive function deficits was mediated by midfrontal/hippocampal NFT ratio (β = 0.21, 95% CI 0.08-0.38) and not by concomitant non-AD pathologies. Midfrontal/hippocampal NFT ratio also mediated an association between earlier age at onset and faster decline on tests of global cognition, executive function, and visuospatial abilities.<br><br>DISCUSSION: Worse executive dysfunction and faster cognitive decline in people with sporadic AD with earlier rather than later age at onset is mediated by greater relative midfrontal neocortical to hippocampal NFT burden and not by concomitant non-AD neuropathology.},
}
@article {pmid34810243,
year = {2022},
author = {Bown, CW and Carare, RO and Schrag, MS and Jefferson, AL},
title = {Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain.},
journal = {Neurology},
volume = {98},
number = {3},
pages = {107-117},
pmid = {34810243},
issn = {1526-632X},
support = {F32 AG022773/AG/NIA NIH HHS/United States ; F31 AG066358/AG/NIA NIH HHS/United States ; T32 AG058524/AG/NIA NIH HHS/United States ; R01 AG034962/AG/NIA NIH HHS/United States ; R01 AG056534/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; R01 NS100980/NS/NINDS NIH HHS/United States ; S10 OD032380/OD/NIH HHS/United States ; },
mesh = {Aging ; *Alzheimer Disease/complications/diagnostic imaging ; Biomarkers ; Brain/diagnostic imaging ; *Cerebral Small Vessel Diseases/complications/diagnostic imaging ; Humans ; Magnetic Resonance Imaging/methods ; },
abstract = {Perivascular spaces (PVS) are fluid-filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on MRI. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as 2 possible mechanisms that drive ePVS formation. We describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the 2 most prominent theoretical views and review ePVS associations with other common small vessel disease markers. Because ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.},
}
@article {pmid34810241,
year = {2022},
author = {Acosta, LM},
title = {I Wasn't There: Caring for a Patient With Trisomy 21, Alzheimer Disease, and Epilepsy Until His Final Days With COVID-19.},
journal = {Neurology},
volume = {98},
number = {6},
pages = {246-248},
doi = {10.1212/WNL.0000000000013109},
pmid = {34810241},
issn = {1526-632X},
mesh = {*Alzheimer Disease/complications/therapy ; *COVID-19/mortality ; *Caregivers ; *Down Syndrome/complications/therapy ; *Epilepsy/complications/therapy ; Humans ; },
}
@article {pmid34808910,
year = {2021},
author = {Le, B and White, ACG and Chaudhari, A and Al-Mutawaly, N and White, JE and Lee, WK and Hsu, YL and White, JD},
title = {Dynamic white lighting to aid sleep and vision for persons living with dementia using off-the-shelf LED strips.},
journal = {Optics express},
volume = {29},
number = {23},
pages = {38606-38614},
doi = {10.1364/OE.443050},
pmid = {34808910},
issn = {1094-4087},
mesh = {Aged ; Alzheimer Disease/*complications ; Circadian Clocks/physiology ; Humans ; *Light ; Lighting/instrumentation/*methods ; Melatonin/metabolism ; Phototherapy/instrumentation/*methods ; Sleep Wake Disorders/etiology/*therapy ; Time Factors ; Vision, Ocular/*physiology ; },
abstract = {Alzheimer disease and related dementias affect 15-20% of elderly people, and 60-70% of these suffer from sleep disturbances. Studies suggest that lighting can improve sleep. The key challenge is how to deliver light effectively. We have designed a lighting system that adjusts spectrum and irradiance on a 24-hour timetable to provide spatially uniform, shadow-free white light with CRI>85 and up to 1000 Lux for day vision and amber light for night vision. To aid sleep, melanopic illuminance varies over 3 orders of magnitude to enable strong suppression of melatonin in the morning/early afternoon, moderate suppression in the evening, and no suppression at night.},
}
@article {pmid34808623,
year = {2021},
author = {Adana Díaz, L and Arango, A and Parra, C and Rodríguez-Lorenzana, A and Yacelga-Ponce, T},
title = {Impact of Educational Level on Versions (Basic and Complete) of the Montreal Cognitive Assessment.},
journal = {Dementia and geriatric cognitive disorders},
volume = {50},
number = {4},
pages = {341-348},
doi = {10.1159/000518747},
pmid = {34808623},
issn = {1421-9824},
mesh = {Aged ; *Cognitive Dysfunction/diagnosis ; Educational Status ; Humans ; Mental Status and Dementia Tests ; Neuropsychological Tests ; Psychometrics ; Reproducibility of Results ; },
abstract = {BACKGROUND: One of the most marked problems in the use of screening instruments for the diagnosis of dementia or cognitive impairment in the elderly is the influence of educational level on the results of psychometric tests. The Montreal Cognitive Assessment (MoCA) questionnaire is one of the most widely used dementia screening instruments internationally and with greater proven validity. There is a version of this instrument called MoCA "Basic" which was developed to reduce education bias. The aim of the study was to compare the psychometric characteristics of the MoCA, full versus basic, versions in older adults.<br><br>METHOD: Participants (N = 214) completed both versions of the MoCA, and screening measures to corroborate their health status.<br><br>RESULTS: Internal consistency was satisfactory in both versions: MoCA full (0.79) and MoCA basic (0.76). The overall correlation between both tests was high (0.73). There was no relationship between the dimensions included in each version. Educational level and age explained 33.8% of the total variance in MoCA Full and 31.8% in MoCA Basic. Among educational levels, there are statistically significant differences in participants with <6 years of education.<br><br>CONCLUSIONS: The results confirm that both versions are reliable instruments and also show that in both versions the educational level of <6 years of education continues to have an impact on performance. Therefore, it can be considered that the MoCA Basic version for the Ecuadorian population with <6 years of education continues to imply literacy competencies.},
}
@article {pmid34808269,
year = {2022},
author = {George, B and D Gokhale, S and Yaswanth, PM and Vijayan, A and Devika, S and Suchithra, TV},
title = {Identification of Alzheimer associated differentially expressed gene through microarray data and transfer learning-based image analysis.},
journal = {Neuroscience letters},
volume = {766},
number = {},
pages = {136357},
doi = {10.1016/j.neulet.2021.136357},
pmid = {34808269},
issn = {1872-7972},
mesh = {Alzheimer Disease/*genetics ; Animals ; Gene Expression Profiling/*methods ; *Hippocampus ; Humans ; Image Processing, Computer-Assisted/*methods ; Microarray Analysis ; *Neural Networks, Computer ; Rats ; Transcriptome ; },
abstract = {Major factors contribute to mental stress and enhance the progression of late-onset Alzheimer's disease (AD). The factors that lead to neurodegeneration, such as tau protein hyperphosphorylation and increased amyloid-beta production, can be mimicked in animal stress models. The present study identifies differentially expressed genes (DEGs) data and its corresponding predictive image analysis in rat models. The gene expression profile of GSE72062, GSE85162, GSE143951 and GSE85238 was downloaded from NCBI, GEO archive to analyse DEGs. Functional enrichment and pathway relationship networks, gene signal, protein interaction and micro-RNA interaction DEGs networks were constructed and investigated. The image analysis of histopathological slides of rat brain images corresponding to AD microarray-based DEGs profile was undertaken using the convolution neural networks (ConvNets) model. Enrichment of network in terms of GO concluded with 10 DEGs, namely ARHGAP32, GNA11, NR5A1, GNAT3, FOSL1, HELZ2, NMUR2, BDKRB1, RPL3L and RPL39L as potential gene targets to control neurodegeneration and progression of sporadic AD. The image analysis of AD microarray-based DEGs profile builds a successful predictive model of 89% and 61% training and test accuracy with a minimum of 2.480% loss using transfer learning, VGG16 model. Interestingly, the ARHGAP32 gene, a Rho GTPase activating class, was identified to have a functional relationship with two significant genes BCL2 and MMP9, that are well explored in AD. The current investigation upgrades the traditional pre-clinical AD research using microarray data analysis and ConvNets. The model successfully predicts DEG from histopathology slides of rat brain samples, paving the way for image analysis to determine the underlying molecular makeup of the test samples.},
}
@article {pmid34801832,
year = {2022},
author = {Casotto, V and Ranzato, F and Girardi, P and Fedeli, U},
title = {Increasing epilepsy-related mortality: A multiple causes of death study in Northern Italy.},
journal = {Seizure},
volume = {94},
number = {},
pages = {1-6},
doi = {10.1016/j.seizure.2021.11.003},
pmid = {34801832},
issn = {1532-2688},
mesh = {Cause of Death ; Comorbidity ; *Epilepsy/epidemiology ; Europe ; Female ; Humans ; Italy/epidemiology ; Male ; },
abstract = {PURPOSE: to assess the burden of epilepsy as the underlying or contributory cause of death, to investigate time trends in mortality with epilepsy, and to examine the main associated comorbidities.<br><br>METHODS: All deaths from January 1, 2008 to December 31, 2019 with any mention of epilepsy were retrieved from the mortality register of the Veneto Region (Italy). The average annual percent change (AAPC) in age-standardized mortality rates was estimated by log-linear models. The association between mention of epilepsy and of selected disease categories in death certificates was assessed by conditional logistic regression.<br><br>RESULTS: Any mention of epilepsy was reported in 5,907 death certificates; of these, epilepsy was selected as the underlying cause in 1,020 decedents. Deaths with epilepsy represented 0.8% of total mortality in 2008-2011, increasing to 1.3% in 2016-2019. The AAPC was 4.7% for males (95% CI 3.0-6.4, p<0.001) and 6.2% for females (95% CI 4.5-7.9, p<0.001). A strong association was found between mention of epilepsy and meningitis/encephalitis, congenital anomalies/cerebral palsy and other paralytic syndromes, central nervous system tumours, cerebrovascular diseases, and dementia/Alzheimer.<br><br>CONCLUSIONS: The present analysis from Southern Europe confirms recent reports limited to the UK and the US on increasing epilepsy-related mortality rates. aging of the population and the growing prevalence of neurological disorders are among long-term causes of this unfavorable trend; further studies on mortality data and other health archives are warranted.},
}
@article {pmid34800280,
year = {2021},
author = {Aldakheel, RK and Gondal, MA and Alsayed, HN and Almessiere, MA and Nasr, MM and Shemsi, AM},
title = {Rapid Determination and Quantification of Nutritional and Poisonous Metals in Vastly Consumed Ayurvedic Herbal Medicine (Rejuvenator Shilajit) by Humans Using Three Advanced Analytical Techniques.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {34800280},
issn = {1559-0720},
abstract = {‏Shilajit is used commonly as Ayurvedic medicine worldwide which is Rasayana herbo-mineral substance and consumed to restore the energetic balance and to prevent diseases like cognitive disorders and Alzheimer. Locally, Shilajit is applied for patients diagnosed with bone fractures. For safety of the patients, the elemental analysis of Shilajit is imperative to evaluate its nutritional quality as well as contamination from heavy metals. The elemental composition of Shilajit was conducted using three advanced analytical techniques (LIBS, ICP, and EDX). For the comparative studies, the two Shilajit kinds mostly sold globally produced in India and Pakistan were collected. Our main focus is to highlight nutritional eminence and contamination of heavy metals to hinge on Shilajit therapeutic potential. In this work, laser-induced breakdown spectroscopy (LIBS) was applied for qualitative and quantitative analysis of the Shilajit. Our LIBS analysis revealed that Shilajit samples composed of several elements like Ca, S, K, Mg, Al, Na, Sr, Fe, P, Si, Mn, Ba, Zn, Ni, B, Cr, Co, Pb, Cu, As, Hg, Se, and Ti. Indian and Pakistani Shilajits were highly enriched with Ca, S, and K nutrients and contained Al, Sr, Mn, Ba, Zn, Ni, B, Cr, Pb, As, and Hg toxins in amounts that exceeded the standard permissible limit. Even though the content of most elements was comparable among both Shilajits, nutrients, and toxins, in general, were accentuated more in Indian Shilajit with the sole detection of Hg and Ti. The elemental quantification was done using self-developed calibration-free laser-induced breakdown spectroscopy (CF-LIBS) method, and LIBS results are in well agreement with the concentrations determined by standard ICP-OES/MS method. To verify our results by LIBS and ICP-OES/MS techniques, EDX spectroscopy was also conducted which confirmed the presence above mentioned elements. This work is highly significant for creating awareness among people suffering due to overdose of this product and save many human lives.},
}
@article {pmid34797599,
year = {2022},
author = {Zhou, M and Li, H and Wang, Y and Pan, Y and Wang, Y},
title = {Causal effect of insulin resistance on small vessel stroke and Alzheimer's disease: A Mendelian randomization analysis.},
journal = {European journal of neurology},
volume = {29},
number = {3},
pages = {698-706},
doi = {10.1111/ene.15190},
pmid = {34797599},
issn = {1468-1331},
mesh = {*Alzheimer Disease/complications/genetics ; Genome-Wide Association Study ; Humans ; *Insulin Resistance/genetics ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide/genetics ; *Stroke/complications/genetics ; },
abstract = {BACKGROUND AND PURPOSE: The causal effect of insulin resistance on small vessel stroke and Alzheimer's disease (AD) was controversial in previous studies. We therefore applied Mendelian randomization (MR) analyses to identify the causal effect of insulin resistance on small vessel stroke and AD.<br><br>METHODS: We selected 12 single-nucleotide polymorphisms (SNPs) associated with fasting insulin levels and five SNPs associated with "gold standard" measures of insulin resistance as instrumental variables in MR analyses. Summary statistical data on SNP-small vessel stroke and on SNP-AD associations were derived from studies by the Multi-ancestry Genome-Wide Association Study of Stroke consortium (MEGASTROKE) and the Psychiatric Genomics Consortium-Alzheimer Disease Workgroup (PGC-ALZ) in individuals of European ancestry. Two-sample MR estimates were conducted with inverse-variance-weighted, robust inverse-variance-weighted, simple median, weighted median, weighted mode-based estimator, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods.<br><br>RESULTS: Genetically predicted higher insulin resistance had a higher odds ratio (OR) of small vessel stroke (OR 1.23, 95% confidence interval [CI] 1.05-1.44, p = 0.01 using fasting insulin; OR 1.25, 95% CI 1.07-1.46, p = 0.006 using gold standard measures of insulin resistance) and AD (OR 1.13, 95% CI 1.04-1.23, p = 0.004 using fasting insulin; OR 1.02, 95% CI 1.00-1.03, p = 0.03 using gold standard measures of insulin resistance) using the inverse-variance-weighted method. No evidence of pleiotropy was found using MR-Egger regression.<br><br>CONCLUSION: Our findings provide genetic support for a potential causal effect of insulin resistance on small vessel stroke and AD.},
}
@article {pmid34797294,
year = {2021},
author = {Zhang, J and Kuang, X and Tang, C and Xu, N and Xiao, S and Xiao, L and Wang, S and Dong, Y and Lu, L and Zhang, L},
title = {Acupuncture for amnestic mild cognitive impairment: A pilot multicenter, randomized, parallel controlled trial.},
journal = {Medicine},
volume = {100},
number = {46},
pages = {e27686},
pmid = {34797294},
issn = {1536-5964},
support = {No. 81303043//National Outstanding Youth Science Fund Project of National Natural Science Foundation of China/ ; XK2018001//Key Construction Project of Double First Class University Plan of Guangzhou University of Chinese Medicine/ ; 2017TQ04R627//the Young Top Talent Project of Scientific and Technological Innovation in Special Support Plan for Training High-level Talents in Guangdong/ ; 2019QNPY02//the Youth Research and Cultivation Project of Guangzhou University of Chinese Medicine/ ; },
mesh = {Acupuncture Therapy/*methods ; Alzheimer Disease/diagnosis/*therapy ; Amnesia/therapy ; Cognitive Dysfunction/diagnosis/*therapy ; Diagnostic and Statistical Manual of Mental Disorders ; Feasibility Studies ; Humans ; Mental Status and Dementia Tests ; Pilot Projects ; Treatment Outcome ; },
abstract = {INTRODUCTION: Patients with amnesic mild cognitive impairment (aMCI) are more likely to develop Alzheimer disease than corresponding age normal population. Because Alzheimer disease is irreversible, early intervention for aMCI patients seems important and urgent. We have designed a pilot multicenter, randomized, parallel controlled trial to assess the efficacy and safety of acupuncture on aMCI, explore the feasibility of acupuncture in the treatment of aMCI, so as to provide a reference for large-sample clinical trials in the next stage.<br><br>METHOD: We designed a pilot multicenter, randomized, parallel controlled trial. This trial aims to test the feasibility of carrying out a large-sample clinical trial. In this trial, 50 eligible patients with aMCI will be included and allocated to acupuncture group (n = 25) or sham acupuncture group (n = 25) at random. Subjects will accept treatment 2 times a week for 12 weeks continuously, with a total of 24 treatment sessions. We will select 6 acupoints (GV20, GV14, bilateral BL18, bilateral BL23). For the clinical outcomes, the primary outcome is Montreal cognitive assessment, which will be assessed from baseline to the end of this trial. And the secondary outcomes are Mini-mental State Examination, Delayed Story Recall, Clinical Dementia Rating scale, Global Deterioration Scale, Activity of Daily Life, Alzheimer Disease Assessment Scale-Cognitive Section, brain magnetic resonance imaging, brain functional magnetic resonance imaging, and event-related potential P300, which will be assessed before and after treatment. In addition, we will assess the safety outcomes from baseline to the end of this trial and feasibility outcome after treatment. We will evaluate neuropsychological assessment scale (Montreal cognitive assessment, Mini-mental State Examination, Alzheimer Disease Assessment Scale-Cognitive Section) at 3 months and 6 months after treatment.<br><br>DISCUSSION: This pilot trial aims to explore the feasibility of the trial, verify essential information of its efficacy and safety. This pilot study will provide a preliminary basis for carrying out a larger clinical trial of acupuncture on aMCI in near future.},
}
@article {pmid34796967,
year = {2021},
author = {Ma, T},
title = {Roles of eukaryotic elongation factor 2 kinase (eEF2K) in neuronal plasticity, cognition, and Alzheimer disease.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.15541},
pmid = {34796967},
issn = {1471-4159},
support = {R01 AG073823/AG/NIA NIH HHS/United States ; R01 AG055581/AG/NIA NIH HHS/United States ; A2017457S//BrightFocus Foundation/ ; R01 AG055581/NH/NIH HHS/United States ; R01 AG073823/NH/NIH HHS/United States ; NIRG-15-362799/ALZ/Alzheimer's Association/United States ; R01 AG056622/NH/NIH HHS/United States ; R01 AG056622/AG/NIA NIH HHS/United States ; },
abstract = {Understanding the molecular signaling mechanisms underlying cognition and neuronal plasticity would provide insights into the pathogenesis of neuronal disorders characterized by cognitive syndromes such as Alzheimer disease (AD). Phosphorylation of the mRNA translational factor eukaryotic elongation factor 2 (eEF2) by its specific kinase eEF2K is critically involved in protein synthesis regulation. In this review, we discussed recent studies on the roles of eEF2K/eEF2 signaling in the context of regulation/dysregulation of cognitive function and synaptic plasticity. We specifically focus on the discussion of recent evidence indicating suppression of eEF2K signaling as a potential novel therapeutic avenue for AD and related dementias (ADRDs).},
}
@article {pmid34795768,
year = {2021},
author = {Kim, KW and Na, SH and Chung, YC and Shin, BS},
title = {A Comparison of Speech Features between Mild Cognitive Impairment and Healthy Aging Groups.},
journal = {Dementia and neurocognitive disorders},
volume = {20},
number = {4},
pages = {52-61},
pmid = {34795768},
issn = {2384-0757},
abstract = {BACKGROUND AND PURPOSE: Language dysfunction is a symptom common to patients with Alzheimer's disease (AD). Speech feature analysis may be a patient-friendly screening test for early-stage AD. We aimed to investigate the speech features of amnestic mild cognitive impairment (aMCI) compared to normal controls (NCs).<br><br>METHODS: Spoken responses to test questions were recorded with a microphone placed 15 cm in front of each participant. Speech samples delivered in response to four spoken test prompts (free speech test, Mini-Mental State Examination [MMSE], picture description test, and sentence repetition test) were obtained from 98 patients with aMCI and 139 NCs. Each recording was transcribed, with speech features noted. The frequency of the ten speech features assessed was evaluated to compare speech abilities between the test groups.<br><br>RESULTS: Among the ten speech features, the frequency of pauses (p=0.001) and mumbles (p=0.001) were significantly higher in patients with aMCI than in NCs. Moreover, MMSE score was found to negatively correlate with the frequency of pauses (r=-0.441, p<0.001) and mumbles (r=-0.341, p<0.001).<br><br>CONCLUSIONS: Frequent pauses and mumbles reflect cognitive decline in aMCI patients in episodic and semantic memory tests. Speech feature analysis may prove to be a speech-based biomarker for screening early-stage cognitive impairment.},
}
@article {pmid34792590,
year = {2021},
author = {Tian, Q and Studenski, SA and An, Y and Kuo, PL and Schrack, JA and Wanigatunga, AA and Simonsick, EM and Resnick, SM and Ferrucci, L},
title = {Association of Combined Slow Gait and Low Activity Fragmentation With Later Onset of Cognitive Impairment.},
journal = {JAMA network open},
volume = {4},
number = {11},
pages = {e2135168},
pmid = {34792590},
issn = {2574-3805},
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology/*psychology ; Alzheimer Disease/*diagnosis/physiopathology ; Baltimore ; Cognitive Dysfunction/*diagnosis/physiopathology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Proportional Hazards Models ; Prospective Studies ; Risk Assessment/*methods/*statistics &amp; numerical data ; Walking Speed/*physiology ; },
abstract = {Importance: Among older people, slow walking is an early indicator of risk for Alzheimer disease (AD). However, studies that have assessed this association have not considered that slow walking may have different causes, some of which are not necessarily associated with higher AD risk.<br><br>Objective: To evaluate whether low activity fragmentation among older adults with slow gait speed indicates neurological causes of slow walking that put these individuals at higher risk of AD.<br><br>This prospective cohort study performed survival analyses using data from the Baltimore Longitudinal Study of Aging. Participants included 520 initially cognitively normal persons aged 60 years or older. New diagnoses of mild cognitive impairment (MCI) or AD were adjudicated during a mean (SD) follow-up of 7.3 (2.7) years. Initial assessment of gait speed and activity fragmentation occurred from January 3, 2007, to May 11, 2015, with follow-up completed on December 31, 2020. Data were analyzed from February 1 to May 15, 2021.<br><br>Exposures: Gait speed for 6 m and activity fragmentation assessed by accelerometry.<br><br>Main Outcomes and Measures: Associations of gait speed, activity fragmentation, and their interaction with incident MCI/AD were evaluated using Cox proportional hazards models, adjusted for covariates.<br><br>Results: Among the 520 participants (265 women [51.0%]; 125 Black participants [24.0%]; 367 White participants [70.6%]; mean [SD] age, 73 [8] years), MCI/AD developed in 64 participants. Each 0.05-m/s slower gait was associated with a 7% increase in risk of developing MCI/AD (hazard ratio [HR], 1.07 [95% CI, 1.00-1.15]; P = .04). Activity fragmentation alone was not associated with MCI/AD risk (HR, 0.83 [95% CI, 0.56-1.23]; P = .35), but there was a significant interaction between gait speed and activity fragmentation (HR, 0.92 [95% CI, 0.87-0.98]; P = .01). At low activity fragmentation (-1 SD), each 0.05-m/s slower gait speed was associated with a 19% increase in hazard of developing MCI/AD (HR, 1.19 [95% CI, 1.07-1.32]), whereas at higher activity fragmentation (+1 SD), gait speed was not associated with MCI/AD (HR, 1.01 [95% CI, 0.93-1.10]). Among participants with slow gait, higher activity fragmentation was associated with higher odds of having lower extremity osteoarthritis (odds ratio, 1.31 [95% CI, 1.01-1.69]) and less decline in pegboard dominant hand performance (β = 0.026 [SE, 0.009]; P > .05).<br><br>Conclusions and Relevance: These findings suggest that frequent rests among older adults with slow gait speed are associated with lower risk of future MCI/AD and that this behavioral strategy is associated with a lower likelihood of subclinical neurological impairment.},
}
@article {pmid34792198,
year = {2022},
author = {Solders, SK and Galinsky, VL and Clark, AL and Sorg, SF and Weigand, AJ and Bondi, MW and Frank, LR},
title = {Diffusion MRI tractography of the locus coeruleus-transentorhinal cortex connections using GO-ESP.},
journal = {Magnetic resonance in medicine},
volume = {87},
number = {4},
pages = {1816-1831},
pmid = {34792198},
issn = {1522-2594},
support = {U01 MH093765/MH/NIMH NIH HHS/United States ; R01 AG054049/AG/NIA NIH HHS/United States ; S10 RR019307/RR/NCRR NIH HHS/United States ; R01 AR070830/AR/NIAMS NIH HHS/United States ; S10 RR023043/RR/NCRR NIH HHS/United States ; R01 HD088437/HD/NICHD NIH HHS/United States ; P41 EB015896/EB/NIBIB NIH HHS/United States ; S10 RR023401/RR/NCRR NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; Entropy ; Humans ; *Locus Coeruleus/diagnostic imaging/metabolism/pathology ; Magnetic Resonance Imaging ; tau Proteins/metabolism ; },
abstract = {PURPOSE: The locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion-like manner along the LC-transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC-TEC pathway may be an earlier observable change that can improve detection of preclinical AD.<br><br>THEORY AND METHODS: Diffusion-weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric-optics based entropy spectrum pathways (GO-ESP) and produce a new measure of connectivity: the equilibrium probability (EP).<br><br>RESULTS: We demonstrated reliable reconstruction of LC-TEC pathways in 50 cognitively normal older adults and showed a negative association between LC-TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC-TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings.<br><br>CONCLUSIONS: AD-related tau pathology may be detectable within GO-ESP-identified LC-TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC-TEC connectome and its role in AD pathogenesis.},
}
@article {pmid34789544,
year = {2021},
author = {Chiong, W and Tolchin, BD and Bonnie, RJ and Busl, K and Cruz-Flores, S and Epstein, LG and Greene, EP and Illes, J and Kirschen, M and Larriviere, DG and Mantri, S and Rubin, MA and Stern, BJ and Taylor, LP and , },
title = {Decisions With Patients and Families Regarding Aducanumab in Alzheimer Disease, With Recommendations for Consent: AAN Position Statement.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000013053},
pmid = {34789544},
issn = {1526-632X},
}
@article {pmid34786131,
year = {2021},
author = {Zhang, C and Li, B},
title = {The correlation between LncRNA-17A expression in peripheral blood mononuclear cells and Wnt/β-catenin signaling pathway and cognitive function in patients with Alzheimer disease.},
journal = {American journal of translational research},
volume = {13},
number = {10},
pages = {11981-11986},
pmid = {34786131},
issn = {1943-8141},
abstract = {OBJECTIVE: This study investigated the correlation between LncRNA-17A expression in peripheral blood mononuclear cells (PBMC) and the Wnt/β-catenin signaling pathway and cognitive function in patients sufferer from Alzheimer disease (AD).<br><br>METHODS: 90 cases of AD patients hospitalized during March 2019 to July 2020 were selected into the AD-group, and another 90 healthy volunteers who underwent physical examination during the same period were randomly enrolled as the control-group. The Mini-mental State Examination (MMSE) was applied to measure the cognitive function of the two groups of subjects, and the qRT-PCR was to detect the expressions of LncRNA-17A, Wnt mRNA, Tcf-4 mRNA and β-catenin mRNA in PBMC, and the correlation between LncRNA-17A expression and cognitive function and Wnt/β-catenin signaling pathway was analyzed.<br><br>RESULTS: MMSE score in AD-group was remarkably lower than that in control-group (P<0.05). The relative LncRNA-17A expression in PBMC of AD patients was evidently higher than that of the control-group (P>0.05). LncRNA-17A expression in PBMC of AD patients with different severity degree had statistical significance (P<0.05); and the relative expression level of LncRNA-17A increased notably with the disease progression (P<0.05). The relative expression of Wnt mRNA, Tcf-4 mRNA and β-catenin mRNA in AD-group were apparently superior to those in control-group (P<0.05). LncRNA-17A expression in PBMC of AD patients was negatively correlated with MSME score (P<0.05), and was positively correlated with Wnt mRNA, Tcf-4 mRNA and β-catenin mRNA (P<0.05).<br><br>CONCLUSION: LncRNA-17A expression is abnormally reduced in PBMC of AD patients, and is associated with patient's disease progression which is regulated by the activation of Wnt/β-catenin signaling pathway. LncRNA-17A might be the potential molecular markers of AD with diagnostic and prognostic value.},
}
@article {pmid34784866,
year = {2021},
author = {Germán, F and Andres, D and Leandro, U and Nicolás, N and Graciela, L and Yanina, B and Patricio, C and Adriana, Q and Cecilia, B and Ismael, C and Ismael, C and de León, MP and Valeria, C and Feuerstein, V and Sergio, D and Ricardo, A and Henry, E and Silvia, V},
title = {Connectivity and Patterns of Regional Cerebral Blood Flow, Cerebral Glucose Uptake, and Aβ-Amyloid Deposition in Alzheimer's Disease (Early and Late-Onset) Compared to Normal Ageing.},
journal = {Current Alzheimer research},
volume = {18},
number = {8},
pages = {646-655},
doi = {10.2174/1567205018666211116095035},
pmid = {34784866},
issn = {1875-5828},
support = {002722/15//CONICET/ ; MOV_-CO_2015_1_109713//ANII/ ; },
mesh = {Aging ; *Alzheimer Disease/diagnostic imaging ; Aniline Compounds ; Brain/diagnostic imaging ; Cerebrovascular Circulation ; Glucose ; Humans ; Positron Emission Tomography Computed Tomography ; Positron-Emission Tomography/methods ; Thiazoles ; },
abstract = {PURPOSE: The aim of this study was to investigate the differences in early (EOAD) and late (LOAD) onset of Alzheimer´s disease, as well as glucose uptake, regional cerebral blood flow (R1), amyloid depositions, and functional brain connectivity between normal young (YC) and Old Controls (OC).<br><br>METHODOLOGY: The study included 22 YC (37 ± 5 y), 22 OC (73 ± 5.9 y), 18 patients with EOAD (63 ± 9.5 y), and 18 with LOAD (70.6 ± 7.1 y). Patients underwent FDG and PIB PET/CT. R1 images were obtained from the compartmental analysis of the dynamic PIB acquisitions. Images were analyzed by a voxel-wise and a VOI-based approach. Functional connectivity was studied from the R1 and glucose uptake images.<br><br>RESULTS: OC had a significant reduction of R1 and glucose uptake compared to YC, predominantly at the dorsolateral and mesial frontal cortex. EOAD and LOAD vs. OC showed a decreased R1 and glucose uptake at the posterior parietal cortex, precuneus, and posterior cingulum. EOAD vs. LOAD showed a reduction in glucose uptake and R1 at the occipital and parietal cortex and an increased at the mesial frontal and temporal cortex. There was a mild increase in an amyloid deposition at the frontal cortex in LOAD vs. EOAD. YC presented higher connectivity than OC in R1 but lower connectivity considering glucose uptake. Moreover, EOAD and LOAD showed a decreased connectivity compared to controls that were more pronounced in glucose uptake than R1.<br><br>CONCLUSION: Our results demonstrated differences in amyloid deposition and functional imaging between groups and a differential pattern of functional connectivity in R1 and glucose uptake in each clinical condition. These findings provide new insights into the pathophysiological processes of AD and may have an impact on patient diagnostic evaluation.},
}
@article {pmid34784296,
year = {2021},
author = {Chylinski, DO and Van Egroo, M and Narbutas, J and Grignard, M and Koshmanova, E and Berthomier, C and Berthomier, P and Brandewinder, M and Salmon, E and Bahri, MA and Bastin, C and Collette, F and Phillips, C and Maquet, P and Muto, V and Vandewalle, G},
title = {Heterogeneity in the links between sleep arousals, amyloid-β, and cognition.},
journal = {JCI insight},
volume = {6},
number = {24},
pages = {},
pmid = {34784296},
issn = {2379-3708},
mesh = {Aged ; Amyloid beta-Peptides/*metabolism ; Arousal ; Cognition/*physiology ; Female ; *Genetic Heterogeneity ; Humans ; Male ; Middle Aged ; Sleep/*genetics ; *Sleep Quality ; },
abstract = {BACKGROUNDTight relationships between sleep quality, cognition, and amyloid-β (Aβ) accumulation, a hallmark of Alzheimer's disease (AD) neuropathology, have been shown. Sleep arousals become more prevalent with aging and are considered to reflect poorer sleep quality. However, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established.METHODSWe recorded undisturbed night-time sleep with EEG in 101 healthy individuals aged 50-70 years, devoid of cognitive and sleep disorders. We classified spontaneous arousals according to their association with muscular tone increase (M+/M-) and sleep stage transition (T+/T-). We assessed cortical Aβ burden over earliest affected regions via PET imaging and assessed cognition via neuropsychological testing.RESULTSArousal types differed in their oscillatory composition in θ (4-8 Hz) and β (16-30 Hz) EEG bands. Furthermore, T+M- arousals, interrupting sleep continuity, were positively linked to Aβ burden (P = 0.0053, R²β* = 0.08). By contrast, more prevalent T-M+ arousals, upholding sleep continuity, were associated with lower Aβ burden (P = 0.0003, R²β* = 0.13), and better cognition, particularly over the attentional domain (P < 0.05, R²β* ≥ 0.04).CONCLUSIONContrasting with what is commonly accepted, we provide empirical evidence that arousals are diverse and differently associated with early AD-related neuropathology and cognition. This suggests that sleep arousals, and their coalescence with other brain oscillations during sleep, may actively contribute to the beneficial functions of sleep and constitute markers of favorable brain and cognitive health trajectories.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGFRS-FNRS Belgium (FRSM 3.4516.11), Actions de Recherche Concertées Fédération Wallonie-Bruxelles (SLEEPDEM 17/27-09), ULiège, and European Regional Development Fund (Radiomed Project).},
}
@article {pmid34781953,
year = {2021},
author = {Lee, CW and Chuang, HM},
title = {Design of a seniors and Alzheimer's disease caring service platform.},
journal = {BMC medical informatics and decision making},
volume = {21},
number = {Suppl 10},
pages = {273},
pmid = {34781953},
issn = {1472-6947},
mesh = {Activities of Daily Living ; Aged ; *Alzheimer Disease/diagnosis ; Caregivers ; Humans ; *Internet of Things ; Nursing Homes ; },
abstract = {BACKGROUND: To meet the needs of aging and dementia patients in Taiwan, this study designed a nursing system that includes communication, location tracking, and fall detection, and early warning services. The main purpose of this research is to provide timely services to the elderly and patients and hope to reduce the burden when the number of nursing staff decreases. This article is a remote disease care service platform with the Internet of Things (IoT) devices to monitor the location of the elderly and whether they have dropped warning alerts.<br><br>RESULTS: The device is connected to the patient's waist and chest, monitors the patient's movement and behavior, and transmits messages to the back-end system, and informs caregivers through mobile phone applications when unexpected or shocking events occur. The system can identify whether the patient has fallen, accidentally, or long-term inactivity. The device is equipped with sensors that enable it to monitor the patient's location and behavior data through Bluetooth and GPS technology. Finally, we proposed a basic model and an integrated model that will industrialize the system and is expected to play a role in a larger patient population.<br><br>CONCLUSIONS: The system developed in this research has passed the Activities of Daily Living (ADL) test and verification, and is expected to provide appropriate safety care services for nursing homes and elderly residences.},
}
@article {pmid34779640,
year = {2021},
author = {Joaquim, AR and Gionbelli, MP and Gosmann, G and Fuentefria, AM and Lopes, MS and Fernandes de Andrade, S},
title = {Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure-Activity Relationships, and Perspectives.},
journal = {Journal of medicinal chemistry},
volume = {64},
number = {22},
pages = {16349-16379},
doi = {10.1021/acs.jmedchem.1c01318},
pmid = {34779640},
issn = {1520-4804},
mesh = {Anti-Infective Agents/chemistry/*pharmacology ; Bacteria/classification/drug effects ; *Drug Development ; Fungi/classification/drug effects ; Microbial Sensitivity Tests ; Oxyquinoline/chemistry/*pharmacology ; Structure-Activity Relationship ; },
abstract = {The search for new antimicrobials is imperative due to the emergent resistance of new microorganism strains. In this context, revisiting known classes like 8-hydroxyquinolines could be an interesting strategy to discover new agents. The 8-hydroxyquinoline derivatives nitroxoline and clioquinol are used to treat microbial infections; however, these drugs are underused, being available in few countries or limited to topical use. After years of few advances, in the last two decades, the potent activity of clioquinol and nitroxoline against several targets and the privileged structure of 8-hydroxyquinoline nucleus have prompted an increased interest in the design of novel antimicrobial, anticancer, and anti-Alzheimer agents based on this class. Herein, we discuss the current development and antimicrobial structure-activity relationships of this class in the perspective of using the 8-hydroxyquinoline nucleus for the search for novel antimicrobial agents. Furthermore, the most investigated molecular targets concerning 8-hydroxyquinoline derivatives are explored in the final section.},
}
@article {pmid34775786,
year = {2022},
author = {Lee, CJ and Lee, JY and Han, K and Kim, DH and Cho, H and Kim, KJ and Kang, ES and Cha, BS and Lee, YH and Park, S},
title = {Blood Pressure Levels and Risks of Dementia: a Nationwide Study of 4.5 Million People.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {79},
number = {1},
pages = {218-229},
doi = {10.1161/HYPERTENSIONAHA.121.17283},
pmid = {34775786},
issn = {1524-4563},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/epidemiology/physiopathology ; Antihypertensive Agents/therapeutic use ; Blood Pressure/*physiology ; Comorbidity ; Dementia/*epidemiology/physiopathology ; Dementia, Vascular/epidemiology/physiopathology ; Female ; Humans ; Hypertension/drug therapy/*epidemiology/physiopathology ; Incidence ; Male ; Middle Aged ; Risk ; },
abstract = {There are inconsistent results on the impacts of controlling blood pressure (BP) on the risk of dementia. We investigated the association between BP and risk of dementia subtypes by antihypertensive treatment and comorbidities. Using the Korean National Health Insurance Service-Health Screening Database from 2009 to 2012, a total of 4 522 447 adults aged 60+ years without a history of dementia were analyzed and followed up for a mean of 5.4 years. Individuals were classified according to their baseline systolic BP (SBP) and diastolic BP; SBP 130 to <140 mm Hg and diastolic BP 80 to <90 mm Hg were used as reference groups. The risk of overall dementia and probable Alzheimer disease was significantly higher in the SBP≥160 and lower SBP groups. These U-shaped associations were consistent regardless of antihypertensive use or comorbidities. The risk of probable vascular dementia (VaD) was not higher among lower SBP groups and increased gradually as SBP increased. Although there was a linear association between SBP and the risk of probable VaD in individuals not taking antihypertensives or without comorbidities, there was a U-shaped association in individuals taking antihypertensives or with comorbidities. Patterns of association between diastolic BP and risk of probable Alzheimer disease or probable VaD were similar to those with SBP, except for the risk of probable VaD in individuals taking antihypertensives. In conclusion, risks of probable Alzheimer disease and probable VaD were different among lower BP groups. Although the risk of dementia appears higher in people with lower BP receiving antihypertensives, this finding may be affected by comorbidities.},
}
@article {pmid34775673,
year = {2021},
author = {He, K and Nie, L and Ali, T and Wang, S and Chen, X and Liu, Z and Li, W and Zhang, K and Xu, J and Liu, J and Yu, ZJ and Yang, X and Li, S},
title = {Adiponectin alleviated Alzheimer-like pathologies via autophagy-lysosomal activation.},
journal = {Aging cell},
volume = {20},
number = {12},
pages = {e13514},
pmid = {34775673},
issn = {1474-9726},
mesh = {Adiponectin/*metabolism ; Animals ; Autophagy/*genetics ; Humans ; Lysosomes/*metabolism ; Male ; Mice ; Proteomics/*methods ; },
abstract = {Adiponectin (APN) deficiency has also been associated with Alzheimer-like pathologies. Recent studies have illuminated the importance of APN signaling in reducing Aβ accumulation, and the Aβ elimination mechanism remains rudimentary. Therefore, we aimed to elucidate the APN role in reducing Aβ accumulation and its associated abnormalities by targeting autophagy and lysosomal protein changes. To assess, we performed a combined pharmacological and genetic approach while using preclinical models and human samples. Our results demonstrated that the APN level significantly diminished in the plasma of patients with dementia and 5xFAD mice (6 months old), which positively correlated with Mini-Mental State Examination (MMSE), and negatively correlated with Clinical Dementia Rating (CDR), respectively. APN deficiency accelerated cognitive impairment, Aβ deposition, and neuroinflammation in 5xFAD mice (5xFAD*APN KO), which was significantly rescued by AdipoRon (AR) treatment. Furthermore, AR treatment also markedly reduced Aβ deposition and attenuated neuroinflammation in APP/PS1 mice without altering APP expression and processing. Interestingly, AR treatment triggered autophagy by mediating AMPK-mTOR pathway signaling. Most importantly, APN deficiency dysregulated lysosomal enzymes level, which was recovered by AR administration. We further validated these changes by proteomic analysis. These findings reveal that APN is the negative regulator of Aβ deposition and its associated pathophysiologies. To eliminate Aβ both extra- and intracellular deposition, APN contributes via the autophagic/lysosomal pathway. It presents a therapeutic avenue for AD therapy by targeting autophagic and lysosomal signaling.},
}
@article {pmid34775332,
year = {2022},
author = {He, X and Hui, Z and Xu, L and Bai, R and Gao, Y and Wang, Z and Xie, T and Ye, XY},
title = {Medicinal chemistry updates of novel HDACs inhibitors (2020 to present).},
journal = {European journal of medicinal chemistry},
volume = {227},
number = {},
pages = {113946},
doi = {10.1016/j.ejmech.2021.113946},
pmid = {34775332},
issn = {1768-3254},
mesh = {Chemistry, Pharmaceutical ; Histone Deacetylase Inhibitors/chemistry/*pharmacology ; Histone Deacetylases/*metabolism ; Humans ; Molecular Structure ; },
abstract = {Epigentic enzymes histone deacetylases (HDACs) catalyze the removal of acetyl groups from the ε-N-acetylated lysine residues of various protein substrates including both histone and non-histone proteins. Different HDACs have distinct biological functions and are recruited to specific regions of the genome. Due to their important biological functions, HDACs have been validated in clinics for anticancer therapy, and are being explored for potential treatment of several other diseases such as Alzheimer disease (AD), metabolic disease, viral infection, and multiple sclerosis, etc. Besides five approved drugs, there are more than thirty HDACs inhibitors currently being investigated in clinical trials. Centering on the advances of drug discovery programs in this field since 2020, this review discusses HDACs inhibitors from the aspects of the structure-based rational design, isoform selectivity, pharmacology, and toxicology of the compounds of interest. The hope is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in this area.},
}
@article {pmid34771817,
year = {2021},
author = {Bhanderi, M and Shah, J and Gorain, B and Nair, AB and Jacob, S and Asdaq, SMB and Fattepur, S and Alamri, AS and Alsanie, WF and Alhomrani, M and Nagaraja, S and Anwer, MK},
title = {Optimized Rivastigmine Nanoparticles Coated with Eudragit for Intranasal Application to Brain Delivery: Evaluation and Nasal Ciliotoxicity Studies.},
journal = {Materials (Basel, Switzerland)},
volume = {14},
number = {21},
pages = {},
pmid = {34771817},
issn = {1996-1944},
support = {TURSP (2020/257).//Taif University/ ; },
abstract = {Rivastigmine, a reversible cholinesterase inhibitor, is frequently indicated in the management of demented conditions associated with Alzheimer disease. The major hurdle of delivering this drug through the oral route is its poor bioavailability, which prompted the development of novel delivery approaches for improved efficacy. Due to numerous beneficial properties associated with nanocarriers in the drug delivery system, rivastigmine nanoparticles were fabricated to be administer through the intranasal route. During the development of the nanoparticles, preliminary optimization of processing and formulation parameters was done by the design of an experimental approach. The drug-polymer ratio, stirrer speed, and crosslinking time were fixed as independent variables, to analyze the effect on the entrapment efficiency (% EE) and in vitro drug release of the drug. The formulation (D8) obtained from 23 full factorial designs was further coated using Eudragit EPO to extend the release pattern of the entrapped drug. Furthermore, the 1:1 ratio of core to polymer depicted spherical particle size of ~175 nm, % EE of 64.83%, 97.59% cumulative drug release, and higher flux (40.39 ± 3.52 µg.h/cm2). Finally, the intranasal ciliotoxicity study on sheep nasal mucosa revealed that the exposure of developed nanoparticles was similar to the negative control group, while destruction of normal architecture was noticed in the positive control test group. Overall, from the in vitro results it could be summarized that the optimization of nanoparticles' formulation of rivastigmine for intranasal application would be retained at the application site for a prolonged duration to release the entrapped drug without producing any local toxicity at the mucosal region.},
}
@article {pmid34770940,
year = {2021},
author = {Friedli, MJ and Inestrosa, NC},
title = {Huperzine A and Its Neuroprotective Molecular Signaling in Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {21},
pages = {},
pmid = {34770940},
issn = {1420-3049},
support = {AFB-170005//Agencia Nacional de Investigación y Desarrollo/ ; },
mesh = {Acetylcholinesterase/metabolism ; Alkaloids/chemistry/*pharmacology ; Alzheimer Disease/*drug therapy/metabolism ; Animals ; Cholinesterase Inhibitors/chemistry/*pharmacology ; Humans ; Huperzia/chemistry ; Molecular Structure ; Neuroprotective Agents/chemistry/*pharmacology ; Sesquiterpenes/chemistry/*pharmacology ; Signal Transduction/drug effects ; },
abstract = {Huperzine A (HupA), an alkaloid found in the club moss Huperzia serrata, has been used for centuries in Chinese folk medicine to treat dementia. The effects of this alkaloid have been attributed to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), acting as an acetylcholinesterase inhibitor (AChEI). The biological functions of HupA have been studied both in vitro and in vivo, and its role in neuroprotection appears to be a good therapeutic candidate for Alzheimer´s disease (AD). Here, we summarize the neuroprotective effects of HupA on AD, with an emphasis on its interactions with different molecular signaling avenues, such as the Wnt signaling, the pre- and post-synaptic region mechanisms (synaptotagmin, neuroligins), the amyloid precursor protein (APP) processing, the amyloid-β peptide (Aβ) accumulation, and mitochondrial protection. Our goal is to provide an integrated overview of the molecular mechanisms through which HupA affects AD.},
}
@article {pmid34770082,
year = {2021},
author = {Calderón-Garcidueñas, L and Stommel, EW and Rajkumar, RP and Mukherjee, PS and Ayala, A},
title = {Particulate Air Pollution and Risk of Neuropsychiatric Outcomes. What We Breathe, Swallow, and Put on Our Skin Matters.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {21},
pages = {},
pmid = {34770082},
issn = {1660-4601},
mesh = {*Air Pollutants/analysis/toxicity ; *Air Pollution/analysis/statistics &amp; numerical data ; Dust ; Particulate Matter/analysis/toxicity ; Vehicle Emissions/analysis ; },
abstract = {We appraise newly accumulated evidence of the impact of particle pollution on the brain, the portals of entry, the neural damage mechanisms, and ultimately the neurological and psychiatric outcomes statistically associated with exposures. PM pollution comes from natural and anthropogenic sources such as fossil fuel combustion, engineered nanoparticles (NP ≤ 100 nm), wildfires, and wood burning. We are all constantly exposed during normal daily activities to some level of particle pollution of various sizes-PM2.5 (≤2.5 µm), ultrafine PM (UFP ≤ 100 nm), or NPs. Inhalation, ingestion, and dermal absorption are key portals of entry. Selected literature provides context for the US Environmental Protection Agency (US EPA) ambient air quality standards, the conclusions of an Independent Particulate Matter Review Panel, the importance of internal combustion emissions, and evidence suggesting UFPs/NPs cross biological barriers and reach the brain. NPs produce oxidative stress and neuroinflammation, neurovascular unit, mitochondrial, endoplasmic reticulum and DNA damage, protein aggregation and misfolding, and other effects. Exposure to ambient PM2.5 concentrations at or below current US standards can increase the risk for TIAs, ischemic and hemorrhagic stroke, cognitive deficits, dementia, and Alzheimer's and Parkinson's diseases. Residing in a highly polluted megacity is associated with Alzheimer neuropathology hallmarks in 99.5% of residents between 11 months and ≤40 y. PD risk and aggravation are linked to air pollution and exposure to diesel exhaust increases ALS risk. Overall, the literature supports that particle pollution contributes to targeted neurological and psychiatric outcomes and highlights the complexity of the pathophysiologic mechanisms and the marked differences in pollution profiles inducing neural damage. Factors such as emission source intensity, genetics, nutrition, comorbidities, and others also play a role. PM2.5 is a threat for neurological and psychiatric diseases. Thus, future research should address specifically the potential role of UFPs/NPs in inducing neural damage.},
}
@article {pmid34768981,
year = {2021},
author = {El-Battari, A and Rodriguez, L and Chahinian, H and Delézay, O and Fantini, J and Yahi, N and Di Scala, C},
title = {Gene Therapy Strategy for Alzheimer's and Parkinson's Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells.},
journal = {International journal of molecular sciences},
volume = {22},
number = {21},
pages = {},
pmid = {34768981},
issn = {1422-0067},
support = {//H2020 SME Phase 1/ ; },
mesh = {Alzheimer Disease/*drug therapy/*metabolism ; Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloidogenic Proteins/metabolism ; Brain/drug effects/metabolism ; Calcium/metabolism ; Cell Line ; Cell Membrane/drug effects/metabolism ; Gangliosides/metabolism ; Genetic Therapy/methods ; Humans ; Parkinson Disease/*drug therapy/*metabolism ; Peptide Fragments/*metabolism ; },
abstract = {We present here a gene therapy approach aimed at preventing the formation of Ca2+-permeable amyloid pore oligomers that are considered as the most neurotoxic structures in both Alzheimer's and Parkinson's diseases. Our study is based on the design of a small peptide inhibitor (AmyP53) that combines the ganglioside recognition properties of the β-amyloid peptide (Aβ, Alzheimer) and α-synuclein (α-syn, Parkinson). As gangliosides mediate the initial binding step of these amyloid proteins to lipid rafts of the brain cell membranes, AmyP53 blocks, at the earliest step, the Ca2+ cascade that leads to neurodegeneration. Using a lentivirus vector, we genetically modified brain cells to express the therapeutic coding sequence of AmyP53 in a secreted form, rendering these cells totally resistant to oligomer formation by either Aβ or α-syn. This protection was specific, as control mCherry-transfected cells remained fully sensitive to these oligomers. AmyP53 was secreted at therapeutic concentrations in the supernatant of cultured cells, so that the therapy was effective for both transfected cells and their neighbors. This study is the first to demonstrate that a unique gene therapy approach aimed at preventing the formation of neurotoxic oligomers by targeting brain gangliosides may be considered for the treatment of two major neurodegenerative disorders, Alzheimer's and Parkinson's diseases.},
}
@article {pmid34768454,
year = {2021},
author = {Allocca, M and Linguanti, F and Calcagni, ML and Cistaro, A and Gaudieri, V and Guerra, UP and Morbelli, S and Nobili, F and Pappatà, S and Sestini, S and Volterrani, D and Berti, V and For The Neurology Study Group Of The Italian Association Of Nuclear Medicine, },
title = {Evaluation of Age and Sex-Related Metabolic Changes in Healthy Subjects: An Italian Brain 18F-FDG PET Study.},
journal = {Journal of clinical medicine},
volume = {10},
number = {21},
pages = {},
pmid = {34768454},
issn = {2077-0383},
abstract = {BACKGROUND: 18F-fluorodeoxyglucose (18F-FDG) positron-emission-tomography (PET) allows detection of cerebral metabolic alterations in neurological diseases vs. normal aging. We assess age- and sex-related brain metabolic changes in healthy subjects, exploring impact of activity normalization methods.<br><br>METHODS: brain scans of Italian Association of Nuclear Medicine normative database (151 subjects, 67 Males, 84 Females, aged 20-84) were selected. Global mean, white matter, and pons activity were explored as normalization reference. We performed voxel-based and ROI analyses using SPM12 and IBM-SPSS software.<br><br>RESULTS: SPM proved a negative correlation between age and brain glucose metabolism involving frontal lobes, anterior-cingulate and insular cortices bilaterally. Narrower clusters were detected in lateral parietal lobes, precuneus, temporal pole and medial areas bilaterally. Normalizing on pons activity, we found a more significant negative correlation and no positive one. ROIs analysis confirmed SPM results. Moreover, a significant age × sex interaction effect was revealed, with worse metabolic reduction in posterior-cingulate cortices in females than males, especially in post-menopausal age.<br><br>CONCLUSIONS: this study demonstrated an age-related metabolic reduction in frontal lobes and in some parieto-temporal areas more evident in females. Results suggested pons as the most appropriate normalization reference. Knowledge of age- and sex-related cerebral metabolic changes is critical to correctly interpreting brain 18F-FDG PET imaging.},
}
@article {pmid34767756,
year = {2021},
author = {He, Z and Le Guen, Y and Liu, L and Lee, J and Ma, S and Yang, AC and Liu, X and Rutledge, J and Losada, PM and Song, B and Belloy, ME and Butler, RR and Longo, FM and Tang, H and Mormino, EC and Wyss-Coray, T and Greicius, MD and Ionita-Laza, I},
title = {Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics.},
journal = {American journal of human genetics},
volume = {108},
number = {12},
pages = {2336-2353},
pmid = {34767756},
issn = {1537-6605},
support = {U24 AG021886/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 AG033193/AG/NIA NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AG066206/AG/NIA NIH HHS/United States ; R01 MH095797/MH/NIMH NIH HHS/United States ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; R01 AG060747/AG/NIA NIH HHS/United States ; RF1 AG072272/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/*genetics ; *Biological Specimen Banks ; *Gene Knockout Techniques ; Genes, erbB-1 ; Genetic Variation ; Genome-Wide Association Study ; Humans ; RNA-Seq ; Transcriptome ; Whole Genome Sequencing ; },
abstract = {Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects.},
}
@article {pmid34766133,
year = {2021},
author = {Sajan, MP and Hansen, BC and Acevedo-Duncan, M and Kindy, MS and Cooper, DR and Farese, RV},
title = {Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin-resistant forms of obesity and type 2 diabetes mellitus.},
journal = {MedComm},
volume = {2},
number = {1},
pages = {3-16},
pmid = {34766133},
issn = {2688-2663},
support = {R01 ES016774/ES/NIEHS NIH HHS/United States ; R21 AG043718/AG/NIA NIH HHS/United States ; },
abstract = {Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using "spare receptors" to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ-plaque precursors and Alzheimer risk; in kidney, hyperinsulinemia activates the renin-angiotensin-adrenal axis, thus increasing vasoconstriction, sodium retention, and cardiovascular risk; and in liver, hyperinsulinemia increases lipogenesis, obesity, hepatosteatosis, hyperlipidemia, and cardiovascular risk. In summary, increases in hepatic aPKC are critically required for development of DIO/MetS/T2DM and its adverse sequelae, and therapeutic approaches that limit hepatic aPKC may be particularly effective.},
}
@article {pmid34763525,
year = {Wint},
author = {McGinnis, SM and Stern, AM and Woods, JK and Torre, M and Feany, MB and Miller, MB and Silbersweig, DA and Gale, SA and Daffner, KR},
title = {Case Study 1: A 55-Year-Old Woman With Progressive Cognitive, Perceptual, and Motor Impairments.},
journal = {The Journal of neuropsychiatry and clinical neurosciences},
volume = {34},
number = {1},
pages = {8-15},
pmid = {34763525},
issn = {1545-7222},
support = {K08 AG065502/AG/NIA NIH HHS/United States ; T32 HL007627/HL/NHLBI NIH HHS/United States ; },
mesh = {*Alzheimer Disease/pathology ; Atrophy/pathology ; Cerebral Cortex/pathology ; Cognition ; Female ; Humans ; Middle Aged ; *Motor Disorders ; },
}
@article {pmid34763376,
year = {2021},
author = {Louhija, UM and Martola, J and Juva, K and Appelberg, BG},
title = {Brain Atrophy in First-Episode Psychosis of the Elderly Is Associated With Cognitive Decline.},
journal = {The primary care companion for CNS disorders},
volume = {23},
number = {6},
pages = {},
doi = {10.4088/PCC.20m02865},
pmid = {34763376},
issn = {2155-7780},
mesh = {Aged ; Atrophy/pathology ; Brain/diagnostic imaging/pathology ; *Cognitive Dysfunction/etiology ; Humans ; *Psychotic Disorders/complications ; *Schizophrenia ; },
abstract = {Objective: To study brain atrophy and cognitive decline in elderly patients with first-episode psychosis (FEP).<br><br>Methods: Elderly patients aged ≥ 60 years with FEP and onset of psychotic symptoms of ≤ 1 year remitted to the Helsinki University Hospital from December 2009 to December 2011 were included in the study. Diagnoses were made using DSM-IV-TR criteria. All patients had a brain scan, magnetic resonance imaging, or computed tomography. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer`s Disease cognitive test battery.<br><br>Results: Of the 85 patients with FEP, 18 had very late-onset schizophrenia-like psychosis (VLOSP), 20 had delusional psychosis, 12 had depressive psychosis, and 35 had psychosis due to a general medical condition. Fifteen of the patients had an earlier history of schizophrenia not known at the time of admittance. These patients were analyzed separately. A vast majority of the FEP patients in all diagnostic groups exhibited signs of cortical atrophy, which was associated with early stage cognitive decline. Multivariate analyses showed that brain atrophy was associated with a decline in Mini-Mental State Examination, Clock Drawing Test, and verbal fluency scores in FEP patients.<br><br>Conclusions: Brain atrophy is a frequent finding in elderly FEP patients and is associated with cognitive decline. Elderly patients with FEP should always undergo brain atrophy and cognition screening, as they may constitute an etiologic factor in such patients.},
}
@article {pmid34763094,
year = {2021},
author = {Kshirsagar, S and Sawant, N and Morton, H and Reddy, AP and Reddy, PH},
title = {Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.},
journal = {Pharmacological research},
volume = {174},
number = {},
pages = {105973},
pmid = {34763094},
issn = {1096-1186},
support = {R56 AG066347/AG/NIA NIH HHS/United States ; R03 AG063162/AG/NIA NIH HHS/United States ; R01 AG042178/AG/NIA NIH HHS/United States ; R01 AG069333/AG/NIA NIH HHS/United States ; R56 AG060767/AG/NIA NIH HHS/United States ; R01 AG047812/AG/NIA NIH HHS/United States ; R01 NS105473/NS/NINDS NIH HHS/United States ; },
mesh = {Alzheimer Disease/*metabolism ; Animals ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line ; Coumarins/*pharmacology ; DNA-Binding Proteins/genetics/metabolism ; High Mobility Group Proteins/genetics/metabolism ; Hippocampus/cytology ; Mice ; Mitochondria/drug effects/ultrastructure ; Mitochondrial Dynamics/drug effects ; Mitophagy/*drug effects ; NF-E2-Related Factor 2/genetics/metabolism ; Neurons/metabolism ; Nuclear Respiratory Factor 1/genetics/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; Phosphorylation ; Synapses/drug effects ; Synaptophysin/metabolism ; tau Proteins/genetics/*metabolism ; },
abstract = {The purpose of our study is to determine the protective effects of mitophagy enhancers against phosphorylated tau (P-tau)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Mitochondrial abnormalities, including defective mitochondrial dynamics, biogenesis, axonal transport and impaired clearance of dead mitochondria are linked to P-tau in AD. Mitophagy enhancers are potential therapeutic candidates to clear dead mitochondria and improve synaptic and cognitive functions in AD. We recently optimized the doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. In the current study, we treated mutant Tau expressed in HT22 (mTau-HT22) cells with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial/synaptic genes, cell survival and mitochondrial respiration. We also assessed mitochondrial morphology in mTau-HT22 cells treated and untreated with mitophagy enhancers. Mutant Tau-HT22 cells showed increased fission, decreased fusion, synaptic &amp; mitophagy genes, reduced cell survival and defective mitochondrial respiration. However, these events were reversed in mitophagy enhancers treated mTau-HT22 cells. Cell survival was increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mTau-HT22 cells. Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.},
}
@article {pmid34761857,
year = {2022},
author = {Álvarez-Fernández, B and Bernal-López, MR and Gómez-Huelgas, R},
title = {Role of aripiprazole in the management of behavioural and psychological symptoms of dementia: a narrative review.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {22},
number = {1},
pages = {137-144},
doi = {10.1111/psyg.12787},
pmid = {34761857},
issn = {1479-8301},
support = {CB06/03/0018//Centros de Investigación En Red/ ; C1- 0005-2020//Fondo Europeo de Desarrollo Regional-FEDER and Nicolás Monardes Program/ ; CPII/00014//Miguel Servet Type II Program, Fondo Europeo de Desarrollo Regional-FEDER/ ; },
mesh = {Aggression ; *Antipsychotic Agents/therapeutic use ; Aripiprazole/therapeutic use ; *Dementia/drug therapy ; Humans ; Quality of Life ; },
abstract = {Behavioural and psychological symptoms of dementia affect in a great way quality of life of both patients and their caregivers, which increases the risk of patient institutionalisation when such symptoms are poorly controlled. One of the drugs that are used for controlling behavioural and psychological symptoms of dementia (BPSD) is aripiprazole. This narrative review aims to solve three basic questions. Is aripiprazole useful for the management of these symptoms? Does aripiprazole play a substantial role regarding safety and efficacy, compared with the other pharmacological options available for the same purpose? Has aripiprazole gained importance in treatment regimens of these symptoms, in current clinical practice? We conclude that aripiprazole is effective to manage BPSD. Moreover, it has shown a good safety profile compared with other antipsychotics in advanced disease and frail patients. Thus, aripiprazole has gained importance in current management algorithms for dementia patients mainly due to its efficacy regarding rapid control of agitation and aggressiveness.},
}
@article {pmid34761053,
year = {2021},
author = {Kofoed, RH and Heinen, S and Silburt, J and Dubey, S and Dibia, CL and Maes, M and Simpson, EM and Hynynen, K and Aubert, I},
title = {Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis.},
journal = {Molecular therapy. Methods &amp; clinical development},
volume = {23},
number = {},
pages = {390-405},
pmid = {34761053},
issn = {2329-0501},
abstract = {Efficient disease-modifying treatments for Alzheimer disease, the most common form of dementia, have yet to be established. Gene therapy has the potential to provide the long-term production of therapeutic in the brain following a single administration. However, the blood-brain barrier poses a challenge for gene delivery to the adult brain. We investigated the transduction efficiency and immunological response following non-invasive gene-delivery strategies to the brain of a mouse model of amyloidosis. Two emerging technologies enabling gene delivery across the blood-brain barrier were used to establish the minimal vector dosage required to reach the brain: (1) focused ultrasound combined with intravenous microbubbles, which increases the permeability of the blood-brain barrier at targeted sites and (2) the recombinant adeno-associated virus (rAAV)-based capsid named rAAV-PHP.B. We found that equal intravenous dosages of rAAV9 combined with focused ultrasound, or rAAV-PHP.B, were required for brain gene delivery. In contrast to rAAV9, focused ultrasound did not decrease the rAAV-PHP.B dosage required to transduce brain cells in a mouse model of amyloidosis. The non-invasive rAAV delivery to the brain using rAAV-PHP.B or rAAV9 with focused ultrasound triggered an immune reaction including major histocompatibility complex class II expression, complement system and microglial activation, and T cell infiltration.},
}
@article {pmid34760921,
year = {2021},
author = {Bleuzé, L and Triaca, V and Borreca, A},
title = {FMRP-Driven Neuropathology in Autistic Spectrum Disorder and Alzheimer's disease: A Losing Game.},
journal = {Frontiers in molecular biosciences},
volume = {8},
number = {},
pages = {699613},
pmid = {34760921},
issn = {2296-889X},
abstract = {Fragile X mental retardation protein (FMRP) is an RNA binding protein (RBP) whose absence is essentially associated to Fragile X Syndrome (FXS). As an RNA Binding Protein (RBP), FMRP is able to bind and recognize different RNA structures and the control of specific mRNAs is important for neuronal synaptic plasticity. Perturbations of this pathway have been associated with the autistic spectrum. One of the FMRP partners is the APP mRNA, the main protagonist of Alzheimer's disease (AD), thereby regulating its protein level and metabolism. Therefore FMRP is associated to two neurodevelopmental and age-related degenerative conditions, respectively FXS and AD. Although these pathologies are characterized by different features, they have been reported to share a number of common molecular and cellular players. The aim of this review is to describe the double-edged sword of FMRP in autism and AD, possibly allowing the elucidation of key shared underlying mechanisms and neuronal circuits. As an RBP, FMRP is able to regulate APP expression promoting the production of amyloid β fragments. Indeed, FXS patients show an increase of amyloid β load, typical of other neurological disorders, such as AD, Down syndrome, Parkinson's Disease, etc. Beyond APP dysmetabolism, the two neurodegenerative conditions share molecular targets, brain circuits and related cognitive deficits. In this review, we will point out the potential common neuropathological pattern which needs to be addressed and we will hopefully contribute to clarifying the complex phenotype of these two neurorological disorders, in order to pave the way for a novel, common disease-modifying therapy.},
}
@article {pmid34759373,
year = {2022},
author = {Nassan, M and Videnovic, A},
title = {Circadian rhythms in neurodegenerative disorders.},
journal = {Nature reviews. Neurology},
volume = {18},
number = {1},
pages = {7-24},
pmid = {34759373},
issn = {1759-4766},
mesh = {Animals ; Circadian Clocks ; *Circadian Rhythm ; Humans ; Neurodegenerative Diseases/pathology/*physiopathology ; },
abstract = {Endogenous biological clocks, orchestrated by the suprachiasmatic nucleus, time the circadian rhythms that synchronize physiological and behavioural functions in humans. The circadian system influences most physiological processes, including sleep, alertness and cognitive performance. Disruption of circadian homeostasis has deleterious effects on human health. Neurodegenerative disorders involve a wide range of symptoms, many of which exhibit diurnal variations in frequency and intensity. These disorders also disrupt circadian homeostasis, which in turn has negative effects on symptoms and quality of life. Emerging evidence points to a bidirectional relationship between circadian homeostasis and neurodegeneration, suggesting that circadian function might have an important role in the progression of neurodegenerative disorders. Therefore, the circadian system has become an attractive target for research and clinical care innovations. Studying circadian disruption in neurodegenerative disorders could expand our understanding of the pathophysiology of neurodegeneration and facilitate the development of novel, circadian-based interventions for these disabling disorders. In this Review, we discuss the alterations to the circadian system that occur in movement (Parkinson disease and Huntington disease) and cognitive (Alzheimer disease and frontotemporal dementia) neurodegenerative disorders and provide directions for future investigations in this field.},
}
@article {pmid34759019,
year = {2022},
author = {Bubak, AN and Como, CN and Hassell, JE and Mescher, T and Frietze, SE and Niemeyer, CS and Cohrs, RJ and Nagel, MA},
title = {Targeted RNA Sequencing of VZV-Infected Brain Vascular Adventitial Fibroblasts Indicates That Amyloid May Be Involved in VZV Vasculopathy.},
journal = {Neurology(R) neuroimmunology &amp; neuroinflammation},
volume = {9},
number = {1},
pages = {},
pmid = {34759019},
issn = {2332-7812},
mesh = {*Adventitia/cytology/metabolism/pathology/virology ; Amyloid beta-Peptides/*metabolism ; Cells, Cultured ; *Cerebrovascular Disorders/metabolism/pathology/virology ; *Fibroblasts/cytology/metabolism/pathology/virology ; Humans ; Sequence Analysis, RNA ; Transcriptome/physiology ; *Varicella Zoster Virus Infection/metabolism/pathology/virology ; *Vascular Remodeling/physiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Compared with stroke controls, patients with varicella zoster virus (VZV) vasculopathy have increased amyloid in CSF, along with increased amylin (islet amyloid polypeptide [IAPP]) and anti-VZV antibodies. Thus, we examined the gene expression profiles of VZV-infected primary human brain vascular adventitial fibroblasts (HBVAFs), one of the initial arterial cells infected in VZV vasculopathy, to determine whether they are a potential source of amyloid that can disrupt vasculature and potentiate inflammation.<br><br>METHODS: Mock- and VZV-infected quiescent HBVAFs were harvested at 3 days postinfection. Targeted RNA sequencing of the whole-human transcriptome (BioSpyder Technologies, TempO-Seq) was conducted followed by gene set enrichment and pathway analysis. Selected pathways unique to VZV-infected cells were confirmed by enzyme-linked immunoassays, migration assays, and immunofluorescence analysis (IFA) that included antibodies against amylin and amyloid-beta, as well as amyloid staining by Thioflavin-T.<br><br>RESULTS: Compared with mock, VZV-infected HBVAFs had significantly enriched gene expression pathways involved in vascular remodeling and vascular diseases; confirmatory studies showed secretion of matrix metalloproteinase-3 and -10, as well increased migration of infected cells and uninfected cells when exposed to conditioned media from VZV-infected cells. In addition, significantly enriched pathways involved in amyloid-associated diseases (diabetes mellitus, amyloidosis, and Alzheimer disease), tauopathy, and progressive neurologic disorder were identified; predicted upstream regulators included amyloid precursor protein, apolipoprotein E, microtubule-associated protein tau, presenilin 1, and IAPP. Confirmatory IFA showed that VZV-infected HBVAFs contained amyloidogenic peptides (amyloid-beta and amylin) and intracellular amyloid.<br><br>DISCUSSION: Gene expression profiles and pathway enrichment analysis of VZV-infected HBVAFs, as well as phenotypic studies, reveal features of pathologic vascular remodeling (e.g., increased cell migration and changes in the extracellular matrix) that can contribute to cerebrovascular disease. Furthermore, the discovery of amyloid-associated transcriptional pathways and intracellular amyloid deposition in HBVAFs raise the possibility that VZV vasculopathy is an amyloid disease. Amyloid deposition may contribute to cell death and loss of vascular wall integrity, as well as potentiate chronic inflammation in VZV vasculopathy, with disease severity and recurrence determined by the host's ability to clear virus infection and amyloid deposition and by the coexistence of other amyloid-associated diseases (i.e., Alzheimer disease and diabetes mellitus).},
}
@article {pmid34758331,
year = {2021},
author = {Pomeshchik, Y and Klementieva, O and Gil, J and Martinsson, I and Hansen, MG and de Vries, T and Sancho-Balsells, A and Russ, K and Savchenko, E and Collin, A and Vaz, AR and Bagnoli, S and Nacmias, B and Rampon, C and Sorbi, S and Brites, D and Marko-Varga, G and Kokaia, Z and Rezeli, M and Gouras, GK and Roybon, L},
title = {Human iPSC-derived hippocampal spheroids: An innovative tool for stratifying Alzheimer disease patient-specific cellular phenotypes and developing therapies.},
journal = {Stem cell reports},
volume = {16},
number = {11},
pages = {2838},
doi = {10.1016/j.stemcr.2021.10.003},
pmid = {34758331},
issn = {2213-6711},
}
@article {pmid34757642,
year = {2022},
author = {Jabeen, K and Rehman, K and Akash, MSH},
title = {Genetic mutations of APOEε4 carriers in cardiovascular patients lead to the development of insulin resistance and risk of Alzheimer's disease.},
journal = {Journal of biochemical and molecular toxicology},
volume = {36},
number = {2},
pages = {e22953},
doi = {10.1002/jbt.22953},
pmid = {34757642},
issn = {1099-0461},
mesh = {*Alzheimer Disease/etiology/genetics ; Apolipoprotein E4/*genetics ; Apolipoproteins E/*genetics ; *Cardiovascular Diseases/complications/genetics ; Humans ; Insulin Resistance/*genetics ; *Mutation ; },
abstract = {Type 2 diabetes mellitus and Alzheimer's disease (AD), both are chronic and progressive diseases. Many cardiovascular and genetic risk factors are considered responsible for the development of AD and diabetes mellitus (DM). Genetic risk factor such as apolipoprotein E (APOE) plays a critical role in the progression of AD. Specifically, APOEε4 is genetically the strongest isoform associated with neuronal insulin deficiency, altered lipid homeostasis, and metabolism, decreased glucose uptake, impaired gray matter volume, and cerebrovascular functions. In this article, we have summarized the mechanisms of cardiovascular disturbances associated with AD and DM, impact of amyloid-β aggregation, and neurofibrillary tangles formation in AD. Moreover, cardiovascular risk factors leading to insulin resistance (IR) and amyloid-β aggregation are highlighted along with the effects of APOE risk alleles on cerebral, lipid, and cholesterol metabolism leading to CVD-mediated IR. Correspondingly, the contribution of IR, genetic and cardiovascular risk factors in amyloid-β aggregation, which may lead to the late onset of AD and DM, has been also discussed. In short, IR is related to significantly lower cerebral glucose metabolism, which sequentially forecasts poorer memory performance. Hence, there will be more chances for neural glucose intolerance and impairment of cognitive function in cardiac patients, particularly APOEε4 carriers having IR. Hence, this review provides a better understanding of the corresponding crosstalk among different pathways. This will help to investigate the rational application of preventive measures against IR and cognitive dysfunction, specifically in APOEε4 carriers' cardio-metabolic patients.},
}
@article {pmid34756135,
year = {2022},
author = {Yoo, H and Kim, H and Koh, I and Lee, K and Ok, J},
title = {Effect of Metabolic Syndrome on the Incidence of Dementia Based on National Insurance Data in Korea.},
journal = {Metabolic syndrome and related disorders},
volume = {20},
number = {1},
pages = {29-35},
doi = {10.1089/met.2021.0046},
pmid = {34756135},
issn = {1557-8518},
mesh = {*Alzheimer Disease/diagnosis/epidemiology ; *Dementia, Vascular/diagnosis/epidemiology ; Female ; Humans ; Incidence ; *Insurance ; Longitudinal Studies ; Male ; *Metabolic Syndrome/complications/diagnosis/epidemiology ; Republic of Korea/epidemiology ; Risk Factors ; },
abstract = {Background: To evaluate the association between metabolic syndrome (MetS) and the incidence of dementia using big data from national health claims and health examinations. Methods: This study involved 3,619,388 subjects categorized with MetS of three status based on the results of health examinations conducted in 2009. This was a longitudinal study of the incidence of dementia based on the national health claims from the date of health examinations in 2009 until December 31, 2018. This study was conducted for men and women aged 50 to 69 years living in Korea. A Cox proportional hazard regression was performed to analyze the risk of dementia according to the status of MetS. Results: The cumulative incidence of Alzheimer dementia was 0.41% in the non-Mets group, 0.54% in the pre-MetS group, and 0.67% in the MetS group. The cumulative incidence of vascular dementia was 0.19% in the non-Mets group, 0.27% in the pre-MetS group, and 0.34% in the MetS group. The risk of Alzheimer dementia in the pre-MetS group compared to the non-Mets group was 1.20-fold greater (95% confidence interval, CI: 1.14-1.26) and was 1.39-fold (95% CI: 1.31-1.48) greater in the MetS group. The risk of vascular dementia in the pre-MetS group compared to the non-Mets group was 1.30-fold greater (95% CI: 1.21-1.40) and the risk of vascular dementia was 1.53-fold (95% CI: 1.44 1.71) greater. Conclusions: This study showed that pre-MetS and MetS were related to an increased incidence of Alzheimer dementia and vascular dementia. Also, these results support efforts to decrease the incidence of Alzheimer dementia and vascular dementia through managing the Mets.},
}
@article {pmid34756134,
year = {2021},
author = {Dutta, S and Rahman, S and Ahmad, R and Kumar, T and Dutta, G and Banerjee, S and Abubakar, AR and Rowaiye, AB and Dhingra, S and Ravichandiran, V and Kumar, S and Sharma, P and Haque, M and Charan, J},
title = {An evidence-based review of neuronal cholesterol role in dementia and statins as a pharmacotherapy in reducing risk of dementia.},
journal = {Expert review of neurotherapeutics},
volume = {21},
number = {12},
pages = {1455-1472},
doi = {10.1080/14737175.2021.2003705},
pmid = {34756134},
issn = {1744-8360},
mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Cholesterol ; Humans ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; },
abstract = {INTRODUCTION: Dementia is a progressive neurodegenerative disorder impairing memory and cognition. Alzheimer's Disease, followed by vascular dementia - the most typical form. Risk factors for vascular dementia include diabetes, cardiovascular disease, hyperlipidemia. Lipids' levels are significantly associated with vascular changes in the brain.<br><br>AREAS COVERED: The present article reviews the cholesterol metabolism in the brain, which includes: the synthesis, transport, storage, and elimination process. Additionally, it reviews the role of cholesterol in the pathogenesis of dementia and statin as a therapeutic intervention in dementia. In addition to the above, it further reviews evidence in support of as well as against statin therapy in dementia, recent updates of statin pharmacology, and demerits of use of statin pharmacotherapy.<br><br>EXPERT OPINION: Amyloid-β peptides and intraneuronal neurofibrillary tangles are markers of Alzheimer's disease. Evidence shows cholesterol modulates the functioning of enzymes associated with Amyloid-β peptide processing and synthesis. Lowering cholesterol using statin may help prevent or delay the progression of dementia. This paper reviews the role of statin in dementia and recommends extensive future studies, including genetic research, to obtain a precise medication approach for patients with dementia.},
}
@article {pmid34755432,
year = {2022},
author = {Parveen, S and Mehra, A and Kumar, K and Grover, S},
title = {Knowledge and attitude of caregivers of people with dementia.},
journal = {Geriatrics &amp; gerontology international},
volume = {22},
number = {1},
pages = {19-25},
doi = {10.1111/ggi.14304},
pmid = {34755432},
issn = {1447-0594},
mesh = {Aged ; *Alzheimer Disease ; *Caregivers ; Family ; Female ; Humans ; Male ; },
abstract = {AIM: This study aimed to evaluate the knowledge and attitude of caregivers of people with dementia towards the disease (Alzheimer disease). The secondary objective of the study was to assess the association of attitude and knowledge towards dementia.<br><br>METHODS: In total, 50 patients with dementia and their caregivers were included in the present study. Caregivers were evaluated on the Dementia Attitude Scale and Alzheimer's Disease Knowledge Scale (ADKS) to assess the level of knowledge and attitude.<br><br>RESULTS: The mean age of patients was 72.2 years, and the majority of them were men, married, from joint/extended family setup, urban background, and upper or upper-middle socioeconomic status. The mean age of the caregivers was 48.04 years, and the majority was educated more than the matric level. Nearly half of the caregivers were children, and about one-third were the spouse of the person with dementia. The mean duration of the caregiver role was 3.6 ± 3.0 years, while the average time spent in caregiving was 7.4 ± 2.9 h/day. Using the Alzheimer's Disease Knowledge Scale, the mean knowledge score for the caregivers was 16.9 ± 2.7. In terms of individual items on the knowledge scale, most of the caregivers were aware of most aspects of dementia. In terms of the mean weighted score, the maximum score was for the domains of course and symptoms and this was followed by the domain of "treatment and management." The lowest score was obtained for the domain of assessment and diagnosis on ADKS. On the Dementia Attitude Scale, the mean total score was 76.4 ± 18.4. The mean total score for the knowledge domain was higher than the support domain.<br><br>CONCLUSION: The current study suggests that most caregivers with dementia have a reasonable level of knowledge about dementia. However, in terms of attitude, caregivers of people with dementia have a less positive attitude towards dementia. The study's finding suggests that there is a need to evaluate the knowledge and attitude of the caregivers of people with dementia and the gaps must be addressed to improve the outcome, both for the people with dementia and their caregivers. Geriatr Gerontol Int 2022; 22: 19-25.},
}
@article {pmid34752348,
year = {2021},
author = {Altuna-Azkargorta, M and Mendioroz-Iriarte, M},
title = {Blood biomarkers in Alzheimer's disease.},
journal = {Neurologia (Barcelona, Spain)},
volume = {36},
number = {9},
pages = {704-710},
doi = {10.1016/j.nrleng.2018.03.006},
pmid = {34752348},
issn = {2173-5808},
mesh = {*Alzheimer Disease/diagnosis ; Biomarkers ; Early Diagnosis ; Humans ; Metabolomics ; },
abstract = {INTRODUCTION: Early diagnosis of Alzheimer disease (AD) through the use of biomarkers could assist in the implementation and monitoring of early therapeutic interventions, and has the potential to significantly modify the course of the disease.<br><br>DEVELOPMENT: The classic cerebrospinal fluid and approved structural and functional neuroimaging biomarkers are of limited clinical application given their invasive nature and/or high cost. The identification of more accessible and less costly biomarkers, such as blood biomarkers, would increase their use in clinical practice. We review the available published evidence on the main blood biochemical biomarkers potentially useful for diagnosing AD.<br><br>CONCLUSIONS: Blood biomarkers are more cost- and time-effective than CSF biomarkers. However, immediate applicability in clinical practice is relatively unlikely. The main limitations come from the difficulty of measuring and standardising thresholds between different laboratories and the failure to replicate results. Of all the molecules studied, apoptosis and neurodegeneration biomarkers and the biomarker panels obtained through "omics" approaches, such as isolated or combined metabolomics, offer the most promising results.},
}
@article {pmid34752346,
year = {2021},
author = {Cruz-Sanabria, F and Bonilla-Vargas, K and Estrada, K and Mancera, O and Vega, E and Guerrero, E and Ortega-Rojas, J and Mahecha María, F and Romero, A and Montañés, P and Celeita, V and Arboleda, H and Pardo, R},
title = {Analysis of cognitive performance and polymorphisms of SORL1, PVRL2, CR1, TOMM40, APOE, PICALM, GWAS_14q, CLU, and BIN1 in patients with mild cognitive impairment and cognitively healthy controls.},
journal = {Neurologia (Barcelona, Spain)},
volume = {36},
number = {9},
pages = {681-691},
doi = {10.1016/j.nrleng.2018.07.012},
pmid = {34752346},
issn = {2173-5808},
mesh = {Adaptor Proteins, Signal Transducing ; Apolipoproteins E/genetics ; Clusterin/genetics ; Cognition ; *Cognitive Dysfunction/genetics ; Cross-Sectional Studies ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; LDL-Receptor Related Proteins ; Membrane Transport Proteins/genetics ; Mitochondrial Precursor Protein Import Complex Proteins ; *Monomeric Clathrin Assembly Proteins/genetics ; Nuclear Proteins ; Polymorphism, Single Nucleotide ; Prospective Studies ; Receptors, Complement 3b/genetics ; Tumor Suppressor Proteins ; },
abstract = {INTRODUCTION: Alzheimer disease risk polymorphisms have been studied in patients with dementia, but have not yet been explored in mild cognitive impairment (MCI) in our population; nor have they been addressed in relation to cognitive variables, which can be predictive biomarkers of disease.<br><br>OBJECTIVE: To evaluate cognitive performance and presence of polymorphisms of the genes SORL1(rs11218304), PVRL2(rs6859), CR1(rs6656401), TOMM40(rs2075650), APOE (isoforms ε2, ε3, ε4), PICALM(rs3851179), GWAS_14q(rs11622883), BIN1(rs744373), and CLU(rs227959 and rs11136000) in patients with MCI and healthy individuals.<br><br>METHODOLOGY: We performed a cross-sectional, exploratory, descriptive study of a prospective cohort of participants selected by non-probabilistic sampling, evaluated with neurological, neuropsychological, and genetic testing, and classified as cognitively healthy individuals and patients with MCI. Cognition was evaluated with the Neuronorma battery and analysed in relation to the polymorphic variants by means of measures of central tendency, confidence intervals, and nonparametric statistics.<br><br>RESULTS: We found differences in performance in language and memory tasks between carriers and non-carriers of BIN1, CLU, and CR1 variants and a trend towards poor cognitive performance for PICALM, GWAS_14q, SORL1, and PVRL2 variants; the APOE and TOMM40 variants were not associated with poor cognitive performance.<br><br>DISCUSSION: Differences in cognitive performance associated with these polymorphic variants may suggest that the mechanisms regulating these genes could have an effect on cognition in the absence of dementia; however, this study was exploratory and hypotheses based on these results must be explored in larger samples.},
}
@article {pmid34752345,
year = {2021},
author = {Solleiro-Villavicencio, H and Hernández-Orozco, E and Rivas-Arancibia, S},
title = {Effect of exposure to low doses of ozone on interleukin 17A expression during progressive neurodegeneration in the rat hippocampus.},
journal = {Neurologia (Barcelona, Spain)},
volume = {36},
number = {9},
pages = {673-680},
doi = {10.1016/j.nrleng.2018.08.003},
pmid = {34752345},
issn = {2173-5808},
mesh = {Animals ; *Hippocampus/metabolism ; *Interleukin-17/metabolism ; Microglia/metabolism ; *Ozone/adverse effects ; Rats ; Rats, Wistar ; },
abstract = {INTRODUCTION: Chronic exposure to low doses of ozone causes oxidative stress and loss of regulation of the inflammatory response, leading to progressive neurodegeneration.<br><br>OBJECTIVE: We studied the effect of chronic exposure to low doses of ozone on IL-17A concentration and expression in neurons, microglia, astrocytes, and T cells in the rat hippocampus.<br><br>METHODS: We used 72 Wistar rats, divided into 6 groups (n=12): a control group (no ozone exposure) and 5 groups exposed to ozone (0.25ppm, 4h daily) for 7, 15, 30, 60, and 90 days. We processed 6 rats from each group to quantify IL-17A by ELISA; the remaining 6 were processed for immunohistochemistry (against IL-17A and GFAP, Iba1, NeuN, and CD3).<br><br>RESULTS: The ELISA study data showed a significant increase in IL-17A concentrations in the 7-, 15-, 30-, and 60-day exposure groups, with regard to the control group (P<.05). Furthermore, they indicate that hippocampal neurons were the cells showing greatest immunoreactivity against IL-17A between 60 and 90 days of exposure to ozone; we also observed an increase in activated astrocytes in the 30- and 60-day exposure groups.<br><br>CONCLUSION: Exposure to ozone in rats induces an increase in IL-17A expression, mainly in hippocampal neurons, accompanied by hippocampal astrocyte activation during chronic neurodegeneration, similar to that observed in Alzheimer disease in humans.},
}
@article {pmid34750588,
year = {2022},
author = {Blanchard, JW and Victor, MB and Tsai, LH},
title = {Dissecting the complexities of Alzheimer disease with in vitro models of the human brain.},
journal = {Nature reviews. Neurology},
volume = {18},
number = {1},
pages = {25-39},
pmid = {34750588},
issn = {1759-4766},
mesh = {Alzheimer Disease/genetics/*pathology/physiopathology ; Animals ; Brain/*pathology/physiology/physiopathology ; Genetic Predisposition to Disease ; Humans ; *Models, Anatomic ; *Models, Neurological ; },
abstract = {Alzheimer disease (AD) is the most prevalent type of dementia. It is marked by severe memory loss and cognitive decline, and currently has limited effective treatment options. Although individuals with AD have common neuropathological hallmarks, emerging data suggest that the disease has a complex polygenic aetiology, and more than 25 genetic loci have been linked to an elevated risk of AD and dementia. Nevertheless, our ability to decipher the cellular and molecular mechanisms that underlie genetic susceptibility to AD, and its progression and severity, remains limited. Here, we discuss ongoing efforts to leverage genomic data from patients using cellular reprogramming technologies to recapitulate complex brain systems and build in vitro discovery platforms. Much attention has already been given to methodologies to derive major brain cell types from pluripotent stem cells. We therefore focus on technologies that combine multiple cell types to recreate anatomical and physiological properties of human brain tissue in vitro. We discuss the advances in the field for modelling four domains that have come into view as key contributors to the pathogenesis of AD: the blood-brain barrier, myelination, neuroinflammation and neuronal circuits. We also highlight opportunities for the field to further interrogate the complex genetic and environmental factors of AD using in vitro models.},
}
@article {pmid34749616,
year = {2021},
author = {Pakdin, M and Toutounchian, S and Namazi, S and Arabpour, Z and Pouladi, A and Afsahi, S and Poudineh, M and Nasab, MMM and Yaghoobpoor, S and Deravi, N},
title = {Type 2 Diabetes Mellitus and Alzheimer Disease: A Review of the Potential Links.},
journal = {Current diabetes reviews},
volume = {},
number = {},
pages = {},
doi = {10.2174/1573399818666211105122545},
pmid = {34749616},
issn = {1875-6417},
abstract = {Diabetes mellitus and Alzheimer's disease are considered the most prevalent diseases in older ages worldwide. The main pathology of Alzheimer's disease is highly related with accumulation of misfolded proteins that lead to neuronal dysfunction in the brain. On the other hand, diabetes mellitus is associated with alteration of insulin signaling, which could cause the reduction of glu-cose uptake, metabolic prohibition of energy consuming cells, as well as suppression of glucose to fat conversion in the liver. In spite of having seemingly different pathological features, both dis-eases share common underlying biological mechanisms. Besides, the epidemiological and envi-ronmental links between these two diseases should not be overlooked. In this study, we aim to review shared pathological mechanisms of Alzheimer's disease and diabetes mellitus, including impaired glucose metabolism, increased Amyloid-Beta (Aβ) production, impaired lipid metabo-lism, mitochondrial dysfunction, increased inflammation and elevated oxidative stress. Further-more, we discuss epidemiological/environmental association between these two diseases and also review animal investigations, which have evaluated the potential links between the two diseases.},
}
@article {pmid34747789,
year = {2021},
author = {Chakraborty, S and Joardar, A and Roy, S and Gangopadhyay, G and Biswas, A},
title = {ApoE ε4 and IL-6-174G/C Polymorphism may Lead to Early Onset of Alzheimer's Disease with Atypical Presentation.},
journal = {Neurology India},
volume = {69},
number = {5},
pages = {1228-1233},
doi = {10.4103/0028-3886.329604},
pmid = {34747789},
issn = {1998-4022},
mesh = {Alleles ; *Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; Gene Frequency ; Genotype ; Humans ; Interleukin-6/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia. Although genetic mutations are known in rare familial form, exact cause of neurodegeneration in sporadic AD is still unknown. While ApoE ε4 and IL-6 C-174G/C patterns have been found to increase the risk of AD in Caucasians, the results are inconsistent in other ethnic groups.<br><br>OBJECTIVE: The aim of this study was to evaluate the effect of ApoE and IL-6-174G/C polymorphisms among patients of AD in the Eastern part of India.<br><br>MATERIALS AND METHODS: Consecutive patients of probable AD diagnosed as per National Institute on Aging-Alzheimer's Association (NIA-AA) criteria with age, gender, and education-matched healthy controls were recruited between December 2015 and September 2018. Patients were clinically evaluated and along with controls were genotyped for ApoE and IL-6-174G/C polymorphisms by the polymerase chain reaction method.<br><br>RESULTS: A total 115 patients and 162 controls showed a similar pattern of ApoE and IL-6-174G/C polymorphism pattern. While ε3ε3 and GG patterns were the commonest, followed by ε3ε4 and GC pattern in ApoE and IL-6 respectively, the effect of ApoE ε4 and IL-6-174 C allele on AD symptoms could not be established. However, patients with onset before 50 years were found to have significantly higher proportion of ApoE ε4 and C allele of IL-6-174 in comparison to patients with onset above 50. These young patients were also having more atypical presentation than their older counterpart.<br><br>CONCLUSION: Our study revealed a novel role of both ApoE ε4 and C allele of IL-6-174 together in developing early onset AD with more atypical clinical features.},
}
@article {pmid34743630,
year = {2022},
author = {Robb, WH and Khan, OA and Ahmed, HA and Li, J and Moore, EE and Cambronero, FE and Pechman, KR and Liu, D and Gifford, KA and Landman, BA and Donahue, MJ and Hohman, TJ and Jefferson, AL},
title = {Lower cerebral oxygen utilization is associated with Alzheimer's disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {42},
number = {4},
pages = {642-655},
pmid = {34743630},
issn = {1559-7016},
support = {P20 AG068082/AG/NIA NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; R01 AG056534/AG/NIA NIH HHS/United States ; T32 GM007347/GM/NIGMS NIH HHS/United States ; F30 AG064847/AG/NIA NIH HHS/United States ; K01 AG049164/AG/NIA NIH HHS/United States ; R01 NS100980/NS/NINDS NIH HHS/United States ; T32 AG058524/AG/NIA NIH HHS/United States ; R01 AG034962/AG/NIA NIH HHS/United States ; K23 AG045966/AG/NIA NIH HHS/United States ; S10 OD023680/OD/NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; K24 AG046373/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/genetics/physiopathology ; *Apolipoprotein E4/genetics ; Apolipoproteins E ; Cognition/physiology ; *Cognitive Dysfunction ; Female ; Genotype ; Humans ; Male ; Neuropsychological Tests ; *Oxygen/physiology ; },
abstract = {Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are markers of cerebral oxygen homeostasis and metabolism that may offer insights into abnormal changes in brain aging. The present study cross-sectionally related OEF and CMRO2 to cognitive performance and structural neuroimaging variables among older adults (n = 246, 74 ± 7 years, 37% female) and tested whether apolipoprotein E (APOE)-ε4 status modified these associations. Main effects of OEF and CMRO2 were null (p-values >0.06), and OEF interactions with APOE-ε4 status on cognitive and structural imaging outcomes were null (p-values >0.06). However, CMRO2 interacted with APOE-ε4 status on language (p = 0.002), executive function (p = 0.03), visuospatial (p = 0.005), and episodic memory performances (p = 0.03), and on hippocampal (p = 0.006) and inferior lateral ventricle volumes (p = 0.02). In stratified analyses, lower oxygen metabolism related to worse language (p = 0.02) and episodic memory performance (p = 0.03) among APOE-ε4 carriers only. Associations between CMRO2 and cognitive performance were primarily driven by APOE-ε4 carriers with existing cognitive impairment. Congruence across language and episodic memory results as well as hippocampal and inferior lateral ventricle volume findings suggest that APOE-ε4 may interact with cerebral oxygen metabolism in the pathogenesis of Alzheimer's disease and related neurodegeneration.},
}
@article {pmid34740867,
year = {2022},
author = {Oedekoven, C and Egeri, L and Jessen, F and Wagner, M and Dodel, R},
title = {Subjective cognitive decline in idiopathic Parkinson´s disease: A systematic review.},
journal = {Ageing research reviews},
volume = {74},
number = {},
pages = {101508},
doi = {10.1016/j.arr.2021.101508},
pmid = {34740867},
issn = {1872-9649},
mesh = {Cognition ; *Cognitive Dysfunction/diagnosis/epidemiology/etiology ; Humans ; Neuropsychological Tests ; *Parkinson Disease/complications/epidemiology ; },
abstract = {Cognitive symptoms of Parkinson's disease (PD) have been long underestimated, but are some of the most disabling non-motor features of the disease. In order to establish signs that allow for earlier detection of cognitive decline in PD, the concept of `subjective cognitive decline´ (SCD) has gained a growing interest. SCD refers to patients who report a decline in subjective cognitive capacities, while their results on neuropsychological tests are within the normal performance range, indicating adequate cognitive functions. The aim of this review was to evaluate the concept of SCD in PD and give an overview of the current research. A systematic literature search in PubMed was performed to identify articles published before December 2020. We included 18 studies with a total of n = 2,654 patients. While there is currently no consensus on research or clinical criteria for SCD in PD, this review presents the accumulated evidence for SCD in PD patients and supports the importance of early identification of cognitive deficits, due to the relatively high prevalence for SCD in PD and the added risk of future cognitive impairment it entails. The publications included in this review indicate that SCD may be part of the PD spectrum but further research is needed. Expanding research on SCD in PD will allow for earlier detection of cognitive impairment and may foster preventive interventions.},
}
@article {pmid34740367,
year = {2021},
author = {Park, SH and Baik, K and Jeon, S and Chang, WS and Ye, BS and Chang, JW},
title = {Extensive frontal focused ultrasound mediated blood-brain barrier opening for the treatment of Alzheimer's disease: a proof-of-concept study.},
journal = {Translational neurodegeneration},
volume = {10},
number = {1},
pages = {44},
pmid = {34740367},
issn = {2047-9158},
mesh = {*Alzheimer Disease/diagnostic imaging/therapy ; *Blood-Brain Barrier/diagnostic imaging ; Humans ; Plaque, Amyloid ; Prospective Studies ; Tomography, X-Ray Computed ; },
abstract = {BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening has shown efficacy in removal of amyloid plaque and improvement of cognitive functions in preclinical studies, but this is rarely reported in clinical studies. This study was conducted to evaluate the safety, feasibility and potential benefits of repeated extensive BBB opening.<br><br>METHODS: In this open-label, prospective study, six patients with Alzheimer's disease (AD) were enrolled at Severance Hospital in Korea between August 2020 and September 2020. Five of them completed the study. FUS-mediated BBB opening, targeting the bilateral frontal lobe regions over 20 cm3, was performed twice at three-month intervals. Magnetic resonance imaging, 18F-Florbetaben (FBB) positron emission tomography, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI) and comprehensive neuropsychological tests were performed before and after the procedures.<br><br>RESULTS: FUS targeted a mean volume of 21.1 ± 2.7 cm3 and BBB opening was confirmed at 95.7% ± 9.4% of the targeted volume. The frontal-to-other cortical region FBB standardized uptake value ratio at 3 months after the procedure showed a slight decrease, which was statistically significant, compared to the pre-procedure value (- 1.6%, 0.986 vs1.002, P = 0.043). The CGA-NPI score at 2 weeks after the second procedure significantly decreased compared to baseline (2.2 ± 3.0 vs 8.6 ± 6.0, P = 0.042), but recovered after 3 months (5.2 ± 5.8 vs 8.6 ± 6.0, P = 0.89). No adverse effects were observed.<br><br>CONCLUSIONS: The repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD. In addition, the BBB opening is potentially beneficial for amyloid removal in AD patients.},
}
@article {pmid34737037,
year = {2021},
author = {Butterfield, DA},
title = {Ubiquitin carboxyl-terminal hydrolase L-1 in brain: Focus on its oxidative/nitrosative modification and role in brains of subjects with Alzheimer disease and mild cognitive impairment.},
journal = {Free radical biology &amp; medicine},
volume = {177},
number = {},
pages = {278-286},
pmid = {34737037},
issn = {1873-4596},
support = {R01 AG060056/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/genetics ; Brain/metabolism ; *Cognitive Dysfunction/genetics ; Humans ; Oxidative Stress ; Ubiquitin/metabolism ; Ubiquitin Thiolesterase/genetics/metabolism ; },
abstract = {Neurons must remove aggregated, damaged proteins in order to survive. Among the ways of facilitating this protein quality control is the ubiquitin-proteasomal system (UPS). Aggregated, damaged proteins are targeted for destruction by the UPS by acquiring a polymer of ubiquitin residues that serves as a signal for transport to the UPS. However, before this protein degradation can occur, the polyubiquitin chain must be removed, one residue at a time, a reaction facilitated by the enzyme, ubiquitin C-terminal hydrolase (UCH-L1). In Alzheimer disease brain, this normally abundant protein is both of lower levels and oxidatively and nitrosatively modified than in control brain. This causes diminished function of the pleiotropic UCH-L1 enzyme with consequent pathological alterations in AD brain, and the author asserts the oxidative and nitrosative alterations of UCH-L1 are major contributors to mechanisms of neuronal death in this devastating dementing disorder and its earlier stage, mild cognitive impairment (MCI). This review paper outlines these findings in AD and MCI brain.},
}
@article {pmid34735921,
year = {2022},
author = {Chen, H and Meng, L and Shen, L},
title = {Multiple roles of short-chain fatty acids in Alzheimer disease.},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {93},
number = {},
pages = {111499},
doi = {10.1016/j.nut.2021.111499},
pmid = {34735921},
issn = {1873-1244},
mesh = {Aged ; *Alzheimer Disease ; Epigenesis, Genetic ; Fatty Acids, Volatile ; Humans ; *Neurodegenerative Diseases ; Neuroinflammatory Diseases ; },
abstract = {Alzheimer disease (AD) is the most common form of neurodegenerative disease in older adults and has a complicated etiology. Recently, the roles of short-chain fatty acids (SCFAs), the main metabolites generated by fermentation of dietary fiber by gut microbiota, in the pathogenesis of AD have attracted considerable interest. This study analyzed the multiple roles of SCFAs in AD pathogenesis from five aspects, including: 1) epigenetic regulation; 2) modulation of neuroinflammation; 3) maintenance of the blood-brain barrier (BBB); 4) regulation of brain metabolism; and 5) interference in amyloid protein formation. According to the currently available evidence, SCFAs, particularly butyrate, cause important biological effects that interfere with the development of AD. However, the effect of other SCFAs, such as propionate, on AD might be either beneficial or harmful to different pathways, indicating that the role of SCFAs in the pathogenesis of AD is rather complicated and warrants further investigations.},
}
@article {pmid34733087,
year = {2021},
author = {Faraj, J and Takanti, V and Tavakoli, HR},
title = {The Gut-Brain Axis: Literature Overview and Psychiatric Applications.},
journal = {Federal practitioner : for the health care professionals of the VA, DoD, and PHS},
volume = {38},
number = {8},
pages = {356-362},
pmid = {34733087},
issn = {1078-4497},
abstract = {IMPORTANCE: Literature exploring the relationship between the intestinal microbiome and its effects on general health and well-being has grown significantly in recent years, and our knowledge of this subject continues to grow. Mounting evidence indicates that the intestinal microbiome is a potential target for therapeutic intervention in psychiatric illness and in neurodegenerative disorders such as Alzheimer disease. It is reasonable to consider modulating not just a patient's neurochemistry, behavior, or cognitive habits, but also their intestinal microbiome in an effort to improve psychiatric symptoms.<br><br>OBSERVATIONS: In this review paper, we show that intestinal microbiota possess the ability to directly influence both physical and mental well-being; therefore, should be included in future discussions regarding psychiatric treatment.<br><br>CONCLUSIONS: Clinicians are encouraged to consider patients' gut health when evaluating and treating psychiatric conditions, such as anxiety and depression. Optimization and diversification of gut flora through the use of psychobiotics-probiotics that confer mental health benefits-may soon become standard practice in conjunction with traditional psychiatric treatment modalities such as pharmacotherapy and psychotherapy.},
}
@article {pmid34733055,
year = {2021},
author = {Sadananda, G and Velmurugan, JD and Subramaniam, JR},
title = {DMSO Delays Alzheimer Disease Causing Aβ-induced Paralysis in C. elegans Through Modulation of Glutamate/Acetylcholine Neurotransmission.},
journal = {Annals of neurosciences},
volume = {28},
number = {1-2},
pages = {55-64},
pmid = {34733055},
issn = {0972-7531},
abstract = {BACKGROUND: Alzheimer's disease (AD), a prevalent neurodegenerative disease with progressive dementia and neurotransmission (NT)-dysfunction-related complications in older adults, is known to be caused by abnormal Amyloid-β (Aβ) peptide and associated amyloid plaques in the brain. Drugs to cure AD are not in sight. Two major excitatory neurotransmitters, glutamate (Glu) and acetylcholine (ACh), and their signaling systems are implicated in AD.<br><br>OBJECTIVE: To determine the effect of various NT-altering compounds including fenobam, quisqualic acid, and dimethyl sulfoxide (DMSO) in the protection against Aβ toxicity. Further, to identify the potential mechanism through which the protection happens.<br><br>METHODS: The well-known C. elegans AD model, CL4176, in which human Aβ expression is turned on upon a temperature shift to 25 °C that leads to paralysis, was screened for protection/delay in paralysis because of Αβ toxicity. While screening the compounds, dimethyl sulfoxide (DMSO), a universal solvent used to solubilize compounds, was identified to provide protection. Aldicarb and levamisole assays were performed to identify the contribution of ACh neurotransmission in Αβ toxicity protection by DMSO.<br><br>RESULTS: One percent and two percent DMSO delayed paralysis by 48% and 90%, respectively. DMSO was dominant over one of the Glu-NT pathway-related compounds, Fenobam-Group I mGluR antagonist. But DMSO provided only 30% to 50% protection against Quisqualic acid, the Glu-agonist. DMSO (2%) delayed ACh-NT, both presynaptic acetylcholine esterase inhibitor (AchEi)-aldicarb and postsynaptic-iAChR-agonst-levamisole induced paralysis, by ∼70% in CL4176. DMSO seems to be altering Ca2+ ion permeability essential for NT as EthyleneDiamine Tetra-Acetic acid (EDTA) and DMSO provided similar aldicarb resistance either combined or alone in wildtype worms. But postsynaptic Ca2+ depletion by EDTA could reverse DMSO-induced levamisole hypersensitivity. Surprisingly, the absence of FOrkhead boXO (FOXO) transcription factor homolog, daf-16 (loss-of-function mutant), a critical transcription factor in the reduced IIS-mediated longevity in C. elegans, abolished DMSO-mediated AldR.<br><br>CONCLUSION: DMSO and Fenobam protect against Aβ toxicity through modulation of NT.},
}
@article {pmid34732544,
year = {2021},
author = {Schelbaum, E and Loughlin, L and Jett, S and Zhang, C and Jang, G and Malviya, N and Hristov, H and Pahlajani, S and Isaacson, R and Dyke, JP and Kamel, H and Brinton, RD and Mosconi, L},
title = {Association of Reproductive History With Brain MRI Biomarkers of Dementia Risk in Midlife.},
journal = {Neurology},
volume = {97},
number = {23},
pages = {e2328-e2339},
pmid = {34732544},
issn = {1526-632X},
support = {P01 AG026572/AG/NIA NIH HHS/United States ; R01 AG057931/AG/NIA NIH HHS/United States ; UL1 TR002384/TR/NCATS NIH HHS/United States ; R01 AG035137/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; *Alzheimer Disease/diagnostic imaging/metabolism ; Biomarkers/metabolism ; Brain/diagnostic imaging/metabolism ; Child ; Female ; Gray Matter/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; Male ; *Reproductive History ; },
abstract = {BACKGROUND AND OBJECTIVES: To examine associations between indicators of estrogen exposure from women's reproductive history and brain MRI biomarkers of Alzheimer disease (AD) in midlife.<br><br>METHODS: We evaluated 99 cognitively normal women 52 ± 6 years of age and 29 men 52 ± 7 years of age with reproductive history data, neuropsychological testing, and volumetric MRI scans. We used multiple regressions to examine associations among reproductive history indicators, voxel-wise gray matter volume (GMV), and memory and global cognition scores, adjusting for demographics and midlife health indicators. Exposure variables were menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, and use of menopause hormonal therapy (HT) and hormonal contraceptives (HC).<br><br>RESULTS: All menopausal groups exhibited lower GMV in AD-vulnerable regions compared to men, with perimenopausal and postmenopausal groups also exhibiting lower GMV in temporal cortex compared to the premenopausal group. Reproductive span, number of children and pregnancies, and use of HT and HC were positively associated with GMV, chiefly in temporal cortex, frontal cortex, and precuneus, independent of age, APOE ε4 status, and midlife health indicators. Although reproductive history indicators were not directly associated with cognitive measures, GMV in temporal regions was positively associated with memory and global cognition scores.<br><br>DISCUSSION: Reproductive history events signaling more estrogen exposure such as premenopausal status, longer reproductive span, higher number of children, and use of HT and HC were associated with larger GMV in women in midlife. Further studies are needed to elucidate sex-specific biological pathways through which reproductive history influences cognitive aging and AD risk.},
}
@article {pmid34729858,
year = {2022},
author = {Sala, A and Malpetti, M and Farsad, M and Lubian, F and Magnani, G and Frasca Polara, G and Epiney, JB and Abutalebi, J and Assal, F and Garibotto, V and Perani, D},
title = {Lifelong bilingualism and mechanisms of neuroprotection in Alzheimer dementia.},
journal = {Human brain mapping},
volume = {43},
number = {2},
pages = {581-592},
pmid = {34729858},
issn = {1097-0193},
support = {320030_169876/SNSF_/Swiss National Science Foundation/Switzerland ; 320030_185028/SNSF_/Swiss National Science Foundation/Switzerland ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/*physiopathology ; Cerebral Cortex/diagnostic imaging/*physiopathology ; *Connectome ; Female ; Humans ; Male ; *Multilingualism ; Nerve Net/diagnostic imaging/*physiopathology ; Neuroprotection/*physiology ; Positron-Emission Tomography ; Protective Factors ; },
abstract = {Lifelong bilingualism is associated with delayed dementia onset, suggesting a protective effect on the brain. Here, we aim to study the effects of lifelong bilingualism as a dichotomous and continuous phenomenon, on brain metabolism and connectivity in individuals with Alzheimer's dementia. Ninety-eight patients with Alzheimer's dementia (56 monolinguals; 42 bilinguals) from three centers entered the study. All underwent an [18F]-fluorodeoxyglucose positron emission tomography (PET) imaging session. A language background questionnaire measured the level of language use for conversation and reading. Severity of brain hypometabolism and strength of connectivity of the major neurocognitive networks was compared across monolingual and bilingual individuals, and tested against the frequency of second language life-long usage. Age, years of education, and MMSE score were included in all above mentioned analyses as nuisance covariates. Cerebral hypometabolism was more severe in bilingual compared to monolingual patients; severity of hypometabolism positively correlated with the degree of second language use. The metabolic connectivity analyses showed increased connectivity in the executive, language, and anterior default mode networks in bilingual compared to monolingual patients. The change in neuronal connectivity was stronger in subjects with higher second language use. All effects were most pronounced in the left cerebral hemisphere. The neuroprotective effects of lifelong bilingualism act both against neurodegenerative processes and through the modulation of brain networks connectivity. These findings highlight the relevance of lifelong bilingualism in brain reserve and compensation, supporting bilingual education and social interventions aimed at usage, and maintenance of two or more languages, including dialects, especially crucial in the elderly people.},
}
@article {pmid34729690,
year = {2021},
author = {Trejo-Lopez, JA and Yachnis, AT and Prokop, S},
title = {Neuropathology of Alzheimer's Disease.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {},
pmid = {34729690},
issn = {1878-7479},
support = {P30AG066506/AG/NIA NIH HHS/United States ; P50AG047266/AG/NIA NIH HHS/United States ; },
abstract = {The key pathological hallmarks-extracellular plaques and intracellular neurofibrillary tangles (NFT)-described by Alois Alzheimer in his seminal 1907 article are still central to the postmortem diagnosis of Alzheimer's disease (AD), but major advances in our understanding of the underlying pathophysiology as well as significant progress in clinical diagnosis and therapy have changed the perspective and importance of neuropathologic evaluation of the brain. The notion that the pathological processes underlying AD already start decades before symptoms are apparent in patients has brought a major change reflected in the current neuropathological classification of AD neuropathological changes (ADNC). The predictable progression of beta-amyloid (Aβ) plaque pathology from neocortex, over limbic structures, diencephalon, and basal ganglia, to brainstem and cerebellum is captured in phases described by Thal and colleagues. The progression of NFT pathology from the transentorhinal region to the limbic system and ultimately the neocortex is described in stages proposed by Braak and colleagues. The density of neuritic plaque pathology is determined by criteria defined by the Consortium to establish a registry for Alzheimer's diseases (CERAD). While these changes neuropathologically define AD, it becomes more and more apparent that the majority of patients present with a multitude of additional pathological changes which are possible contributing factors to the clinical presentation and disease progression. The impact of co-existing Lewy body pathology has been well studied, but the importance of more recently described pathologies including limbic-predominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy (CTE), and aging-related tau astrogliopathy (ARTAG) still needs to be evaluated in large cohort studies. In addition, it is apparent that vascular pathology plays an important role in the AD patient population, but a lack of standardized reporting criteria has hampered progress in elucidating the importance of these changes for clinical presentation and disease progression. More recently a key role was ascribed to the immune response to pathological protein aggregates, and it will be important to analyze these changes systematically to better understand the temporal and spatial distribution of the immune response in AD and elucidate their importance for the disease process. Advances in digital pathology and technologies such as single cell sequencing and digital spatial profiling have opened novel avenues for improvement of neuropathological diagnosis and advancing our understanding of underlying molecular processes. Finally, major strides in biomarker-based diagnosis of AD and recent advances in targeted therapeutic approaches may have shifted the perspective but also highlight the continuous importance of postmortem analysis of the brain in neurodegenerative diseases.},
}
@article {pmid34727857,
year = {2021},
author = {Casas-Fernández, E and Peña-Bautista, C and Baquero, M and Cháfer-Pericás, C},
title = {Lipids as early and minimally invasive biomarkers for Alzheimer disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/1570159X19666211102150955},
pmid = {34727857},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Specifically, typical late-onset AD is a sporadic form with a complex etiology that affects over 90% of patients. The current gold standard for AD diagnosis is based on the determination of amyloid status by the analysis of cerebrospinal fluid samples or by brain positron emission tomography. These procedures have some disadvantages to become widely used (expensive, invasive). As alternative, blood metabolites have recently emerged as promising AD biomarkers. Small molecules that cross the compromised AD blood-brain barrier, could be determined in plasma to improve clinical AD diagnosis at early stages through minimally invasive techniques. Specifically, lipids could play an important role in AD since brain has a high lipid content and they are present ubiquitously inside amyloid plaques. Therefore, a systematic review was performed with the aim of identifying blood lipid metabolites as potential early AD biomarkers. In conclusion, some lipid families (fatty acids, glycerolipids, glycerophospholipids, sphingolipids, lipid peroxidation compounds) showed impaired levels at early AD stages. Ceramide levels were significantly higher in AD subjects and polyunsaturated fatty acids levels were significantly lower in AD. Also, high arachidonic acid levels were found in AD patients in contrast to low sphingomyelin levels. Consequently, these lipid biomarkers could be used for minimally invasive and early AD clinical diagnosis.},
}
@article {pmid34727017,
year = {2021},
author = {Peng, S and Roth, AR and Perry, BL},
title = {A latent variable approach to measuring bridging social capital and examining its association to older adults' cognitive health.},
journal = {Social neuroscience},
volume = {16},
number = {6},
pages = {684-694},
pmid = {34727017},
issn = {1747-0927},
support = {R01 AG070931/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; UL1 TR002529/TR/NCATS NIH HHS/United States ; R01 AG057739/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease ; Cognition ; Humans ; *Social Capital ; Social Networking ; Social Support ; },
abstract = {Access to cognitive stimulation through social interactions is a key mechanism used to explain the association between personal networks, cognitive health, and brain structure in older adults. However, little research has assessed how best to operationalize access to novel or diverse social stimuli using social network measures, many of which were designed to study information diffusion within large whole networks (e.g., structural holes and bridging social capital). Using data from 277 adults in the Social Networks and Alzheimer Disease (SNAD) study, we aimed to evaluate such measures for use in research on cognitive aging using personal social networks. We found a positive association between individual measures of structural holes and cognitive health, but not with brain structure. Further, we extracted a latent measure of bridging social capital using multiple individual measures (i.e., structural holes, network diversity, weak ties, and network size) and found it was significantly associated with cognitive health and brain structure, supporting the utility of this concept and related measures in the study of cognitive aging. Finally, individual measures may underestimate the effects of multidimensional bridging social capital on cognitive health and brain structure compared to a latent measure that combines them.},
}
@article {pmid34725519,
year = {2021},
author = {Padmanabhan, P and Kneynsberg, A and Götz, J},
title = {Super-resolution microscopy: a closer look at synaptic dysfunction in Alzheimer disease.},
journal = {Nature reviews. Neuroscience},
volume = {22},
number = {12},
pages = {723-740},
pmid = {34725519},
issn = {1471-0048},
mesh = {Alzheimer Disease/*pathology ; Animals ; Humans ; Microscopy/*methods ; Synapses/*ultrastructure ; },
abstract = {The synapse has emerged as a critical neuronal structure in the degenerative process of Alzheimer disease (AD), in which the pathogenic signals of two key players - amyloid-β (Aβ) and tau - converge, thereby causing synaptic dysfunction and cognitive deficits. The synapse presents a dynamic, confined microenvironment in which to explore how key molecules travel, localize, interact and assume different levels of organizational complexity, thereby affecting neuronal function. However, owing to their small size and the diffraction-limited resolution of conventional light microscopic approaches, investigating synaptic structure and dynamics has been challenging. Super-resolution microscopy (SRM) techniques have overcome the resolution barrier and are revolutionizing our quantitative understanding of biological systems in unprecedented spatio-temporal detail. Here we review critical new insights provided by SRM into the molecular architecture and dynamic organization of the synapse and, in particular, the interactions between Aβ and tau in this compartment. We further highlight how SRM can transform our understanding of the molecular pathological mechanisms that underlie AD. The application of SRM for understanding the roles of synapses in AD pathology will provide a stepping stone towards a broader understanding of dysfunction in other subcellular compartments and at cellular and circuit levels in this disease.},
}
@article {pmid34725027,
year = {2021},
author = {Smyth, BJ and Polaski, RS and Safer, A and Boettcher, FA and Konrad-Martin, D and Gratton, MA},
title = {Point-of-Care Glucose and Lipid Profile Measures Using a Human Point-of-Care Device in Mouse Models of Type 2 Diabetes Mellitus, Aging, and Alzheimer Disease.},
journal = {Journal of the American Association for Laboratory Animal Science : JAALAS},
volume = {60},
number = {6},
pages = {609-615},
pmid = {34725027},
issn = {1559-6109},
support = {I01 RX000559/RX/RRD VA/United States ; },
mesh = {Aged ; Aging ; *Alzheimer Disease ; Animals ; *Diabetes Mellitus, Type 2 ; Glucose ; Humans ; Lipids ; Mice ; Mice, Inbred C57BL ; Point-of-Care Systems ; },
abstract = {A point-of-care (POC) device to measure mouse glucose and lipid profiles is an important unmet need for cost-effective, immediate decision making in research. We compared metabolic analyte profiles obtained using a human clinical POC device with those from a veterinary laboratory chemical analyzer (LCA). Unfasted terminal blood samples were obtained by cardiac puncture from C57Bl/6J mice used in a diet-induced obesity model of type 2 diabetes mellitus; age-matched C57Bl/6J controls; a transgenic mouse model of Alzheimer's disease on a C57BL/6J background (16 wk old); and aged C57BL/6J mice (24 to 60 wk old). Aliquots of the blood were immediately assayed onsite using the POC device. Corresponding serum aliquots were sent analyzed by LCA. Measures from the POC and LCA devices were compared by using the Bland-Altman and Passing-Bablok methods. Of a total of 40 aliquots, LCA results were within reported reference ranges for each model. POC results that fell beyond the device range were excluded from the analyses. The coefficient of determination and Passing-Bablok analysis demonstrated that POC glucose and HDL had the best agreement with LCA. The Bland-Altman analysis found no value-dependent bias in glucose and no significant bias in HDL. The remaining lipid analytes (cholesterol and triglyceride) showed significant bias. Until an improved, validated mouse POC device with lipid profile capability is available, the POC device that we tested appears adequate for screening glucose and HDL in mouse blood. Disadvantages of this clinical POC device are the narrow human ranges relative to ranges found in mice and its limited precision as compared with the LCA. This study demonstrates that when the samples are within the device range limits, this human POC device can accurately track metabolic syndrome and be used to compare patterns in glucose and HDL.},
}
@article {pmid34722519,
year = {2021},
author = {Sorenson, CM and Song, YS and Zaitoun, IS and Wang, S and Hanna, BA and Darjatmoko, SR and Gurel, Z and Fisk, DL and McDowell, CM and McAdams, RM and Sheibani, N},
title = {Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {737426},
pmid = {34722519},
issn = {2296-634X},
support = {P30 CA014520/CA/NCI NIH HHS/United States ; P30 EY016665/EY/NEI NIH HHS/United States ; R01 EY026078/EY/NEI NIH HHS/United States ; R01 EY030076/EY/NEI NIH HHS/United States ; },
abstract = {Adenosine receptors (AR) are widely expressed in a variety of tissues including the retina and brain. They are involved in adenosine-mediated immune responses underlying the onset and progression of neurodegenerative diseases. The expression of AR has been previously demonstrated in some retinal cells including endothelial cells and retinal pigment epithelial cells, but their expression in the choroid and choroidal cells remains unknown. Caffeine is a widely consumed AR antagonist that can influence inflammation and vascular cell function. It has established roles in the treatment of neonatal sleep apnea, acute migraine, and post lumbar puncture headache as well as the neurodegenerative diseases such as Parkinson and Alzheimer. More recently, AR antagonism with caffeine has been shown to protect preterm infants from ischemic retinopathy and retinal neovascularization. However, whether caffeine impacts the development and progression of ocular age-related diseases including neovascular age-related macular degermation remains unknown. Here, we examined the expression of AR in retinal and choroidal tissues and cells. We showed that antagonism of AR with caffeine or istradefylline decreased sprouting of thoracic aorta and choroid/retinal pigment epithelium explants in ex vivo cultures, consistent with caffeine's ability to inhibit endothelial cell migration in culture. In vivo studies also demonstrated the efficacy of caffeine in inhibition of choroidal neovascularization and mononuclear phagocyte recruitment to the laser lesion sites. Istradefylline, a specific AR 2A antagonist, also decreased choroidal neovascularization. Collectively, our studies demonstrate an important role for expression of AR in the choroid whose antagonism mitigate choroidal inflammatory and angiogenesis activities.},
}
@article {pmid34721498,
year = {2021},
author = {Soto-Añari, M and Camargo, L and Ramos-Henderson, M and Rivera-Fernández, C and Denegri-Solís, L and Calle, U and Mori, N and Ocampo-Barbá, N and López, F and Porto, M and Caldichoury-Obando, N and Saldías, C and Gargiulo, P and Castellanos, C and Shelach-Bellido, S and López, N},
title = {Prevalence of Dementia and Associated Factors among Older Adults in Latin America during the COVID-19 Pandemic.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {11},
number = {3},
pages = {213-221},
pmid = {34721498},
issn = {1664-5464},
abstract = {BACKGROUND: The COVID-19 pandemic has had a great impact on cognitive health in Latin American older adults, increasing the risk of cognitive impairment and dementia. Our objective was to analyze the prevalence of dementia and the associated factors in Latin American older adults during SARS-CoV-2 pandemic.<br><br>METHODS: A multicentric first phase cross-sectional observational study was conducted during the SARS-CoV-2 pandemic. Five thousand two hundred and forty-five Latin American adults over 60 years of age were studied in 10 countries: Argentina, Bolivia, Chile, Colombia, Ecuador, Guatemala, Mexico, Peru, the Dominican Republic, and Venezuela. We used the telephone version of Montreal Cognitive Assessment, the "Alzheimer Disease 8" scale for functional and cognitive changes, and the abbreviated version of the Yesavage depression scale. We also asked for sociodemographic and lockdown data. All the evaluation was made by telephone. Cross-tabulations and χ2 tests were used to determine the variability of the prevalence of impairment by sociodemographic characteristics and binary logistic regression to assess the association between dementia and sociodemographic factors.<br><br>RESULTS: We observed that the prevalence of dementia in Latin America is 15.6%, varying depending on the country (Argentine = 7.83 and Bolivia = 28.5%). The variables most associated with dementia were race and age. It does not seem to be associated with the pandemic but with social and socio-health factors.<br><br>CONCLUSION: The prevalence of dementia shows a significant increase in Latin America, attributable to a constellation of ethnic, demographic, and socioeconomic factors.},
}
@article {pmid34719771,
year = {2022},
author = {Pathak, N and Vimal, SK and Tandon, I and Agrawal, L and Hongyi, C and Bhattacharyya, S},
title = {Neurodegenerative Disorders of Alzheimer, Parkinsonism, Amyotrophic Lateral Sclerosis and Multiple Sclerosis: An Early Diagnostic Approach for Precision Treatment.},
journal = {Metabolic brain disease},
volume = {37},
number = {1},
pages = {67-104},
pmid = {34719771},
issn = {1573-7365},
mesh = {Aged ; *Alzheimer Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Humans ; *Multiple Sclerosis ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Parkinson Disease ; },
abstract = {Neurodegenerative diseases (NDs) are characterised by progressive dysfunction of synapses, neurons, glial cells and their networks. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormalities. The most common neurodegenerative disorders are amyloidosis, tauopathies, a-synucleinopathy, and TAR DNA-binding protein 43 (TDP-43) proteopathy. The protein abnormalities in these disorders have abnormal conformational properties along with altered cellular mechanisms, and they exhibit motor deficit, mitochondrial malfunction, dysfunctions in autophagic-lysosomal pathways, synaptic toxicity, and more emerging mechanisms such as the roles of stress granule pathways and liquid-phase transitions. Finally, for each ND, microglial cells have been reported to be implicated in neurodegeneration, in particular, because the microglial responses can shift from neuroprotective to a deleterious role. Growing experimental evidence suggests that abnormal protein conformers act as seed material for oligomerization, spreading from cell to cell through anatomically connected neuronal pathways, which may in part explain the specific anatomical patterns observed in brain autopsy sample. In this review, we mention the human pathology of select neurodegenerative disorders, focusing on how neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis) represent a great healthcare problem worldwide and are becoming prevalent because of the increasing aged population. Despite many studies have focused on their etiopathology, the exact cause of these diseases is still largely unknown and until now with the only available option of symptomatic treatments. In this review, we aim to report the systematic and clinically correlated potential biomarker candidates. Although future studies are necessary for their use in early detection and progression in humans affected by NDs, the promising results obtained by several groups leads us to this idea that biomarkers could be used to design a potential therapeutic approach and preclinical clinical trials for the treatments of NDs.},
}
@article {pmid34719765,
year = {2022},
author = {Farrell, K and Kim, S and Han, N and Iida, MA and Gonzalez, EM and Otero-Garcia, M and Walker, JM and Richardson, TE and Renton, AE and Andrews, SJ and Fulton-Howard, B and Humphrey, J and Vialle, RA and Bowles, KR and de Paiva Lopes, K and Whitney, K and Dangoor, DK and Walsh, H and Marcora, E and Hefti, MM and Casella, A and Sissoko, CT and Kapoor, M and Novikova, G and Udine, E and Wong, G and Tang, W and Bhangale, T and Hunkapiller, J and Ayalon, G and Graham, RR and Cherry, JD and Cortes, EP and Borukov, VY and McKee, AC and Stein, TD and Vonsattel, JP and Teich, AF and Gearing, M and Glass, J and Troncoso, JC and Frosch, MP and Hyman, BT and Dickson, DW and Murray, ME and Attems, J and Flanagan, ME and Mao, Q and Mesulam, MM and Weintraub, S and Woltjer, RL and Pham, T and Kofler, J and Schneider, JA and Yu, L and Purohit, DP and Haroutunian, V and Hof, PR and Gandy, S and Sano, M and Beach, TG and Poon, W and Kawas, CH and Corrada, MM and Rissman, RA and Metcalf, J and Shuldberg, S and Salehi, B and Nelson, PT and Trojanowski, JQ and Lee, EB and Wolk, DA and McMillan, CT and Keene, CD and Latimer, CS and Montine, TJ and Kovacs, GG and Lutz, MI and Fischer, P and Perrin, RJ and Cairns, NJ and Franklin, EE and Cohen, HT and Raj, T and Cobos, I and Frost, B and Goate, A and White Iii, CL and Crary, JF},
title = {Genome-wide association study and functional validation implicates JADE1 in tauopathy.},
journal = {Acta neuropathologica},
volume = {143},
number = {1},
pages = {33-53},
pmid = {34719765},
issn = {1432-0533},
support = {R01 AG021055/AG/NIA NIH HHS/United States ; P01 AG000538/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; K99 AG070109/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; U01 AG006781/AG/NIA NIH HHS/United States ; R01 AG054008/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; K08 AG065463/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; R01 CA079830/CA/NCI NIH HHS/United States ; P50 AG005131/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; P01 AG017586/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; R01 AG054449/AG/NIA NIH HHS/United States ; R01 AG059848/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; /DH_/Department of Health/United Kingdom ; R01 AG062348/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; 75N95019C00049/DA/NIDA NIH HHS/United States ; P30 AG072980/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; U54 NS115266/NS/NINDS NIH HHS/United States ; K23 NS109284/NS/NINDS NIH HHS/United States ; R01 AG066152/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; R01 NS086736/NS/NINDS NIH HHS/United States ; G0400074/MRC_/Medical Research Council/United Kingdom ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 NS095252/NS/NINDS NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; P01 AG066597/AG/NIA NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; RF1 AG060961/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; U01 AG058635/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; F32 AG056098/AG/NIA NIH HHS/United States ; P30 NS055077/NS/NINDS NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Aging/pathology ; Animals ; Cohort Studies ; Drosophila ; Female ; Genome-Wide Association Study ; Homeodomain Proteins/*genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Tauopathies/*genetics/*pathology ; Tumor Suppressor Proteins/*genetics ; },
abstract = {Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.},
}
@article {pmid34714233,
year = {2021},
author = {Grau-Guinea, L and Pérez Enríquez, C and García-Escobar, G and Arrondo Elizarán, C and Pereira Cutiño, B and Florido Santiago, M and Piqué Candini, J and Planas, A and Paez, M and Peña Casanova, J and Sánchez-Benavides, G},
title = {Development, equivalence study, and normative data of version B of the Spanish-language Free and Cued Selective Reminding Test.},
journal = {Neurologia (Barcelona, Spain)},
volume = {36},
number = {5},
pages = {353-360},
doi = {10.1016/j.nrleng.2018.02.001},
pmid = {34714233},
issn = {2173-5808},
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cues ; Humans ; *Language ; *Memory, Episodic ; Mental Recall ; Middle Aged ; Neuropsychological Tests ; Young Adult ; },
abstract = {INTRODUCTION: The Free and Cued Selective Reminding Test (FCSRT) is widely used for the assessment of verbal episodic memory, mainly in patients with Alzheimer disease. A Spanish-language version of the FCSRT and normative data were developed within the NEURONORMA project. Availability of alternative, equivalent versions is useful for following patients up in clinical settings. This study aimed to develop an alternative version of the original FCSRT (version B) and to study its equivalence to the original Spanish-language test (version A), and its performance in a sample of healthy individuals, in order to develop reference data.<br><br>METHODS: We evaluated 232 healthy participants of the NEURONORMA-Plus project, aged between 18 and 90. Thirty-three participants were assessed with both test versions using a counterbalanced design.<br><br>RESULTS: High intra-class correlation coefficients (between 0.8 and 0.9) were observed in the equivalence study. While no significant differences in performance were observed in total recall scores, free recall scores were significantly lower for version B.<br><br>CONCLUSIONS: These preliminary results suggest that the newly developed FCSRT version B is equivalent to version A in the main variables tested. Further studies are necessary to ensure interchangeability between versions. We provide normative data for the new version.},
}
@article {pmid34713156,
year = {2021},
author = {Martin, VP and Rouas, JL and Micoulaud-Franchi, JA and Philip, P and Krajewski, J},
title = {How to Design a Relevant Corpus for Sleepiness Detection Through Voice?.},
journal = {Frontiers in digital health},
volume = {3},
number = {},
pages = {686068},
pmid = {34713156},
issn = {2673-253X},
abstract = {This article presents research on the detection of pathologies affecting speech through automatic analysis. Voice processing has indeed been used for evaluating several diseases such as Parkinson, Alzheimer, or depression. If some studies present results that seem sufficient for clinical applications, this is not the case for the detection of sleepiness. Even two international challenges and the recent advent of deep learning techniques have still not managed to change this situation. This article explores the hypothesis that the observed average performances of automatic processing find their cause in the design of the corpora. To this aim, we first discuss and refine the concept of sleepiness related to the ground-truth labels. Second, we present an in-depth study of four corpora, bringing to light the methodological choices that have been made and the underlying biases they may have induced. Finally, in light of this information, we propose guidelines for the design of new corpora.},
}
@article {pmid34711159,
year = {2021},
author = {de Almeida, RBM and de Almeida Luz, RLS and Leite, FHA and Botura, MB},
title = {A Review on the in vitro Evaluation of the Anticholinesterase Activity Based on Ellman's Method.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/1389557521666211027104638},
pmid = {34711159},
issn = {1875-5607},
abstract = {Inhibition of cholinesterases is a common strategy for the treatment of several disorders, especially Alzheimer´s disease. In vitro assays represent a critical step towards identifying molecules with potential anticholinesterase effect. This study aimed at providing a comprehensive review of the methodologies used in vitro for the anticholinesterase activity based on the spectrophotometry of Ellman's method. This work used two databases (PubMed and ScienceDirect) to search for original articles and selected publications between 1961 and 2019, which reported in vitro spectrophotometry assays for anticholinesterase activity. After the search process and the selection of publications, the final sample consisted of 146 articles published in several journals submitted by researchers from different countries. Although the studies analyzed in this work are all within the same conception of in vitro tests based on Ellman's method, one can observe a wide divergence in the origin and concentration of enzyme, the choice and pH of the buffer, the concentration of the substrate, the sample diluent, incubation time, temperature, and time of the spectrophotometric reading interval. There is no consensus in the methodology of studies with in vitro tests for anticholinesterase assessment. The methodological variations related to kinetic parameters may interfere in the characterization of cholinesterase inhibitors.},
}
@article {pmid34706559,
year = {2021},
author = {Bown, CW and Khan, OA and Moore, EE and Liu, D and Pechman, KR and Cambronero, FE and Terry, JG and Nair, S and Davis, LT and Gifford, KA and Landman, BA and Hohman, TJ and Carr, JJ and Jefferson, AL},
title = {Elevated Aortic Pulse Wave Velocity Relates to Longitudinal Gray and White Matter Changes.},
journal = {Arteriosclerosis, thrombosis, and vascular biology},
volume = {41},
number = {12},
pages = {3015-3024},
pmid = {34706559},
issn = {1524-4636},
support = {P20 AG068082/AG/NIA NIH HHS/United States ; UL1 TR000445/TR/NCATS NIH HHS/United States ; F30 AG064847/AG/NIA NIH HHS/United States ; T32 GM007347/GM/NIGMS NIH HHS/United States ; F31 AG059345/AG/NIA NIH HHS/United States ; R01 NS100980/NS/NINDS NIH HHS/United States ; T32 AG058524/AG/NIA NIH HHS/United States ; R01 AG034962/AG/NIA NIH HHS/United States ; K23 AG045966/AG/NIA NIH HHS/United States ; S10 OD023680/OD/NIH HHS/United States ; F31 AG066358/AG/NIA NIH HHS/United States ; K01 AG049164/AG/NIA NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; K24 AG046373/AG/NIA NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Aged ; Aging/physiology ; Alzheimer Disease/diagnosis/*physiopathology ; Aorta, Thoracic/diagnostic imaging/*physiopathology ; Blood Flow Velocity/*physiology ; Cognition/*physiology ; Female ; Follow-Up Studies ; Gray Matter/*diagnostic imaging/physiopathology ; Humans ; Magnetic Resonance Imaging/*methods ; Male ; Pulse Wave Analysis ; Retrospective Studies ; Time Factors ; Vascular Stiffness ; White Matter/*diagnostic imaging/physiopathology ; },
abstract = {OBJECTIVE: To determine whether baseline aortic stiffness, measured by aortic pulse wave velocity (PWV), relates to longitudinal cerebral gray or white matter changes among older adults. Baseline cardiac magnetic resonance imaging will be used to assess aortic PWV while brain magnetic resonance imaging will be used to assess gray matter and white matter hyperintensity (WMH) volumes at baseline, 18 months, 3 years, 5 years, and 7 years. Approach and Results: Aortic PWV (m/s) was quantified from cardiac magnetic resonance. Multimodal 3T brain magnetic resonance imaging included T1-weighted imaging for quantifying gray matter volumes and T2-weighted fluid-attenuated inversion recovery imaging for quantifying WMHs. Mixed-effects regression models related baseline aortic PWV to longitudinal gray matter volumes (total, frontal, parietal, temporal, occipital, hippocampal, and inferior lateral ventricle) and WMH volumes (total, frontal, parietal, temporal, and occipital) adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham stroke risk profile, APOE (apolipoprotein E)-ε4 carrier status, and intracranial volume. Two hundred seventy-eight participants (73±7 years, 58% male, 87% self-identified as non-Hispanic White, 159 with normal cognition, and 119 with mild cognitive impairment) from the Vanderbilt Memory &amp; Aging Project (n=335) were followed on average for 4.9±1.6 years with PWV measurements occurring from September 2012 to November 2014 and longitudinal brain magnetic resonance imaging measurements occurring from September 2012 to June 2021. Higher baseline aortic PWV was related to greater decrease in hippocampal (β=-3.6 [mm3/y]/[m/s]; [95% CI, -7.2 to -0.02] P=0.049) and occipital lobe (β=-34.2 [mm3/y]/[m/s]; [95% CI, -67.8 to -0.55] P=0.046) gray matter volume over time. Higher baseline aortic PWV was related to greater increase in WMH volume over time in the temporal lobe (β=17.0 [mm3/y]/[m/s]; [95% CI, 7.2-26.9] P<0.001). All associations may be driven by outliers.<br><br>CONCLUSIONS: In older adults, higher baseline aortic PWV related to greater decrease in gray matter volume and greater increase in WMHs over time. Because of unmet cerebral metabolic demands and microvascular remodeling, arterial stiffening may preferentially affect certain highly active brain regions like the temporal lobes. These same regions are affected early in the course of Alzheimer disease.},
}
@article {pmid34706307,
year = {2022},
author = {Surowka, AD and Czyzycki, M and Ziomber-Lisiak, A and Migliori, A and Szczerbowska-Boruchowska, M},
title = {On 2D-FTIR-XRF microscopy - A step forward correlative tissue studies by infrared and hard X-ray radiation.},
journal = {Ultramicroscopy},
volume = {232},
number = {},
pages = {113408},
doi = {10.1016/j.ultramic.2021.113408},
pmid = {34706307},
issn = {1879-2723},
mesh = {Animals ; Fourier Analysis ; *Microscopy ; Spectrometry, X-Ray Emission/methods ; Spectroscopy, Fourier Transform Infrared/methods ; *Synchrotrons ; X-Rays ; },
abstract = {Correlative Fourier Transform Infra-Red (FTIR) and hard X-Ray Fluorescence (XRF) microscopy studies of thin biological samples have recently evolved as complementary methods for biochemical fingerprinting of animal/human tissues. These are seen particularly useful for tracking the mechanisms of neurological diseases, i.e., in Alzheimer/Parkinson disease, in the brain where mishandling of trace metals (Fe, Cu, Zn) seems to be often associated with ongoing damage to molecular components via, among others, oxidative/reductive stress neurotoxicity. Despite substantial progress in state-of-the-art detection and data analysis methods, combined FTIR-XRF experiments have never benefited from correlation and co-localization analysis of molecular moieties and chemical elements, respectively. We here propose for the first time a completely novel data analysis pipeline, utilizing the idea of 2D correlation spectrometry for brain tissue analysis. In this paper, we utilized combined benchtop FTIR - synchrotron XRF mapping experiments on thin brain samples mounted on polypropylene membranes. By implementing our recently developed Multiple Linear Regression Multi-Reference (MLR-MR) algorithm, along with advanced image processing, artifact-free 2D FTIR-XRF spectra could be obtained by mitigating the impact of spectral artifacts, such as Etalon fringes and mild scattering Mie-like signatures, in the FTIR data. We demonstrated that the method is a powerful tool for co-localizing and correlating molecular arrangements and chemical elements (and vice versa) using visually attractive 2D correlograms. Moreover, the methods' applicability for fostering the identification of distinct (biological) materials, involving chemical elements and molecular arrangements, is also shown. Taken together, the 2D FTIR-XRF method opens up for new measures for in-situ investigating hidden complex biochemical correlations, and yet unraveled mechanisms in a biological sample. This step seems crucial for developing new strategies for facilitating the research on the interaction of metals/nonmetals with organic components. This is particularly important for enhancing our understanding of the diseases associated with metal/nonmetal mishandling.},
}
@article {pmid34705667,
year = {2021},
author = {Deng, Y and Zhu, H and Xiao, L and Liu, C and Liu, YL and Gao, W},
title = {Identification of the function and mechanism of m6A reader IGF2BP2 in Alzheimer's disease.},
journal = {Aging},
volume = {13},
number = {21},
pages = {24086-24100},
pmid = {34705667},
issn = {1945-4589},
mesh = {Adenosine/*analogs &amp; derivatives/chemistry/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism/pathology ; Databases, Genetic ; Humans ; RNA Processing, Post-Transcriptional/*genetics ; *RNA-Binding Proteins/chemistry/genetics/metabolism ; },
abstract = {Alzheimer's disease, the most common form of dementia in the elderly, is a kind of neurodegenerative disease. However, its pathogenesis and diagnosis remain unclear. M6A is related to nervous system development and neurodegenerative diseases. Here in this study, using multiple RNA-seq datasets of Alzheimer's brain tissues, along with bioinformatic analysis, we innovatively found that m6A reader protein IGF2BP2 was abnormally highly expressed in Alzheimer's patients. After compared between Alzheimer's and normal brain samples, and between IGF2BP2- high and IGF2BP2- low subgroups of Alzheimer's patients, we took the shared differentially expressed genes as the relevant gene sets of IGF2PB2 affecting Alzheimer's disease occurrence for subsequent analysis. Then, weight gene correlation analysis was conducted and 17 functional modules were identified. The module that most positively correlated with Alzheimer's disease and IGF2PB2-high subgroups were mainly participated in ECM receptor interaction, focal adhesion, cytokine-cytokine receptor interaction, and TGF-beta signaling pathway. Afterwards, a hub gene-based model including 20 genes was constructed by LASSO regression and validated by ROC curve for Alzheimer diagnosis. Finally, we preliminarily elucidated that IGF2BP2 could bind with mRNAs in a m6A-dependent manner. This study first elucidates the pathogenic role of IGF2BP2 in Alzheimer's disease. IGF2BP2 and its relevant m6A modifications are potential to be new diagnostic and therapeutic targets for Alzheimer's patients.},
}
@article {pmid34704025,
year = {2021},
author = {Powell, F and Tosun, D and Raj, A and , },
title = {Network-constrained technique to characterize pathology progression rate in Alzheimer's disease.},
journal = {Brain communications},
volume = {3},
number = {3},
pages = {fcab144},
pmid = {34704025},
issn = {2632-1297},
support = {R01 EB022717/EB/NIBIB NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 NS092802/NS/NINDS NIH HHS/United States ; RF1 AG062196/AG/NIA NIH HHS/United States ; R56 AG064873/AG/NIA NIH HHS/United States ; },
abstract = {Current methods for measuring the chronic rates of cognitive decline and degeneration in Alzheimer's disease rely on the sensitivity of longitudinal neuropsychological batteries and clinical neuroimaging, particularly structural magnetic resonance imaging of brain atrophy, either at a global or regional scale. There is particular interest in approaches predictive of future disease progression and clinical outcomes using a single time point. If successful, such approaches could have great impact on differential diagnosis, therapeutic treatment and clinical trial inclusion. Unfortunately, it has proven quite challenging to accurately predict clinical and degeneration progression rates from baseline data. Specifically, a key limitation of the previously proposed approaches for disease progression based on the brain atrophy measures has been the limited incorporation of the knowledge from disease pathology progression models, which suggest a prion-like spread of disease pathology and hence the neurodegeneration. Here, we present a new metric for disease progression rate in Alzheimer that uses only MRI-derived atrophy data yet is able to infer the underlying rate of pathology transmission. This is enabled by imposing a spread process driven by the brain networks using a Network Diffusion Model. We first fit this model to each patient's longitudinal brain atrophy data defined on a brain network structure to estimate a patient-specific rate of pathology diffusion, called the pathology progression rate. Using machine learning algorithms, we then build a baseline data model and tested this rate metric on data from longitudinal Alzheimer's Disease Neuroimaging Initiative study including 810 subjects. Our measure of disease progression differed significantly across diagnostic groups as well as between groups with different genetic risk factors. Remarkably, hierarchical clustering revealed 3 distinct clusters based on CSF profiles with >90% accuracy. These pathological clusters exhibit progressive atrophy and clinical impairments that correspond to the proposed rate measure. We demonstrate that a subject's degeneration speed can be best predicted from baseline neuroimaging volumetrics and fluid biomarkers for subjects in the middle of their degenerative course, which may be a practical, inexpensive screening tool for future prognostic applications.},
}
@article {pmid34703895,
year = {2021},
author = {Kim, T and Chi, SI and Kim, H and Seo, KS},
title = {Analysis of behavioral management for dental treatment in patients with dementia using the Korean National Health Insurance data.},
journal = {Journal of dental anesthesia and pain medicine},
volume = {21},
number = {5},
pages = {461-469},
pmid = {34703895},
issn = {2383-9309},
abstract = {BACKGROUND: The global population is aging rapidly, and accordingly, the number of patients with dementia is increasing every year. Although the need for dental treatment increases for various reasons in patients with dementia, they cannot cooperate during dental treatment. Therefore, behavioral management, including sedation (SED) or general anesthesia (GA), is required for patients with dementia. Thus, this study aimed to investigate the trends and effects of SED or GA in patients with dementia undergoing dental treatment in South Korea based on the Korean National Health Insurance claims data.<br><br>METHODS: This study utilized customized health information data provided by the Health Insurance Review and Assessment Service. Among patients with records of using sedative drugs during dental treatment from January 2007 to September 2019, patients with the International Classification of Diseases-10 code for dementia (F00, F01, F02, F03, and G30) were selected. We then analyzed the full insurance claims data for dental care. Age, sex, sedative use, and dental treatment of patients were analyzed yearly. In addition, the number of cases of GA or SED per year was analyzed, and changes in behavioral management methods with increasing age were investigated.<br><br>RESULTS: Between January 2007 and September 2019, a total of 4,383 (male, 1,454; female, 2,929) patients with dementia received dental treatment under SED or GA. The total number of SED and GA cases were 1,515 (male, 528 ; female, 987) and 3,396 (male, 1,119 ; female, 2,277) cases, respectively. The total number of cases of dental treatment for 4,383 patients with dementia was 153,051 cases, of which 2.22% were under GA and 0.98% were under SED. Midazolam was the most commonly used drug for SED.<br><br>CONCLUSION: Although gingivitis and pulpitis were the most common reasons for patients with dementia to visit the dentist, GA or SED for patients with dementia was frequently used in oral and maxillofacial or periodontal surgery.},
}
@article {pmid34703453,
year = {2021},
author = {Sbrizzi, C and Sapuppo, W},
title = {Effects of Pet Therapy in Elderly Patients with Neurocognitive Disorders: A Brief Review.},
journal = {Dementia and geriatric cognitive disorders extra},
volume = {11},
number = {3},
pages = {198-206},
pmid = {34703453},
issn = {1664-5464},
abstract = {INTRODUCTION: Neurocognitive disorders (NCDs) are disturbances highly related to age. This means that, with the increasing trend in life expectancy, there is also an increase in this diagnosis, although NCDs are not exclusively found in the population over 65 years old. Likely, they will increase in the coming years together with improvements in diagnosis. In addition to the use of medicines and rehabilitative techniques, pet therapy is also used. Pet therapy makes use of animals with therapeutic, rehabilitative, educational, and recreational purposes for people affected by physical, neuromotor, and psychiatric disorders. Pet therapy seems to be functional for increasing social and communication competencies, facilitating verbal and body language, increasing self-esteem, improving quality of life, and reducing anxiety/stress.<br><br>METHODS: This study was based on scientific papers and publications obtained from the PubMed and Google Scholar databases. Moreover, other articles from further cross-references were included. Specific database research criteria were (a) articles published in 2018 or later, (b) samples containing only adults over 65 years old, (c) written in English or Italian, and (d) on the topic of animal-assisted intervention.<br><br>RESULTS: Uncertain results were obtained. Although a positive effect was found, the included articles were of insufficient methodological rigor.<br><br>DISCUSSION/CONCLUSION: Although many studies reported positive results, these could not be generalized because of the numerous biases present (e.g., small sample size, lack of methodological rigor, lack of protocol, etc.). Future studies, therefore, should seek to address the limitations found in the analyzed studies.},
}
@article {pmid34703027,
year = {2022},
author = {SantaCruz-Calvo, S and Bharath, L and Pugh, G and SantaCruz-Calvo, L and Lenin, RR and Lutshumba, J and Liu, R and Bachstetter, AD and Zhu, B and Nikolajczyk, BS},
title = {Adaptive immune cells shape obesity-associated type 2 diabetes mellitus and less prominent comorbidities.},
journal = {Nature reviews. Endocrinology},
volume = {18},
number = {1},
pages = {23-42},
pmid = {34703027},
issn = {1759-5037},
support = {R01 DK108056/DK/NIDDK NIH HHS/United States ; R01 DE025383/DE/NIDCR NIH HHS/United States ; R56 AG069685/AG/NIA NIH HHS/United States ; R01 NS103785/NS/NINDS NIH HHS/United States ; T32 AG057461/AG/NIA NIH HHS/United States ; },
mesh = {Adaptive Immunity ; Adipose Tissue/metabolism ; *Diabetes Mellitus, Type 2/metabolism ; Female ; *Gastrointestinal Microbiome ; Humans ; Inflammation ; *Insulin Resistance ; Male ; Obesity/metabolism ; },
abstract = {Obesity and type 2 diabetes mellitus (T2DM) are increasing in prevalence owing to decreases in physical activity levels and a shift to diets that include addictive and/or high-calorie foods. These changes are associated with the adoption of modern lifestyles and the presence of an obesogenic environment, which have resulted in alterations to metabolism, adaptive immunity and endocrine regulation. The size and quality of adipose tissue depots in obesity, including the adipose tissue immune compartment, are critical determinants of overall health. In obesity, chronic low-grade inflammation can occur in adipose tissue that can progress to systemic inflammation; this inflammation contributes to the development of insulin resistance, T2DM and other comorbidities. An improved understanding of adaptive immune cell dysregulation that occurs during obesity and its associated metabolic comorbidities, with an appreciation of sex differences, will be critical for repurposing or developing immunomodulatory therapies to treat obesity and/or T2DM-associated inflammation. This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.},
}
@article {pmid34702606,
year = {2022},
author = {Wei, YJ and Chen, C and Winterstein, AG},
title = {Discontinuation of Long-Term Opioid Therapy in Patients With Versus Without Dementia.},
journal = {American journal of preventive medicine},
volume = {62},
number = {2},
pages = {270-274},
pmid = {34702606},
issn = {1873-2607},
support = {K01 AG054764/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Analgesics, Opioid/therapeutic use ; *Chronic Pain/drug therapy ; *Dementia/drug therapy ; Humans ; Medicare ; United States ; },
abstract = {INTRODUCTION: Discontinuation of long-term opioid therapy has increased in recent years, but whether this trend extends to patients with Alzheimer disease and related dementia remains unclear.<br><br>METHODS: Medicare data from 2011 to 2018 were analyzed to compare the trends in the use and discontinuation of long-term opioid therapy between patients with and without Alzheimer disease and related dementia who had chronic noncancer pain. Outcome measures were annual proportions of (1) patients who received long-term opioid therapy and (2) long-term opioid therapy users who subsequently discontinued opioids for ≥30, 60, or 90 days during 12-month follow-up. All analyses were performed in 2021.<br><br>RESULTS: The use of long-term opioid therapy decreased from 2011 to 2017 in both patients with and without Alzheimer disease and related dementia. In long-term opioid therapy users, discontinuation of opioids for ≥30, 60, and 90 days increased by 8% (95% CI=1.04, 1.12, p<0.001), 13% (95% CI=1.06, 1.20, p<0.001), and 18% (95% CI=1.10, 1.28, p<0.001), respectively, between 2011 and 2017 among patients with Alzheimer disease and related dementia, whereas the proportion was largely declining or unchanged among patients without the condition. Differences in long-term opioid therapy discontinuation by Alzheimer disease status widened over time (p<0.01 for interaction).<br><br>CONCLUSIONS: Discontinuation of long-term opioid therapy was consistently higher in patients with than in patients without Alzheimer disease and related dementia, with the gap between the 2 groups widening over time. The reasons for these differences and the risk-benefit of increased long-term opioid therapy discontinuation among patients with Alzheimer disease and related dementia warrant further investigation.},
}
@article {pmid34700200,
year = {2022},
author = {Rothwell, ES and Workman, KP and Wang, D and Lacreuse, A},
title = {Sex differences in cognitive aging: a 4-year longitudinal study in marmosets.},
journal = {Neurobiology of aging},
volume = {109},
number = {},
pages = {88-99},
pmid = {34700200},
issn = {1558-1497},
support = {F32 AG064925/AG/NIA NIH HHS/United States ; R01 AG046266/AG/NIA NIH HHS/United States ; },
mesh = {Aging/*physiology/*psychology ; Animals ; Behavior, Animal ; *Callithrix ; Cognition ; Cognitive Aging/*physiology ; Female ; Longitudinal Studies ; Male ; Models, Animal ; Reversal Learning ; *Sex Characteristics ; Social Behavior ; Time Factors ; },
abstract = {Longitudinal studies are essential to understand healthy and pathological neurocognitive aging such as Alzheimer's Disease, but longitudinal designs are rare in both humans and non-human primate models of aging because of the difficulty of tracking cognitive change in long-lived primates. Common marmosets (Callithrix jacchus) are uniquely suited for aging studies due to their naturally short lifespan (10-12 years), sophisticated cognitive and social abilities and Alzheimer Disease-like neuropathology. We report the first longitudinal study of cognitive aging in marmosets (N = 28) as they transitioned from middle- (∼5 years) to old age (∼9 years). We characterized aging trajectories using reversal learning with different stimuli each year. Marmosets initially improved on cognitive performance due to practice, but worsened in the final year, suggesting the onset of age-related decline. Cognitive impairment emerged earlier in females than males and was more prominent for discrimination than for reversal learning. Sex differences in cognitive aging could not be explained by differences in motivation or motor abilities, which improved or remained stable across aging. Likewise, males and females did not differ in aging trajectories of overall behavior or reactivity to a social stressor, with the exception of a progressive decline in the initiation of social behavior in females. Patterns of cognitive aging were highly variable across marmosets of both sexes, suggesting the potential for pathological aging for some individuals. Future work will link individual cognitive trajectories to neuropathology in order to better understand the relationships between neuropathologic burden and vulnerability to age-related cognitive decline in each sex.},
}
@article {pmid34696749,
year = {2021},
author = {Wang, XF and Xiao, HH and Wu, YT and Kong, L and Chen, JC and Yang, JX and Hu, XL},
title = {Active constituent of Polygala tenuifolia attenuates cognitive deficits by rescuing hippocampal neurogenesis in APP/PS1 transgenic mice.},
journal = {BMC complementary medicine and therapies},
volume = {21},
number = {1},
pages = {267},
pmid = {34696749},
issn = {2662-7671},
mesh = {Alzheimer Disease/*drug therapy ; Animals ; Disease Models, Animal ; Hippocampus/*drug effects ; Medicine, Chinese Traditional/*methods ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Structure ; Morris Water Maze Test ; Neural Stem Cells/*drug effects ; Neurogenesis/*drug effects ; Polygala/chemistry ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common dementia worldwide, and there is still no satisfactory drug or therapeutic strategy. Polygala tenuifolia is a traditional Chinese medicine with multiple neuroprotective effects. In present study, we investigated the effects of three active constituents [3,6'-disinapoyl sucrose (DISS), onjisaponin B (OB) and tenuifolin (TEN)] of Polygala tenuifolia (PT) on the proliferation and differentiation of neural stem cells (NSCs) to identify the potential active constituent of PT promoting hippocampal neurogenesis.<br><br>METHODS: NSCs were isolated from hippocampi of newborn C57BL/6 mice, and transfected with mutant amyloid precursor protein (APP) gene to establish an AD cell model (APP-NSCs). 3-(4,5- Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays were performed, and the proliferation and differentiation of NSCs were assessed by neurosphere formation assay, 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and immunofluorescence (IF) staining analysis. APP/PS1 transgenic mice were administrated with the potential active constituent DISS for 4 weeks. Morris water maze (MWM), Nissl staining assay and IF staining assays were carried out to evaluate the cognitive function, neural damages and hippocampal neurogenesis, respectively.<br><br>RESULTS: DISS exerted the optimal ability to strengthen APP-NSCs proliferation and neuronal differentiation, followed by OB and TEN. Furthermore, DISS treatment for 4 weeks strikingly rescued the cognitive deficits, neuronal injures, and neurogenesis disorder in adult APP/PS1 transgenic mice.<br><br>CONCLUSIONS: Our findings demonstrated that DISS is the constituent of PT that triggers the most potent increase of hippocampal neurogenesis in our mouse model of AD.},
}
@article {pmid34695453,
year = {2022},
author = {Chenfei, Z and Haizhen, Y and Jie, X and Na, Z and Bo, X},
title = {Effects of aerobic exercise on hippocampal SUMOylation in APP/PS1 transgenic mice.},
journal = {Neuroscience letters},
volume = {767},
number = {},
pages = {136303},
doi = {10.1016/j.neulet.2021.136303},
pmid = {34695453},
issn = {1872-7972},
mesh = {Alzheimer Disease/*metabolism/pathology ; Amyloid beta-Peptides ; Animals ; Cysteine Endopeptidases/metabolism ; Hippocampus/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Physical Conditioning, Animal/*physiology ; Presenilin-1 ; SUMO-1 Protein/*metabolism ; *Sumoylation ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disease. SUMOylation, a post-translational modification, has been found to be dysregulated in the AD brain and to exacerbate learning and memory disabilities and increase amyloid beta (Aβ) expression further. To investigate whether exercise-induced alleviation of AD was associated with SUMOylation, which still remains unknown, 3-month-old C57BL/6 mice and APP/PS1 transgenic mice were randomly divided into the wild-type control (WC), wild-type exercise (WE), APP/PS1 control (AC), and APP/PS1 exercise (AE) groups. Mice in the exercise groups underwent a 3-month treadmill exercise regimen. We observed impaired learning and memory abilities in APP/PS1 mice, but the 3-month treadmill exercise regimen improved spatial learning and memory abilities in wild-type and APP/PS1 mice. In addition, senile plaques, SUMO1 mRNA, and SENP1 mRNA levels increased in the hippocampi of APP/PS1 mice. However, 3-month treadmill exercise decreased the levels of senile plaques, SUMO1 mRNA and SENP1 mRNA as well as may reduce SUMO1 modification in 6-month-old APP/PS1 mice, but SUMO2 mRNA expression, SUMO2/3 modification, and overall SUMOylation levels did not significantly change. Our results suggest that the impaired learning and memory abilities and aggregations of Aβ may relate to increased hippocampal SUMO1 transcription levels; the beneficial effects of treadmill exercise on learning and memory performances and AD pathogenesis may associated with the abatement of SUMO1 modification, but may not with SUMO2/3 modification.},
}
@article {pmid34695393,
year = {2021},
author = {Hashemi-Firouzi, N and Shahidi, S and Soleimani Asl, S},
title = {Chronic stimulation of the serotonergic 5-HT4 receptor modulates amyloid-beta-related impairments in synaptic plasticity and memory deficits in male rats.},
journal = {Brain research},
volume = {1773},
number = {},
pages = {147701},
doi = {10.1016/j.brainres.2021.147701},
pmid = {34695393},
issn = {1872-6240},
mesh = {Amyloid beta-Peptides/*pharmacology ; Animals ; Apoptosis/drug effects ; Avoidance Learning/drug effects ; Behavior, Animal/drug effects ; Benzimidazoles/pharmacology/therapeutic use ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology/therapeutic use ; Dentate Gyrus/drug effects/metabolism ; Excitatory Postsynaptic Potentials/drug effects ; Hippocampus/*drug effects/metabolism ; Male ; Memory/*drug effects ; Memory Disorders/*drug therapy/metabolism ; Neuronal Plasticity/*drug effects ; Neurons/drug effects/metabolism ; Rats ; Rats, Wistar ; Receptors, Serotonin, 5-HT4/*metabolism ; Serotonin 5-HT4 Receptor Agonists/*pharmacology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory decline and impaired hippocampal synaptic plasticity. The serotonin 5-HT4 receptor is involved in learning and memory processes. This study explored the effects of chronic stimulation of 5-HT4R on cognition, memory, long-term potentiation (LTP), paired-pulse ratio (PPR), and neuronal apoptosis in a rat model of amyloid-beta (Aβ)-induced AD. Thirty-five male Wistar rats were randomly divided into three groups as follows: the sham, Aβ, and Aβ + BIMU8 groups. Aβ (6 µg/µl) was administrated by intracerebroventricular (icv) injection. The animals were treated with BIMU8 (1 μg/μL, ICV) as a 5-HT4R agonist for 30 days. Memory and behavioral changes were assessed by the passive avoidance learning, novel object recognition, open field, and elevated plus maze tests. Hippocampal synaptic plasticity was evaluated in the dentate gyrus (DG) in response to the stimulation applied to the perforant pathway. Furthermore, neuronal apoptosis was measured in the hippocampus. Data were analyzed by SPSS version 19 using one-way ANOVA, followed by Tukey's post hoc test. Aβ induced memory deficits and neuronal loss and inhibited LTP induction. Aβ also increased the normalized PPR. BIMU8 enhanced the slope of the field excitatory postsynaptic potential in LTP and improved cognition behavior. Paired-pulse inhibition or facilitation was not affected by LTP induction in Aβ animals receiving the BIMU8. It can be concluded that the stimulation of the 5-HT4 receptor modulated the Aβ-induced cognition and memory deficits, probably via a decrease in the hippocampal apoptotic neurons and an improvement in the hippocampal synaptic functions without involving its inhibitory interneurons.},
}
@article {pmid34694126,
year = {2021},
author = {Sahu, AK and Mishra, AK},
title = {Curcumin-Induced Membrane Property Changes in DMPC Multilamellar Vesicles and the Effects of Membrane-Destabilizing Molecules on Curcumin-Loaded Multilamellar Vesicles.},
journal = {Langmuir : the ACS journal of surfaces and colloids},
volume = {37},
number = {43},
pages = {12753-12766},
doi = {10.1021/acs.langmuir.1c02407},
pmid = {34694126},
issn = {1520-5827},
mesh = {Calorimetry, Differential Scanning ; *Curcumin/pharmacology ; *Dimyristoylphosphatidylcholine ; Lipid Bilayers ; Scattering, Small Angle ; X-Ray Diffraction ; },
abstract = {Curcumin (CUR) is the major bioactive component of turmeric (Curcuma longa), commonly used as a spice and traditional medicine in India. CUR possesses a wide range of pharmacological benefits, including antioxidant, anticarcinogenic, antimutagenic, anti-inflammatory, anti-Alzheimer, and anti-Parkinson effects. The CUR-membrane interaction is believed to be the reason for such biological activity of CUR. Several research groups have modeled the interaction of CUR with artificial model lipid membranes using various techniques such as nuclear magnetic resonance (NMR), small-angle X-ray scattering (SAXS), and differential scanning calorimetry (DSC). However, the mechanism of its action is still unclear. A fluorescent-probe-based technique could be advantageous to study the CUR-lipid membrane interaction due to its sensitivity toward the local environment and its multiparametric nature. In this work, we have used the intrinsic fluorescence properties of CUR to investigate CUR-induced physical property changes in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) multilamellar vesicles (MLVs) at various CUR concentrations. By rationalizing the results of steady-state fluorescence intensity, fluorescence anisotropy, temperature-dependent fluorescence intensity, temperature-dependent fluorescence anisotropy, and quenching experiments, we have proposed a model showing concentration-dependent effects of CUR on the DMPC bilayer membrane. We suggest that at low concentrations (≤1 mol %), CUR is homogeneously distributed in the DMPC bilayer membrane in both the solid gel (SG) and liquid crystalline (LC) phases. At high concentrations (>1 mol %), CUR molecules form segregated domains that fluidize both membrane phases. However, the CUR-induced fluidization is less pronounced in the LC phase as some CUR molecules from the domain partition into the bilayer core. Further, the effects of membrane-destabilizing molecules such as bile salts, capsaicin (CAP), and piperine (PIP) on CUR-loaded DMPC multilamellar vesicles were studied. Our work also shows that CUR has a stabilizing effect on the DMPC membrane at high concentrations.},
}
@article {pmid34690119,
year = {2021},
author = {Youn, H and Choi, M and Lee, S and Kim, D and Suh, S and Han, CE and Jeong, HG},
title = {Decreased Cortical Thickness and Local Gyrification in Individuals with Subjective Cognitive Impairment.},
journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology},
volume = {19},
number = {4},
pages = {640-652},
pmid = {34690119},
issn = {1738-1088},
abstract = {OBJECTIVE: Subjective cognitive impairment (SCI) is associated with future cognitive decline. This study aimed to compare cortical thickness and local gyrification index (LGI) between individuals with SCI and normal control (NC) subjects.<br><br>METHODS: Forty-seven participants (27 SCI and 20 NC) were recruited. All participants underwent brain magnetic resonance imaging scanning and were clinically assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of tests. We compared cortical thickness and LGI between the two groups and analyzed correlations between cortical thickness/LGI and scores on CERAD protocol subtests in the SCI group for region of interests with significant between-group differences.<br><br>RESULTS: Cortical thickness reduction in the left entorhinal, superior temporal, insular, rostral middle frontal, precentral, superior frontal, and supramarginal regions, and right supramarginal, precentral, insular, postcentral, and posterior cingulate regions was observed in the SCI compared to the NC group. Cortical thickness in these regions correlated with scores of constructional praxis, word list memory, word list recall, constructional recall, trail making test A, and verbal fluency under the CERAD protocol. Significantly decreased gyrification was observed in the left lingual gyrus of the SCI group. In addition, gyrification of this region was positively associated with scores of constructional praxis.<br><br>CONCLUSION: Our results may provide an additional reference to the notion that SCI may be associated with future cognitive impairment. This study may help clinicians to assess individuals with SCI who may progress to mild cognitive impairment and Alzheimer's dementia.},
}
@article {pmid34689322,
year = {2022},
author = {Tournier, M and Pambrun, E and Maumus-Robert, S and Pariente, A and Verdoux, H},
title = {The risk of dementia in patients using psychotropic drugs: Antidepressants, mood stabilizers or antipsychotics.},
journal = {Acta psychiatrica Scandinavica},
volume = {145},
number = {1},
pages = {56-66},
doi = {10.1111/acps.13380},
pmid = {34689322},
issn = {1600-0447},
mesh = {Aged ; Antidepressive Agents/adverse effects ; *Antipsychotic Agents/adverse effects ; Case-Control Studies ; *Dementia/drug therapy/epidemiology ; Humans ; Middle Aged ; Psychotropic Drugs/therapeutic use ; },
abstract = {OBJECTIVE: The risk of dementia associated with the use of psychotropic drugs is not fully understood. A nested case-control study was carried out to assess the risk of dementia broadly defined or Alzheimer's disease associated with antidepressants, mood stabilizers or antipsychotics.<br><br>METHODS: A cohort was formed from healthcare claim databases including all patients aged 50 and over with a first dispensing of the psychotropic drugs concerned between 2006 and 2017. Patients who developed dementia over the study period were considered as cases. The association between drug exposure prior to a five-year lag time and diagnosis of dementia was assessed by conditional logistic regression models.<br><br>RESULTS: No association was found between dementia, either broadly defined or Alzheimer disease, and antidepressant or mood stabilizers. Findings were conflicting with regard to antipsychotics. First- and second-generation antipsychotics (FGA and SGA) were not associated with Alzheimer disease. SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (Odds ratio [OR] 2.00; 95%CI 1.06-3.79; p = 0.03). In a sensitivity analysis using a lag time of 3 years, ever use of SGA and SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (OR 1.71; 1.10-2.67; p = 0.02 and OR 1.84; 1.03-3.32; p = 0.04, respectively).<br><br>CONCLUSION: The association between antipsychotics and dementia should be further investigated to establish patients, specific drugs, and patterns of treatment at risk. Prescribers should remain cautious when prescribing them.},
}
@article {pmid34688826,
year = {2021},
author = {Rivas-Fernández, MÁ and Lindín, M and Díaz, F and Zurrón, M and Galdo-Álvarez, S},
title = {Changes in brain activity related to episodic memory retrieval in adults with single domain amnestic mild cognitive impairment.},
journal = {Biological psychology},
volume = {166},
number = {},
pages = {108208},
doi = {10.1016/j.biopsycho.2021.108208},
pmid = {34688826},
issn = {1873-6246},
mesh = {Brain/diagnostic imaging ; Brain Mapping ; *Cognitive Dysfunction/diagnostic imaging ; Humans ; Magnetic Resonance Imaging ; *Memory, Episodic ; Neuropsychological Tests ; },
abstract = {The present fMRI study aimed to characterize the performance and the brain activity changes related to episodic memory retrieval in adults with single domain aMCI (sdaMCI), relative to cognitively unimpaired adults. Participants performed an old/new recognition memory task with words while BOLD signal was acquired. The sdaMCI group showed lower hits (correct recognition of old words), lower ability to discriminate old and new words, higher errors and longer reaction times for hits. This group also displayed brain hypoactivation in left precuneus and the left midcingulate cortex during the successful recognition of old words. These changes in brain activity suggest the presence of neural dysregulations in brain regions involved during successful episodic memory retrieval. Moreover, hypoactivation in these brain areas discriminated both groups with moderate sensitivity and specificity values, suggesting that it might constitute a potential neurocognitive biomarker of sdaMCI.},
}
@article {pmid34687079,
year = {2021},
author = {Bagheri, S and Haddadi, R and Saki, S and Kourosh-Arami, M and Komaki, A},
title = {The effect of sodium channels on neurological/neuronal disorders: A systematic review.},
journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
volume = {81},
number = {8},
pages = {669-685},
doi = {10.1002/jdn.10153},
pmid = {34687079},
issn = {1873-474X},
support = {9412257459; IR.UMSHA.REC.1394.582//Hamadan University of Medical Sciences/ ; },
mesh = {Brain/*metabolism ; Epilepsy/*metabolism ; Humans ; Multiple Sclerosis/*metabolism ; Neurons/*metabolism ; Voltage-Gated Sodium Channels/*metabolism ; },
abstract = {Neurological and neuronal disorders are associated with structural, biochemical, or electrical abnormalities in the nervous system. Many neurological diseases have not yet been discovered. Interventions used for the treatment of these disorders include avoidance measures, lifestyle changes, physiotherapy, neurorehabilitation, pain management, medication, and surgery. In the sodium channelopathies, alterations in the structure, expression, and function of voltage-gated sodium channels (VGSCs) are considered as the causes of neurological and neuronal diseases. Online databases, including Scopus, Science Direct, Google Scholar, and PubMed were assessed for studies published between 1977 and 2020 using the keywords of review, sodium channels blocker, neurological diseases, and neuronal diseases. VGSCs consist of one α subunit and two β subunits. These subunits are known to regulate the gating kinetics, functional characteristics, and localization of the ion channel. These channels are involved in cell migration, cellular connections, neuronal pathfinding, and neurite outgrowth. Through the VGSC, the action potential is triggered and propagated in the neurons. Action potentials are physiological functions and passage of impermeable ions. The electrophysiological properties of these channels and their relationship with neurological and neuronal disorders have been identified. Subunit mutations are involved in the development of diseases, such as epilepsy, multiple sclerosis, autism, and Alzheimer's disease. Accordingly, we conducted a review of the link between VGSCs and neurological and neuronal diseases. Also, novel therapeutic targets were introduced for future drug discoveries.},
}
@article {pmid34685728,
year = {2021},
author = {Siddiqui, T and Bhattarai, P and Popova, S and Cosacak, MI and Sariya, S and Zhang, Y and Mayeux, R and Tosto, G and Kizil, C},
title = {KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer's Disease.},
journal = {Cells},
volume = {10},
number = {10},
pages = {},
pmid = {34685728},
issn = {2073-4409},
support = {386893015//Deutsche Forschungsgemeinschaft/ ; VH-NG-1021//German Center for Neurodegenerative Diseases/ ; R56AG069118//National Institute of Health/ ; R56AG066889//National Institute of Health/ ; R56AG051876//National Institute of Health/ ; R01AG067501//National Institute of Health/ ; RC2 AG036547/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG039495/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; },
mesh = {Alzheimer Disease/*pathology/*physiopathology ; Animals ; Brain/metabolism/pathology ; Cell Proliferation ; Cohort Studies ; Disease Models, Animal ; Humans ; Kynurenic Acid/*metabolism ; Models, Biological ; Neural Stem Cells/*metabolism ; *Neurogenesis ; *Neuronal Plasticity ; Receptors, Aryl Hydrocarbon/*metabolism ; Signal Transduction ; Transcriptome/genetics ; Zebrafish/*metabolism ; Zebrafish Proteins/genetics/metabolism ; },
abstract = {Neurogenesis decreases in Alzheimer's disease (AD) patients, suggesting that restoring the normal neurogenic response could be a disease modifying intervention. To study the mechanisms of pathology-induced neuro-regeneration in vertebrate brains, zebrafish is an excellent model due to its extensive neural regeneration capacity. Here, we report that Kynurenic acid (KYNA), a metabolite of the amino acid tryptophan, negatively regulates neural stem cell (NSC) plasticity in adult zebrafish brain through its receptor, aryl hydrocarbon receptor 2 (Ahr2). The production of KYNA is suppressed after amyloid-toxicity through reduction of the levels of Kynurenine amino transferase 2 (KAT2), the key enzyme producing KYNA. NSC proliferation is enhanced by an antagonist for Ahr2 and is reduced with Ahr2 agonists or KYNA. A subset of Ahr2-expressing zebrafish NSCs do not express other regulatory receptors such as il4r or ngfra, indicating that ahr2-positive NSCs constitute a new subset of neural progenitors that are responsive to amyloid-toxicity. By performing transcriptome-wide association studies (TWAS) in three late onset Alzheimer disease (LOAD) brain autopsy cohorts, we also found that several genes that are components of KYNA metabolism or AHR signaling are differentially expressed in LOAD, suggesting a strong link between KYNA/Ahr2 signaling axis to neurogenesis in LOAD.},
}
@article {pmid34685098,
year = {2021},
author = {Pinheiro, RGR and Pinheiro, M and Neves, AR},
title = {Nanotechnology Innovations to Enhance the Therapeutic Efficacy of Quercetin.},
journal = {Nanomaterials (Basel, Switzerland)},
volume = {11},
number = {10},
pages = {},
pmid = {34685098},
issn = {2079-4991},
support = {PT2020 UID/MULTI/04378/2013 - POCI/01/0145/FEDER/007728.//Fundação para a Ciência e Tecnologia/ ; NORTE-01-0145-FEDER-000011//Fundação para a Ciência e Tecnologia/ ; ARDITI-CQM_2017_011-PDG//ARDITI/ ; DL 57/2016 - Norma transitória//Fundação para a Ciência e Tecnologia/ ; },
abstract = {Quercetin is a flavonol present in many vegetables and fruits. Generally, quercetin can be found in aglycone and glycoside forms, mainly in leaves. The absorption of this compound occurs in the large and small intestine, where it suffers glucuronidation, sulfidation, and methylation to improve hydrophilicity. After metabolization, which occurs mainly in the gut, it is distributed throughout the whole organism and is excreted by feces, urine, and exhalation of carbon dioxide. Despite its in vitro cytotoxicity effects, in vivo studies with animal models ensure its safety. This compound can protect against cancer, cardiovascular diseases, chronic inflammation, oxidative stress, and neurodegenerative diseases due to its radical scavenging and anti-inflammatory properties. However, its poor bioavailability dampens the potential beneficial effects of this flavonoid. In that sense, many types of nanocarriers have been developed to improve quercetin solubility, as well as to design tissue-specific delivery systems. All these studies manage to improve the bioavailability of quercetin, allowing it to increase its concentration in the desired places. Collectively, quercetin can become a promising compound if nanotechnology is employed as a tool to enhance its therapeutic efficacy.},
}
@article {pmid34683928,
year = {2021},
author = {Abbas, H and Gad, HA and Khattab, MA and Mansour, M},
title = {The Tragedy of Alzheimer's Disease: Towards Better Management via Resveratrol-Loaded Oral Bilosomes.},
journal = {Pharmaceutics},
volume = {13},
number = {10},
pages = {},
pmid = {34683928},
issn = {1999-4923},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease where oxidative stress plays a major role as a key pathologic factor. The study aims to develop resveratrol (RES)-loaded bilosomes for oral use, aiming to enhance RES bioavailability. RES-loaded bilosomes were prepared using the thin-film hydration technique. The effect of different formulation variables viz. the number of extrusion cycles, drug concentration and the effect of pH of the medium and cholesterol addition on the physicochemical properties of the prepared bilosomes was investigated. Results revealed the successful entrapment of RES into bilosomes. An optimized formula was selected, showing the lowest particle size (189 ± 2.14), acceptable PDI (0.116) and entrapment efficiency (76.2 ± 1.36). In vivo studies on a streptozotocin-induced animal model of AD showed the preeminence of bilosomes over traditional drug suspension to enhance mice memory via Y-maze and Morris water maze tests. Moreover, mice treated with the optimized formula exhibited decreased COX2, IL-6, amyloid-beta peptide and Tau protein levels compared to the drug suspension. Immuno-histochemical analysis revealed a significant decrease of glial fibrillary acidic protein values and microglial cell count in mice treated with bilosomes. Finally, it could be advocated that RES-loaded bilosomes could be a promising drug delivery system to control AD.},
}
@article {pmid34683848,
year = {2021},
author = {Wu, ATH and Lawal, B and Wei, L and Wen, YT and Tzeng, DTW and Lo, WC},
title = {Multiomics Identification of Potential Targets for Alzheimer Disease and Antrocin as a Therapeutic Candidate.},
journal = {Pharmaceutics},
volume = {13},
number = {10},
pages = {},
pmid = {34683848},
issn = {1999-4923},
support = {DP2-110-21121-03-C-09//Ministry of Science and Technology, Taiwan/ ; },
abstract = {Alzheimer's disease (AD) is the most frequent cause of neurodegenerative dementia and affects nearly 50 million people worldwide. Early stage diagnosis of AD is challenging, and there is presently no effective treatment for AD. The specific genetic alterations and pathological mechanisms of the development and progression of dementia remain poorly understood. Therefore, identifying essential genes and molecular pathways that are associated with this disease's pathogenesis will help uncover potential treatments. In an attempt to achieve a more comprehensive understanding of the molecular pathogenesis of AD, we integrated the differentially expressed genes (DEGs) from six microarray datasets of AD patients and controls. We identified ATPase H+ transporting V1 subunit A (ATP6V1A), BCL2 interacting protein 3 (BNIP3), calmodulin-dependent protein kinase IV (CAMK4), TOR signaling pathway regulator-like (TIPRL), and the translocase of outer mitochondrial membrane 70 (TOMM70) as upregulated DEGs common to the five datasets. Our analyses revealed that these genes exhibited brain-specific gene co-expression clustering with OPA1, ITFG1, OXCT1, ATP2A2, MAPK1, CDK14, MAP2K4, YWHAB, PARK2, CMAS, HSPA12A, and RGS17. Taking the mean relative expression levels of this geneset in different brain regions into account, we found that the frontal cortex (BA9) exhibited significantly (p < 0.05) higher expression levels of these DEGs, while the hippocampus exhibited the lowest levels. These DEGs are associated with mitochondrial dysfunction, inflammation processes, and various pathways involved in the pathogenesis of AD. Finally, our blood-brain barrier (BBB) predictions using the support vector machine (SVM) and LiCABEDS algorithm and molecular docking analysis suggested that antrocin is permeable to the BBB and exhibits robust ligand-receptor interactions with high binding affinities to CAMK4, TOMM70, and T1PRL. Our results also revealed good predictions for ADMET properties, drug-likeness, adherence to Lipinskís rules, and no alerts for pan-assay interference compounds (PAINS) Conclusions: These results suggest a new molecular signature for AD parthenogenesis and antrocin as a potential therapeutic agent. Further investigation is warranted.},
}
@article {pmid34683131,
year = {2021},
author = {Lee, HJ and Yu, H and Gil Myeong, S and Park, K and Kim, DK},
title = {Mid- and Late-Life Migraine Is Associated with an Increased Risk of All-Cause Dementia and Alzheimer's Disease, but Not Vascular Dementia: A Nationwide Retrospective Cohort Study.},
journal = {Journal of personalized medicine},
volume = {11},
number = {10},
pages = {},
pmid = {34683131},
issn = {2075-4426},
support = {2021R1C1C1005746//National Research Foundation of Korea/ ; },
abstract = {We used a nationwide cohort sample of data from 2002 to 2013, representing approximately 1 million patients to investigate the prospective association between migraine and dementia. The migraine group (n = 1472) included patients diagnosed between 2002 and 2004, aged over 55 years; the comparison group was selected using propensity score matching (n = 5888). Cox proportional hazards regression analyses was used to calculate the hazard ratios (HRs). The incidence of dementia was 13.5 per 1000 person-years in the migraine group. Following adjustment for sociodemographic and comorbidities variables, patients with migraine developed dementia more frequently than those in the comparison group (adjusted HR = 1.37, 95% confidence interval [CI], 1.16-1.61). In the subgroup analysis, we found a higher HR of dementia events in male, the presence of comorbidities, and older age (≥65) patients with migraine, compared to those without migraine. Moreover, patients with migraine had a significantly higher incidence of Alzheimer's disease (adjusted HR = 1.31, 95% CI, 1.08-1.58), but not vascular dementia, than those without migraine. Therefore, our findings suggest that mid- and late-life migraines may be associated with an increased incidence of all-cause dementia and Alzheimer's disease, but not vascular dementia.},
}
@article {pmid34682452,
year = {2021},
author = {Gómez-Gallego, M and Gómez-Gallego, JC},
title = {Predictors of Caregiver Burden of Patients with Alzheimer Disease Attending Day-Care Centres.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {20},
pages = {},
pmid = {34682452},
issn = {1660-4601},
mesh = {Activities of Daily Living ; *Alzheimer Disease ; Caregiver Burden ; Caregivers ; Cost of Illness ; Humans ; },
abstract = {Nowadays, there are plenty of programs and resources to prevent caregiver burden of patients with Alzheimer's disease. In spite of that, many caregivers suffer high levels of burden and stress, which leads to an earlier institutionalization of patients. This study aimed to explore the predictors of burden in relative caregivers of patients attending day-care centers and the moderating role of caregiver kinship in these associations. A sample of a hundred and two patient-caregiver dyads was recruited. Burden was measured with a Zarit Burden Interview. Measures of patients' cognition, insight, depression, behavioral disturbances, functional ability and overall physical health were considered as predictors. We found that apathy, irritability and delusions and, patients' mobility are the main determinants of caregivers' burden. The strength of relationship between delusions and irritability was higher in spouse caregivers. Interventions to reduce burden should be adapted to the specific needs of a particular type caregiver.},
}
@article {pmid34681766,
year = {2021},
author = {Alfaro-Ruiz, R and Martín-Belmonte, A and Aguado, C and Hernández, F and Moreno-Martínez, AE and Ávila, J and Luján, R},
title = {The Expression and Localisation of G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channels Is Differentially Altered in the Hippocampus of Two Mouse Models of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {22},
number = {20},
pages = {},
pmid = {34681766},
issn = {1422-0067},
support = {RTI2018-095812-B-I00//Ministry of Economy, Industry and Competitiveness/ ; SBPLY/17/180501/000229//Regional Government of Castile-La Mancha/ ; },
mesh = {Alzheimer Disease/genetics/*metabolism/pathology ; Animals ; CA1 Region, Hippocampal/metabolism/pathology ; Cell Membrane/metabolism ; Disease Models, Animal ; G Protein-Coupled Inwardly-Rectifying Potassium Channels/*metabolism ; Hippocampus/*metabolism/pathology ; Male ; Mice, Transgenic ; Neuronal Plasticity/physiology ; Presenilin-1/genetics ; tau Proteins/genetics ; },
abstract = {G protein-gated inwardly rectifying K+ (GIRK) channels are the main targets controlling excitability and synaptic plasticity on hippocampal neurons. Consequently, dysfunction of GIRK-mediated signalling has been implicated in the pathophysiology of Alzheimer´s disease (AD). Here, we provide a quantitative description on the expression and localisation patterns of GIRK2 in two transgenic mice models of AD (P301S and APP/PS1 mice), combining histoblots and immunoelectron microscopic approaches. The histoblot technique revealed differences in the expression of GIRK2 in the two transgenic mice models. The expression of GIRK2 was significantly reduced in the hippocampus of P301S mice in a laminar-specific manner at 10 months of age but was unaltered in APP/PS1 mice at 12 months compared to age-matched wild type mice. Ultrastructural approaches using the pre-embedding immunogold technique, demonstrated that the subcellular localisation of GIRK2 was significantly reduced along the neuronal surface of CA1 pyramidal cells, but increased in its frequency at cytoplasmic sites, in both P301S and APP/PS1 mice. We also found a decrease in plasma membrane GIRK2 channels in axon terminals contacting dendritic spines of CA1 pyramidal cells in P301S and APP/PS1 mice. These data demonstrate for the first time a redistribution of GIRK channels from the plasma membrane to intracellular sites in different compartments of CA1 pyramidal cells. Altogether, the pre- and post-synaptic reduction of GIRK2 channels suggest that GIRK-mediated alteration of the excitability in pyramidal cells could contribute to the cognitive dysfunctions as described in the two AD animal models.},
}
@article {pmid34681567,
year = {2021},
author = {Ordóñez-Gutiérrez, L and Fábrias, G and Casas, J and Wandosell, F},
title = {Diets with Higher ω-6/ω-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice.},
journal = {International journal of molecular sciences},
volume = {22},
number = {20},
pages = {},
pmid = {34681567},
issn = {1422-0067},
support = {RTI 2018-096303-B-C1//Spanish Ministry of Science, Innovation and University/ ; CAM-Biomedicina, B2017/BMD-3700//Comunidad de Madrid/ ; (CIBERNED) [PI2016/01//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativa/ ; (Project ID: CTQ2017-85378-R).//Spanish Ministry of Science, Innovation and University/ ; },
mesh = {Alzheimer Disease/genetics/*metabolism ; Amyloid beta-Protein Precursor/*genetics/metabolism ; Animals ; Ceramides/*metabolism ; Disease Models, Animal ; Erucic Acids/metabolism ; Fatty Acids, Omega-3/*administration &amp; dosage/adverse effects ; Fatty Acids, Omega-6/*administration &amp; dosage/adverse effects ; Gangliosides/metabolism ; Hippocampus/metabolism ; Humans ; Male ; Mice ; Mice, Transgenic ; },
abstract = {Senile plaque formation as a consequence of amyloid-β peptide (Aβ) aggregation constitutes one of the main hallmarks of Alzheimer's disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent or revert it, different therapeutic approaches have been proposed, and some of them are focused on diet modification. Modification of the ω-6/ω-3 fatty acids (FA) ratio in diets has been proven to affect Aβ production and senile plaque formation in the hippocampus and cortex of female transgenic (TG) mice. In these diets, linoleic acid is the main contribution of ω-6 FA, whereas alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are the contributors of ω-3 FA. In the present work, we have explored the effect of ω-6/ω-3 ratio modifications in the diets of male double-transgenic APPswe/PS1ΔE9 (AD model) and wild-type mice (WT). Amyloid burden in the hippocampus increased in parallel with the increase in dietary ω-6/ω-3 ratio in TG male mice. In addition, there was a modification in the brain lipid profile proportional to the ω-6/ω-3 ratio of the diet. In particular, the higher the ω-6/ω-3 ratio, the lower the ceramides and higher the FAs, particularly docosatetraenoic acid. Modifications to the cortex lipid profile was mostly similar between TG and WT mice, except for gangliosides (higher levels in TG mice) and some ceramide species (lower levels in TG mice).},
}
@article {pmid34679586,
year = {2021},
author = {Joseph, CR},
title = {Utilizing 3D Arterial Spin Labeling to Identify Cerebrovascular Leak and Glymphatic Obstruction in Neurodegenerative Disease.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {11},
number = {10},
pages = {},
pmid = {34679586},
issn = {2075-4418},
abstract = {New approaches are required to successfully intervene therapeutically in neurodegenerative diseases. Addressing the earliest phases of disease, blood brain barrier (BBB) leak before the accumulation of misfolded proteins has significant potential for success. To do so, however, a reliable, noninvasive and economical test is required. There are two potential methods of identifying the BBB fluid leak that results in the accumulation of normally excluded substances which alter neuropil metabolism, protein synthesis and degradation with buildup of misfolded toxic proteins. The pros and cons of dynamic contrast imaging (DCI or DCE) and 3D TGSE PASL are discussed as potential early identifying methods. The results of prior publications of the 3D ASL technique and an overview of the associated physiologic challenges are discussed. Either method may serve well as reliable physiologic markers as novel therapeutic interventions directed at the vasculopathy of early neurodegenerative disease are developed. They may serve well in addressing other neurologic diseases associated with either vascular leak and/or reduced glymphatic flow.},
}
@article {pmid34677598,
year = {2021},
author = {Lin, PJ and Neumann, PJ},
title = {Valuing Alzheimer Disease Therapies-Considering Costs and Benefits Beyond the Patient.},
journal = {JAMA network open},
volume = {4},
number = {10},
pages = {e2131913},
doi = {10.1001/jamanetworkopen.2021.31913},
pmid = {34677598},
issn = {2574-3805},
mesh = {*Alzheimer Disease/therapy ; Cost-Benefit Analysis ; Health Care Costs ; Humans ; },
}
@article {pmid34677596,
year = {2021},
author = {Ito, K and Chapman, R and Pearson, SD and Tafazzoli, A and Yaffe, K and Gurwitz, JH},
title = {Evaluation of the Cost-effectiveness of Drug Treatment for Alzheimer Disease in a Simulation Model That Includes Caregiver and Societal Factors.},
journal = {JAMA network open},
volume = {4},
number = {10},
pages = {e2129392},
pmid = {34677596},
issn = {2574-3805},
mesh = {Alzheimer Disease/*drug therapy/economics ; Caregivers/economics/psychology ; Cohort Studies ; Computer Simulation/*standards/statistics &amp; numerical data ; Cost-Benefit Analysis/*methods/statistics &amp; numerical data ; Humans ; Quality-Adjusted Life Years ; Social Norms ; },
abstract = {Importance: The possibility of widespread use of a novel effective therapy for Alzheimer disease (AD) will present important clinical, policy, and financial challenges.<br><br>Objective: To describe how including different patient, caregiver, and societal treatment-related factors affects estimates of the cost-effectiveness of a hypothetical disease-modifying AD treatment.<br><br>In this economic evaluation, the Alzheimer Disease Archimedes Condition Event Simulator was used to simulate the prognosis of a hypothetical cohort of patients selected from the Alzheimer Disease Neuroimaging Initiative database who received the diagnosis of mild cognitive impairment (MCI). Scenario analyses that varied costs and quality of life inputs relevant to patients and caregivers were conducted. The analysis was designed and conducted from June 15, 2019, to September 30, 2020.<br><br>Exposures: A hypothetical drug that would delay progression to dementia in individuals with MCI compared with usual care.<br><br>Main Outcomes and Measures: Incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life-year (QALY) gained.<br><br>Results: The model included a simulated cohort of patients who scored between 24 and 30 on the Mini-Mental State Examination and had a global Clinical Dementia Rating scale of 0.5, with a required memory box score of 0.5 or higher, at baseline. Using a health care sector perspective, which included only individual patient health care costs, the ICER for the hypothetical treatment was $192 000 per QALY gained. The result decreased to $183 000 per QALY gained in a traditional societal perspective analysis with the inclusion of patient non-health care costs. The inclusion of estimated caregiver health care costs produced almost no change in the ICER, but the inclusion of QALYs gained by caregivers led to a substantial reduction in the ICER for the hypothetical treatment, to $107 000 per QALY gained in the health sector perspective. In the societal perspective scenario, with the broadest inclusion of patient and caregiver factors, the ICER decreased to $74 000 per added QALY.<br><br>Conclusions and Relevance: The findings of this economic evaluation suggest that policy makers should be aware that efforts to estimate and include the effects of AD treatments outside those on patients themselves can affect the results of the cost-effectiveness analyses that often underpin assessments of the value of new treatments. Further research and debate on including these factors in assessments that will inform discussions on fair pricing for new treatments are needed.},
}
@article {pmid34676349,
year = {2021},
author = {Verma, R and Hoda, F and Arshad, M and Iqubal, A and Siddiqui, AN and Khan, MA and Haque, SE and Akhtar, M and Najmi, AK},
title = {Cannabis, a Miracle Drug with Polyvalent Therapeutic Utility: Preclinical and Clinical-Based Evidence.},
journal = {Medical cannabis and cannabinoids},
volume = {4},
number = {1},
pages = {43-60},
pmid = {34676349},
issn = {2504-3889},
abstract = {Cannabis sativa L. is an annual herbaceous dioecious plant which was first cultivated by agricultural human societies in Asia. Over the period of time, various parts of the plant like leaf, flower, and seed were used for recreational as well as therapeutic purposes. The main chemical components of Cannabis sativa are termed as cannabinoids, among them the key psychoactive constituent is Δ-9-tetrahydrocannabinol and cannabidiol (CBD) as active nonpsychotic constituent. Upon doing extensive literature review, it was found that cannabis has been widely studied for a number of disorders. Very recently, a pure CBD formulation, named Epidiolex, got a green flag from both United States Food and Drug Administration and Drug Enforcement Administration for 2 rare types of epilepsies. This laid a milestone in medical cannabis research. This review intends to give a basic and extensive assessment, from past till present, of the ethnological, plant, chemical, pharmacological, and legal aspects of C. sativa. Further, this review contemplates the evidence the studies obtained of cannabis components on Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, multiple sclerosis, emesis, epilepsy, chronic pain, and cancer as a cytotoxic agent as well as a palliative therapy. The assessment in this study was done by reviewing in extensive details from studies on historical importance, ethnopharmacological aspects, and legal grounds of C. sativa from extensive literature available on the scientific databases, with a vision for elevating further pharmaceutical research to investigate its total potential as a therapeutic agent.},
}
@article {pmid34674762,
year = {2021},
author = {Vega, AR and Chkheidze, R and Jarmale, V and Shang, P and Foong, C and Diamond, MI and White, CL and Rajaram, S},
title = {Deep learning reveals disease-specific signatures of white matter pathology in tauopathies.},
journal = {Acta neuropathologica communications},
volume = {9},
number = {1},
pages = {170},
pmid = {34674762},
issn = {2051-5960},
support = {RF1 AG059689/AG/NIA NIH HHS/United States ; 1R21AG066012-01A11/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/classification/*pathology ; Brain/*pathology ; Corticobasal Degeneration/classification/*pathology ; *Deep Learning ; Humans ; Supranuclear Palsy, Progressive/classification/*pathology ; Tauopathies/classification/pathology ; White Matter/*pathology ; },
abstract = {Although pathology of tauopathies is characterized by abnormal tau protein aggregation in both gray and white matter regions of the brain, neuropathological investigations have generally focused on abnormalities in the cerebral cortex because the canonical aggregates that form the diagnostic criteria for these disorders predominate there. This corticocentric focus tends to deemphasize the relevance of the more complex white matter pathologies, which remain less well characterized and understood. We took a data-driven machine-learning approach to identify novel disease-specific morphologic signatures of white matter aggregates in three tauopathies: Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We developed automated approaches using whole slide images of tau immunostained sections from 49 human autopsy brains (16 AD,13 CBD, 20 PSP) to identify cortex/white matter regions and individual tau aggregates, and compared tau-aggregate morphology across these diseases. Tau burden in the gray and white matter for individual subjects strongly correlated in a highly disease-specific fashion. We discovered previously unrecognized tau morphologies for AD, CBD and PSP that may be of importance in disease classification. Intriguingly, our models classified diseases equally well based on either white or gray matter tau staining. Our results suggest that tau pathology in white matter is informative, disease-specific, and linked to gray matter pathology. Machine learning has the potential to reveal latent information in histologic images that may represent previously unrecognized patterns of neuropathology, and additional studies of tau pathology in white matter could improve diagnostic accuracy.},
}
@article {pmid34668959,
year = {2021},
author = {Lucey, BP and Wisch, J and Boerwinkle, AH and Landsness, EC and Toedebusch, CD and McLeland, JS and Butt, OH and Hassenstab, J and Morris, JC and Ances, BM and Holtzman, DM},
title = {Sleep and longitudinal cognitive performance in preclinical and early symptomatic Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {144},
number = {9},
pages = {2852-2862},
doi = {10.1093/brain/awab272},
pmid = {34668959},
issn = {1460-2156},
support = {P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG057680/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; R01 AG052550/AG/NIA NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; K76 AG054863/AG/NIA NIH HHS/United States ; KL2 TR000450/TR/NCATS NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease ; Cognition/*physiology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Sleep/*physiology ; },
abstract = {Sleep monitoring may provide markers for future Alzheimer's disease; however, the relationship between sleep and cognitive function in preclinical and early symptomatic Alzheimer's disease is not well understood. Multiple studies have associated short and long sleep times with future cognitive impairment. Since sleep and the risk of Alzheimer's disease change with age, a greater understanding of how the relationship between sleep and cognition changes over time is needed. In this study, we hypothesized that longitudinal changes in cognitive function will have a non-linear relationship with total sleep time, time spent in non-REM and REM sleep, sleep efficiency and non-REM slow wave activity. To test this hypothesis, we monitored sleep-wake activity over 4-6 nights in 100 participants who underwent standardized cognitive testing longitudinally, APOE genotyping, and measurement of Alzheimer's disease biomarkers, total tau and amyloid-β42 in the CSF. To assess cognitive function, individuals completed a neuropsychological testing battery at each clinical visit that included the Free and Cued Selective Reminding test, the Logical Memory Delayed Recall assessment, the Digit Symbol Substitution test and the Mini-Mental State Examination. Performance on each of these four tests was Z-scored within the cohort and averaged to calculate a preclinical Alzheimer cognitive composite score. We estimated the effect of cross-sectional sleep parameters on longitudinal cognitive performance using generalized additive mixed effects models. Generalized additive models allow for non-parametric and non-linear model fitting and are simply generalized linear mixed effects models; however, the linear predictors are not constant values but rather a sum of spline fits. We found that longitudinal changes in cognitive function measured by the cognitive composite decreased at low and high values of total sleep time (P < 0.001), time in non-REM (P < 0.001) and REM sleep (P < 0.001), sleep efficiency (P < 0.01) and <1 Hz and 1-4.5 Hz non-REM slow wave activity (P < 0.001) even after adjusting for age, CSF total tau/amyloid-β42 ratio, APOE ε4 carrier status, years of education and sex. Cognitive function was stable over time within a middle range of total sleep time, time in non-REM and REM sleep and <1 Hz slow wave activity, suggesting that certain levels of sleep are important for maintaining cognitive function. Although longitudinal and interventional studies are needed, diagnosing and treating sleep disturbances to optimize sleep time and slow wave activity may have a stabilizing effect on cognition in preclinical or early symptomatic Alzheimer's disease.},
}
@article {pmid34668650,
year = {2021},
author = {Gallo, V and McElvenny, DM and Seghezzo, G and Kemp, S and Williamson, E and Lu, K and Mian, S and James, L and Hobbs, C and Davoren, D and Arden, N and Davies, M and Malaspina, A and Loosemore, M and Stokes, K and Cross, M and Crutch, S and Zetterberg, H and Pearce, N},
title = {Concussion and long-term cognitive function among rugby players-The BRAIN Study.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.12455},
pmid = {34668650},
issn = {1552-5279},
support = {//Drake Foundation/ ; },
abstract = {OBJECTIVE: The BRAIN Study was established to assess the associations between self-reported concussions and cognitive function among retired rugby players.<br><br>METHODS: Former elite-level male rugby union players (50+ years) in England were recruited. Exposure to rugby-related concussion was collected using the BRAIN-Q tool. The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC). Linear regressions were conducted for the association between concussion and PACC score, adjusting for confounders.<br><br>RESULTS: A total of 146 participants were recruited. The mean (standard deviation) length of playing career was 15.8 (5.4) years. A total of 79.5% reported rugby-related concussion(s). No association was found between concussion and PACC (β -0.03 [95% confidence interval (CI): -1.31, 0.26]). However, participants aged 80+ years reporting 3+ concussions had worse cognitive function than those without concussion (β -1.04 [95% CI: -1.62, -0.47]).<br><br>CONCLUSIONS: Overall there was no association between concussion and cognitive function; however, a significant interaction with age revealed an association in older participants.},
}
@article {pmid34668150,
year = {2022},
author = {Gns, HS and Rajalekshmi, SG and Burri, RR},
title = {Revelation of Pivotal Genes Pertinent to Alzheimer's Pathogenesis: A Methodical Evaluation of 32 GEO Datasets.},
journal = {Journal of molecular neuroscience : MN},
volume = {72},
number = {2},
pages = {303-322},
pmid = {34668150},
issn = {1559-1166},
mesh = {Aged ; *Alzheimer Disease/genetics/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Aspartic Acid Endopeptidases/metabolism ; Gene Expression Profiling ; Humans ; Phosphatidylinositol 3-Kinases/metabolism ; *Protein Interaction Maps/genetics ; },
abstract = {Alzheimer's disease (AD), a dreadful neurodegenerative disorder that affects cognitive and behavioral function in geriatric populations, is characterized by the presence of amyloid deposits and neurofibrillary tangles in brain regions. The International D World Alzheimer Report 2018 noted a global prevalence of 50 million AD cases and forecasted a threefold rise to 139 million by 2050. Although there exist numerous genetic association studies pertinent to AD in different ethnicities, critical genetic factors and signaling pathways underlying its pathogenesis remain ambiguous. This study was aimed to analyze the genetic data retrieved from 32 Gene Expression Omnibus datasets belonging to diverse ethnic cohorts in order to identify overlapping differentially expressed genes (DEGs). Stringent selection criteria were framed to shortlist appropriate datasets based on false discovery rate (FDR) p-value and log FC, and relevant details of upregulated and downregulated DEGs were retrieved. Among the 32 datasets, only six satisfied the selection criteria. The GEO2R tool was employed to retrieve significant DEGs. Nine common DEGs, i.e., SLC5A3, BDNF, SST, SERPINA3, RTN3, RGS4, NPTX, ENC1 and CRYM were found in more than 60% of the selected datasets. These DEGs were later subjected to protein-protein interaction analysis with 18 AD-specific literature-derived genes. Among the nine common DEGs, BDNF, SST, SERPINA3, RTN3 and RGS4 exhibited significant interactions with crucial proteins including BACE1, GRIN2B, APP, APOE, COMT, PSEN1, INS, NEP and MAPT. Functional enrichment analysis revealed involvement of these genes in trans-synaptic signaling, chemical transmission, PI3K pathway signaling, receptor-ligand activity and G protein signaling. These processes are interlinked with AD pathways.},
}
@article {pmid34665876,
year = {2021},
author = {Hanrieder, J},
title = {Preface: Mass spectrometry in Alzheimer disease: This is the Preface for the special issue "Mass Spectrometry in Alzheimer Disease".},
journal = {Journal of neurochemistry},
volume = {159},
number = {2},
pages = {207-210},
doi = {10.1111/jnc.15512},
pmid = {34665876},
issn = {1471-4159},
mesh = {Alzheimer Disease/*genetics/*metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; Humans ; Mass Spectrometry/*methods ; tau Proteins/genetics ; },
abstract = {This preface introduces the content of the special issue on 'Mass Spectrometry in Alzheimer Disease'. Here, an overview is provided on how mass spectrometry is contributing to a broader understanding of AD pathobiology. Mass spectrometry has become a major technology in biomedical analysis and research. This includes biochemical and clinical studies that aim to detail our understanding of Alzheimer disease pathogenesis and pathobiology (AD). In this special issue, key experts in the field present exciting developments and applications of MS in the context of studying AD pathology. These studies span from basic biochemical and neuropathological studies, over advanced metabolomics- and proteomics, towards comprehensive biomarker studies, as well as more recently, in situ mass spectrometry-based imaging (MSI). Together, these studies highlight the key relevance of current and emerging MS technologies to detect, delineate and understand principle pathogenic mechanisms underlying AD.},
}
@article {pmid34664858,
year = {2021},
author = {Jeong, JH and Jung, C and Kim, J and Kim, JY and Kim, HS and Park, YC and Lee, JH and Jung, IC},
title = {Investigation of combined treatment of acupuncture and neurofeedback for improving cognitive function in mild neurocognitive disorder: A randomized, assessor-blind, pilot study.},
journal = {Medicine},
volume = {100},
number = {37},
pages = {e27218},
pmid = {34664858},
issn = {1536-5964},
support = {KSN2021240, HB16C0044//Korea National Institute of Health/ ; },
mesh = {Acupuncture Therapy/*methods/standards/statistics &amp; numerical data ; Aged ; Cognition/*drug effects ; Cognitive Dysfunction/physiopathology/*therapy ; Combined Modality Therapy/methods/*standards/statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Neurofeedback/*methods ; Pilot Projects ; Republic of Korea ; },
abstract = {BACKGROUND: Mild neurocognitive disorder (MND) is an intermediate state that can progress to dementia, and the cognitive reserve of MND is an important task in preventing dementia. Acupuncture and neurofeedback (NF) training have been used to improve cognitive function and treat MND or dementia, but their effectiveness remains controversial. In this trial, we will evaluate the efficacy and safety of combined NF-acupuncture treatment in comparison with single acupuncture treatment.<br><br>METHODS AND DESIGN: This study is a randomized, assessor-blind, pilot trial. It is designed in accordance with the Standards for Reporting Interventions in Controlled Trials of Acupuncture. A total of 44 MND participants who meet the inclusion and exclusion criteria will be enrolled, and each will be randomly assigned to 1 of 2 groups of 22 subjects. Each subject will visit 24 times over 12 weeks and receive either acupuncture or NF-acupuncture combined treatment. At visit 25 (week 13), a follow-up evaluation will be performed, and then the investigator will analyze the results. The primary outcome is defined by the Korean version of the Montreal Cognitive Assessment score from screening to visit 25. The secondary outcome includes the following: change in Alzheimer Disease Assessment Scale-Cognitive, the Korean version of the Beck Depression Inventory, Body Awareness Questionnaire, delayed matching to sample task scores, and functional near-infrared spectroscopy values, from visit 1 to visit 25; heart rate variability values from visit 1 to visit 5, visit 9, visit 13, visit 21, visit 25; breath per minute values from visit 1 to visit 1 to 25.<br><br>DISCUSSION: We will evaluate the effectiveness and safety of combined NF-acupuncture therapy, and expect that it will serve as the basis for the use of NF together with acupuncture in the clinical setting.<br><br>TRIAL REGISTRATION NUMBER: KCT0004972 (registered in Clinical Research Information Service of the Republic of Korea, https://cris.nih.go.kr/cris/search/detailSearch.do/16239).},
}
@article {pmid34663503,
year = {2022},
author = {Terracciano, A and Bilgel, M and Aschwanden, D and Luchetti, M and Stephan, Y and Moghekar, AR and Wong, DF and Ferrucci, L and Sutin, AR and Resnick, SM},
title = {Personality Associations With Amyloid and Tau: Results From the Baltimore Longitudinal Study of Aging and Meta-analysis.},
journal = {Biological psychiatry},
volume = {91},
number = {4},
pages = {359-369},
pmid = {34663503},
issn = {1873-2402},
support = {R01 AG053297/AG/NIA NIH HHS/United States ; R01 AG068093/AG/NIA NIH HHS/United States ; },
mesh = {Aging ; *Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides ; Baltimore ; Humans ; Longitudinal Studies ; Personality ; Positron-Emission Tomography ; *tau Proteins ; },
abstract = {BACKGROUND: Higher neuroticism and lower conscientiousness are risk factors for Alzheimer's disease and related dementias, but the underlying neuropathological correlates remain unclear. Our aim was to examine whether personality traits are associated with amyloid and tau neuropathology in a new sample and meta-analyses.<br><br>METHODS: Participants from the BLSA (Baltimore Longitudinal Study of Aging) completed the Revised NEO Personality Inventory and underwent amyloid (11C-labeled Pittsburgh compound B) and tau (18F-flortaucipir) positron emission tomography.<br><br>RESULTS: Among cognitively normal BLSA participants, neuroticism was associated with higher cortical amyloid burden (odds ratio 1.68, 95% CI 1.20-2.34), and conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% CI 0.44-0.86). These associations remained significant after accounting for age, sex, education, depressive symptoms, hippocampal volume, and APOE ε4. Similar associations were found with tau in the entorhinal cortex. Random-effects meta-analyses of 12 studies found that higher neuroticism (N = 3015, r = 0.07, p = .008) and lower conscientiousness (N = 2990, r = -0.11, p < .001) were associated with more amyloid deposition. Meta-analyses of 8 studies found that higher neuroticism (N = 2231, r = 0.15, p < .001) and lower conscientiousness (N = 2206, r = -0.14, p < .001) were associated with more tau pathology. The associations were moderated by cognitive status, with stronger effects in cognitively normal compared with heterogeneous samples, suggesting that the associations between personality and proteopathies are not phenomena that emerge with neuropsychiatric clinical symptoms.<br><br>CONCLUSIONS: By aggregating results across samples, this study advances knowledge on the association between personality and neuropathology. Neuroticism and conscientiousness may contribute to resistance against amyloid and tau neuropathology.},
}
@article {pmid34663153,
year = {2021},
author = {Arab, A and Mostafalou, S},
title = {Neurotoxicity of pesticides in the context of CNS chronic diseases.},
journal = {International journal of environmental health research},
volume = {},
number = {},
pages = {1-38},
doi = {10.1080/09603123.2021.1987396},
pmid = {34663153},
issn = {1369-1619},
abstract = {Following the introduction and application of pesticides in human life, they have always been along with health concerns both in acute poisoning and chronic toxicities. Neurotoxicity of pesticides in chronic exposures has been known as one of the most important human health problems, as most of these chemicals act through interacting with some elements of nervous system. Pesticide-induced neurotoxicity can be defined in different categories of neurological disorders including neurodegenerative (Alzheimer, Parkinson, amyotrophic lateral sclerosis, multiple sclerosis), neurodevelopmental (attention deficit hyperactivity disorder, autism spectrum disorders, developmental delay, and intellectual disability), neurobehavioral and neuropsychiatric (depression/suicide attempt, anxiety/insomnia, and cognitive impairment) disorders some of which are among the most debilitating human health problems. In this review, neurotoxicity of pesticides in the mentioned categories and sub-categories of neurological diseases have been systematically presented in relation to different route of exposures including general, occupational, environmental, prenatal, postnatal, and paternal.},
}
@article {pmid34662373,
year = {2021},
author = {Wu, X and Xiao, Z and Yi, J and Ding, S and Gu, H and Wu, W and Luo, J and Liang, X and Zheng, L and Xu, H and Zhao, Q and Ding, D},
title = {Development of a Plasma Biomarker Diagnostic Model Incorporating Ultrasensitive Digital Immunoassay as a Screening Strategy for Alzheimer Disease in a Chinese Population.},
journal = {Clinical chemistry},
volume = {67},
number = {12},
pages = {1628-1639},
doi = {10.1093/clinchem/hvab192},
pmid = {34662373},
issn = {1530-8561},
support = {201905-XH-CHJ-H25-201//Shanghai Zhangjiang National Innovation Demonstration Zone/ ; SHDC2020CR4007//Shanghai Hospital Development Center/ ; JIH2642001/028//MOE Frontiers Center for Brain Science/ ; 17411950106//Scientific Research Plan Project of Shanghai Science and Technology Committee/ ; 2016YFC1306402//National Project of Chronic Disease/ ; 82071200//National Natural Science Foundation of China/ ; 2018SHZDZX01//Shanghai Municipal Science and Technology Major Project/ ; 20YF1404000//Shanghai Sailing Program/ ; //ZJLab/ ; },
mesh = {*Alzheimer Disease/diagnosis ; Amyloid beta-Peptides ; Biomarkers ; China ; Humans ; Immunoassay ; tau Proteins ; },
abstract = {BACKGROUND: The ultrasensitive detection of blood-based biomarkers such as amyloid β (Aβ), tau, and neurofilament light (NFL) has drawn much attention in Alzheimer disease (AD) diagnosis. However, few studies have been conducted in the Chinese population. This study aimed to evaluate the ability of plasma biomarker diagnostic models for AD in the Chinese population based on a novel digital immunoassay technology.<br><br>METHODS: 159 patients with AD, 148 patients with amnestic mild cognitive impairment (aMCI), and 121 cognitively normal control participants were recruited from 2 cohorts. The concentrations of plasma Aβ42, Aβ40, Aβ42/Aβ40, total tau (t-tau), phosphorylated tau 181 (p-tau 181), and NFL were quantified using an ultrasensitive single molecule array (Simoa) platform. Comprehensive and simplified diagnostic models were established based on the plasma biomarker profile and clinical characteristics.<br><br>RESULTS: Among all blood biomarkers, p-tau181 had the greatest potential for identifying patients with cognitive impairment. The simplified diagnostic model, which combined plasma p-tau181, Aβ42, and clinical features, achieved 93.3% area under the curve (AUC), 78.6% sensitivity, and 94.2% specificity for distinguishing AD from control participants, indicating a diagnostic ability approaching that of the comprehensive diagnostic model including 5 plasma biomarkers and clinical characteristics (95.1% AUC, 85.5% sensitivity, 94.2% specificity). Moreover, the simplified model reached 95.9% AUC and 94.0% AUC for early- and late-onset AD/control participants, respectively.<br><br>CONCLUSIONS: We established AD diagnostic models using plasma biomarkers for Chinese participants. These findings suggest the simplified diagnostic model provides an accessible and practical way for large-scale screening in the clinic and community, especially in developing countries.},
}
@article {pmid34661615,
year = {2021},
author = {Benedet, AL and Milà-Alomà, M and Vrillon, A and Ashton, NJ and Pascoal, TA and Lussier, F and Karikari, TK and Hourregue, C and Cognat, E and Dumurgier, J and Stevenson, J and Rahmouni, N and Pallen, V and Poltronetti, NM and Salvadó, G and Shekari, M and Operto, G and Gispert, JD and Minguillon, C and Fauria, K and Kollmorgen, G and Suridjan, I and Zimmer, ER and Zetterberg, H and Molinuevo, JL and Paquet, C and Rosa-Neto, P and Blennow, K and Suárez-Calvet, M and , },
title = {Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum.},
journal = {JAMA neurology},
volume = {78},
number = {12},
pages = {1471-1483},
doi = {10.1001/jamaneurol.2021.3671},
pmid = {34661615},
issn = {2168-6157},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*blood/*cerebrospinal fluid ; Biomarkers/*blood/*cerebrospinal fluid ; Cohort Studies ; Cross-Sectional Studies ; Glial Fibrillary Acidic Protein/*blood/*cerebrospinal fluid ; Humans ; Middle Aged ; },
abstract = {Importance: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP.<br><br>Objective: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP.<br><br>This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD.<br><br>Main Outcomes and Measures: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD.<br><br>Results: A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology.<br><br>Conclusions and Relevance: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.},
}
@article {pmid34660786,
year = {2021},
author = {Yong-Peng Yu, and Zheng, YL},
title = {Relationship between Urinary AD7c-NTP with Cerebral Microbleeds Based on APOE Genotype.},
journal = {BioMed research international},
volume = {2021},
number = {},
pages = {3928060},
pmid = {34660786},
issn = {2314-6141},
mesh = {Aged ; Alzheimer Disease/genetics/*pathology/urine ; Apolipoproteins E/*genetics ; Biomarkers/*urine ; Cerebral Hemorrhage/genetics/*pathology/urine ; Diagnostic Tests, Routine ; Female ; Genotype ; Humans ; Magnetic Resonance Imaging/*methods ; Male ; Nerve Tissue Proteins/*urine ; },
abstract = {OBJECTIVE: This study was performed to investigate the association between urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) with cerebral microbleeds (CMBs) based on the apolipoprotein E (APOE) genotypes.<br><br>METHODS: A total of 471 patients with acute cerebral infarction screened by magnetic sensitive imaging were enrolled in this study. Among them, twenty-seven cases of mixed CMBs were excluded. A total of 444 patients were divided into two groups according to the presence or absence of CMBs: CMBs group (n = 92) and noncerebral microbleeds group (nCMBs) (n = 352). Urine AD7c-NTP levels were measured using a human enzyme immunoassay kit.<br><br>RESULTS: In patients with lobar CMBs, there was an interaction between urine AD7c-NTP levels and APOE genotypes (p = 0.01). In patients with APOE ε3/ε3 allele, the odds ratio of lobar CMBs per standard deviation of urinary AD7c-NTP levels was 0.92 (95% CI: 0.70-1.19). In patients with APOE ε2+ or ε4+ allele, the multivariate-corrected odds ratio of lobar CMBs per standard deviation of urinary AD7c-NTP levels was 2.95 (95% CI: 1.38-6.27).<br><br>CONCLUSION: A higher level of urinary AD7c-NTP is involved in lobar CMBs, not deep CMBs.},
}
@article {pmid34658840,
year = {2021},
author = {Milanesi, E and Cucos, CA and Matias-Guiu, JA and Piñol-Ripoll, G and Manda, G and Dobre, M and Cuadrado, A},
title = {Reduced Blood RGS2 Expression in Mild Cognitive Impairment Patients.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {738244},
pmid = {34658840},
issn = {1663-4365},
abstract = {Regulator of G protein signaling 2 (RGS2) is a gene involved in neuronal plasticity and synaptic signaling, whose expression in the brain is altered in neuropsychiatric and neurodegenerative disorders. Microarray data from large datasets suggested reduced RGS2 mRNA levels in the post-mortem brain tissue and blood of Alzheimer's disease (AD) patients. The results were previously confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) only ex vivo in lymphoblastoid cell lines derived from AD patients and controls. In this study, we compared RGS2 mRNA levels in peripheral blood samples from 69 mild cognitive impairment (MCI) patients to 50 age- and sex-matched non-cognitively impaired controls, out of which 25 patients were monitored at 1 year. We found that RGS2 was indeed downregulated in the peripheral blood of these patients (FR = -1.60, p < 0.001), and despite disease-specific therapy, RGS2 transcript levels continued to decrease at 1 year. The results suggest that RGS2 seems to be involved in AD pathology and progression and can be introduced in a panel of blood AD biomarkers.},
}
@article {pmid34657891,
year = {2021},
author = {Høilund-Carlsen, PF and Alavi, A},
title = {Aducanumab (Marketed as Aduhelm) Approval Is Likely Based on Misinterpretation of PET Imaging Data.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {84},
number = {4},
pages = {1457-1460},
doi = {10.3233/JAD-215275},
pmid = {34657891},
issn = {1875-8908},
mesh = {Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/*therapeutic use ; *Data Interpretation, Statistical ; Drug Approval ; Humans ; Plaque, Amyloid/*metabolism ; *Positron-Emission Tomography ; United States ; United States Food and Drug Administration ; },
abstract = {According to the FDA, aducanumab (Aduhelm), the recently approved anti-Alzheimer drug, reduces the level of cerebral amyloid plaques-a hallmark finding in patients with Alzheimer's disease-and this will result in a reduction in clinical decline. The authors of this article are not convinced that amyloid deposits are a hallmark of Alzheimer's disease and are of the opinion that the apparent reduction in amyloid accumulation following aducanumab treatment is likely instead a result of continued and advanced cerebral cell death and, thus, not a sign of improvement but of an even more advanced disease.},
}
@article {pmid34657824,
year = {2021},
author = {Izquierdo Delgado, E and Gutiérrez Ríos, R and Andrés Calvo, M and Repiso Gento, I and Castrillo Sanz, A and Rodríguez Herrero, R and Rodríguez Sanz, MF and Tola-Arribas, MA},
title = {Nutritional status assessment in Alzheimer disease and its influence on disease progression.},
journal = {Neurologia (Barcelona, Spain)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.nrleng.2019.11.006},
pmid = {34657824},
issn = {2173-5808},
abstract = {INTRODUCTION: Nutritional deficiencies are frequent in Alzheimer disease (AD), even in early stages. Nutritional impairment (NI) may be associated with faster disease progression. The objective of this study was to describe the frequency of NI and the associated risk factors at the time of diagnosis and to analyse its influence on subsequent progression.<br><br>METHODS: We performed a prospective, multicentre, observational study of patients recently diagnosed with prodromal AD (pAD) or dementia due to AD (ADd). Two clinical assessments were conducted over a period of 18 months. The Mini Nutritional Assessment test (MNA; score range, 0-30; cut-off point for NI, < 24) was used to estimate nutritional status. Progression was defined as an increase of ≥ 3 points on the Clinical Dementia Rating-sum of boxes test.<br><br>RESULTS: The sample included 50 patients with pAD (mean [standard deviation] age, 76.1 [5.3] years; 68% women), and 127 with ADd (80 [5.9] years; 72.4% women). A total of 141 (79.7%) completed both evaluations. The prevalence of NI was 28.2% (24% for pAD, 29.9% for ADd; P = .43), with the majority (92%) at risk of malnutrition. NI was associated with female sex (odds ratio [OR]: 4.2; 95% confidence interval [CI]: 1.7-10.5; P < .001) and greater behavioural involvement (OR: 5.8; 95% CI: 2.6-12.7; P < .001). A larger proportion of patients with progression was observed among those with NI than among those with normal nutritional status (50% vs 28.7%, P < .05; ADd: 53.6% vs 31.8%, P < .05; pAD: 41.7% vs 22.9%, P = .21). Greater cognitive impairment (OR: 2.1; 95% CI: 1.03-4.4; P < .05) and NI (OR: 2.4; 95% CI: 1.1-5.1; P < .05) were independent risk factors for disease progression.<br><br>CONCLUSIONS: NI is highly prevalent in patients with AD. Assessing nutritional status at the time of diagnosis may enable identification of patients at greater risk of disease progression.},
}
@article {pmid34655982,
year = {2022},
author = {Barini, E and Plotzky, G and Mordashova, Y and Hoppe, J and Rodriguez-Correa, E and Julier, S and LePrieult, F and Mairhofer, I and Mezler, M and Biesinger, S and Cik, M and Meinhardt, MW and Ercan-Herbst, E and Ehrnhoefer, DE and Striebinger, A and Bodie, K and Klein, C and Gasparini, L and Schlegel, K},
title = {Tau in the brain interstitial fluid is fragmented and seeding-competent.},
journal = {Neurobiology of aging},
volume = {109},
number = {},
pages = {64-77},
doi = {10.1016/j.neurobiolaging.2021.09.013},
pmid = {34655982},
issn = {1558-1497},
mesh = {Animals ; Brain/*metabolism ; Disease Models, Animal ; Extracellular Fluid/*metabolism ; HEK293 Cells ; Humans ; Mice, Transgenic ; Microdialysis ; Peptide Fragments/metabolism ; Phosphorylation ; Protein Aggregation, Pathological/metabolism ; Tauopathies/*metabolism ; tau Proteins/*metabolism ; },
abstract = {In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding-competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology.},
}
@article {pmid34655980,
year = {2022},
author = {Koenig, LN and LaMontagne, P and Glasser, MF and Bateman, R and Holtzman, D and Yakushev, I and Chhatwal, J and Day, GS and Jack, C and Mummery, C and Perrin, RJ and Gordon, BA and Morris, JC and Shimony, JS and Benzinger, TLS and , },
title = {Regional age-related atrophy after screening for preclinical alzheimer disease.},
journal = {Neurobiology of aging},
volume = {109},
number = {},
pages = {43-51},
pmid = {34655980},
issn = {1558-1497},
support = {K01 AG053474/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; UF1 AG032438/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; },
mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging/*pathology ; Alzheimer Disease/*diagnosis/*pathology ; Atrophy ; Brain/diagnostic imaging/metabolism/*pathology ; Cross-Sectional Studies ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Myelin Sheath/metabolism ; Positron-Emission Tomography ; Young Adult ; },
abstract = {Brain atrophy occurs in aging even in the absence of dementia, but it is unclear to what extent this is due to undetected preclinical Alzheimer disease. Here we examine a cross-sectional cohort (ages 18-88) free from confounding influence of preclinical Alzheimer disease, as determined by amyloid PET scans and three years of clinical evaluation post-imaging. We determine the regional strength of age-related atrophy using linear modeling of brain volumes and cortical thicknesses with age. Age-related atrophy was seen in nearly all regions, with greatest effects in the temporal lobe and subcortical regions. When modeling age with the estimated derivative of smoothed aging curves, we found that the temporal lobe declined linearly with age, subcortical regions declined faster at later ages, and frontal regions declined slower at later ages than during midlife. This age-derivative pattern was distinct from the linear measure of age-related atrophy and significantly associated with a measure of myelin. Atrophy did not detectably differ from a preclinical Alzheimer disease cohort when age ranges were matched.},
}
@article {pmid34655901,
year = {2021},
author = {Ghosh, N and Saha, I and Sharma, N},
title = {Interactome of human and SARS-CoV-2 proteins to identify human hub proteins associated with comorbidities.},
journal = {Computers in biology and medicine},
volume = {138},
number = {},
pages = {104889},
doi = {10.1016/j.compbiomed.2021.104889},
pmid = {34655901},
issn = {1879-0534},
mesh = {Antiviral Agents ; *COVID-19 ; Comorbidity ; Humans ; *SARS-CoV-2 ; Viral Proteins ; },
abstract = {SARS-CoV-2 has a higher chance of progression in adults of any age with certain underlying health conditions or comorbidities like cancer, neurological diseases and in certain cases may even lead to death. Like other viruses, SARS-CoV-2 also interacts with host proteins to pave its entry into host cells. Therefore, to understand the behaviour of SARS-CoV-2 and design of effective antiviral drugs, host-virus protein-protein interactions (PPIs) can be very useful. In this regard, we have initially created a human-SARS-CoV-2 PPI database from existing works in the literature which has resulted in 7085 unique PPIs. Subsequently, we have identified at most 10 proteins with highest degrees viz. hub proteins from interacting human proteins for individual virus protein. The identification of these hub proteins is important as they are connected to most of the other human proteins. Consequently, when they get affected, the potential diseases are triggered in the corresponding pathways, thereby leading to comorbidities. Furthermore, the biological significance of the identified hub proteins is shown using KEGG pathway and GO enrichment analysis. KEGG pathway analysis is also essential for identifying the pathways leading to comorbidities. Among others, SARS-CoV-2 proteins viz. NSP2, NSP5, Envelope and ORF10 interacting with human hub proteins like COX4I1, COX5A, COX5B, NDUFS1, CANX, HSP90AA1 and TP53 lead to comorbidities. Such comorbidities are Alzheimer, Parkinson, Huntington, HTLV-1 infection, prostate cancer and viral carcinogenesis. Subsequently, using Enrichr tool possible repurposable drugs which target the human hub proteins are reported in this paper as well. Therefore, this work provides a consolidated study for human-SARS-CoV-2 protein interactions to understand the relationship between comorbidity and hub proteins so that it may pave the way for the development of anti-viral drugs.},
}
@article {pmid34655218,
year = {2021},
author = {Perry, BL and Roth, AR and Peng, S and Risacher, SL and Saykin, AJ and Apostolova, LG},
title = {Social Networks and Cognitive Reserve: Network Structure Moderates the Association between Amygdalar Volume and Cognitive Outcomes.},
journal = {The journals of gerontology. Series B, Psychological sciences and social sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/geronb/gbab192},
pmid = {34655218},
issn = {1758-5368},
support = {P30 AG072976/AG/NIA NIH HHS/United States ; R01 AG057739/AG/NIA NIH HHS/United States ; R01 AG070931/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: The cognitive reserve hypothesis has been proposed as a key mechanism explaining the link between social networks and cognitive function but has rarely been empirically tested using neuroimaging data. This study examines whether social network attributes moderate the association between amygdalar volume and cognitive function.<br><br>METHODS: Data were from the Social Networks in Alzheimer Disease study (N=154) and Indiana Alzheimer's Disease Research Center. Social networks were measured using the PhenX Social Network Battery. Regional data from MRI (amygdalar volume; AV) were analyzed using FreeSurfer software. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) and consensus diagnosis. Linear regression analyses were conducted to test the moderating role of social networks on the association between AV and cognitive function.<br><br>RESULTS: Participants with greater ability to span multiple social roles and subgroups within their networks scored higher on the MoCA after adjusting for sociodemographic variables, depression, frequency of contact, and AV. Social networks moderated the association between AV and cognitive function.<br><br>CONCLUSIONS: Among participants who engaged in diverse and loosely connected social networks, the expected adverse cognitive effects of brain volume in regions implicated in socioemotional processing were attenuated. These findings suggest that cognitive stimulation achieved through social interaction with a diverse array of social relationships across multiple contexts may help promote cognitive reserve.},
}
@article {pmid34655092,
year = {2022},
author = {Bossoni, L and Hegeman-Kleinn, I and van Duinen, SG and Bulk, M and Vroegindeweij, LHP and Langendonk, JG and Hirschler, L and Webb, A and van der Weerd, L},
title = {Off-resonance saturation as an MRI method to quantify mineral- iron in the post-mortem brain.},
journal = {Magnetic resonance in medicine},
volume = {87},
number = {3},
pages = {1276-1288},
doi = {10.1002/mrm.29041},
pmid = {34655092},
issn = {1522-2594},
mesh = {Brain/diagnostic imaging ; Humans ; *Iron ; *Iron Metabolism Disorders ; Magnetic Resonance Imaging ; Minerals ; },
abstract = {PURPOSE: To employ an off-resonance saturation method to measure the mineral-iron pool in the postmortem brain, which is an endogenous contrast agent that can give information on cellular iron status.<br><br>METHODS: An off-resonance saturation acquisition protocol was implemented on a 7 Tesla preclinical scanner, and the contrast maps were fitted to an established analytical model. The method was validated by correlation and Bland-Altman analysis on a ferritin-containing phantom. Mineral-iron maps were obtained from postmortem tissue of patients with neurological diseases characterized by brain iron accumulation, that is, Alzheimer disease, Huntington disease, and aceruloplasminemia, and validated with histology. Transverse relaxation rate and magnetic susceptibility values were used for comparison.<br><br>RESULTS: In postmortem tissue, the mineral-iron contrast colocalizes with histological iron staining in all the cases. Iron concentrations obtained via the off-resonance saturation method are in agreement with literature.<br><br>CONCLUSIONS: Off-resonance saturation is an effective way to detect iron in gray matter structures and partially mitigate for the presence of myelin. If a reference region with little iron is available in the tissue, the method can produce quantitative iron maps. This method is applicable in the study of diseases characterized by brain iron accumulation and can complement existing iron-sensitive parametric methods.},
}
@article {pmid34654479,
year = {2021},
author = {Li, QS and Vasanthakumar, A and Davis, JW and Idler, KB and Nho, K and Waring, JF and Saykin, AJ and , },
title = {Association of peripheral blood DNA methylation level with Alzheimer's disease progression.},
journal = {Clinical epigenetics},
volume = {13},
number = {1},
pages = {191},
pmid = {34654479},
issn = {1868-7083},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//DoD Alzheimer's Disease Neuroimaging Initiative (US)/ ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/blood/diagnosis/*genetics ; Biomarkers/analysis/blood ; Cognitive Dysfunction/genetics ; Cohort Studies ; DNA Methylation/*genetics/physiology ; Disease Progression ; Female ; Humans ; Male ; },
abstract = {BACKGROUND: Identifying biomarkers associated with Alzheimer's disease (AD) progression may enable patient enrichment and improve clinical trial designs. Epigenome-wide association studies have revealed correlations between DNA methylation at cytosine-phosphate-guanine (CpG) sites and AD pathology and diagnosis. Here, we report relationships between peripheral blood DNA methylation profiles measured using Infinium® MethylationEPIC BeadChip and AD progression in participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.<br><br>RESULTS: The rate of cognitive decline from initial DNA sampling visit to subsequent visits was estimated by the slopes of the modified Preclinical Alzheimer Cognitive Composite (mPACC; mPACCdigit and mPACCtrailsB) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) plots using robust linear regression in cognitively normal (CN) participants and patients with mild cognitive impairment (MCI), respectively. In addition, diagnosis conversion status was assessed using a dichotomized endpoint. Two CpG sites were significantly associated with the slope of mPACC in CN participants (P < 5.79 × 10-8 [Bonferroni correction threshold]); cg00386386 was associated with the slope of mPACCdigit, and cg09422696 annotated to RP11-661A12.5 was associated with the slope of CDR-SB. No significant CpG sites associated with diagnosis conversion status were identified. Genes involved in cognition and learning were enriched. A total of 19, 13, and 5 differentially methylated regions (DMRs) associated with the slopes of mPACCtrailsB, mPACCdigit, and CDR-SB, respectively, were identified by both comb-p and DMRcate algorithms; these included DMRs annotated to HOXA4. Furthermore, 5 and 19 DMRs were associated with conversion status in CN and MCI participants, respectively. The most significant DMR was annotated to the AD-associated gene PM20D1 (chr1: 205,818,956 to 205,820,014 [13 probes], Sidak-corrected P = 7.74 × 10-24), which was associated with both the slope of CDR-SB and the MCI conversion status.<br><br>CONCLUSION: Candidate CpG sites and regions in peripheral blood were identified as associated with the rate of cognitive decline in participants in the ADNI cohort. While we did not identify a single CpG site with sufficient clinical utility to be used by itself due to the observed effect size, a biosignature composed of DNA methylation changes may have utility as a prognostic biomarker for AD progression.},
}
@article {pmid34654436,
year = {2021},
author = {Hoyer-Kimura, C and Konhilas, JP and Mansour, HM and Polt, R and Doyle, KP and Billheimer, D and Hay, M},
title = {Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia.},
journal = {Journal of neuroinflammation},
volume = {18},
number = {1},
pages = {236},
pmid = {34654436},
issn = {1742-2094},
support = {P30 ES006694/ES/NIEHS NIH HHS/United States ; U01 AG066623/AG/NIA NIH HHS/United States ; NIA U01AG066623-01/AG/NIA NIH HHS/United States ; },
mesh = {Angiotensin I/*agonists/*metabolism/therapeutic use ; Animals ; Biomarkers/metabolism ; Cognitive Dysfunction/drug therapy/*metabolism/pathology ; Cytokines/*metabolism ; Dementia, Vascular/drug therapy/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Neurofilament Proteins/*metabolism ; Peptide Fragments/*agonists/*metabolism/therapeutic use ; Prognosis ; Stroke Volume/physiology ; },
abstract = {BACKGROUND: Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1-7 (Ang-(1-7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1-7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model.<br><br>METHODS: VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1-7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05.<br><br>RESULTS: Treatment with Ang-(1-7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain.<br><br>CONCLUSIONS: These data show that treatment with Ang-(1-7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.},
}
@article {pmid34652580,
year = {2022},
author = {Taché, Y and Saavedra, JM},
title = {Introduction to the Special Issue "The Brain-Gut Axis".},
journal = {Cellular and molecular neurobiology},
volume = {42},
number = {2},
pages = {311-313},
pmid = {34652580},
issn = {1573-6830},
mesh = {Amyloid beta-Peptides/metabolism ; Brain/metabolism ; *Brain-Gut Axis ; Dysbiosis ; *Gastrointestinal Microbiome/physiology ; Humans ; Solitary Nucleus/metabolism ; },
abstract = {This special Issue presents comprehensive and state-of-the-art advances in supporting the crucial role of the bidirectional interactions between the Brain-Gut Axis in health and diseases with an emphasis on the microbiome-gut-brain axis and its implications in variety of neurological disorders. There are intimate connections between the brain and the digestive system. Gut microbiota dysbiosis activates the intestinal immune system, enhances intestinal permeability and bacterial translocation, leading to neuroinflammation, epigenetic changes, cerebrovascular alterations, amyloid β formation and α-synuclein protein aggregates. These alterations may participate in the development of hypertension, Alzheimer, Parkinson, stroke, epilepsy and autism. Brainstem nuclei such as the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) regulate gastric motor function by way of bidirectional inputs through the vagus nerve.},
}
@article {pmid34651647,
year = {2021},
author = {Bennett, DA},
title = {Reducing Your Risk of Alzheimer's Dementia: Building a Better Brain as We Age.},
journal = {Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists},
volume = {36},
number = {7},
pages = {1257-1265},
pmid = {34651647},
issn = {1873-5843},
support = {R01AG17917/AG/NIA NIH HHS/United States ; },
mesh = {Aging ; *Alzheimer Disease/prevention &amp; control ; Brain ; Cohort Studies ; Humans ; Neuropsychological Tests ; },
abstract = {Alzheimer' dementia is a large and growing public health problem. Of utmost importance for limiting the impact of the disease on society is the prevention of dementia, that is, delay onset either by years whereby death ensues prior to dementia onset. The Religious Orders Study and the Rush Memory and Aging Project are two harmonized cohort studies of aging and dementia that include organ donation at death. Ongoing since 1994 and 1997, respectively, we published on the association of numerous experiential, psychological, and medical risk factors for dementia, many of which are potentially modifiable. Here, selected findings are reviewed based on a presentation at the 2020 National Academy of Neuropsychology given virtually in Chicago in October of 2020.},
}
@article {pmid34651585,
year = {2021},
author = {Musiek, ES and Gomez-Isla, T and Holtzman, DM},
title = {Aducanumab for Alzheimer disease: the amyloid hypothesis moves from bench to bedside.},
journal = {The Journal of clinical investigation},
volume = {131},
number = {20},
pages = {},
pmid = {34651585},
issn = {1558-8238},
support = {R01 AG054517/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/*drug therapy/etiology ; Amyloid beta-Peptides/*physiology ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Clinical Trials, Phase III as Topic ; Drug Approval ; Humans ; },
}
@article {pmid34647694,
year = {2021},
author = {Tosun, D and Demir, Z and Veitch, DP and Weintraub, D and Aisen, P and Jack, CR and Jagust, WJ and Petersen, RC and Saykin, AJ and Shaw, LM and Trojanowski, JQ and Weiner, MW and , },
title = {Contribution of Alzheimer's biomarkers and risk factors to cognitive impairment and decline across the Alzheimer's disease continuum.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
pmid = {34647694},
issn = {1552-5279},
support = {R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG062542/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; R01 MH112775/MH/NIMH NIH HHS/United States ; U24 AG067418/AG/NIA NIH HHS/United States ; R01 AG062624/AG/NIA NIH HHS/United States ; R44 AG046025/AG/NIA NIH HHS/United States ; RF1 AG054106/AG/NIA NIH HHS/United States ; R01 AG062689/AG/NIA NIH HHS/United States ; RF1 AG059009/AG/NIA NIH HHS/United States ; R01 AG034570/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; R01 AG058676/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 AG069090/AG/NIA NIH HHS/United States ; U19 AG024904/AG/NIA NIH HHS/United States ; R01 AG031164/AG/NIA NIH HHS/United States ; R01 LM011360/LM/NLM NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG061303/AG/NIA NIH HHS/United States ; U19 AG062418.//National Institutes of Health Grants/ ; R01 AG053798/AG/NIA NIH HHS/United States ; U19 AG062418/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; RF1 AG054019/AG/NIA NIH HHS/United States ; R01 MH098062/MH/NIMH NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 LM013463/LM/NLM NIH HHS/United States ; },
abstract = {INTRODUCTION: Amyloid beta (Aβ), tau, and neurodegeneration jointly with the Alzheimer's disease (AD) risk factors affect the severity of clinical symptoms and disease progression.<br><br>METHODS: Within 248 Aβ-positive elderly with and without cognitive impairment and dementia, partial least squares structural equation pathway modeling was used to assess the direct and indirect effects of imaging biomarkers (global Aβ-positron emission tomography [PET] uptake, regional tau-PET uptake, and regional magnetic resonance imaging-based atrophy) and risk-factors (age, sex, education, apolipoprotein E [APOE], and white-matter lesions) on cross-sectional cognitive impairment and longitudinal cognitive decline.<br><br>RESULTS: Sixteen percent of variance in cross-sectional cognitive impairment was accounted for by Aβ, 46% to 47% by tau, and 25% to 29% by atrophy, although 53% to 58% of total variance in cognitive impairment was explained by incorporating mediated and direct effects of AD risk factors. The Aβ-tau-atrophy pathway accounted for 50% to 56% of variance in longitudinal cognitive decline while Aβ, tau, and atrophy independently explained 16%, 46% to 47%, and 25% to 29% of the variance, respectively.<br><br>DISCUSSION: These findings emphasize that treatments that remove Aβ and completely stop downstream effects on tau and neurodegeneration would only be partially effective in slowing of cognitive decline or reversing cognitive impairment.},
}
@article {pmid34645914,
year = {2021},
author = {Siafarikas, N and Kirsebom, BE and Srivastava, DP and Eriksson, CM and Auning, E and Hessen, E and Selbaek, G and Blennow, K and Aarsland, D and Fladby, T},
title = {Cerebrospinal fluid markers for synaptic function and Alzheimer type changes in late life depression.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {20375},
pmid = {34645914},
issn = {2045-2322},
mesh = {Aged ; Alzheimer Disease/*cerebrospinal fluid/classification ; Amyloid Precursor Protein Secretases/*cerebrospinal fluid ; Amyloid beta-Peptides/*cerebrospinal fluid ; Aspartic Acid Endopeptidases/*cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Cross-Sectional Studies ; Depression/*cerebrospinal fluid ; Humans ; Middle Aged ; Neurogranin/*cerebrospinal fluid ; Peptide Fragments/*cerebrospinal fluid ; Synapses/*metabolism ; },
abstract = {To explore markers for synaptic function and Alzheimer disease (AD) pathology in late life depression (LLD), predementia AD and normal controls (NC). A cross-sectional study to compare cerebrospinal fluid (CSF) levels of neurogranin (Ng), Beta-site amyloid-precursor-protein cleaving enzyme1 (BACE1), Ng/BACE1 ratio and Amyloid-β 42/40 ratio, phosphorylated-tau and total-tau in LLD with (LLD AD) or without (LLD NoAD) AD pathology, predementia AD and normal controls (NC). We included 145 participants (NC = 41; predementia AD = 66 and LLD = 38). LLD comprised LLD AD (n = 16), LLD NoAD (n = 19), LLD with non-AD typical changes (n = 3, excluded). LLD AD (pADJ < 0.05) and predementia AD (pADJ < 0.0001) showed significantly higher Ng than NC. BACE1 and Ng/BACE1 ratio were altered similarly. Compared to LLD NoAD, LLD AD showed significantly higher Ng (pADJ < 0.001), BACE1 (pADJ < 0.05) and Ng/BACE1 ratio (pADJ < 0.01). All groups had significantly lower Aβ 42/40 ratio than NC (predementia AD and LLD AD, p < 0.0001; LLD NoAD, p < 0.05). Both LLD groups performed similarly on tests of memory and executive function, but significantly poorer than NC. Synaptic function in LLD depended on AD pathology. LLD showed an association to Amyloid dysmetabolism. The LLD groups performed poorer cognitively than NC. LLD AD may be conceptualized as "predementia AD with depression".},
}
@article {pmid34644262,
year = {2021},
author = {Cheng, XS and Shi, FX and Zhao, KP and Lin, W and Li, XY and Zhang, J and Bu, YY and Zhu, R and Li, XH and Duan, DX and Ji, XY and Wei, JS and Wang, JZ and Du, J and Zhou, XW},
title = {Nmnat2 attenuates amyloidogenesis and up-regulates ADAM10 in AMPK activity-dependent manner.},
journal = {Aging},
volume = {13},
number = {20},
pages = {23620-23636},
pmid = {34644262},
issn = {1945-4589},
mesh = {*ADAM10 Protein/genetics/metabolism ; *AMP-Activated Protein Kinases/genetics/metabolism ; *Amyloid/genetics/metabolism ; *Amyloid Precursor Protein Secretases/genetics/metabolism ; Animals ; Cell Line ; Humans ; *Membrane Proteins/genetics/metabolism ; Mice ; *Nicotinamide-Nucleotide Adenylyltransferase/genetics/metabolism ; Up-Regulation/genetics ; },
abstract = {Amyloid-β (Aβ) accumulating is considered as a causative factor for formation of senile plaque in Alzheimer's disease (AD), but its mechanism is still elusive. The Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2), a key redox cofactor for energy metabolism, is reduced in AD. Accumulative evidence has shown that the decrease of α-secretase activity, a disintegrin and metalloprotease domain 10 (ADAM10), is responsible for the increase of Aβ productions in AD patient's brain. Here, we observe that the activity of α-secretase ADAM10 and levels of Nmnat2 are significantly decreased, meanwhile there is a simultaneous elevation of Aβ in Tg2576 mice. Over-expression of Nmnat2 increases the mRNA expression of α-secretase ADAM10 and its activity and inhibits Aβ production in N2a/APPswe cells, which can be abolished by Compound C, an AMPK antagonist, suggesting that AMPK is involved in over-expression of Nmnat2 against Aβ production. The further assays demonstrate that Nmnat2 activates AMPK by up-regulating the ratio of NAD+/NADH, moreover AMPK agonist AICAR can also increase ADAM10 activity and reduces Aβ1-40/1-42. Taken together, Nmnat2 suppresses Aβ production and up-regulates ADAM10 in AMPK activity-dependent manner, suggesting that Nmnat2 may serve as a new potential target in arresting AD.},
}
@article {pmid34641980,
year = {2021},
author = {Lam, S and Petit, F and Hérard, AS and Boluda, S and Eddarkaoui, S and Guillermier, M and , and Buée, L and Duyckaerts, C and Haïk, S and Picq, JL and Dhenain, M},
title = {Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate.},
journal = {Acta neuropathologica communications},
volume = {9},
number = {1},
pages = {165},
pmid = {34641980},
issn = {2051-5960},
mesh = {Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/*toxicity ; Animals ; Brain/*metabolism/*pathology ; Cheirogaleidae ; *Cognitive Dysfunction/metabolism/pathology ; Humans ; Iatrogenic Disease ; tau Proteins/*toxicity ; },
abstract = {Amyloid-β (Aβ) pathology transmission has been described in patients following iatrogenic exposure to compounds contaminated with Aβ proteins. It can induce cerebral Aβ angiopathy resulting in brain hemorrhages and devastating clinical impacts. Iatrogenic transmission of tau pathology is also suspected but not experimentally proven. In both scenarios, lesions were detected several decades after the putatively triggering medico-surgical act. There is however little information regarding the cognitive repercussions in individuals who do not develop cerebral hemorrhages. In the current study, we inoculated the posterior cingulate cortex and underlying corpus callosum of young adult primates (Microcebus murinus) with either Alzheimer's disease or control brain extracts. This led to widespread Aβ and tau pathologies in all of the Alzheimer-inoculated animals following a 21-month-long incubation period (n = 12) whereas none of the control brain extract-inoculated animals developed such lesions (n = 6). Aβ deposition affected almost all cortical regions. Tau pathology was also detected in Aβ-deposit-free regions distant from the inoculation sites (e.g. in the entorhinal cortex), while some regions adjacent, but not connected, to the inoculation sites were spared (e.g. the occipital cortex). Alzheimer-inoculated animals developed cognitive deficits and cerebral atrophy compared to controls. These pathologies were induced using two different batches of Alzheimer brain extracts. This is the first experimental demonstration that tau can be transmitted by human brain extracts inoculations in a primate. We also showed for the first time that the transmission of widespread Aβ and tau pathologies can be associated with cognitive decline. Our results thus reinforce the need to organize a systematic monitoring of individuals who underwent procedures associated with a risk of Aβ and tau iatrogenic transmission. They also provide support for Alzheimer brain-inoculated primates as relevant models of Alzheimer pathology.},
}
@article {pmid34640600,
year = {2021},
author = {Rujeedawa, T and Carrillo Félez, E and Clare, ICH and Fortea, J and Strydom, A and Rebillat, AS and Coppus, A and Levin, J and Zaman, SH},
title = {The Clinical and Neuropathological Features of Sporadic (Late-Onset) and Genetic Forms of Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {10},
number = {19},
pages = {},
pmid = {34640600},
issn = {2077-0383},
support = {Horizon21//Fondation Jérôme Lejeune/ ; },
abstract = {The purpose of this review is to compare and highlight the clinical and pathological aspects of genetic versus acquired Alzheimer's disease: Down syndrome-associated Alzheimer's disease in (DSAD) and Autosomal Dominant Alzheimer's disease (ADAD) are compared with the late-onset form of the disease (LOAD). DSAD and ADAD present in a younger population and are more likely to manifest with non-amnestic (such as dysexecutive function features) in the prodromal phase or neurological features (such as seizures and paralysis) especially in ADAD. The very large variety of mutations associated with ADAD explains the wider range of phenotypes. In the LOAD, age-associated comorbidities explain many of the phenotypic differences.},
}
@article {pmid34638764,
year = {2021},
author = {Raber, HF and Kubiczek, DH and Bodenberger, N and Kissmann, AK and D'souza, D and Xing, H and Mayer, D and Xu, P and Knippschild, U and Spellerberg, B and Weil, T and Rosenau, F},
title = {FluCell-SELEX Aptamers as Specific Binding Molecules for Diagnostics of the Health Relevant Gut Bacterium Akkermansia muciniphila.},
journal = {International journal of molecular sciences},
volume = {22},
number = {19},
pages = {},
pmid = {34638764},
issn = {1422-0067},
support = {BiofMO_005//Baden-Württemberg Stiftung/ ; 686271//Horizon 2020 Framework Programme/ ; 7533-10-5-186A and 7533-10-5-190//Ministry of Science, Research and the Arts of Baden-Württemberg/ ; },
mesh = {Akkermansia ; Alzheimer Disease/*microbiology ; Aptamers, Nucleotide/*chemistry ; Feces/*microbiology ; *Gastrointestinal Microbiome ; Humans ; *SELEX Aptamer Technique ; },
abstract = {Based on their unique properties, oligonucleotide aptamers have been named a gift of biological chemistry to life science. We report the development of DNA aptamers as the first high-affinity binding molecules available for fast and rapid labeling of the human gut bacterium Akkermansia muciniphila with a certain impact on Alzheimer´s disease. Fast and reliable analyses of the composition of microbiomes is an emerging field in microbiology. We describe the molecular evolution and biochemical characterization of a specific aptamer library by a FluCell-SELEX and the characterization of specific molecules from the library by bioinformatics. The aptamer AKK13.1 exerted universal applicability in different analysis techniques in modern microbiology, including fluorimetry, confocal laser scanning microscopy and flow cytometry. It was also functional as a specific binding entity hybridized to anchor primers chemically coupled via acrydite-modification to the surface of a polyacrylamide-hydrogel, which can be prototypically used for the construction of affinity surfaces in sensor chips. Together, the performance and methodological flexibility of the aptamers presented here may open new routes not only to develop novel Akkermansia-specific assays for clinical microbiology and the analyses of human stool samples but may also be an excellent starting point for the construction of novel electronic biosensors.},
}
@article {pmid34638632,
year = {2021},
author = {Gil, L and Niño, SA and Guerrero, C and Jiménez-Capdeville, ME},
title = {Phospho-Tau and Chromatin Landscapes in Early and Late Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {22},
number = {19},
pages = {},
pmid = {34638632},
issn = {1422-0067},
support = {1.010.924.//Fundación Banco Santander/ ; },
mesh = {Alzheimer Disease/etiology/genetics/*metabolism ; Chromatin/genetics/*metabolism ; DNA/chemistry/genetics/metabolism ; DNA Damage ; Epigenesis, Genetic ; Genomic Instability ; Histone Code ; Humans ; Nucleosomes/metabolism ; Phosphorylation ; Time Factors ; tau Proteins/chemistry/genetics/*metabolism ; },
abstract = {Cellular identity is determined through complex patterns of gene expression. Chromatin, the dynamic structure containing genetic information, is regulated through epigenetic modulators, mainly by the histone code. One of the main challenges for the cell is maintaining functionality and identity, despite the accumulation of DNA damage throughout the aging process. Replicative cells can remain in a senescent state or develop a malign cancer phenotype. In contrast, post-mitotic cells such as pyramidal neurons maintain extraordinary functionality despite advanced age, but they lose their identity. This review focuses on tau, a protein that protects DNA, organizes chromatin, and plays a crucial role in genomic stability. In contrast, tau cytosolic aggregates are considered hallmarks of Alzheimer´s disease (AD) and other neurodegenerative disorders called tauopathies. Here, we explain AD as a phenomenon of chromatin dysregulation directly involving the epigenetic histone code and a progressive destabilization of the tau-chromatin interaction, leading to the consequent dysregulation of gene expression. Although this destabilization could be lethal for post-mitotic neurons, tau protein mediates profound cellular transformations that allow for their temporal survival.},
}
@article {pmid34636642,
year = {2022},
author = {McEvoy, LK},
title = {Disruption of White Matter Connectivity Precedes Development of Dementia in Alzheimer Disease.},
journal = {Radiology},
volume = {302},
number = {1},
pages = {151-152},
pmid = {34636642},
issn = {1527-1315},
mesh = {*Alzheimer Disease/diagnostic imaging ; Brain/diagnostic imaging ; Humans ; Neural Pathways ; *White Matter/diagnostic imaging ; },
}
@article {pmid34636637,
year = {2022},
author = {Prescott, JW and Doraiswamy, PM and Gamberger, D and Benzinger, T and Petrella, JR and , },
title = {Diffusion Tensor MRI Structural Connectivity and PET Amyloid Burden in Preclinical Autosomal Dominant Alzheimer Disease: The DIAN Cohort.},
journal = {Radiology},
volume = {302},
number = {1},
pages = {143-150},
doi = {10.1148/radiol.2021210383},
pmid = {34636637},
issn = {1527-1315},
support = {U19 AG032438/AG/NIA NIH HHS/United States ; UF1 AG032438/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Alzheimer Disease/*metabolism/*pathology ; Amyloid/*metabolism ; Brain/diagnostic imaging/metabolism ; Cohort Studies ; Diffusion Tensor Imaging/*methods ; Female ; *Genetic Predisposition to Disease ; Humans ; Male ; Positron-Emission Tomography/*methods ; Prospective Studies ; },
abstract = {Background Pathologic evidence of Alzheimer disease (AD) is detectable years before onset of clinical symptoms. Imaging-based identification of structural changes of the brain in people at genetic risk for early-onset AD may provide insights into how genes influence the pathologic cascade that leads to dementia. Purpose To assess structural connectivity differences in cortical networks between cognitively normal autosomal dominant Alzheimer disease (ADAD) mutation carriers versus noncarriers and to determine the cross-sectional relationship of structural connectivity and cortical amyloid burden with estimated years to symptom onset (EYO) of dementia in carriers. Materials and Methods In this exploratory analysis of a prospective trial, all participants enrolled in the Dominantly Inherited Alzheimer Network between January 2009 and July 2014 who had normal cognition at baseline, T1-weighted MRI scans, and diffusion tensor imaging (DTI) were analyzed. Amyloid PET imaging using Pittsburgh compound B was also analyzed for mutation carriers. Areas of the cerebral cortex were parcellated into three cortical networks: the default mode network, frontoparietal control network, and ventral attention network. The structural connectivity of the three networks was calculated from DTI. General linear models were used to examine differences in structural connectivity between mutation carriers and noncarriers and the relationship between structural connectivity, amyloid burden, and EYO in mutation carriers. Correlation network analysis was performed to identify clusters of related clinical and imaging markers. Results There were 30 mutation carriers (mean age ± standard deviation, 34 years ± 10; 17 women) and 38 noncarriers (mean age, 37 years ± 10; 20 women). There was lower structural connectivity in the frontoparietal control network in mutation carriers compared with noncarriers (estimated effect of mutation-positive status, -0.0266; P = .04). Among mutation carriers, there was a correlation between EYO and white matter structural connectivity in the frontoparietal control network (estimated effect of EYO, -0.0015, P = .01). There was no significant relationship between cortical global amyloid burden and EYO among mutation carriers (P > .05). Conclusion White matter structural connectivity was lower in autosomal dominant Alzheimer disease mutation carriers compared with noncarriers and correlated with estimated years to symptom onset. Clinical trial registration no. NCT00869817 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by McEvoy in this issue.},
}
@article {pmid34635841,
year = {2021},
author = {Ferretti, MT and Santuccione Chadha, A},
title = {The missing X factor in Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {17},
number = {12},
pages = {727-728},
pmid = {34635841},
issn = {1759-4766},
mesh = {*Alzheimer Disease/genetics ; Humans ; },
}
@article {pmid34634492,
year = {2021},
author = {Zakusilo, FT and Kerry O'Banion, M and Gelbard, HA and Seluanov, A and Gorbunova, V},
title = {Matters of size: Roles of hyaluronan in CNS aging and disease.},
journal = {Ageing research reviews},
volume = {72},
number = {},
pages = {101485},
pmid = {34634492},
issn = {1872-9649},
support = {P01 AG047200/AG/NIA NIH HHS/United States ; R01 AG027237/AG/NIA NIH HHS/United States ; R61 AR078093/AR/NIAMS NIH HHS/United States ; T32 GM007356/GM/NIGMS NIH HHS/United States ; },
mesh = {Aging ; Central Nervous System ; Humans ; *Hyaluronan Receptors ; *Hyaluronic Acid ; Molecular Weight ; },
abstract = {Involvement of extracellular matrix (ECM) components in aging and age-related neurodegeneration is not well understood. The role of hyaluronan (HA), a major extracellular matrix glycosaminoglycan, in malignancy and inflammation is gaining new understanding. In particular, the differential biological effects of high molecular weight (HMW-HA) and low molecular weight hyaluronan (LMW-HA), and the mechanism behind such differences are being uncovered. Tightly regulated in the brain, HA can have diverse effects on cellular development, growth and degeneration. In this review, we summarize the homeostasis and signaling of HA in healthy tissue, discuss its distribution and ontogeny in the central nervous system (CNS), summarize evidence for its involvement in age-related neurodegeneration and Alzheimer Disease (AD), and assess the potential of HA as a therapeutic target in the CNS.},
}
@article {pmid34633146,
year = {2021},
author = {Islam, MR and Kaurani, L and Berulava, T and Heilbronner, U and Budde, M and Centeno, TP and Elerdashvili, V and Zafieriou, MP and Benito, E and Sertel, SM and Goldberg, M and Senner, F and Kalman, JL and Burkhardt, S and Oepen, AS and Sakib, MS and Kerimoglu, C and Wirths, O and Bickeböller, H and Bartels, C and Brosseron, F and Buerger, K and Cosma, NC and Fliessbach, K and Heneka, MT and Janowitz, D and Kilimann, I and Kleinedam, L and Laske, C and Metzger, CD and Munk, MH and Perneczky, R and Peters, O and Priller, J and Rauchmann, BS and Roy, N and Schneider, A and Spottke, A and Spruth, EJ and Teipel, S and Tscheuschler, M and Wagner, M and Wiltfang, J and Düzel, E and Jessen, F and , and Rizzoli, SO and Zimmermann, WH and Schulze, TG and Falkai, P and Sananbenesi, F and Fischer, A},
title = {A microRNA signature that correlates with cognition and is a target against cognitive decline.},
journal = {EMBO molecular medicine},
volume = {13},
number = {11},
pages = {e13659},
pmid = {34633146},
issn = {1757-4684},
mesh = {*Alzheimer Disease ; Brain ; Cognition ; *Cognitive Dysfunction/genetics ; Humans ; *MicroRNAs/genetics ; },
abstract = {While some individuals age without pathological memory impairments, others develop age-associated cognitive diseases. Since changes in cognitive function develop slowly over time in these patients, they are often diagnosed at an advanced stage of molecular pathology, a time point when causative treatments fail. Thus, there is great need for the identification of inexpensive and minimal invasive approaches that could be used for screening with the aim to identify individuals at risk for cognitive decline that can then undergo further diagnostics and eventually stratified therapies. In this study, we use an integrative approach combining the analysis of human data and mechanistic studies in model systems to identify a circulating 3-microRNA signature that reflects key processes linked to neural homeostasis and inform about cognitive status. We furthermore provide evidence that expression changes in this signature represent multiple mechanisms deregulated in the aging and diseased brain and are a suitable target for RNA therapeutics.},
}
@article {pmid34632577,
year = {2022},
author = {Engelborghs, S},
title = {Adults with cerebral palsy and Alzheimer disease: a missing link?.},
journal = {Developmental medicine and child neurology},
volume = {64},
number = {3},
pages = {284},
doi = {10.1111/dmcn.15080},
pmid = {34632577},
issn = {1469-8749},
mesh = {Adult ; *Alzheimer Disease/complications ; *Cerebral Palsy/complications ; Humans ; },
}
@article {pmid34630919,
year = {2021},
author = {da Silva, RCR and de Carvalho, RLS and Dourado, MCN},
title = {Deficits in emotion processing in Alzheimer's disease: a systematic review.},
journal = {Dementia &amp; neuropsychologia},
volume = {15},
number = {3},
pages = {314-330},
pmid = {34630919},
issn = {1980-5764},
abstract = {Emotional processing involves the ability of the individual to infer emotional information. There is no consensus about how Alzheimer's disease (AD) affects emotional processing. Objective: Our aim is to systematically review the impact of AD on emotion processing.<br><br>METHODS: We conducted a search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The literature search was performed using the electronic databases MEDLINE (PubMed) and Science Citation Index (Institute for Scientific Information [ISI]). The following descriptors were used in the review process: emotion or emotional processing, cognition or cognitive functions, and Alzheimer disease or Alzheimer's disease. This systematic review was recorded in the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42018115891.<br><br>RESULTS: We identified 425 articles, 19 of which met our criteria. Visual emotional stimuli were the most used among studies. Most studies used tasks of emotional naming, discrimination, identification, and correspondence. The results were contradictory. Many studies reported that individuals with AD were impaired on emotional perception tasks, while other results reported preserved skills. The relationship between emotional processing and cognition is also unclear. Some studies suggested that general cognitive performance affects performance in emotional perception tasks among people with AD, but other studies have shown deficits in recognizing emotion, regardless of cognitive performance.<br><br>CONCLUSIONS: Studies are scarce, present contradictory results, and report impairment in emotional processing in relation to cognition. Moreover, the analyses of the correlation between emotion processing and cognitive functioning failed to reveal clear relationships.},
}
@article {pmid34630027,
year = {2021},
author = {Muzio, L and Viotti, A and Martino, G},
title = {Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {742065},
pmid = {34630027},
issn = {1662-4548},
abstract = {Microglia are the resident macrophages of the central nervous system (CNS) acting as the first line of defense in the brain by phagocytosing harmful pathogens and cellular debris. Microglia emerge from early erythromyeloid progenitors of the yolk sac and enter the developing brain before the establishment of a fully mature blood-brain barrier. In physiological conditions, during brain development, microglia contribute to CNS homeostasis by supporting cell proliferation of neural precursors. In post-natal life, such cells contribute to preserving the integrity of neuronal circuits by sculpting synapses. After a CNS injury, microglia change their morphology and down-regulate those genes supporting homeostatic functions. However, it is still unclear whether such changes are accompanied by molecular and functional modifications that might contribute to the pathological process. While comprehensive transcriptome analyses at the single-cell level have identified specific gene perturbations occurring in the "pathological" microglia, still the precise protective/detrimental role of microglia in neurological disorders is far from being fully elucidated. In this review, the results so far obtained regarding the role of microglia in neurodegenerative disorders will be discussed. There is solid and sound evidence suggesting that regulating microglia functions during disease pathology might represent a strategy to develop future therapies aimed at counteracting brain degeneration in multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.},
}
@article {pmid34626530,
year = {2021},
author = {Priyanka, A and Ganesan, K},
title = {Hippocampus segmentation and classification for dementia analysis using pre-trained neural network models.},
journal = {Biomedizinische Technik. Biomedical engineering},
volume = {66},
number = {6},
pages = {581-592},
doi = {10.1515/bmt-2021-0070},
pmid = {34626530},
issn = {1862-278X},
mesh = {*Alzheimer Disease/diagnosis ; Brain ; *Cognitive Dysfunction ; Hippocampus ; Humans ; Magnetic Resonance Imaging ; Neural Networks, Computer ; },
abstract = {The diagnostic and clinical overlap of early mild cognitive impairment (EMCI), mild cognitive impairment (MCI), late mild cognitive impairment (LMCI) and Alzheimer disease (AD) is a vital oncological issue in dementia disorder. This study is designed to examine Whole brain (WB), grey matter (GM) and Hippocampus (HC) morphological variation and identify the prominent biomarkers in MR brain images of demented subjects to understand the severity progression. Curve evolution based on shape constraint is carried out to segment the complex brain structure such as HC and GM. Pre-trained models are used to observe the severity variation in these regions. This work is evaluated on ADNI database. The outcome of the proposed work shows that curve evolution method could segment HC and GM regions with better correlation. Pre-trained models are able to show significant severity difference among WB, GM and HC regions for the considered classes. Further, prominent variation is observed between AD vs. EMCI, AD vs. MCI and AD vs. LMCI in the whole brain, GM and HC. It is concluded that AlexNet model for HC region result in better classification for AD vs. EMCI, AD vs. MCI and AD vs. LMCI with an accuracy of 93, 78.3 and 91% respectively.},
}
@article {pmid34625724,
year = {2021},
author = {Bettcher, BM and Tansey, MG and Dorothée, G and Heneka, MT},
title = {Publisher Correction: Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus.},
journal = {Nature reviews. Neurology},
volume = {17},
number = {11},
pages = {724},
doi = {10.1038/s41582-021-00579-5},
pmid = {34625724},
issn = {1759-4766},
}
@article {pmid34625662,
year = {2022},
author = {Flores, J and Noël, A and Fillion, ML and LeBlanc, AC},
title = {Therapeutic potential of Nlrp1 inflammasome, Caspase-1, or Caspase-6 against Alzheimer disease cognitive impairment.},
journal = {Cell death and differentiation},
volume = {29},
number = {3},
pages = {657-669},
pmid = {34625662},
issn = {1476-5403},
support = {2011MOP-243413-BCA-CGAG-45097//Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre)/ ; 201610PJT-377052-PJT-CFAF-45097//Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (Skin Research Training Centre)/ ; },
mesh = {*Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Caspase 1/*metabolism ; Caspase 6/genetics/*metabolism ; *Cognitive Dysfunction/genetics ; Disease Models, Animal ; Inflammasomes/metabolism ; Inflammation ; Mice ; Mice, Transgenic ; },
abstract = {The sequential activation of Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing protein 1 (Nlrp1) inflammasome, Caspase-1 (Casp1), and Caspase-6 (Casp6) is implicated in primary human neuron cultures and Alzheimer Disease (AD) neurodegeneration. To validate the Nlrp1-Casp1-Casp6 pathway in vivo, the APPSwedish/Indiana J20 AD transgenic mouse model was generated on either a Nlrp1, Casp1 or Casp6 null genetic background and mice were studied at 4-5 months of age. Episodic memory deficits assessed with novel object recognition were normalized by genetic ablation of Nlrp1, Casp1, or Casp6 in J20 mice. Spatial learning deficits, assessed with the Barnes Maze, were normalized in genetically ablated J20, whereas memory recall was normalized in J20/Casp1-/- and J20/Casp6-/-, and improved in J20/Nlrp1-/- mice. Hippocampal CA1 dendritic spine density of the mushroom subtype was reduced in J20, and normalized in genetically ablated J20 mice. Reduced J20 hippocampal dentate gyrus and CA3 synaptophysin levels were normalized in genetically ablated J20. Increased Iba1+-microglia in the hippocampus and cortex of J20 brains were normalized by Casp1 and Casp6 ablation and reduced by Nlrp1 ablation. Increased pro-inflammatory cytokines, TNF-α and CXCL1, in the J20 hippocampus were normalized by Nlrp1 or Casp1 genetic ablation. CXCL1 was also normalized by Casp6 genetic ablation. IFN-γ was increased and total amyloid β peptide was decreased in genetically ablated Nlrp1, Casp1 or Casp6 J20 hippocampi. We conclude that Nlrp1, Casp1, or Casp6 are implicated in AD-related cognitive impairment, inflammation, and amyloidogenesis. These results indicate that Nlrp1, Casp1, and Casp6 represent rational therapeutic targets against cognitive impairment and inflammation in AD.},
}
@article {pmid34622190,
year = {2021},
author = {Nielsen, JE and Maltesen, RG and Havelund, JF and Færgeman, NJ and Gotfredsen, CH and Vestergård, K and Kristensen, SR and Pedersen, S},
title = {Characterising Alzheimer's disease through integrative NMR- and LC-MS-based metabolomics.},
journal = {Metabolism open},
volume = {12},
number = {},
pages = {100125},
pmid = {34622190},
issn = {2589-9368},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a complex and multifactorial disease and novel approaches are needed to illuminate the underlying pathology. Metabolites comprise the end-product of genes, transcripts, and protein regulations and might reflect disease pathogenesis. Blood is a common biofluid used in metabolomics; however, since extracellular vesicles (EVs) hold cell-specific biological material and can cross the blood-brain barrier, their utilization as biological material warrants further investigation. We aimed to investigate blood- and EV-derived metabolites to add insigts to the pathological mechanisms of AD.<br><br>METHODS: Blood samples were collected from 10 AD and 10 Mild Cognitive Impairment (MCI) patients, and 10 healthy controls. EVs were enriched from plasma using 100,000×g, 1 h, 4 °C with a wash. Metabolites from serum and EVs were measured using liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy. Multivariate and univariate analyses were employed to identify altered metabolites in cognitively impaired individuals.<br><br>RESULTS: While no significant EV-derived metabolites were found differentiating patients from healthy individuals, six serum metabolites were found important; valine (p = 0.001, fold change, FC = 0.8), histidine (p = 0.001, FC = 0.9), allopurinol riboside (p = 0.002, FC = 0.2), inosine (p = 0.002, FC = 0.3), 4-pyridoxic acid (p = 0.006, FC = 1.6), and guanosine (p = 0.004, FC = 0.3). Pathway analysis revealed branched-chain amino acids, purine and histidine metabolisms to be downregulated, and vitamin B6 metabolism upregulated in patients compared to controls.<br><br>CONCLUSION: Using a combination of LC-MS and NMR methodologies we identified several altered mechanisms possibly related to AD pathology. EVs require additional optimization prior to their possible utilization as a biological material for AD-related metabolomics studies.},
}
@article {pmid34620589,
year = {2021},
author = {Borzage, M and Saunders, A and Hughes, J and McComb, JG and Blüml, S and King, KS},
title = {The First Examination of Diagnostic Performance of Automated Measurement of the Callosal Angle in 1856 Elderly Patients and Volunteers Indicates That 12.4% of Exams Met the Criteria for Possible Normal Pressure Hydrocephalus.},
journal = {AJNR. American journal of neuroradiology},
volume = {42},
number = {11},
pages = {1942-1948},
pmid = {34620589},
issn = {1936-959X},
support = {R01 AG043434/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; UL1 TR000448/TR/NCATS NIH HHS/United States ; UL1 TR002345/TR/NCATS NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; //CIHR/Canada ; },
mesh = {Aged ; Corpus Callosum/diagnostic imaging ; Humans ; *Hydrocephalus, Normal Pressure/diagnostic imaging ; Magnetic Resonance Imaging ; Neuroimaging ; Volunteers ; },
abstract = {BACKGROUND AND PURPOSE: Many patients with dementia may have comorbid or misdiagnosed normal pressure hydrocephalus, a treatable neurologic disorder. The callosal angle is a validated biomarker for normal pressure hydrocephalus with 93% diagnostic accuracy. Our purpose was to develop and evaluate an algorithm for automatically computing callosal angles from MR images of the brain.<br><br>MATERIALS AND METHODS: This article reports the results of analyzing callosal angles from 1856 subjects with 5264 MR images from the Open Access Series of Imaging Studies and the Alzheimer's Disease Neuroimaging Initiative databases. Measurement variability was examined between 2 neuroradiologists (n = 50) and between manual and automatic measurements (n = 281); from differences in simulated head orientation; and from real-world changes in patients with multiple examinations (n = 906). We evaluated the effectiveness of the automatic callosal angle to differentiate normal pressure hydrocephalus from Alzheimer disease in a simulated cohort.<br><br>RESULTS: The algorithm identified that 12.4% of subjects from these carefully screened cohorts had callosal angles of <90°, a published threshold for possible normal pressure hydrocephalus. The intraclass correlation coefficient was 0.97 for agreement between neuroradiologists and 0.90 for agreement between manual and automatic measurement. The method was robust to different head orientations. The median coefficient of variation for repeat examinations was 4.2% (Q1 = 3.1%, Q3 = 5.8%). The simulated classification of normal pressure hydrocephalus versus Alzheimer using the automatic callosal angle had an accuracy, sensitivity, and specificity of 0.87 each.<br><br>CONCLUSIONS: In even the most pristine research databases, analyses of the callosal angle indicate that some patients may have normal pressure hydrocephalus. The automatic callosal angle measurement can rapidly and objectively screen for normal pressure hydrocephalus in patients who would otherwise be misdiagnosed.},
}
@article {pmid34619465,
year = {2021},
author = {Li, Y and Sang, S and Ren, W and Pei, Y and Bian, Y and Chen, Y and Sun, H},
title = {Inhibition of Histone Deacetylase 6 (HDAC6) as a therapeutic strategy for Alzheimer's disease: A review (2010-2020).},
journal = {European journal of medicinal chemistry},
volume = {226},
number = {},
pages = {113874},
doi = {10.1016/j.ejmech.2021.113874},
pmid = {34619465},
issn = {1768-3254},
mesh = {Acetamides/chemical synthesis/chemistry/*pharmacology ; Alzheimer Disease/*drug therapy/metabolism ; Histone Deacetylase 6/*antagonists &amp; inhibitors/metabolism ; Histone Deacetylase Inhibitors/chemical synthesis/chemistry/*pharmacology ; Humans ; Hydroxamic Acids/chemical synthesis/chemistry/*pharmacology ; Models, Molecular ; Molecular Structure ; Neuroprotective Agents/chemical synthesis/chemistry/*pharmacology ; },
abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which is characterized by the primary risk factor, age. Several attempts have been made to treat AD, while most of them end in failure. However, with the deepening study of pathogenesis of AD, the expression of HDAC6 in the hippocampus, which plays a major role of the memory formation, is becoming worth of notice. Neurofibrillary tangles (NFTs), a remarkable lesion in AD, has been characterized in association with the abnormal accumulation of hyperphosphorylated Tau, which is mainly caused by the high expression of HDAC6. On the other hand, the hypoacetylated tubulin induced by HDAC6 is also fatal for the neuronal transport, which is the key impact of the formation of axons and dendrites. Overall, the significantly increased expression of HDAC6 in brain regions is deleterious to neuron survival in AD patients. Based on the above research, the inhibition of HDAC6 seems to be a potential therapeutic method for the treatment of AD. Up to now, various types of HDAC6 inhibitors have been discovered. This review mainly analyzes the HDAC6 inhibitors reported amid 2010-2020 in terms of their structure, selectivity and pharmacological impact towards AD. And we aim at facilitating the design and development of better HDAC6 inhibitors in the future.},
}
@article {pmid34619027,
year = {2022},
author = {Eggert, S and Kins, S and Endres, K and Brigadski, T},
title = {Brothers in arms: proBDNF/BDNF and sAPPα/Aβ-signaling and their common interplay with ADAM10, TrkB, p75NTR, sortilin, and sorLA in the progression of Alzheimer's disease.},
journal = {Biological chemistry},
volume = {403},
number = {1},
pages = {43-71},
doi = {10.1515/hsz-2021-0330},
pmid = {34619027},
issn = {1437-4315},
mesh = {ADAM10 Protein ; Adaptor Proteins, Vesicular Transport ; *Alzheimer Disease ; Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; *Brain-Derived Neurotrophic Factor ; Humans ; LDL-Receptor Related Proteins ; Membrane Glycoproteins ; Membrane Proteins ; Membrane Transport Proteins ; Nerve Tissue Proteins ; Receptor, trkB ; Receptors, Nerve Growth Factor ; },
abstract = {Brain-derived neurotrophic factor (BDNF) is an important modulator for a variety of functions in the central nervous system (CNS). A wealth of evidence, such as reduced mRNA and protein level in the brain, cerebrospinal fluid (CSF), and blood samples of Alzheimer's disease (AD) patients implicates a crucial role of BDNF in the progression of this disease. Especially, processing and subcellular localization of BDNF and its receptors TrkB and p75 are critical determinants for survival and death in neuronal cells. Similarly, the amyloid precursor protein (APP), a key player in Alzheimer's disease, and its cleavage fragments sAPPα and Aβ are known for their respective roles in neuroprotection and neuronal death. Common features of APP- and BDNF-signaling indicate a causal relationship in their mode of action. However, the interconnections of APP- and BDNF-signaling are not well understood. Therefore, we here discuss dimerization properties, localization, processing by α- and γ-secretase, relevance of the common interaction partners TrkB, p75, sorLA, and sortilin as well as shared signaling pathways of BDNF and sAPPα.},
}
@article {pmid34617021,
year = {2021},
author = {Huang, W and Li, X and Li, H and Wang, W and Chen, K and Xu, K and Zhang, J and Chen, Y and Wei, D and Shu, N and Zhang, Z},
title = {Accelerated Brain Aging in Amnestic Mild Cognitive Impairment: Relationships with Individual Cognitive Decline, Risk Factors for Alzheimer Disease, and Clinical Progression.},
journal = {Radiology. Artificial intelligence},
volume = {3},
number = {5},
pages = {e200171},
pmid = {34617021},
issn = {2638-6100},
abstract = {PURPOSE: To determine whether a brain age prediction model could quantify individual deviations from a healthy brain-aging trajectory (predicted age difference [PAD]) in patients with amnestic mild cognitive impairment (aMCI) and to determine if PAD was associated with individual cognitive impairment.<br><br>MATERIALS AND METHODS: In this retrospective study, a machine learning approach was trained to determine brain age based on T1-weighted MRI scans. Two datasets were used for model training and testing-the Beijing Aging Brain Rejuvenation Initiative (BABRI) (616 healthy controls and 80 patients with aMCI, 2010-2018) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (589 healthy controls and 144 patients with aMCI, 2010-2018). A total of 974 healthy controls were used for model training (490 from BABRI and 484 from ADNI; age range, 49-95 years). The trained model was then tested on both healthy controls (126 from BABRI and 105 from ADNI) and patients with aMCI (80 from BABRI and 144 from ADNI) to estimate PAD (predicted age - actual age). Furthermore, the associations between PAD with cognitive impairment, genetic risk factors and pathologic markers of Alzheimer disease (AD), and clinical progression in patients with aMCI were examined using a partial correlation analysis, a two-way analysis of covariance, and a general linear model, respectively.<br><br>RESULTS: Based on the prediction model, patients with aMCI were found to have higher PADs than those of healthy controls (BABRI: 2.65 ± 4.91 [standard deviation] vs 0.18 ± 4.79 [P < .001]; ADNI: 1.68 ± 5.28 vs 0.05 ± 4.41 [P < .001]). Moreover, the PAD was significantly associated with individual cognitive impairment in several cognitive domains in patients with aMCI (P < .05, corrected). When considering different AD-related risk factors, apolipoprotein E ε4 allele carriers were observed to have higher PADs than noncarriers (3.76 ± 4.82 vs 0.10 ± 5.05; P = .017), and patients with amyloid-positive aMCI were observed to have higher PADs than patients with amyloid-negative status (2.40 ± 5.25 vs 0.93 ± 5.20; P = .003). Finally, PAD combined with other markers of AD at baseline for differentiating between progressive and stable aMCI resulted in an area under the curve value of 0.87.<br><br>CONCLUSION: The PAD is a sensitive imaging marker related to individual cognitive differences in patients with aMCI.Keywords: MR Imaging, Brain/Brain Stem, Brain Age, Machine Learning, Mild Cognitive Impairment, Structural MRI Supplemental material is available for this article. © RSNA, 2021.},
}
@article {pmid34613972,
year = {2021},
author = {Kaldun, JC and Lone, SR and Humbert Camps, AM and Fritsch, C and Widmer, YF and Stein, JV and Tomchik, SM and Sprecher, SG},
title = {Dopamine, sleep, and neuronal excitability modulate amyloid-β-mediated forgetting in Drosophila.},
journal = {PLoS biology},
volume = {19},
number = {10},
pages = {e3001412},
pmid = {34613972},
issn = {1545-7885},
mesh = {Amyloid beta-Peptides/*toxicity ; Animals ; Brain/metabolism ; Dopamine/*metabolism ; Drosophila melanogaster/drug effects/*physiology ; Memory/drug effects/*physiology ; Mushroom Bodies/drug effects/metabolism ; Neurons/drug effects/*physiology ; Sleep/*physiology ; },
abstract = {Alzheimer disease (AD) is one of the main causes of age-related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a central component of the molecular disease pathways. Pan-neuronal expression of Aβ42Arctic peptides in Drosophila melanogaster results in learning and memory defects. Surprisingly, targeted expression to the mushroom bodies, a center for olfactory memories in the fly brain, does not interfere with learning but accelerates forgetting. We show here that reducing neuronal excitability either by feeding Levetiracetam or silencing of neurons in the involved circuitry ameliorates the phenotype. Furthermore, inhibition of the Rac-regulated forgetting pathway could rescue the Aβ42Arctic-mediated accelerated forgetting phenotype. Similar effects are achieved by increasing sleep, a critical regulator of neuronal homeostasis. Our results provide a functional framework connecting forgetting signaling and sleep, which are critical for regulating neuronal excitability and homeostasis and are therefore a promising mechanism to modulate forgetting caused by toxic Aβ peptides.},
}
@article {pmid34610666,
year = {2021},
author = {Young, S and Chung, E and Chen, MA},
title = {Cardiovascular Complications of Acetylcholinesterase Inhibitors in Patients with Alzheimer's Disease: A Narrative Review.},
journal = {Annals of geriatric medicine and research},
volume = {25},
number = {3},
pages = {170-177},
pmid = {34610666},
issn = {2508-4909},
abstract = {While acetylcholinesterase inhibitors are used to treat a wide range of patients with Alzheimer's disease, acetylcholinesterase inhibitor use has also been associated with a variety of cardiovascular complications, including bradycardia and syncope. Herein, we review the pathophysiology and clinical evidence for cardiovascular complications caused by acetylcholinesterase inhibitors in patients being treated for dementia and discuss options for their management.},
}
@article {pmid34609497,
year = {2021},
author = {Rizvi, B and Lao, PJ and Chesebro, AG and Dworkin, JD and Amarante, E and Beato, JM and Gutierrez, J and Zahodne, LB and Schupf, N and Manly, JJ and Mayeux, R and Brickman, AM},
title = {Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults.},
journal = {JAMA network open},
volume = {4},
number = {10},
pages = {e2125166},
pmid = {34609497},
issn = {2574-3805},
support = {P30 AG066462/AG/NIA NIH HHS/United States ; R01 AG072474/AG/NIA NIH HHS/United States ; RF1 AG054023/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/*physiopathology ; Brain/*abnormalities/diagnostic imaging/physiopathology ; Female ; Humans ; Magnetic Resonance Imaging/methods/statistics &amp; numerical data ; Male ; Monte Carlo Method ; Neurodegenerative Diseases/*diagnosis/diagnostic imaging ; New York ; White Matter/*diagnostic imaging/physiopathology ; },
abstract = {Importance: Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups.<br><br>Objective: To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups.<br><br>This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights-Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020.<br><br>Exposures: Total and regional WMH volumes.<br><br>Main Outcomes and Measures: The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome.<br><br>Results: In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P < .001), paracentral (P < .001), and pars triangularis (P = .02) cortices. Thinning of the right caudal middle frontal and left entorhinal cortices was related to lower scores on a memory test administered closest to the second MRI visit (right caudal middle frontal cortex: standardized β = 0.129; unstandardized b = 0.335; 95% CI, 0.055 to 0.616; P = .01; left entorhinal cortex: β = 0.119; b = 0.290; 95% CI, 0.018 to 0.563; P = .03). The association of total WMH with thinning in the right caudal middle frontal and right paracentral cortex was greater in non-Hispanic Black participants compared with White participants (right caudal middle frontal cortex: β = -0.222; b = -0.059; 95% CI, -0.114 to -0.004; P = .03; right paracentral cortex: β = -0.346; b = -0.155; 95% CI, -0.244 to -0.066; P = .001). The association of parietal WMH with cortical thinning of the right rostral middle frontal, right pars triangularis, and right paracentral cortices was also stronger among non-Hispanic Black participants compared with White participants (right rostral middle frontal cortex: β = -0.252; b = -0.202; 95% CI, -0.349 to -0.055; P = .007; right pars triangularis cortex: β = -0.327; b = -0.253; 95% CI, -0.393 to -0.113; P < .001; right paracentral cortex: β = -0.263; b = -0.337; 95% CI, -0.567 to -0.107; P = .004).<br><br>Conclusions and Relevance: In this study, small vessel cerebrovascular disease, operationalized as WMH, was associated with subsequent cortical atrophy in regions that overlap with typical AD neurodegeneration patterns, particularly among non-Hispanic Black older adults. Cerebrovascular disease may affect risk and progression of AD by promoting neurodegeneration and subsequent memory decline.},
}
@article {pmid34609493,
year = {2021},
author = {Zacharias, HU and Weihs, A and Habes, M and Wittfeld, K and Frenzel, S and Rashid, T and Stubbe, B and Obst, A and Szentkirályi, A and Bülow, R and Berger, K and Fietze, I and Penzel, T and Hosten, N and Ewert, R and Völzke, H and Grabe, HJ},
title = {Association Between Obstructive Sleep Apnea and Brain White Matter Hyperintensities in a Population-Based Cohort in Germany.},
journal = {JAMA network open},
volume = {4},
number = {10},
pages = {e2128225},
pmid = {34609493},
issn = {2574-3805},
support = {P30 AG066546/AG/NIA NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aging/physiology ; Cohort Studies ; Cross-Sectional Studies ; Female ; Germany/epidemiology ; Humans ; Magnetic Resonance Imaging/methods/statistics &amp; numerical data ; Male ; Middle Aged ; Sleep Apnea, Obstructive/*complications/diagnostic imaging/epidemiology ; White Matter/abnormalities/*physiopathology ; },
abstract = {Importance: Underlying pathomechanisms of brain white matter hyperintensities (WMHs), commonly observed in older individuals and significantly associated with Alzheimer disease and brain aging, have not yet been fully elucidated. One potential contributing factor to WMH burden is chronic obstructive sleep apnea (OSA), a disorder highly prevalent in the general population with readily available treatment options.<br><br>Objective: To investigate potential associations between OSA and WMH burden.<br><br>Analyses were conducted in 529 study participants of the Study of Health in Pomerania-Trend baseline (SHIP-Trend-0) study with complete WMH, OSA, and important clinical data available. SHIP-Trend-0 is a general population-based, cross-sectional, observational study to facilitate the investigation of a large spectrum of common risk factors, subclinical disorders, and clinical diseases and their relationships among each other with patient recruitment from Western Pomerania, Germany, starting on September 1, 2008, with data collected until December 31, 2012. Data analysis was performed from February 1, 2019, to January 31, 2021.<br><br>Exposures: The apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) were assessed during a single-night, laboratory-based polysomnography measurement.<br><br>Main Outcomes and Measures: The primary outcome was WMH data automatically segmented from 1.5-T magnetic resonance images.<br><br>Results: Of 529 study participants (mean [SD] age, 52.15 [13.58] years; 282 female [53%]), a total of 209 (40%) or 102 (19%) individuals were diagnosed with OSA according to AHI or ODI criteria (mean [SD] AHI, 7.98 [12.55] events per hour; mean [SD] ODI, 3.75 [8.43] events per hour). Both AHI (β = 0.024; 95% CI, 0.011-0.037; P <.001) and ODI (β = 0.033; 95% CI, 0.014-0.051; P <. 001) were significantly associated with brain WMH volumes. These associations remained even in the presence of additional vascular, metabolic, and lifestyle WMH risk factors. Region-specific WMH analyses found the strongest associations between periventricular frontal WMH volumes and both AHI (β = 0.0275; 95% CI, 0.013-0.042, P < .001) and ODI (β = 0.0381; 95% CI, 0.016-0.060, P < .001) as well as periventricular dorsal WMH volumes and AHI (β = 0.0165; 95% CI, 0.004-0.029, P = .008).<br><br>Conclusions and Relevance: This study found significant associations between OSA and brain WMHs, indicating a novel, potentially treatable WMH pathomechanism.},
}
@article {pmid34607546,
year = {2021},
author = {Rema, J and Novais, F and Telles-Correia, D},
title = {Precision Psychiatry: Machine learning as a tool to find new pharmacological targets.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/1568026621666211004095917},
pmid = {34607546},
issn = {1873-4294},
abstract = {There is an increasing amount of data arising from neurobehavioral sciences and medical records that cannot be adequately analyzed by traditional research methods. New drugs develop at a slow rate and seem unsatisfactory for the majority of neurobehavioral disorders. Machine learning (ML) techniques, instead, can incorporate psychopathological, computational, cognitive, and neurobiological underpinning knowledge leading to a refinement of detection, diagnosis, prognosis, treatment, research, and support. Machine and deep learning methods are currently used to accelerate the process of discovering new pharmacological targets and drugs.<br><br>OBJECTIVE: The present work reviews current evidence regarding the contribution of machine learning to the discovery of new drug targets.<br><br>METHODS: Scientific articles from PubMed, SCOPUS, EMBASE, and Web of Science Core Collection published until May 2021 were included in this review.<br><br>RESULTS: The most significant areas of research are schizophrenia, depression and anxiety, Alzheimer´s disease, and substance use disorders. ML techniques have pinpointed target gene candidates and pathways, new molecular substances, and several biomarkers regarding psychiatric disorders. Drug repositioning studies using ML have identified multiple drug candidates as promising therapeutic agents.<br><br>CONCLUSION: Next-generation ML techniques and subsequent deep learning may power new findings regarding the discovery of new pharmacological agents by bridging the gap between biological data and chemical drug information.},
}
@article {pmid34606321,
year = {2021},
author = {Shiels, MS and Haque, AT and Haozous, EA and Albert, PS and Almeida, JS and García-Closas, M and Nápoles, AM and Pérez-Stable, EJ and Freedman, ND and Berrington de González, A},
title = {Racial and Ethnic Disparities in Excess Deaths During the COVID-19 Pandemic, March to December 2020.},
journal = {Annals of internal medicine},
volume = {174},
number = {12},
pages = {1693-1699},
doi = {10.7326/M21-2134},
pmid = {34606321},
issn = {1539-3704},
mesh = {Adolescent ; Adult ; Age Distribution ; Aged ; Aged, 80 and over ; COVID-19/*ethnology/*mortality ; Cause of Death ; Child ; Child, Preschool ; Ethnic and Racial Minorities/*statistics &amp; numerical data ; Female ; *Health Status Disparities ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; *Pandemics ; Population Surveillance ; SARS-CoV-2 ; Sex Distribution ; United States/epidemiology ; Young Adult ; },
abstract = {BACKGROUND: Although racial/ethnic disparities in U.S. COVID-19 death rates are striking, focusing on COVID-19 deaths alone may underestimate the true effect of the pandemic on disparities. Excess death estimates capture deaths both directly and indirectly caused by COVID-19.<br><br>OBJECTIVE: To estimate U.S. excess deaths by racial/ethnic group.<br><br>DESIGN: Surveillance study.<br><br>SETTING: United States.<br><br>PARTICIPANTS: All decedents.<br><br>MEASUREMENTS: Excess deaths and excess deaths per 100 000 persons from March to December 2020 were estimated by race/ethnicity, sex, age group, and cause of death, using provisional death certificate data from the Centers for Disease Control and Prevention (CDC) and U.S. Census Bureau population estimates.<br><br>RESULTS: An estimated 2.88 million deaths occurred between March and December 2020. Compared with the number of expected deaths based on 2019 data, 477 200 excess deaths occurred during this period, with 74% attributed to COVID-19. Age-standardized excess deaths per 100 000 persons among Black, American Indian/Alaska Native (AI/AN), and Latino males and females were more than double those in White and Asian males and females. Non-COVID-19 excess deaths also disproportionately affected Black, AI/AN, and Latino persons. Compared with White males and females, non-COVID-19 excess deaths per 100 000 persons were 2 to 4 times higher in Black, AI/AN, and Latino males and females, including deaths due to diabetes, heart disease, cerebrovascular disease, and Alzheimer disease. Excess deaths in 2020 resulted in substantial widening of racial/ethnic disparities in all-cause mortality from 2019 to 2020.<br><br>LIMITATIONS: Completeness and availability of provisional CDC data; no estimates of precision around results.<br><br>CONCLUSION: There were profound racial/ethnic disparities in excess deaths in the United States in 2020 during the COVID-19 pandemic, resulting in rapid increases in racial/ethnic disparities in all-cause mortality between 2019 and 2020.<br><br>PRIMARY FUNDING SOURCE: National Institutes of Health Intramural Research Program.},
}
@article {pmid34605885,
year = {2021},
author = {Manly, JJ and Glymour, MM},
title = {What the Aducanumab Approval Reveals About Alzheimer Disease Research.},
journal = {JAMA neurology},
volume = {78},
number = {11},
pages = {1305-1306},
doi = {10.1001/jamaneurol.2021.3404},
pmid = {34605885},
issn = {2168-6157},
mesh = {Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Clinical Trials as Topic/methods/*standards ; *Drug Approval ; *Ethnic and Racial Minorities ; Humans ; United States ; United States Food and Drug Administration ; },
}
@article {pmid34605039,
year = {2022},
author = {Lu, K and Yong, KXX and Skorupinska, I and Deriziotis, S and Collins, JD and Henley, SMD and Hanna, MG and Rossor, MN and Ridha, BH and Machado, PM},
title = {A cross-sectional study of memory and executive functions in patients with sporadic inclusion body myositis.},
journal = {Muscle &amp; nerve},
volume = {65},
number = {1},
pages = {105-109},
doi = {10.1002/mus.27426},
pmid = {34605039},
issn = {1097-4598},
support = {U01 AG016976/AG/NIA NIH HHS/United States ; /DH_/Department of Health/United Kingdom ; },
mesh = {*Alzheimer Disease ; Cross-Sectional Studies ; Executive Function/physiology ; Humans ; Middle Aged ; *Myositis, Inclusion Body ; Neuropsychological Tests ; },
abstract = {INTRODUCTION/AIMS: Sporadic inclusion body myositis (IBM) is a degenerative and inflammatory acquired myopathy characterized by muscle deposition of various proteins typically associated with Alzheimer disease and other neurodegenerative diseases. Although cognitive impairment is not noted as a clinical feature of IBM, evidence is lacking. In this study we investigated whether cognitive performance of patients with IBM differs from population norms, focusing on cognitive domains affected in early Alzheimer disease (memory, executive function), and to test whether disease duration and the level of disability of IBM are associated with cognitive function.<br><br>METHODS: Twenty-four patients with IBM (mean [standard deviation]: age, 62.0 [7.2] years; disease duration, 9.6 [4.8] years) were assessed cross-sectionally on neuropsychological tests covering multiple cognitive domains, including the Preclinical Alzheimer Cognitive Composite (PACC). Performance was compared with published normative data adjusted for age, sex, and education (National Alzheimer's Coordinating Center; N = 3268). Associations were examined between PACC score, disease duration, and level of disability (assessed using the IBM Functional Rating Scale [IBMFRS]).<br><br>RESULTS: Across all cognitive tests, group performance was within ±1 standard deviation of the normative mean. There was no evidence of associations between PACC score and either disease duration (ρ = -0.04, P = .87) or IBMFRS total score (ρ = 0.14, P = .52).<br><br>DISCUSSION: Memory and executive function in patients with IBM did not differ from normative data, and we observed no evidence of associations between the cognitive composite and disease duration or level of disability. This addresses a question frequently asked by patients and will be of value for clinicians and patients alike.},
}
@article {pmid34603320,
year = {2021},
author = {Chee, SEJ and Solito, E},
title = {The Impact of Ageing on the CNS Immune Response in Alzheimer's Disease.},
journal = {Frontiers in immunology},
volume = {12},
number = {},
pages = {738511},
pmid = {34603320},
issn = {1664-3224},
mesh = {Age Factors ; Aging/*immunology/metabolism/pathology ; Alzheimer Disease/*immunology/metabolism/pathology/therapy ; Alzheimer Vaccines/therapeutic use ; Amyloid beta-Peptides/immunology/metabolism ; Animals ; Anti-Inflammatory Agents/therapeutic use ; Biomarkers/metabolism ; Brain/*immunology/metabolism/pathology ; Humans ; *Immunosenescence ; Immunotherapy ; Nerve Degeneration ; *Neuroimmunomodulation ; },
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disease strongly associated with increasing age. Neuroinflammation and the accumulation of amyloid protein are amongst the hallmarks of this disease and most translational research to date has focused on targeting these two processes. However, the exact etiology of AD remains to be fully elucidated. When compared alongside, the immune response in AD closely resembles the central nervous system (CNS) immune changes seen in elderly individuals. It is possible that AD is a pathological consequence of an aged immune system secondary to chronic stimulation by a previous or ongoing insult. Pathological changes like amyloid accumulation and neuronal cell death may reflect this process of immunosenescence as the CNS immune system fails to maintain homeostasis in the CNS. It is likely that future treatments designed to modulate the aged immune system may prove beneficial in altering the disease course. The development of new tests for appropriate biomarkers would also be essential in screening for patients most likely to benefit from such treatments.},
}
@article {pmid34602969,
year = {2021},
author = {Salcedo-Arellano, MJ and Sanchez, D and Wang, JY and McLennan, YA and Clark, CJ and Juarez, P and Schneider, A and Tassone, F and Hagerman, RJ and Martínez-Cerdeño, V},
title = {Case Report: Coexistence of Alzheimer-Type Neuropathology in Fragile X-Associated Tremor Ataxia Syndrome.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {720253},
pmid = {34602969},
issn = {1662-4548},
support = {P50 HD103526/HD/NICHD NIH HHS/United States ; R01 HD036071/HD/NICHD NIH HHS/United States ; R01 NS107131/NS/NINDS NIH HHS/United States ; },
abstract = {This case documents the co-occurrence of the fragile X-associated tremor ataxia syndrome (FXTAS) and Alzheimer-type neuropathology in a 71-year-old premutation carrier with 85 CGG repeats in the fragile X mental retardation 1 (FMR1) gene, in addition to an apolipoprotein E (APOE) ε4 allele. FXTAS and Alzheimer's Disease (AD) are late-onset neurodegenerative diseases that share overlapping cognitive deficits including processing speed, working memory and executive function. The prevalence of coexistent FXTAS-AD pathology remains unknown. The clinical picture in this case was marked with rapid cognitive decline between age 67 and 71 years in addition to remarkable MRI changes. Over the 16 months between the two clinical evaluations, the brain atrophied 4.12% while the lateral ventricles increased 26.4% and white matter hyperintensities (WMH) volume increased 15.6%. Other regions atrophied substantially faster than the whole brain included the thalamus (-6.28%), globus pallidus (-10.95%), hippocampus (-6.95%), and amygdala (-7.58%). A detailed postmortem assessment included an MRI with confluent WMH and evidence of cerebral microbleeds (CMB). The histopathological study demonstrated FXTAS inclusions in neurons and astrocytes, a widespread presence of phosphorylated tau protein and, amyloid β plaques in cortical areas and the hippocampus. CMBs were noticed in the precentral gyrus, middle temporal gyrus, visual cortex, and brainstem. There were high amounts of iron deposits in the globus pallidus and the putamen consistent with MRI findings. We hypothesize that coexistent FXTAS-AD neuropathology contributed to the steep decline in cognitive abilities.},
}
@article {pmid34602046,
year = {2021},
author = {Herrmann, FR and Montandon, ML and Garibotto, V and Rodriguez, C and Haller, S and Giannakopoulos, P},
title = {Determinants of Cognitive Trajectories in Normal Aging: A Longitudinal PET-MRI Study in a Community-based Cohort.},
journal = {Current Alzheimer research},
volume = {18},
number = {6},
pages = {482-491},
doi = {10.2174/1567205018666210930111806},
pmid = {34602046},
issn = {1875-5828},
support = {320030-169390//Swiss National Foundation/ ; },
mesh = {Aged ; Aged, 80 and over ; Aging/*physiology ; Amyloid/*metabolism ; Atrophy/pathology ; Cerebral Small Vessel Diseases/metabolism ; Cognition/*physiology ; Cohort Studies ; Female ; Healthy Volunteers/*statistics &amp; numerical data ; Humans ; *Independent Living ; Longitudinal Studies ; Magnetic Resonance Imaging ; Male ; Neuropsychological Tests/*statistics &amp; numerical data ; Personality ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: The determinants of the progressive decrement of cognition in normal aging are still a matter of debate. Alzheimer disease (AD)-signature markers and vascular lesions, but also psychological variables such as personality factors, are thought to have an impact on the longitudinal trajectories of neuropsychological performances in healthy elderly individuals.<br><br>OBJECTIVE: The current research aimed to identify the main determinants associated with cognitive trajectories in normal aging.<br><br>METHODS: We performed a 4.5-year longitudinal study in 90 older community-dwellers coupling two neuropsychological assessments, medial temporal atrophy (MTA), number of cerebral microbleeds (CMB), and white matter hyperintensities (WMH) at inclusion, visual rating of amyloid and FDG PET at follow-up, and APOE genotyping. Personality factors were assessed at baseline using the NEO-PIR. Univariate and backward stepwise regression models were built to explore the association between the continuous cognitive score (CCS) and both imaging and personality variables.<br><br>RESULTS: The number of strictly lobar CMB at baseline (4 or more) was related to a significant increase in the risk of cognitive decrement. In multivariable models, amyloid positivity was associated with a 1.73 unit decrease of the CCS at follow-up. MTA, WMH and abnormal FDG PET were not related to the cognitive outcome. Among personality factors, only higher agreeableness was related to better preservation of neuropsychological performances.<br><br>CONCLUSION: CMB and amyloid positivity are the only imaging determinants of cognitive trajectories in this highly selected series of healthy controls. Among personality factors, higher agreeableness confers a modest but significant protection against the decline of cognitive performances.},
}
@article {pmid34601898,
year = {2022},
author = {Lamar, M and Leurgans, S and Kapasi, A and Barnes, LL and Boyle, PA and Bennett, DA and Arfanakis, K and Schneider, JA},
title = {Complex Profiles of Cerebrovascular Disease Pathologies in the Aging Brain and Their Relationship With Cognitive Decline.},
journal = {Stroke},
volume = {53},
number = {1},
pages = {218-227},
pmid = {34601898},
issn = {1524-4628},
support = {P30 AG072975/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; R01 AG043379/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; R01 AG034374/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG024480/AG/NIA NIH HHS/United States ; R01 AG042210/AG/NIA NIH HHS/United States ; UH2 NS100599/NS/NINDS NIH HHS/United States ; R01 AG064233/AG/NIA NIH HHS/United States ; RF1 AG022018/AG/NIA NIH HHS/United States ; },
mesh = {Aged, 80 and over ; Aging/*pathology ; Brain/*pathology ; Cerebrovascular Disorders/epidemiology/*pathology ; Cognitive Dysfunction/epidemiology/*pathology ; Cohort Studies ; Female ; Humans ; Male ; Prospective Studies ; },
abstract = {BACKGROUND AND PURPOSE: Cerebrovascular disease (CVD) pathologies including vessel disease (atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) and tissue injury (macroinfarcts and microinfarcts) each contribute to Alzheimer and other forms of dementia. CVD is often a complex mix of neuropathologies, with little known about the frequencies of differing combinations or their associations with cognition.<br><br>METHODS: We investigated 32 possible CVD combinations (3 types of vessel disease and 2 types of tissue injury) using autopsy data from 1474 decedents (≈88 years at death; 65% female) of Rush Alzheimer's Disease Center studies. We determined frequencies of all 32 CVD combinations and their relationships with global and domain-specific cognitive decline using mixed-effect models adjusted for demographics, neuropathologies, time before death, and interactions of these variables with time.<br><br>RESULTS: Of the 1184 decedents with CVD neuropathology (80% of the total sample), 37% had a single CVD (67-148 decedents/group) while 63% had mixed CVD profiles (11-54 decedents/group). When considered as 2 distinct groups, the mixed CVD profile group (but not the single CVD profile group) showed a faster cognitive decline across all domains assessed compared with decedents without CVD neuropathology. Most mixed CVD profiles, especially those involving both atherosclerosis and arteriolosclerosis, showed faster cognitive decline than any single CVD profile considered alone; specific mixed CVD profiles differentially associated with individual cognitive domains.<br><br>CONCLUSIONS: Mixed CVD, more common than single CVD, is associated with cognitive decline, and distinct mixed CVD profiles show domain-specific associations with cognitive decline. CVD is not monolithic but consists of heterogenous person-specific combinations with distinct contributions to cognitive decline.},
}
@article {pmid34600269,
year = {2021},
author = {Vitti-Ruela, BV and Dokkedal-Silva, V and Piovezan, RD and Tufik, S and Andersen, ML},
title = {The role of glutamate in a multifactorial scenario of Alzheimer' disease associated with depression and poor sleep.},
journal = {Psychiatry research},
volume = {305},
number = {},
pages = {114221},
doi = {10.1016/j.psychres.2021.114221},
pmid = {34600269},
issn = {1872-7123},
mesh = {*Alzheimer Disease/complications ; Depression/complications ; Glutamic Acid ; Humans ; Sleep ; *Sleep Initiation and Maintenance Disorders ; },
}
@article {pmid34599319,
year = {2021},
author = {Lemprière, S},
title = {Genome-wide association study identifies new risk loci for Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {17},
number = {11},
pages = {659},
pmid = {34599319},
issn = {1759-4766},
}
@article {pmid34599229,
year = {2021},
author = {Camacho-Castillo, L and Phillips-Farfán, BV and Rosas-Mendoza, G and Baires-López, A and Toral-Ríos, D and Campos-Peña, V and Carvajal, K},
title = {Increased oxidative stress contributes to enhance brain amyloidogenesis and blunts energy metabolism in sucrose-fed rat: effect of AMPK activation.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {19547},
pmid = {34599229},
issn = {2045-2322},
mesh = {AMP-Activated Protein Kinases/*metabolism ; Alzheimer Disease/*etiology/*metabolism/pathology ; Amyloid beta-Peptides/*metabolism ; Animal Feed ; Animals ; Antioxidants/metabolism ; Biomarkers ; Disease Models, Animal ; Disease Susceptibility ; *Energy Metabolism/drug effects ; Gene Expression Regulation, Enzymologic ; Metabolic Syndrome/etiology/metabolism/pathology ; Metformin/pharmacology ; *Oxidative Stress/drug effects ; Rats ; Signal Transduction/drug effects ; Sucrose/*metabolism ; },
abstract = {Metabolic disturbances are linked to neurodegenerative diseases such as Alzheimer disease (AD). However, the cellular mechanisms underlying this connection are unclear. We evaluated the role of oxidative stress (OS), during early metabolic syndrome (MetS), on amyloidogenic processes in a MetS rat model induced by sucrose. MetS caused OS damage as indicated by serum and hypothalamus lipid peroxidation and elevated serum catalase activity. Tissue catalase and superoxide dismutase activity were unchanged by MetS, but gene expression of nuclear factor erythroid-derived 2-like 2 (NFE2L2), which up-regulates expression of antioxidant enzymes, was higher. Expression of amyloid-β cleaving enzyme 1 (BACE-1) and amyloid precursor protein (APP), key proteins in the amyloidogenesis pathway, were slightly increased by sucrose-intake in the hippocampus and hypothalamus. Activation and expression of protein kinase B (PKB) and AMP-dependent protein kinase (AMPK), pivotal proteins in metabolism and energy signaling, were similarly affected in the hippocampus and hypothalamus of MetS rats. Brain creatine kinase activity decreased in brain tissues from rats with MetS, mainly due to irreversible oxidation. Chronic metformin administration partially reversed oxidative damage in sucrose-fed animals, together with increased AMPK activation; probably by modulating BACE-1 and NFE2L2. AMPK activation may be considered as a preventive therapy for early MetS and associated neurodegenerative diseases.},
}
@article {pmid34598900,
year = {2022},
author = {Guo, W and Zeng, Z and Xing, C and Zhang, J and Bi, W and Yang, J and Shah, R and Wang, D and Li, Y and Zhang, X and Bian, Y and Du, H},
title = {Stem cells from human exfoliated deciduous teeth affect mitochondria and reverse cognitive decline in a senescence-accelerated mouse prone 8 model.},
journal = {Cytotherapy},
volume = {24},
number = {1},
pages = {59-71},
doi = {10.1016/j.jcyt.2021.07.018},
pmid = {34598900},
issn = {1477-2566},
mesh = {Aging ; *Alzheimer Disease/therapy ; Animals ; *Cognitive Dysfunction/therapy ; Disease Models, Animal ; Humans ; Maze Learning ; Mice ; Mitochondria ; Stem Cells ; Tooth, Deciduous ; },
abstract = {BACKGROUND AIMS: Stem cell therapy is a novel therapy being explored for AD. The molecular mechanism of its effect is still unclear. The authors investigated the effects and mechanism by injection of SHEDs into an AD mouse model.<br><br>METHODS: SHEDs were cultured in vitro and injected into AD SAMP8 mice by caudal vein, and SHEDs labeled via synthetic dye showed in vivo migration to the head. The cognitive ability of SAMP8 mice was evaluated via Barnes maze and new object recognition. The pathological indicators of AD, including Tau, amyloid plaques and inflammatory factors, were examined at the protein or RNA level. Next, macro-proteomics analysis and weighted gene co-expression network analysis (WGCNA) based on protein groups and behavioral data were applied to discover the important gene cluster involved in the improvement of AD by SHEDs, which was further confirmed in an AD model in both mouse and cell lines.<br><br>RESULTS: SHED treatment improved the cognitive ability and pathological symptoms of SAMP8 mice. Proteomics analysis indicated that these improvements were tightly related to the mitochondria, which was proved through examination of the shape and function of mitochondria both in vivo (SAMP8 brain) and in vitro (SH-SY5Y cells). Finally, the core targets of SHEDs in the mitochondrial pathway, Hook3, Mic13 and MIF, were screened out and confirmed in vivo.<br><br>CONCLUSIONS: SHED treatment significantly relieved AD symptoms, improved cognitive ability and reversed memory loss in an AD mouse model, possibly through the recovery of dysfunctional mitochondria. These results raise the possibility that SHED may ease the symptoms of AD by targeting the mitochondria.},
}
@article {pmid34597878,
year = {2021},
author = {Alsadat, AM and Nikbakht, F and Hossein Nia, H and Golab, F and Khadem, Y and Barati, M and Vazifekhah, S},
title = {GSK-3β as a target for apigenin-induced neuroprotection against Aβ 25-35 in a rat model of Alzheimer's disease.},
journal = {Neuropeptides},
volume = {90},
number = {},
pages = {102200},
doi = {10.1016/j.npep.2021.102200},
pmid = {34597878},
issn = {1532-2785},
mesh = {Alzheimer Disease/*genetics/*prevention &amp; control ; Amyloid Precursor Protein Secretases/biosynthesis/genetics ; Amyloid beta-Peptides/*antagonists &amp; inhibitors/*toxicity ; Animals ; Apigenin/*pharmacology ; Aspartic Acid Endopeptidases/biosynthesis/genetics ; Glycogen Synthase Kinase 3 beta/*drug effects ; Immunohistochemistry ; Male ; Neuroprotective Agents/*pharmacology ; Peptide Fragments/*antagonists &amp; inhibitors/*toxicity ; Phosphorylation ; RNA, Messenger/biosynthesis/genetics ; Rats ; Rats, Wistar ; tau Proteins/metabolism ; },
abstract = {Glycogen synthase kinase-3 (GSK-3) is a critical molecule in Alzheimer's disease (AD) that modulates two histopathological hallmarks of AD: Amyloid beta (Aβ) plaques and neurofibrillary tangles composed of aberrant hyper-phosphorylation of tau protein. This study was performed to investigate the protective effect of flavone apigenin through inhibition of GSK-3 and the involvement of this kinase in the inhibition of BACE1 expression and hyperphosphorylation of tau protein in an AD rat model. 15 nM of aggregated amyloid-beta 25-35 was microinjected into the left lateral ventricle of an AD rat. Apigenin (50 mg/kg) was administered orally 45 min before the Aβ injection and continued daily for three weeks. Immunohistochemistry and western blot analysis showed that apigenin significantly reduced the hyperphosphorylation of tau levels in the hippocampus. Real-time PCR analysis revealed significant inhibition of the mRNA level of β secretase (BACE1) and GSK-3β, but Apigenin had no effect on the level of GSK-3α. The results demonstrate that apigenin has a protective effect against amyloid-beta 25-35 by decreasing the expression of GSK-3β with the consequence of lowering the hyperphosphorylation of tau protein and suppressing BACE1 expression.},
}
@article {pmid34597386,
year = {2021},
author = {Teylan, MA and Mock, C and Gauthreaux, K and Culhane, JE and Jicha, G and Chen, YC and Chan, KCG and Kukull, WA and Nelson, PT and Katsumata, Y},
title = {Differences in Symptomatic Presentation and Cognitive Performance Among Participants With LATE-NC Compared to FTLD-TDP.},
journal = {Journal of neuropathology and experimental neurology},
volume = {80},
number = {11},
pages = {1024–1032},
pmid = {34597386},
issn = {1554-6578},
support = {R01 AG054060/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P50 AG047270/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Aged ; Aged, 80 and over ; Alzheimer Disease/pathology ; Aphasia, Primary Progressive/complications/pathology ; Apolipoprotein E4/genetics ; *Cognition ; Delusions/etiology/psychology ; Female ; Frontotemporal Lobar Degeneration/*diagnosis/genetics/*psychology ; Hallucinations/etiology/psychology ; Heterozygote ; Humans ; Limbic System/*pathology ; Male ; Middle Aged ; Neurofibrillary Tangles/pathology ; Neuropsychological Tests ; Psychomotor Performance ; TDP-43 Proteinopathies/*diagnosis/genetics/*psychology ; },
abstract = {Transactive response DNA-binding protein 43 kDa (TDP-43) is aberrantly aggregated and phosphorylated in frontotemporal lobar degeneration of the TDP-43 type (FTLD-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). We examined data from the National Alzheimer's Coordinating Center to compare clinical features of autopsy-confirmed LATE-NC and FTLD-TDP. A total of 265 LATE-NC and 92 FTLD-TDP participants were included. Cognitive and behavioral symptoms were compared, stratified by level of impairment based on global clinical dementia rating (CDR) score. LATE-NC participants were older at death, more likely to carry APOE ε4, more likely to have Alzheimer disease neuropathology, and had lower (i.e. less severe) final CDR global scores than those with FTLD-TDP. Participants with FTLD-TDP were more likely to present with primary progressive aphasia, or behavior problems such as apathy, disinhibition, and personality changes. Among participants with final CDR score of 2-3, those with LATE-NC were more likely to have visuospatial impairment, delusions, and/or visual hallucinations. These differences were robust after sensitivity analyses excluding older (≥80 years at death), LATE-NC stage 3, or severe Alzheimer cases. Overall, FTLD-TDP was more globally severe, and affected younger participants, whereas psychoses were more common in LATE-NC.},
}
@article {pmid34596132,
year = {2021},
author = {Yao, Z and Liu, B and Wang, Y and Dong, X},
title = {High cortisol and the risk of Alzheimer disease: A protocol for systematic review and meta-analysis.},
journal = {Medicine},
volume = {100},
number = {39},
pages = {e27319},
pmid = {34596132},
issn = {1536-5964},
support = {H2018058//Natural Science Foundation of Heilongjiang Province/ ; ZHY202087//Heilongjiang Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {Alzheimer Disease/*epidemiology ; Hydrocortisone/*blood ; Research Design ; Time Factors ; },
abstract = {BACKGROUND: Morning cortisol levels have been reported to be elevated among patients with Alzheimer disease (AD). We perform a protocol for systematic review and meta-analysis to assess morning central or peripheral cortisol levels in AD patients as compared with cognitively normal individuals.<br><br>METHODS: Studies were identified through systematic searches in August 2021 with no restrictions on date and time, language, and publication status using the following bibliographic databases: Embase, Medline, PubMed, Web of Science, Science Direct, and the Cochrane Library. Studies were identified using search terms related to cortisol, Alzheimer disease, and cognitive impairment. The study quality of included papers was evaluated using the "National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies." Statistical analyses were performed using Stata (version 14, StataCorp, College Station, TX).<br><br>RESULTS: The findings of this study will be submitted to peer-reviewed journals for publication.<br><br>CONCLUSION: Morning cortisol was elevated in AD patients and may have diagnostic and prognostic values for AD.},
}
@article {pmid34595939,
year = {2022},
author = {Barenholtz Levy, H},
title = {Accelerated Approval of Aducanumab: Where Do We Stand Now?.},
journal = {The Annals of pharmacotherapy},
volume = {56},
number = {6},
pages = {736-739},
doi = {10.1177/10600280211050405},
pmid = {34595939},
issn = {1542-6270},
mesh = {*Alzheimer Disease/drug therapy ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Drug Approval ; Humans ; United States ; United States Food and Drug Administration ; },
abstract = {Aducanumab was approved by the Food and Drug Administration (FDA) in June 2021 to treat Alzheimer disease (AD). Its path to approval has been highly scrutinized, with many experts arguing that the FDA's decision was premature. Accelerated approval was based on a surrogate end point, with evidence to support clinical effectiveness pending a postapproval trial by the drug company sponsor Biogen. As a result, the role of aducanumab in treating AD remains uncertain. A summary of key areas of controversy to guide informed decisions about use of this drug is provided, along with a timeline describing preapproval and postapproval events.},
}
@article {pmid34595752,
year = {2021},
author = {Silva, JC and Vivash, L and Malpas, CB and Hao, Y and McLean, C and Chen, Z and O'Brien, TJ and Jones, NC and Kwan, P},
title = {Low prevalence of amyloid and tau pathology in drug-resistant temporal lobe epilepsy.},
journal = {Epilepsia},
volume = {62},
number = {12},
pages = {3058-3067},
doi = {10.1111/epi.17086},
pmid = {34595752},
issn = {1528-1167},
mesh = {Adult ; Aged ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; *Drug Resistant Epilepsy/epidemiology/pathology/surgery ; *Epilepsy, Temporal Lobe/epidemiology/pathology/surgery ; Female ; Humans ; Male ; Middle Aged ; Prevalence ; Retrospective Studies ; Temporal Lobe/pathology ; Young Adult ; tau Proteins/metabolism ; },
abstract = {OBJECTIVE: Cognitive impairment is common in patients with chronic drug-resistant temporal lobe epilepsy (TLE). Hyperphosphorylated tau (pTau) and amyloid-β (Aβ) plaques, pathological hallmarks of Alzheimer disease, have been hypothesized to play a mechanistic role. We investigated Aβ plaques and pTau prevalence in TLE patients who underwent resective surgery and correlated their presence with preoperative psychometric test scores and clinical factors.<br><br>METHODS: Patients were retrospectively selected from the epilepsy surgery register of the Royal Melbourne Hospital, Australia. Sections from the resected temporal lobe were immunostained for pTau and Aβ plaques (antibodies: AT8, 1E8). The presence and severity of pathology were correlated with clinical characteristics, and verbal and visual learning functions as measured by the Verbal Pair Associates (VPA) test and Rey Complex Figure Test.<br><br>RESULTS: Fifty-six patients (55% female) aged 20-68 years (median = 34 years) at surgery were included. Aβ plaques were detected in four patients (7%), all at the moderate level. There was no difference in duration, age at onset of epilepsy, or side of resection between patients with and without Aβ plaques. Sparse pTau was found in two patients (3.5%). Both had moderate Aβ plaques and were >50 years of age. Patients with Aβ plaques had a lower median score for the VPA hard assessment compared to those without (0 vs. 4; p = .02). There was otherwise no correlation between pathology and psychometric test scores.<br><br>SIGNIFICANCE: Aβ plaques and pTau were uncommon in the resected brain tissue of patients who have undergone temporal lobectomy, and did not correlate with clinical characteristics or preoperative psychometric test scores, except for a lower VPA median score in patients with Aβ plaques. Therefore, considering the low prevalence of Aβ plaques and pTau herein observed, it is unlikely that cognitive impairment in TLE is driven by the same mechanisms as in Alzheimer disease.},
}
@article {pmid34593014,
year = {2021},
author = {Zhao, F and Xu, Y and Gao, S and Qin, L and Austria, Q and Siedlak, SL and Pajdzik, K and Dai, Q and He, C and Wang, W and O'Donnell, JM and Tang, B and Zhu, X},
title = {METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.},
journal = {Molecular neurodegeneration},
volume = {16},
number = {1},
pages = {70},
pmid = {34593014},
issn = {1750-1326},
support = {P30 AG072959/AG/NIA NIH HHS/United States ; R01 NS083498/NS/NINDS NIH HHS/United States ; RF1 AG049479/AG/NIA NIH HHS/United States ; P30 AG062428/AG/NIA NIH HHS/United States ; },
mesh = {Adenosine/metabolism ; *Alzheimer Disease/genetics ; Cell Cycle ; Humans ; Methyltransferases/genetics/metabolism ; RNA ; },
abstract = {BACKGROUND: N6-methyladenosine (m6A) modification of RNA influences fundamental aspects of RNA metabolism and m6A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m6A modification in the pathogenesis of Alzheimer disease (AD).<br><br>METHODS: We investigated the m6A modification and the expression of m6A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m6A levels on AD-related deficits both in vitro and in vivo.<br><br>RESULTS: We found decreased neuronal m6A levels along with significantly reduced expression of m6A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m6A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m6A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo.<br><br>CONCLUSIONS: Collectively, these data suggested that METTL3 reduction-mediated m6A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.},
}
@article {pmid34592173,
year = {2021},
author = {Möhle, L and Bascuñana, P and Brackhan, M and Pahnke, J},
title = {Development of deep learning models for microglia analyses in brain tissue using DeePathology™ STUDIO.},
journal = {Journal of neuroscience methods},
volume = {364},
number = {},
pages = {109371},
doi = {10.1016/j.jneumeth.2021.109371},
pmid = {34592173},
issn = {1872-678X},
mesh = {Animals ; Artificial Intelligence ; Brain ; *Deep Learning ; Image Processing, Computer-Assisted ; Mice ; Microglia ; },
abstract = {BACKGROUND: Interest in artificial intelligence-driven analysis of medical images has seen a steep increase in recent years. Thus, our paper aims to promote and facilitate the use of this state-of-the-art technology to fellow researchers and clinicians.<br><br>NEW METHOD: We present custom deep learning models generated in DeePathology™ STUDIO without the need for background knowledge in deep learning and computer science underlined by practical suggestions.<br><br>RESULTS: We describe the general workflow in this commercially available software and present three real-world examples how to detect microglia on IBA1-stained mouse brain sections including their differences, validation results and analysis of a sample slide.<br><br>Deep-learning assisted analysis of histological images is faster than classical analysis methods, and offers a wide variety of detection possibilities that are not available using methods based on staining intensity.<br><br>CONCLUSIONS: Reduced researcher bias, increased speed and extended possibilities make deep-learning assisted analysis of histological images superior to traditional analysis methods for histological images.},
}
@article {pmid34588623,
year = {2021},
author = {Rodriguez-Vieitez, E and Montal, V and Sepulcre, J and Lois, C and Hanseeuw, B and Vilaplana, E and Schultz, AP and Properzi, MJ and Scott, MR and Amariglio, R and Papp, KV and Marshall, GA and Fortea, J and Johnson, KA and Sperling, RA and Vannini, P},
title = {Association of cortical microstructure with amyloid-β and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults.},
journal = {Molecular psychiatry},
volume = {26},
number = {12},
pages = {7813-7822},
pmid = {34588623},
issn = {1476-5578},
support = {P01 AG036694/AG/NIA NIH HHS/United States ; R01 AG061083/AG/NIA NIH HHS/United States ; R21 AG064348/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease/diagnostic imaging/pathology ; Amyloid beta-Peptides ; *Cognitive Dysfunction/diagnostic imaging ; Female ; Humans ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Prospective Studies ; tau Proteins ; },
abstract = {Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11C-Pittsburgh compound-B-PET, 18F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.},
}
@article {pmid34587912,
year = {2021},
author = {Wen, J and Zhao, M and Sun, W and Cheng, X and Yu, L and Cao, D and Li, P},
title = {Publisher Correction to: Uptake of Aβ by OATPs might be a new pathophysiological mechanism of Alzheimer disease.},
journal = {BMC neuroscience},
volume = {22},
number = {1},
pages = {58},
pmid = {34587912},
issn = {1471-2202},
}
@article {pmid34585226,
year = {2021},
author = {Sato, K and Mano, T and Ihara, R and Suzuki, K and Niimi, Y and Toda, T and Iwatsubo, T and Iwata, A},
title = {Cohort-Specific Optimization of Models Predicting Preclinical Alzheimer's Disease, to Enhance Screening Performance in the Middle of Preclinical Alzheimer's Disease Clinical Studies.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {8},
number = {4},
pages = {503-512},
doi = {10.14283/jpad.2021.39},
pmid = {34585226},
issn = {2426-0266},
mesh = {Aged ; *Alzheimer Disease ; Brain ; Female ; Humans ; Japan ; Longitudinal Studies ; Male ; Mental Status and Dementia Tests/*statistics &amp; numerical data ; Middle Aged ; Neuroimaging ; *Prodromal Symptoms ; Retrospective Studies ; United States ; },
abstract = {BACKGROUND: Models that can predict brain amyloid beta (Aβ) status more accurately have been desired to identify participants for clinical trials of preclinical Alzheimer's disease (AD). However, potential heterogeneity between different cohorts and the limited cohort size have been the reasons preventing the development of reliable models applicable to the Asian population, including Japan.<br><br>OBJECTIVES: We aim to propose a novel approach to predict preclinical AD while overcoming these constraints, by building models specifically optimized for ADNI or for J-ADNI, based on the larger samples from A4 study data.<br><br>DESIGN AND PARTICIPANTS: This is a retrospective study including cognitive normal participants (CDR-global = 0) from A4 study, Alzheimer Disease Neuroimaging Initiative (ADNI), and Japanese-ADNI (J-ADNI) cohorts.<br><br>MEASUREMENTS: The model is made up of age, sex, education years, history of AD, Clinical Dementia Rating-Sum of Boxes, Preclinical Alzheimer Cognitive Composite score, and APOE genotype, to predict the degree of amyloid accumulation in amyloid PET as Standardized Uptake Value ratio (SUVr). The model was at first built based on A4 data, and we can choose at which SUVr threshold configuration the A4-based model may achieve the best performance area under the curve (AUC) when applied to the random-split half ADNI or J-ADNI subset. We then evaluated whether the selected model may also achieve better performance in the remaining ADNI or J-ADNI subsets.<br><br>RESULT: When compared to the results without optimization, this procedure showed efficacy of AUC improvement of up to approximately 0.10 when applied to the models "without APOE;" the degree of AUC improvement was larger in the ADNI cohort than in the J-ADNI cohort.<br><br>CONCLUSIONS: The obtained AUC had improved mildly when compared to the AUC in case of literature-based predetermined SUVr threshold configuration. This means our procedure allowed us to predict preclinical AD among ADNI or J-ADNI second-half samples with slightly better predictive performance. Our optimizing method may be practically useful in the middle of the ongoing clinical study of preclinical AD, as a screening to further increase the prior probability of preclinical AD before amyloid testing.},
}
@article {pmid34585218,
year = {2021},
author = {Wang, K and Liu, H},
title = {Early-Onset Subgroup of Type 2 Diabetes and Risk of Dementia, Alzheimer's Disease and Stroke: A Cohort Study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {8},
number = {4},
pages = {442-447},
doi = {10.14283/jpad.2021.35},
pmid = {34585218},
issn = {2426-0266},
mesh = {Age Factors ; *Age of Onset ; Aged ; Alzheimer Disease/*epidemiology ; Dementia/*epidemiology ; Diabetes Mellitus, Type 2/*complications ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Prospective Studies ; Risk Factors ; Stroke/*epidemiology ; },
abstract = {BACKGROUND: This study aimed to assess the relation of early-onset type 2 diabetes (age<55years) versus later in life to the risk of dementia, Alzheimer Disease (AD) dementia and stroke.<br><br>METHODS: This study was based on the Framingham Heart Study Offspring cohort (FHS-OS) which is a community-based prospective cohort. Glycemic status was ascertained at serial examinations over six decades among participants who initially did not have diabetes. Surveillance for incident events including dementia and stroke has been continued for approximately 30 years.<br><br>RESULTS: At baseline, there were 142 (5%) subjects with onset of diabetes prior to age 55 years, 172 (6%) subjects with 55-64 years, 349 (11%) subjects over 65 years and 2389 (78%) subjects without diabetes. The risk of dementia, AD and stroke increased with decreasing age of diabetes onset (P<0.05, for trend). Compared with never developing diabetes, early-onset diabetes conferred a higher risk of all dementia, AD dementia and stroke [HR 2.86(1.16-5.51) for dementia; HR 2.42(1.63-4.33) for AD; HR 2.85(1.37-3.98) for stroke]. Whereas later-onset diabetes was only associated with greater risk for stroke, neither dementia nor AD.<br><br>CONCLUSION: Early-onset diabetes was stronger associated with an increased risk of all dementia, AD dementia and stroke than later-onset.},
}
@article {pmid34585216,
year = {2021},
author = {Costa, N and Mounié, M and Pagès, A and Derumeaux, H and Rapp, T and Guyonnet, S and Coley, N and Cantet, C and Carrié, I and Andrieu, S and Molinier, L},
title = {The Cost-Effectiveness of Three Prevention Strategies in Alzheimer's Disease: Results from the Multidomain Alzheimer Preventive Trial (MAPT).},
journal = {The journal of prevention of Alzheimer's disease},
volume = {8},
number = {4},
pages = {425-435},
doi = {10.14283/jpad.2021.47},
pmid = {34585216},
issn = {2426-0266},
mesh = {Aged ; *Alzheimer Disease/drug therapy/prevention &amp; control ; Cognition/*physiology ; Cost-Benefit Analysis/*economics ; Docosahexaenoic Acids/*administration &amp; dosage ; Exercise/*physiology ; Female ; France ; Humans ; Independent Living ; Male ; Monaco ; Research Design ; },
abstract = {BACKGROUND: To date, no curative treatment is available for Alzheimer's disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems.<br><br>OBJECTIVE: Our aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo.<br><br>DESIGN: The Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group.<br><br>SETTING: Participants were recruited and included in 13 memory centers in France and Monaco.<br><br>PARTICIPANTS: Community-dwelling subject aged 70 years and older were followed during 3 years.<br><br>INTERVENTIONS: We used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone.<br><br>MEASUREMENT: Direct medical and non-medical costs were calculated from a payer's perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria.<br><br>RESULTS: Analyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point.<br><br>CONCLUSION: Our study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.},
}
@article {pmid34583236,
year = {2021},
author = {Yang, Y and Kwan, RYC and Zhai, HM and Xu, XY and Huang, CX and Liang, SJ and Liu, J},
title = {The association among apathy, leisure activity participation, and severity of dementia in nursing home residents with Alzheimer's disease: A cross-sectional study.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {42},
number = {6},
pages = {1373-1378},
doi = {10.1016/j.gerinurse.2021.09.009},
pmid = {34583236},
issn = {1528-3984},
mesh = {*Alzheimer Disease ; *Apathy ; Cross-Sectional Studies ; Humans ; Leisure Activities ; Nursing Homes ; },
abstract = {The purpose of this study was to examine 1) the relationship between apathy and leisure activity participation in nursing home residents with Alzheimer disease (AD) and 2) the moderator effect of the severity of dementia on this relationship. Data were collected from 290 residents with AD using the Apathy Evaluation Scale-informant version (AES-I), Leisure Activities Questionnaire (LAQ), and Clinical Dementia Rating scale (CDR). The multiple linear regression model showed that leisure activity participation (β=-0.452, p<0.001) was negatively associated with apathy, while the severity of dementia (β=0.515, p<0.001) was positively associated with apathy. The severity of dementia moderated the effect of leisure activity participation on apathy (β=-0.108, p=0.015). The results indicate that the effects of leisure activity participation on apathy diminish with the aggravation of AD. The severity of dementia should be considered when designing and delivering leisure activity interventions to manage apathy in nursing home residents with AD.},
}
@article {pmid34582783,
year = {2021},
author = {Musiek, ES and Bennett, DA},
title = {Aducanumab and the "post-amyloid" era of Alzheimer research?.},
journal = {Neuron},
volume = {109},
number = {19},
pages = {3045-3047},
doi = {10.1016/j.neuron.2021.09.007},
pmid = {34582783},
issn = {1097-4199},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; *Amyloid ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Device Approval ; History, 19th Century ; History, 20th Century ; Humans ; Immunotherapy ; Middle Aged ; Plaque, Amyloid ; },
}
@article {pmid34581847,
year = {2022},
author = {Moscoso, A and Silva-Rodríguez, J and Aldrey, JM and Cortés, J and Pías-Peleteiro, JM and Ruibal, Á and Aguiar, P and , },
title = {18F-florbetapir PET as a marker of myelin integrity across the Alzheimer's disease spectrum.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {49},
number = {4},
pages = {1242-1253},
pmid = {34581847},
issn = {1619-7089},
mesh = {*Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Aniline Compounds ; Biomarkers ; *Cognitive Dysfunction/pathology ; Cross-Sectional Studies ; *Demyelinating Diseases/pathology ; Diffusion Tensor Imaging/methods ; Ethylene Glycols ; Humans ; Myelin Sheath/pathology ; Positron-Emission Tomography/methods ; *White Matter/metabolism ; tau Proteins ; },
abstract = {PURPOSE: Recent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer's disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored.<br><br>METHODS: Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline.<br><br>RESULTS: In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals.<br><br>CONCLUSION: These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.},
}
@article {pmid34581265,
year = {2021},
author = {Myette-Côté, É and Soto-Mota, A and Cunnane, SC},
title = {Ketones: potential to achieve brain energy rescue and sustain cognitive health during ageing.},
journal = {The British journal of nutrition},
volume = {},
number = {},
pages = {1-17},
doi = {10.1017/S0007114521003883},
pmid = {34581265},
issn = {1475-2662},
abstract = {Alzheimer’s disease (AD) is the most common major neurocognitive disorder of ageing. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) – to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during ageing. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimising the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.},
}
@article {pmid34580191,
year = {2021},
author = {Kim, YJ and Karceski, S},
title = {Alzheimer Disease and Mood.},
journal = {Neurology},
volume = {97},
number = {13},
pages = {e1363-e1366},
doi = {10.1212/WNL.0000000000012607},
pmid = {34580191},
issn = {1526-632X},
mesh = {Alzheimer Disease/complications/*psychology ; Cognitive Dysfunction/*epidemiology/*etiology ; Humans ; Mood Disorders/*epidemiology/*etiology ; },
}
@article {pmid34574524,
year = {2021},
author = {Furneri, G and Platania, S and Privitera, A and Martelli, F and Smeriglio, R and Razza, G and Maci, T and Castellano, S and Drago, F and Santagati, M and Caponnetto, P and Caraci, F and Di Nuovo, S},
title = {The Apathy Evaluation Scale (AES-C): Psychometric Properties and Invariance of Italian Version in Mild Cognitive Impairment and Alzheimer's Disease.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {18},
pages = {},
pmid = {34574524},
issn = {1660-4601},
mesh = {*Alzheimer Disease/diagnosis ; *Apathy ; *Cognitive Dysfunction/diagnosis ; Humans ; Italy/epidemiology ; Neuropsychological Tests ; Psychometrics ; Reproducibility of Results ; },
abstract = {Apathy is a neuropsychiatric symptom observed in different neurological and psychiatric disorders. Although apathy is considered a symptom, it has been recently reconsidered as a syndrome characterised by three dimensions: cognitive symptoms, affective symptoms and behavioural symptoms. Recent studies have shown that apathy can be considered as a prodromal symptom of Alzheimer's disease (AD), but also an indicator of the transition from mild cognitive impairment to AD. According to this scenario, an early detection of apathy in subjects with Mild Cognitive Impairment (MCI) and Mild AD can be a valid psychometric strategy to improve an early diagnosis and promote a prompt intervention. The Apathy Evaluation Scale is a validated tool composed of 18 items that assess and quantify emotional, behavioural and cognitive aspects of apathy. The aim of this study is to assess the specific reliability and validity of the Italian version of the Apathy Evaluation Scale-Clinician Version (AES-C) to detect apathy both in amnestic MCI and mild AD patients. In the present paper, we therefore examined the psychometric properties and the invariance of the Italian Version of the AES-C conducted on a sample composed of an experimental group of amnestic MCI and AD patients (N = 107) and a control group (N = 107) constituted by Age- and Sex-matched healthy controls. Results confirm the goodness of the scale. Confirmatory factory analysis confirmed that the AES-C Italian Version presents the same stability of one second-order factor and three first-order factors identified in the original version, and all items are predicted by a single general factor. Moreover, the scale was found to be invariant across both populations. Moreover, reliability and discriminant analysis showed good values. We found in the experimental group a negative correlation between the AES-C and Frontal Assessment Battery (FAB) (rs = -0.21, p < 0.001) and Mini Mental State Examination (MMSE) (rs = -0.04, p < 0.001), while a positive correlation was found between the AES-C and Hamilton psychiatric Rating scale for Depression (HAM-D) scores (rs = 0.58, p < 0.001) Overall, our data demonstrated the validity of the Italian version of the AES-C for the assessment of apathy both in MCI and in AD patients.},
}
@article {pmid34573243,
year = {2021},
author = {Lai, F and Mercaldo, ND and Wang, CM and Hersch, MS and Hersch, GG and Rosas, HD},
title = {Association between Hypothyroidism Onset and Alzheimer Disease Onset in Adults with Down Syndrome.},
journal = {Brain sciences},
volume = {11},
number = {9},
pages = {},
pmid = {34573243},
issn = {2076-3425},
abstract = {Adults with Down syndrome (DS) have an exceptionally high frequency of Alzheimer disease (AD) with a wide variability in onset, from 40 to 70 years of age. Equally prevalent in DS is hypothyroidism. In this study, we sought to quantify the relationship between the two. A total of 232 adults with DS and AD were stratified into three AD onset age groups: early (<47 years), typical (48-59), and late (>59). Among patients with available data, differences in the distributions of demographics, hypothyroidism variables (presence, age of onset), thyroid function tests, thyroid autoantibodies, and APOE genotypes were assessed (e.g., chi-squared, Mann-Whitney tests). Spearman and partial Spearman correlations and ordinal logistic regression models were constructed to quantify the association between ages of AD and hypothyroidism onset with and without covariate adjustments. We observed a positive association between the ages of AD and hypothyroidism onset after accounting for APOE-Ɛ4 (correlation: 0.44, 0.24, 0.60; odds ratio: 1.09, 1.05-1.14). However, an early age of hypothyroidism onset and the presence of the APOE-Ɛ4 allele were independently associated with the early age of AD onset. Similar findings were observed when accounting for other factors. Our study provides evidence for the importance of hypothyroidism and associated pathological mechanisms for risk of AD in DS.},
}
@article {pmid34573186,
year = {2021},
author = {Tsatali, M and Moraitou, D and Poptsi, E and Sia, E and Agogiatou, C and Gialaouzidis, M and Tabakis, IM and Avdikou, K and Bakoglidou, E and Batsila, G and Bekiaridis-Moschou, D and Chatziroumpi, O and Diamantidou, A and Gavra, A and Kouroundi, E and Liapi, D and Markou, N and Ouzouni, F and Papasozomenou, C and Soumpourou, A and Tsolaki, M},
title = {Are There Any Cognitive and Behavioral Changes Potentially Related to Quarantine Due to the COVID-19 Pandemic in People with Mild Cognitive Impairment and AD Dementia? A Longitudinal Study.},
journal = {Brain sciences},
volume = {11},
number = {9},
pages = {},
pmid = {34573186},
issn = {2076-3425},
abstract = {The aim of the study was to examine potential cognitive, mood (depression and anxiety) and behavioral changes that may be related to the quarantine and the lockdown applied during the COVID-19 pandemic in Greek older adults with mild cognitive impairment (MCI), and AD dementia in mild and moderate stages.<br><br>METHOD: 407 older adults, diagnosed either with MCI or AD dementia (ADD), were recruited from the Day Centers of the Greek Association of Alzheimer Disease and Related Disorders (GAADRD). Neuropsychological assessment was performed at baseline (at the time of diagnosis) between May and July of 2018, as well as for two consecutive follow-up assessments, identical in period, in 2019 and 2020. The majority of participants had participated in non-pharmacological interventions during 2018 as well as 2019, whereas all of them continued their participation online in 2020.<br><br>RESULTS: Mixed measures analysis of variance showed that participants' 'deterioration difference-D' by means of their performance difference in neuropsychological assessments between 2018-2019 (D1) and 2019-2020 (D2) did not change, except for the FUCAS, RAVLT, and phonemic fluency tests, since both groups resulted in a larger deterioration difference (D2) in these tests. Additionally, three path models examining the direct relationships between performance in tests measuring mood, as well as everyday functioning and cognitive measures, showed that participants' worsened performance in the 2019 and 2020 assessments was strongly affected by NPI performance, in sharp contrast to the 2018 assessment.<br><br>DISCUSSION: During the lockdown period, MCI and ADD patients' neuropsychological performance did not change, except from the tests measuring verbal memory, learning, and phonemic fluency, as well as everyday functioning. However, the natural progression of the MCI as well as ADD condition is the main reason for participants' deterioration. Mood performance became increasingly closely related to cognition and everyday functioning. Hence, the role of quarantine and AD progression are discussed as potential factors associated with impairments.},
}
@article {pmid34572457,
year = {2021},
author = {Gámez-Valero, A and Campdelacreu, J and Vilas, D and Ispierto, L and Gascón-Bayarri, J and Reñé, R and Álvarez, R and Armengol, MP and Borràs, FE and Beyer, K},
title = {Platelet miRNA Biosignature Discriminates between Dementia with Lewy Bodies and Alzheimer's Disease.},
journal = {Biomedicines},
volume = {9},
number = {9},
pages = {},
pmid = {34572457},
issn = {2227-9059},
support = {PI15/00216, PI18/00276//Instituto de Salud Carlos III/ ; },
abstract = {Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia, after Alzheimer's disease (AD), and presents pathological and clinical overlap with both AD and Parkinson's disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets, previously related to neurodegeneration, contain microRNAs (miRNAs) whose analysis may provide disease biomarkers. Here, we profiled the whole platelet miRNA transcriptome from DLB patients and healthy controls. Differentially expressed miRNAs were further validated in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Results comprised a seven-miRNA biosignature, showing the highest diagnostic potential for the differentiation between DLB and AD. Additionally, compared to controls, two miRNAs were down-regulated in DLB, four miRNAs were up-regulated in AD, and two miRNAs were down-regulated in PD. Predictive target analysis identified three disease-specific clusters of pathways as a result of platelet-miRNA deregulation. Our cross-sectional study assesses the identification of a novel, highly specific and sensitive platelet-associated miRNA-based biosignature, which distinguishes DLB from AD.},
}
@article {pmid34572041,
year = {2021},
author = {Marchesi, N and Fahmideh, F and Boschi, F and Pascale, A and Barbieri, A},
title = {Ocular Neurodegenerative Diseases: Interconnection between Retina and Cortical Areas.},
journal = {Cells},
volume = {10},
number = {9},
pages = {},
pmid = {34572041},
issn = {2073-4409},
mesh = {Animals ; Eye Diseases/complications/*pathology ; Humans ; Neurodegenerative Diseases/complications/*pathology ; Retina/*pathology ; Visual Cortex/*pathology ; },
abstract = {The possible interconnection between the eye and central nervous system (CNS) has been a topic of discussion for several years just based on fact that the eye is properly considered an extension of the brain. Both organs consist of neurons and derived from a neural tube. The visual process involves photoreceptors that receive light stimulus from the external environment and send it to retinal ganglionic cells (RGC), one of the cell types of which the retina is composed. The retina, the internal visual membrane of the eye, processes the visual stimuli in electric stimuli to transfer it to the brain, through the optic nerve. Retinal chronic progressive neurodegeneration, which may occur among the elderly, can lead to different disorders of the eye such as glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR). Mainly in the elderly population, but also among younger people, such ocular pathologies are the cause of irreversible blindness or impaired, reduced vision. Typical neurodegenerative diseases of the CSN are a group of pathologies with common characteristics and etiology not fully understood; some risk factors have been identified, but they are not enough to justify all the cases observed. Furthermore, several studies have shown that also ocular disorders present characteristics of neurodegenerative diseases and, on the other hand, CNS pathologies, i.e., Alzheimer disease (AD) and Parkinson disease (PD), which are causes of morbidity and mortality worldwide, show peculiar alterations at the ocular level. The knowledge of possible correlations could help to understand the mechanisms of onset. Moreover, the underlying mechanisms of these heterogeneous disorders are still debated. This review discusses the characteristics of the ocular illnesses, focusing on the relationship between the eye and the brain. A better comprehension could help in future new therapies, thus reducing or avoiding loss of vision and improve quality of life.},
}
@article {pmid34570180,
year = {2021},
author = {Mintzer, J and Lanctôt, KL and Scherer, RW and Rosenberg, PB and Herrmann, N and van Dyck, CH and Padala, PR and Brawman-Mintzer, O and Porsteinsson, AP and Lerner, AJ and Craft, S and Levey, AI and Burke, W and Perin, J and Shade, D and , },
title = {Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {78},
number = {11},
pages = {1324-1332},
doi = {10.1001/jamaneurol.2021.3356},
pmid = {34570180},
issn = {2168-6157},
support = {P30 AG066507/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*complications ; Apathy/*drug effects ; Central Nervous System Stimulants/*therapeutic use ; Female ; Humans ; Male ; Methylphenidate/*therapeutic use ; },
abstract = {Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.<br><br>Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.<br><br>This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included.<br><br>Interventions: Ten milligrams of methylphenidate, twice daily, vs matching placebo.<br><br>Main Outcomes and Measures: The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life.<br><br>Results: Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups.<br><br>Conclusions and Relevance: This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02346201.},
}
@article {pmid34570178,
year = {2021},
author = {Fredericks, C},
title = {Methylphenidate for Apathy in Alzheimer Disease-Why Should We Care?.},
journal = {JAMA neurology},
volume = {78},
number = {11},
pages = {1311-1313},
doi = {10.1001/jamaneurol.2021.2942},
pmid = {34570178},
issn = {2168-6157},
mesh = {*Alzheimer Disease/drug therapy ; *Apathy ; *Central Nervous System Stimulants/therapeutic use ; Double-Blind Method ; Humans ; *Methylphenidate/therapeutic use ; },
}
@article {pmid34570177,
year = {2021},
author = {Vossel, K and Ranasinghe, KG and Beagle, AJ and La, A and Ah Pook, K and Castro, M and Mizuiri, D and Honma, SM and Venkateswaran, N and Koestler, M and Zhang, W and Mucke, L and Howell, MJ and Possin, KL and Kramer, JH and Boxer, AL and Miller, BL and Nagarajan, SS and Kirsch, HE},
title = {Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial.},
journal = {JAMA neurology},
volume = {78},
number = {11},
pages = {1345-1354},
doi = {10.1001/jamaneurol.2021.3310},
pmid = {34570177},
issn = {2168-6157},
support = {K23 AG038357/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/complications/*drug therapy ; Anticonvulsants/*therapeutic use ; Cognition/*drug effects ; Cross-Over Studies ; Double-Blind Method ; Executive Function/drug effects ; Female ; Humans ; Levetiracetam/*therapeutic use ; Male ; Middle Aged ; *Seizures/etiology ; },
abstract = {Importance: Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).<br><br>Objective: To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.<br><br>The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.<br><br>Interventions: Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.<br><br>Main Outcomes and Measures: The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.<br><br>Results: Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.<br><br>Conclusions and Relevance: In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02002819.},
}
@article {pmid34569963,
year = {2021},
author = {Katz, J and Gao, H},
title = {The Alzheimer-E. coli Axis: What Can We Learn from an Electronic Health Record Platform.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {84},
number = {2},
pages = {717-721},
doi = {10.3233/JAD-215004},
pmid = {34569963},
issn = {1875-8908},
mesh = {Alzheimer Disease/*epidemiology ; Cross-Sectional Studies ; Diabetes Mellitus ; Electronic Health Records/*statistics &amp; numerical data ; *Escherichia coli ; Escherichia coli Infections/*epidemiology ; Florida ; *Gastrointestinal Microbiome ; Humans ; Hypertension ; Retrospective Studies ; Stroke ; Urinary Tract Infections/complications ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease with unclear etiology. Recent studies have demonstrated a potential role for gut microbiome. There is, however, a significant dearth in epidemiological correlation between gut bacteria and AD.<br><br>OBJECTIVE: To investigate the association between Escherichia coli (E. coli) infection and AD.<br><br>METHODS: Counts of patients with ICD 10 diagnoses of AD, E. coli, urinary tract infection, and comorbidities were retrieved from the electronic health records at the University of Florida Health Center.<br><br>RESULTS: The relative risk for AD with a previous event of E. coli was 5.17 (95%CI 4.0786 to 6.5446, p < 0.0001). In the unadjusted association, patients with E. coli infection had odds ratio (OR) of 20.83 to have AD (95%CI, 17.7-24.34; p < 0.0001); after adjusting for gender (OR = 12.71; 95%CI, 10.82-14.83; p < 0.0001), race (OR = 13.97; 95%CI, 11.84-16.36; p < 0.0001), age group (OR = 11.51; 95%CI, 9.73-13.54; p < 0.0001), diabetes (OR = 9.23; 95%CI, 7.79-10.87; p < 0.0001), stroke (OR = 5.31; 95%CI, 4.47-6.28; p < 0.0001), and hypertension (OR = 4.55; 95%CI, 3.86-5.32; p < 0.0001).<br><br>CONCLUSION: These results should be taken cautiously. This retrospective cross-sectional study cannot infer causality and had used aggregate data that did not allow simultaneous adjustments of covariates. Future studies are warranted to investigate the link between gut bacteria and AD.},
}
@article {pmid34569854,
year = {2021},
author = {Hairu, R and Close, JCT and Lord, SR and Delbaere, K and Wen, W and Jiang, J and Taylor, ME},
title = {The association between white matter hyperintensity volume and cognitive/physical decline in older people with dementia: A one-year longitudinal study.},
journal = {Aging &amp; mental health},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/13607863.2021.1980859},
pmid = {34569854},
issn = {1364-6915},
abstract = {OBJECTIVES: Understanding the relationship between white matter hyperintensities (WMHs) and cognitive and physical decline in people with dementia will assist in determining potential treatment strategies. Currently there is conflicting evidence describing the association between WMHs and cognitive decline and, WMHs association with declines in objective measures of physical function have not been examined. We examined the relationship between baseline WMH volume and physical/cognitive decline over one-year in older people with dementia.<br><br>METHODS: Twenty-six community-dwelling older people with dementia (mean age = 81 ± 8 years; 35% female) were assessed at baseline and follow-up (one-year) using the Addenbrooke's Cognitive Examination-Revised (including verbal fluency), Trail Making Test A, the Physiological Profile Assessment (PPA), timed-up-and-go (TUG) and gait speed. WMH volumes were quantified using a fully automated segmentation toolbox, UBO Detector.<br><br>RESULTS: In analyses adjusted for baseline performance, higher baseline WMH volume was associated with decline in executive function (verbal fluency), sensorimotor function (PPA) and mobility (TUG). Executive function (semantic/category fluency) was the only domain association that withstood adjustment for age, and additionally hippocampal volume.<br><br>CONCLUSIONS: In unadjusted analyses, WMH volume was associated with one-year declines in cognitive and physical function in older people with dementia. The association with executive function decline withstood adjustment for age. More research is needed to confirm these findings and explore whether vascular risk reduction strategies can reduce WMH volume and associated cognitive and physical impairments in this group.},
}
@article {pmid34567426,
year = {2021},
author = {Skok, M},
title = {Mesenchymal stem cells as a potential therapeutic tool to cure cognitive impairment caused by neuroinflammation.},
journal = {World journal of stem cells},
volume = {13},
number = {8},
pages = {1072-1083},
pmid = {34567426},
issn = {1948-0210},
abstract = {An established contribution of neuroinflammation to multiple brain pathologies has raised the requirement for therapeutic strategies to overcome it in order to prevent age- and disease-dependent cognitive decline. Mesenchymal stem cells (MSCs) produce multiple growth and neurotrophic factors and seem to evade immune rejection due to low expression of major histocompatibility complex class I molecules. Therefore, MSCs are widely used in experiments and clinical trials of regenerative medicine. This review summarizes recent data concerning the optimization of MSC use for therapeutic purposes with the emphasis on the achievements of the last 2 years. Specific attention is paid to extracellular vesicles secreted by MSCs and to the role of α7 nicotinic acetylcholine receptors. The reviewed data demonstrate that MSCs have a significant therapeutic potential in treating neuroinflammation-related cognitive disfunctions including age-related neurodegenerative diseases. The novel data demonstrate that maximal therapeutic effect is being achieved when MSCs penetrate the brain and produce their stimulating factors in situ. Consequently, therapeutic application using MSCs should include measures to facilitate their homing to the brain, support the survival in the brain microenvironment, and stimulate the production of neurotrophic and anti-inflammatory factors. These measures include but are not limited to genetic modification of MSCs and pre-conditioning before transplantation.},
}
@article {pmid34565625,
year = {2022},
author = {Jacus, JP and Voltzenlogel, V and Mayelle, A and Antoine, P and Cuervo-Lombard, CV},
title = {Awareness dimensions and associated factors in Alzheimer's disease.},
journal = {Revue neurologique},
volume = {178},
number = {4},
pages = {363-369},
doi = {10.1016/j.neurol.2021.05.011},
pmid = {34565625},
issn = {0035-3787},
abstract = {OBJECTIVES: We recently reported the major role depression and apathy in awareness among Alzheimer patients, using the stage of the disease as an exposure factor and exploring different assessment methods. Using the same patient data, we aimed here to explore the different dimensions of awareness assessed by different sub-scales in awareness scales.<br><br>METHOD: Sixty-one Alzheimer patients were examined using four awareness scales relating to three assessment methods: (a) patient-caregiver discrepancy; (b) clinical rating; and (c) prediction of performance discrepancy. Global cognition, executive functioning, autonomy, depression and apathy were also assessed. Multivariate logistic models were performed using disease stage as an exposure factor for awareness scales and sub-scales. Correlations across the different factors and patient and caregiver awareness ratings were computed.<br><br>RESULTS: The patient-caregiver discrepancy and clinical rating methods (a, b) both identified the factors associated with awareness in the overall scales and the sub-scales as being depression and/or apathy. Depression correlated with patient self-ratings while apathy correlated with caregiver ratings. The prediction of performance discrepancy method (c) identified different factors in the overall scale, executive factors in three sub-scales involving executive domains and the memory factor in a sub-scale involving the mnesic domain.<br><br>DISCUSSION: The awareness scales using a referential based on a human rating (a, b) suggest that awareness is unidimensional, with depression impacting self-reports and apathy influencing caregiver/clinical reports. Scales based on a test rating (c) appear to be more closely associated with the dimensions assessed. This highlights the role of the reference system for awareness assessment in Alzheimer's disease.},
}
@article {pmid34563212,
year = {2021},
author = {Preman, P and Tcw, J and Calafate, S and Snellinx, A and Alfonso-Triguero, M and Corthout, N and Munck, S and Thal, DR and Goate, AM and De Strooper, B and Arranz, AM},
title = {Human iPSC-derived astrocytes transplanted into the mouse brain undergo morphological changes in response to amyloid-β plaques.},
journal = {Molecular neurodegeneration},
volume = {16},
number = {1},
pages = {68},
pmid = {34563212},
issn = {1750-1326},
mesh = {*Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Astrocytes/metabolism ; Brain/metabolism ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Mice ; Plaque, Amyloid/metabolism ; },
abstract = {BACKGROUND: Increasing evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease comes from molecular and functional studies in rodent models. However, these models may not fully recapitulate human disease as human and rodent astrocytes differ considerably in morphology, functionality, and gene expression.<br><br>RESULTS: To address these challenges, we established an approach to study human astrocytes within the mouse brain by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background.<br><br>CONCLUSIONS: In sum, we describe here a promising approach that consist of transplanting patient-derived and genetically modified astrocytes into the mouse brain to study human astrocyte pathophysiology in the context of Alzheimer´s disease.},
}
@article {pmid34560903,
year = {2021},
author = {Coley, N and Coniasse-Brioude, D and Igier, V and Fournier, T and Poulain, JP and Andrieu, S and , },
title = {Disparities in the participation and adherence of older adults in lifestyle-based multidomain dementia prevention and the motivational role of perceived disease risk and intervention benefits: an observational ancillary study to a randomised controlled trial.},
journal = {Alzheimer's research &amp; therapy},
volume = {13},
number = {1},
pages = {157},
pmid = {34560903},
issn = {1758-9193},
mesh = {Aged ; *Cognitive Dysfunction ; *Dementia/epidemiology/prevention &amp; control ; *Fatty Acids, Omega-3 ; Humans ; Life Style ; Motivation ; },
abstract = {BACKGROUND: Preventive interventions for dementia are urgently needed and must be tested in randomised controlled trials (RCTs). Selection (volunteer) bias may limit efficacy, particularly in trials testing multidomain interventions and may also be indicative of disparities in intervention uptake in real-world settings. We identified factors associated with participation and adherence in a 3-year RCT of multidomain lifestyle intervention and/or omega-3 supplementation for prevention of cognitive decline and explored reasons for (non-) participation.<br><br>METHODS: Ancillary study during recruitment and follow-up of the 3-year Multidomain Alzheimer Preventive Trial (MAPT) conducted in in 13 memory centres in France and Monaco, involving 1630 community-dwelling dementia-free individuals aged ≥ 70 who were pre-screened for MAPT (1270 participated in MAPT; 360 declined to participate).<br><br>RESULTS: Response rates were 76% amongst MAPT participants and 53% amongst non-participants. Older individuals (odds ratio 0.94 [95% confidence interval 0.91-0.98] and those with higher anxiety (0.61 [0.47-0.79]) were less likely to participate in the trial. Those with higher income (4.42 [2.12-9.19]) and family history (1.60 [1.10-2.32]) or greater fear (1.73 [1.30-2.29]) of dementia were more likely to participate, as were those recruited via an intermediary (e.g. pension funds, local Alzheimer's associations, University of the 3rd Age, sports clubs) (2.15 [1.45-3.20]). MAPT participants living in larger towns (0.71 [0.55-0.92]) and with higher depressive symptoms (0.94 [0.90-0.99]) were less likely to adhere to the interventions. Greater perceived social support (1.21 [1.03-1.43]) and cognitive function (1.37 [1.13-1.67]) predicted better adherence. Descriptively, the most frequent reasons for accepting and refusing to participate were, respectively, altruism and logistical constraints, but underlying motivations mainly related to (lack of) perceived benefits.<br><br>CONCLUSIONS: Disparities in uptake of health interventions persist in older age. Those most at risk of dementia may not participate in or adhere to preventive interventions. Barriers to implementing lifestyle changes for dementia prevention include lack of knowledge about potential benefits, lack of support networks, and (perceived) financial costs.<br><br>TRIAL REGISTRATION: NCT00672685 (ClinicalTrials.gov).},
}
@article {pmid34559097,
year = {2021},
author = {Wang, W and Diwu, Y and Liu, Q and Zhou, Y and Sayed, TI and Wang, D and Gou, Y},
title = {Chinese herbal medicine for mild cognitive impairment using mini-mental state examination: A systematic review and meta-analysis.},
journal = {Medicine},
volume = {100},
number = {38},
pages = {e27034},
pmid = {34559097},
issn = {1536-5964},
support = {82074503//National Natural Science Foundation of China/ ; No.2019-QN05//the Disciplinary Innovation Team of Shaanxi University of Traditional Chinese Medicine/ ; },
mesh = {Cognition/drug effects ; Cognitive Dysfunction/diagnosis/*drug therapy ; Drugs, Chinese Herbal/administration &amp; dosage/pharmacology/*therapeutic use ; Humans ; *Mental Status and Dementia Tests ; Phytotherapy ; },
abstract = {INTRODUCTION: The prevalence of mild cognitive impairment (MCI) in the elderly population aged 60 to 84 years ranges from 6.7% to 25.2%, and the effective prevention and reversal of MCI progression to Alzheimer disease (AD) is crucial. The mini mental state examination (MMSE) is the most commonly used screening tool in Chinese outpatient clinics, with sufficient sensitivity and specificity to allow useful stratification from average to abnormal with adequate consideration of age and education.<br><br>OBJECTIVE: To investigate the clinical significance of Chinese herbs on MMSE scores in MCI patients and discuss the effectiveness of Chinese herbs through pharmacology.<br><br>METHODS: Three English databases and 4 Chinese databases we have searched, and the risk of bias was assessed according to the Cochrane tool. Statistics will be used for heterogeneity assessment, sensitivity analysis, data synthesis, funnel plot generation and subgroup analysis. If sufficiently homogeneous studies are found, a Meta-analysis will be performed, with subgroups describing any differences.<br><br>RESULTS: A total of 21 studies were included, 4 studies were placebo-controlled, 14 Chinese Herbal Medicines (CHMs) were compared with other cognitive improvements, 3 CHMs were combined with other medications, and the results of 17 studies favored the herbal group.<br><br>CONCLUSION: The results indicate that herbal medicine can improve MMSE scores, and herbal medicine combined with other drugs that can improve cognition can significantly improve MMSE scores, but there are methodological flaws in the study. Experimental studies have found a basis for the ability of herbs to improve cognition and memory impairment, and herbal medicine has great potential to improve MCI cognition. Keywords mild cognitive impairment, herbal medicine, MMSE, systematic evaluation, meta-analysis. PROSPERO international prospective register of systematic reviews protocol registration number: CRD42020202368.},
}
@article {pmid34558138,
year = {2022},
author = {Erekat, NS},
title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.},
journal = {Clinical anatomy (New York, N.Y.)},
volume = {35},
number = {1},
pages = {65-78},
doi = {10.1002/ca.23792},
pmid = {34558138},
issn = {1098-2353},
mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Humans ; *Huntington Disease ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; },
abstract = {Neurodegenerative disorders are characterized by progressive loss of particular populations of neurons. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. In this review, we focus on the existing notions relevant to comprehending the apoptotic death process, including the morphological features, mediators and regulators of cellular apoptosis. We also highlight the evidence of neuronal apoptotic death in Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Additionally, we present evidence of potential therapeutic agents that could modify the apoptotic pathway in the aforementioned neurodegenerative diseases and delay disease progression. Finally, we review the clinical trials that were conducted to evaluate the use of anti-apoptotic drugs in the treatment of the aforementioned neurodegenerative diseases, in order to highlight the essential need for early detection and intervention of neurodegenerative diseases in humans.},
}
@article {pmid34557567,
year = {2021},
author = {Hanczyc, P and Fita, P},
title = {Laser Emission of Thioflavin T Uncovers Protein Aggregation in Amyloid Nucleation Phase.},
journal = {ACS photonics},
volume = {8},
number = {9},
pages = {2598-2609},
pmid = {34557567},
issn = {2330-4022},
abstract = {There is currently no definitive test for early detection of neurodegeneration which is linked with protein aggregation. Finding methods capable of detecting intermediate states of protein aggregates, named oligomers, is critical for the early stage diagnosis of over 30 neurodegenerative diseases including Alzheimer's or Parkinson's. Currently, fluorescence-based imaging using Thioflavin T (ThT) dye is the gold standard for detecting protein aggregation. It is used to detect aggregation in vitro and in various tissues, including the cerebrospinal fluid (CSF), whereby the disease-related protein recombinant is seeded with the patient's fluid. The major drawback of ThT is its lack of sensitivity to oligomeric forms of protein aggregates. Here, we overcome this limitation by transferring a ThT-oligomer mixture into solid state thin films and detecting fluorescence of ThT amplified in the process of stimulated emission. By monitoring the amplified spontaneous emission (ASE) we achieved a remarkable recognition sensitivity to prefibrillar oligomeric forms of insulin and lysozyme aggregates in vitro, to Aβ42 oligomers in the human protein recombinants seeded with CSF and to Aβ42 oligomers doped into brain tissue. Seeding with Alzheimer patient's CSF containing Aβ42 and Tau aggregates revealed that only Aβ42 oligomers allowed generating ASE. Thus, we demonstrated that, in contrast to the current state-of-the-art, ASE of ThT, a commonly used histological dye, can be used to detect and differentiate amyloid oligomers and evaluate the risk levels of neurodegenerative diseases to potential patients before the clinical symptoms occur.},
}
@article {pmid34557314,
year = {2021},
author = {Lopez-Gutierrez, L and García-Alberca, JM and Mendoza, S and Gris, E and De la Guía, MP and Marin-Carmona, JM and Alarcón-Martín, E and Lobato, A and Cruz-Gamero, JM and Cura, L and Ocejo, O and Torrecilla, J and Nieto, MD and Urbano, C and Pareja, N and Luque, M and García-Peralta, M and Carrillejo, R and Royo, JL},
title = {The Genetic Research in Alzheimer Disease (GERALD) Initiative Finds rs9320913 as a Neural eQTL of lincRNA AL589740.1.},
journal = {International journal of Alzheimer's disease},
volume = {2021},
number = {},
pages = {3064224},
pmid = {34557314},
issn = {2090-8024},
abstract = {Alzheimer's disease is the most common cause of dementia worldwide, and longitudinal studies are crucial to find the factors affecting disease development. Here, we describe a novel initiative from southern Spain designed to contribute in the identification of the genetic component of the cognitive decline of Alzheimer's disease patients. The germline variant rs9320913 is a C>A substitution mapping within a gene desert. Although it has been previously associated to a higher educational achievement and increased fluid intelligence, its role on Alzheimer's disease risk and progression remains elusive. A total of 407 subjects were included in the study, comprising 153 Alzheimer disease patients and 254 healthy controls. We have explored the rs9320913 contribution to both Alzheimer disease risk and progression according to the Mini-Mental State Exams. We found that rs9320913 maps within a central nervous system lincRNA AL589740.1. eQTL results show that rs9320913 correlated with the brain-frontal cortex (beta = -0.15, p value = 0.057) and brain-spinal cord (beta of -0.23, p value = 0.037). We did not find rs9320913 to be associated to AD risk, although AA patients seemed to exhibit a less pronounced Mini-Mental State Exam score decline.},
}
@article {pmid34556565,
year = {2021},
author = {Milà-Alomà, M and Brinkmalm, A and Ashton, NJ and Kvartsberg, H and Shekari, M and Operto, G and Salvadó, G and Falcon, C and Gispert, JD and Vilor-Tejedor, N and Arenaza-Urquijo, EM and Grau-Rivera, O and Sala-Vila, A and Sanchez-Benavides, G and González-de-Echávarri, JM and Minguillon, C and Fauria, K and Niñerola-Baizán, A and Perissinotti, A and Kollmorgen, G and Suridjan, I and Zetterberg, H and Molinuevo, JL and Blennow, K and Suárez-Calvet, M and , },
title = {CSF Synaptic Biomarkers in the Preclinical Stage of Alzheimer Disease and Their Association With MRI and PET: A Cross-sectional Study.},
journal = {Neurology},
volume = {97},
number = {21},
pages = {e2065-e2078},
pmid = {34556565},
issn = {1526-632X},
mesh = {*Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides ; Biomarkers ; Cross-Sectional Studies ; Female ; Humans ; Magnetic Resonance Imaging ; Middle Aged ; Positron-Emission Tomography ; tau Proteins ; },
abstract = {BACKGROUND AND OBJECTIVES: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer continuum and associated with Alzheimer disease (AD) risk factors, primary pathology, and neurodegeneration markers.<br><br>METHODS: This cross-sectional study was performed in the Alzheimer's and Families (ALFA+) cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and growth-associated protein-43 (GAP-43) were measured with immunoassays, and synaptosomal-associated protein-25 (SNAP-25) and synaptotagmin-1 were measured with immunoprecipitation mass spectrometry. AD CSF biomarkers β-amyloid (Aβ)42/40, phosphorylated tau (p-tau), and total tau and the neurodegeneration biomarker neurofilament light chain (NfL) were also measured. Participants underwent structural MRI and fluorodeoxyglucose and Aβ PET imaging. General linear modeling was used to test the associations between CSF synaptic biomarkers and risk factors, Aβ pathology, tau pathology, and neurodegeneration markers.<br><br>RESULTS: All CSF synaptic biomarkers increased with age. CSF neurogranin was higher in females, while CSF SNAP-25 was higher in APOE ε4 carriers. All CSF synaptic biomarkers increased with higher Aβ load (as measured by CSF Aβ42/40 and Aβ PET Centiloid values), and it is important to note that the synaptic biomarkers were increased even in individuals in the earliest stages of Aβ deposition. Higher CSF synaptic biomarkers were also associated with higher CSF p-tau and NfL. Higher CSF neurogranin and GAP-43 were significantly associated with higher brain metabolism but lower cortical thickness in AD-related brain regions.<br><br>DISCUSSION: CSF synaptic biomarkers increase in the early preclinical stages of the Alzheimer continuum even when a low burden of Aβ pathology is present, and they differ in their association with age, sex, APOE ε4, and markers of neurodegeneration.<br><br>ClinicalTrials.gov Identifier NCT02485730.},
}
@article {pmid34556345,
year = {2022},
author = {Fathi, M and Taghizadeh, F and Mojtahedi, H and Zargar Balaye Jame, S and Markazi Moghaddam, N},
title = {The effects of Alzheimer's and Parkinson's disease on 28-day mortality of COVID-19.},
journal = {Revue neurologique},
volume = {178},
number = {1-2},
pages = {129-136},
pmid = {34556345},
issn = {0035-3787},
mesh = {*Alzheimer Disease/epidemiology ; *COVID-19 ; Cohort Studies ; Humans ; *Parkinson Disease/complications/epidemiology ; SARS-CoV-2 ; },
abstract = {We compared the prognosis of inpatients with a known diagnosis of Alzheimer's or Parkinson's disease who have COVID-19 infection with other hospitalized patients with COVID-19. Our cohort study started in October 2020 and ended in May 2021 and included inpatients with COVID-19 infection who were admitted to hospitals. From a total of 67,871 patients with a confirmed diagnosis of COVID-19, a sample of 3732 individuals were selected of which 363 had Alzheimer's, and 259 had Parkinson's disease. All patients had both positive RT-PCR test and positive chest CT for COVID-19. The outcome was dead within 28 days of admission and the predictors were a large number of demographic and clinical features, and comorbidities recorded at patients' bedside. Mortality were 37.5%, 35.1%, and 29.5% in patients with Alzheimer's disease, Parkinson's disease; and in other patients, respectively. The hazard ratio for Alzheimer's disease was 1.27 (95% CI, 1.06-1.53, p=0.010) and for Parkinson's disease was 1.17 (95% CI, 0.94-1.46, p=0.171). Age was a predictor of mortality, hazard ratio=1.04 (95% CI, 1.03-1.05, p<0.001). Patients with Alzheimer's disease and COVID-19 infection were older and more likely to have a loss of consciousness on admission (both p≤0.001). We concluded that inpatients with Alzheimer's disease have an increased risk for 28-day mortality from COVID-19 and healthcare settings should be ready to provide critical care for them such as early intubation and immediate O2 therapy. However, Parkinson's disease does not significantly predict higher mortality of COVID-19.},
}
@article {pmid34556089,
year = {2021},
author = {Jiang, Z and Shi, Y and Zhao, W and Zhou, L and Zhang, B and Xie, Y and Zhang, Y and Tan, G and Wang, Z},
title = {Association between chronic periodontitis and the risk of Alzheimer's disease: combination of text mining and GEO dataset.},
journal = {BMC oral health},
volume = {21},
number = {1},
pages = {466},
pmid = {34556089},
issn = {1472-6831},
mesh = {*Alzheimer Disease/genetics ; *Chronic Periodontitis/genetics ; Computational Biology ; Data Mining ; Gene Expression Profiling ; Gene Regulatory Networks ; Heat-Shock Proteins ; Humans ; Protein Interaction Maps/genetics ; },
abstract = {BACKGROUND: Although chronic periodontitis has previously been reported to be linked with Alzheimer's disease (AD), the pathogenesis between the two is unclear. The purpose of this study is to analyze and screen the relevant and promising molecular markers between chronic periodontitis and Alzheimer's disease (AD).<br><br>METHODS: In this paper, we analyzed three AD expression datasets and extracted differentially expressed genes (DEGs), then intersected them with chronic periodontitis genes obtained from text mining, and finally obtained integrated DEGs. We followed that by enriching the matching the matching cell signal cascade through DAVID analysis. Moreover, the MCODE of Cytoscape software was employed to uncover the protein-protein interaction (PPI) network and the matching hub gene. Finally, we verified our data using a different independent AD cohort.<br><br>RESULTS: The chronic periodontitis gene set acquired from text abstracting was intersected with the previously obtained three AD groups, and 12 common genes were obtained. Functional enrichment assessment uncovered 12 cross-genes, which were mainly linked to cell morphogenesis involved in neuron differentiation, leading edge membrane, and receptor ligand activity. After PPI network creation, the ten hub genes linked to AD were retrieved, consisting of SPP1, THY1, CD44, ITGB1, HSPB3, CREB1, SST, UCHL1, CCL5 and BMP7. Finally, the function terms in the new independent dataset were used to verify the previous dataset, and we found 22 GO terms and one pathway, "ECM-receptor interaction pathways", in the overlapping functional terms.<br><br>CONCLUSIONS: The establishment of the above-mentioned candidate key genes, as well as the enriched signaling cascades, provides promising molecular markers for chronic periodontitis-related AD, which may help the diagnosis and treatment of AD patients in the future.},
}
@article {pmid34556008,
year = {2021},
author = {LaPlume, AA and Paterson, TSE and Gardner, S and Stokes, KA and Freedman, M and Levine, B and Troyer, AK and Anderson, ND},
title = {Interindividual and intraindividual variability in amnestic mild cognitive impairment (aMCI) measured with an online cognitive assessment.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {43},
number = {8},
pages = {796-812},
doi = {10.1080/13803395.2021.1982867},
pmid = {34556008},
issn = {1744-411X},
mesh = {Aged ; Amnesia/psychology ; Brain ; Cognition ; *Cognitive Dysfunction/diagnosis/psychology ; Humans ; Neuropsychological Tests ; Reaction Time ; },
abstract = {INTRODUCTION: Mean cognitive performance is worse in amnestic mild cognitive impairment (aMCI) compared to control groups. However, studies on variability of cognitive performance in aMCI have yielded inconclusive results, with many differences in variability measures and samples from one study to another.<br><br>METHODS: We examined variability in aMCI using an existing older adult sample (n = 91; 51 with aMCI, 40 with normal cognition for age), measured with an online self-administered computerized cognitive assessment (Cogniciti's Brain Health Assessment). Our methodology extended past findings by using pure measures of variability (controlling for confounding effects of group performance or practice), and a clinically representative aMCI sample (reflecting the continuum of cognitive performance between normal cognition and aMCI).<br><br>RESULTS: Between-group t-tests showed significantly greater between-person variability (interindividual variability or diversity) in overall cognitive performance in aMCI than controls, although the effect size was with a small to moderate effect size, d = 0.44. No significant group differences were found in within-person variability (intraindividual variability) across cognitive tasks (dispersion) or across trials of a response time task (inconsistency), which may be because we used a sample measuring the continuum of cognitive performance. Exploratory correlation analyses showed that a worse overall score was associated with greater inter- and intraindividual variability, and that variability measures were correlated with each other, indicating people with worse cognitive performance were more variable.<br><br>DISCUSSION: The current study demonstrates that self-administered online tests can be used to remotely assess different types of variability in people at risk of Alzheimer`s. Our findings show small but significantly more interindividual differences in people with aMCI. This diversity is considered as "noise" in standard assessments of mean performance, but offers an interesting and cognitively informative "signal" in itself.},
}
@article {pmid34555025,
year = {2021},
author = {Carcaillon-Bentata, L and Quintin, C and Boussac-Zarebska, M and Elbaz, A},
title = {Prevalence and incidence of young onset dementia and associations with comorbidities: A study of data from the French national health data system.},
journal = {PLoS medicine},
volume = {18},
number = {9},
pages = {e1003801},
pmid = {34555025},
issn = {1549-1676},
mesh = {Adult ; Age of Onset ; Comorbidity ; Databases, Factual ; Dementia/diagnosis/drug therapy/*epidemiology/psychology ; Female ; France/epidemiology ; Humans ; Incidence ; Male ; Middle Aged ; Prevalence ; Risk Assessment ; Risk Factors ; Sex Factors ; },
abstract = {BACKGROUND: Dementia onset in those aged <65 years (young onset dementia, YOD) has dramatic individual and societal consequences. In the context of population aging, data on YOD are of major importance to anticipate needs for planning and allocation of health and social resources. Few studies have provided precise frequency estimates of YOD. The aim of this study is to provide YOD prevalence and incidence estimates in France and to study the contribution of comorbidities to YOD incidence.<br><br>METHODS AND FINDINGS: Using data from the French national health data system (Système National des Données de Santé, SNDS) for 76% of the French population aged 40 to 64 years in 2016 (n = 16,665,795), we identified all persons with dementia based on at least 1 of 3 criteria: anti-Alzheimer drugs claims, hospitalization with the International Classification of Diseases-10th Revision (ICD-10) dementia codes (F00 to F03, G30, G31.0, G31.1, or F05.1), or registration for free healthcare for dementia. We estimated prevalence rate (PR) and incidence rate (IR) and estimated the association of comorbidities with incident YOD. Sex differences were investigated. We identified 18,466 (PRstandardized = 109.7/100,000) and 4,074 incident (IRstandardized = 24.4/100,000 person-years) persons with prevalent and incident YOD, respectively. PR and IR sharply increased with age. Age-adjusted PR and IR were 33% (95% confidence interval (CI) = 29 to 37) and 39% (95% CI = 31 to 48) higher in men than women (p < 0.001 both for PR and IR). Cardio- and cerebrovascular, neurological, psychiatric diseases, and traumatic brain injury prevalence were associated with incident YOD (age- and sex-adjusted p-values <0.001 for all comorbidities examined, except p = 0.109 for antihypertensive drug therapy). Adjustment for all comorbidities explained more than 55% of the sex difference in YOD incidence. The lack of information regarding dementia subtypes is the main limitation of this study.<br><br>CONCLUSIONS: We estimated that there were approximately 24,000 and approximately 5,300 persons with prevalent and incident YOD, respectively, in France in 2016. The higher YOD frequency in men may be partly explained by higher prevalence of cardiovascular and neurovascular diseases, substance abuse disorders, and traumatic brain injury and warrants further investigation.},
}
@article {pmid34551697,
year = {2021},
author = {Mengr, A and Hrubá, L and Exnerová, A and Holubová, M and Popelová, A and Železná, B and Kuneš, J and Maletínská, L},
title = {Palmitoylated Prolactin-releasing Peptide Reduced Aβ Plaques and Microgliosis in the Cerebellum: APP/PS1 Mice Study.},
journal = {Current Alzheimer research},
volume = {18},
number = {8},
pages = {607-622},
doi = {10.2174/1567205018666210922110652},
pmid = {34551697},
issn = {1875-5828},
support = {20-00546S, RVO:61388963, RVO:67958523//Czech Science Foundation/ ; },
mesh = {*Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Animals ; Cerebellum ; *Diabetes Mellitus, Type 2 ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Plaque, Amyloid/pathology ; Presenilin-1/genetics/metabolism ; Prolactin-Releasing Hormone/metabolism/pharmacology ; },
abstract = {BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s Disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex.<br><br>OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD.<br><br>METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice.<br><br>RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice.<br><br>CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.},
}
@article {pmid34551374,
year = {2021},
author = {Whitwell, JL and Tosakulwong, N and Weigand, SD and Graff-Radford, J and Ertekin-Taner, N and Machulda, MM and Duffy, JR and Schwarz, CG and Senjem, ML and Jack, CR and Lowe, VJ and Josephs, KA and , },
title = {Relationship of APOE, age at onset, amyloid and clinical phenotype in Alzheimer disease.},
journal = {Neurobiology of aging},
volume = {108},
number = {},
pages = {90-98},
pmid = {34551374},
issn = {1558-1497},
support = {R01 AG050603/AG/NIA NIH HHS/United States ; R01 DC010367/DC/NIDCD NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; },
mesh = {Age Factors ; Age of Onset ; Aged ; Alleles ; Alzheimer Disease/*genetics/*metabolism ; Amyloid beta-Peptides/*metabolism ; Apolipoproteins E/*genetics ; Female ; *Genetic Association Studies ; *Genotype ; Heterozygote ; Humans ; Male ; Middle Aged ; *Phenotype ; Risk Factors ; },
abstract = {The apolipoprotein E (APOE) ε4 allele is the most well-established risk factor for Alzheimer's disease (AD), although its relationship to age at onset and clinical phenotype is unclear. We aimed to assess relationships between APOE genotype and age at onset, amyloid-beta (Aβ) deposition and typical versus atypical clinical presentations in AD. Frequency of APOE ε4 carriers by age at onset was assessed in 447 AD patients, 138 atypical AD patients recruited by the Neurodegenerative Research Group at Mayo Clinic, and 309 with typical AD from ADNI. APOE ε4 frequency increased with age at onset in atypical AD but showed a bell-shaped curve in typical AD where highest frequencies were observed between 65 and 70 years. Typical AD showed higher APOE ε4 frequencies than atypical AD only between the ages of 57 and 69 years. Global Aβ standard uptake value ratios did not differ according to APOE e4 status in either group. APOE genotype varies by both age at onset and clinical phenotype in AD, highlighting the heterogeneous nature of AD.},
}
@article {pmid34550903,
year = {2021},
author = {Jutten, RJ and Sikkes, SAM and Van der Flier, WM and Scheltens, P and Visser, PJ and Tijms, BM and , },
title = {Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity.},
journal = {Neurology},
volume = {96},
number = {22},
pages = {e2673-e2684},
pmid = {34550903},
issn = {1526-632X},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; *Disease Progression ; Female ; Humans ; Male ; Middle Aged ; *Models, Statistical ; Neuroprotective Agents/*therapeutic use ; Risk Factors ; *Treatment Outcome ; },
abstract = {OBJECTIVE: To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.<br><br>METHODS: Individuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a "placebo" and "treatment" group and subsequently computed group differences on the CDR-sum of boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale-13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes.<br><br>RESULTS: Individual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).<br><br>CONCLUSIONS: Individuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.},
}
@article {pmid34550902,
year = {2021},
author = {Buckley, RF and Knopman, DS},
title = {Cognitive Heterogeneity in Alzheimer Clinical Trials: Harnessing Noise to Achieve Meaningfulness.},
journal = {Neurology},
volume = {96},
number = {22},
pages = {1017-1018},
doi = {10.1212/WNL.0000000000012027},
pmid = {34550902},
issn = {1526-632X},
mesh = {*Alzheimer Disease/therapy ; Cognition ; Humans ; },
}
@article {pmid34550082,
year = {2021},
author = {Betz, ME and Polzer, E and Nearing, K and Knoepke, CE and Johnson, RL and Meador, L and Matlock, DD},
title = {Feasibility and Acceptability of a Web-Based Caregiver Decision Aid (Safety in Dementia) for Firearm Access: Pilot Randomized Controlled Trial.},
journal = {JMIR formative research},
volume = {5},
number = {9},
pages = {e30990},
pmid = {34550082},
issn = {2561-326X},
support = {R34 MH113539/MH/NIMH NIH HHS/United States ; },
abstract = {BACKGROUND: Firearms are common in the households of persons with Alzheimer disease and related dementias (ADRD). Safety in Dementia (SiD) is a free web-based decision aid that was developed to support ADRD caregivers in addressing firearm access.<br><br>OBJECTIVE: We aimed to evaluate the feasibility and acceptability of SiD among a web-based sample of ADRD caregivers.<br><br>METHODS: SiD was tested in 2 phases by using participants who were recruited from a web-based convenience sample (Amazon Mechanical Turk participants). In phase 1, caregivers were randomized to view either the intervention (SiD) or the control (Alzheimer's Association materials), and the blinding of participants to the study arms was conducted. In phase 2, caregivers of individuals with ADRD and firearm access were recruited; all of these participants viewed the firearm section of SiD. In both phases, participants viewed SiD independently for as long as they wanted. Measures for evaluating decision-making and SiD acceptability were used, and these were assessed via a self-administered web-based questionnaire.<br><br>RESULTS: Participants were recruited for phases 1 (n=203) and 2 (n=54). Although it was feasible to collect the study outcome data in a web-based format, in phase 1, there were no significant differences between SiD and the control in terms of decision-making and self-efficacy. The majority (137/203, 67.5%) of phase 1 participants spent between 5 and 10 minutes reviewing the resources. In phase 2, 61% (33/54) of participants spent 5 to 10 minutes viewing the firearm section, and 31% (17/54) spent 10 to 20 minutes viewing this section. Usability and acceptability were high across the phases.<br><br>CONCLUSIONS: SiD represents a new resource for promoting safety among people with dementia, and high acceptability was achieved in a pilot trial. In this sample, SiD performed similarly to Alzheimer's Association materials in supporting decision-making and self-efficacy.},
}
@article {pmid34549475,
year = {2021},
author = {Lessard-Beaudoin, M and M Gonzalez, L and AlOtaibi, M and Chouinard-Watkins, R and Plourde, M and Calon, F and Graham, RK},
title = {Diet enriched in omega-3 fatty acids alleviates olfactory system deficits in APOE4 transgenic mice.},
journal = {The European journal of neuroscience},
volume = {54},
number = {9},
pages = {7092-7108},
doi = {10.1111/ejn.15472},
pmid = {34549475},
issn = {1460-9568},
support = {MP 119454//CIHR/Canada ; },
mesh = {*Alzheimer Disease/complications/genetics ; Animals ; *Apolipoprotein E4/genetics ; Atrophy ; Diet ; Disease Models, Animal ; Docosahexaenoic Acids/*physiology ; Mice ; Mice, Transgenic ; Olfaction Disorders/*diet therapy/etiology/genetics ; *Olfactory Bulb/growth &amp; development/metabolism/pathology ; },
abstract = {Olfactory dysfunction is observed in several neurological disorders including Mild Cognitive Impairment (MCI) and Alzheimer disease (AD). These deficits occur early and correlate with global cognitive performance, depression and degeneration of olfactory regions in the brain. Despite extensive human studies, there has been little characterization of the olfactory system in models of AD. In order to determine if olfactory structural and/or molecular phenotypes are observed in a model expressing a genetic risk factor for AD, we assessed the olfactory bulb (OB) in APOE4 transgenic mice. A significant decrease in OB weight was observed at 12 months of age in APOE4 mice concurrent with inflammation and decreased NeuN expression. In order to determine if a diet rich in omega-3s may alleviate the olfactory system phenotypes observed, we assessed WT and APOE4 mice on a docosahexaenoic acid (DHA) diet. APOE4 mice on a DHA diet did not present with atrophy of the OB, and the alterations in NeuN and IBA-1 expression were alleviated. Furthermore, alterations in caspase mRNA and protein expression in the APOE4 OB were not observed with a DHA diet. Similar to the human AD condition, OB atrophy is an early phenotype in the APOE4 mice and concurrent with inflammation. These data support a link between the structural olfactory brain region atrophy and the olfactory dysfunction observed in AD and suggest that inflammation and cell death pathways may contribute to the olfactory deficits observed. Furthermore, the results suggest that diets enriched in DHA may provide benefit to APOE4 allele carriers.},
}
@article {pmid34548654,
year = {2021},
author = {McDade, E and Voytyuk, I and Aisen, P and Bateman, RJ and Carrillo, MC and De Strooper, B and Haass, C and Reiman, EM and Sperling, R and Tariot, PN and Yan, R and Masters, CL and Vassar, R and Lichtenthaler, SF},
title = {The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {17},
number = {11},
pages = {703-714},
pmid = {34548654},
issn = {1759-4766},
support = {R01AG053267-S2/AG/NIA NIH HHS/United States ; R56 AG053267/AG/NIA NIH HHS/United States ; R01 AG046179/AG/NIA NIH HHS/United States ; U01 AG042791/AG/NIA NIH HHS/United States ; R01AG053267-S1/AG/NIA NIH HHS/United States ; U01AG42791-S1/AG/NIA NIH HHS/United States ; U01 AG059798/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*prevention &amp; control ; Amyloid Precursor Protein Secretases/*antagonists &amp; inhibitors/genetics ; Amyloid beta-Protein Precursor/metabolism ; Aspartic Acid Endopeptidases/*antagonists &amp; inhibitors/genetics ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Enzyme Inhibitors/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Plaque, Amyloid/prevention &amp; control ; Research Design ; },
abstract = {Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.},
}
@article {pmid34548629,
year = {2021},
author = {Chen, Z and Schwulst, SJ and Mentis, AA},
title = {Correction: APOE4-mediated Alzheimer disease and "Vascular"-"Meningeal Lymphatic" components: towards a novel therapeutic era?.},
journal = {Molecular psychiatry},
volume = {26},
number = {10},
pages = {5475},
doi = {10.1038/s41380-021-01307-7},
pmid = {34548629},
issn = {1476-5578},
}
@article {pmid34545700,
year = {2021},
author = {Smirnova, TA and Viskin, A and Hoskova, M and Habartova, L and Setnicka, V and Cejnar, P and Kuckova, S},
title = {Comparison of proteomic approaches used for the detection of potential biomarkers of Alzheimer's disease in blood plasma.},
journal = {Journal of separation science},
volume = {44},
number = {22},
pages = {4132-4140},
doi = {10.1002/jssc.202100468},
pmid = {34545700},
issn = {1615-9314},
support = {A2_FPBT_2021_016//Specific University Research/ ; A1_FPBT_2021_003//Specific University Research/ ; A2_FCHI-2020_003//Specific University Research/ ; 17-05292S//Czech Science Foundation/ ; LTAIN19007//Ministry of Education, Youth and Sports of the Czech Republic/ ; },
mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/blood/diagnosis ; Biomarkers/*blood ; Blood Proteins/analysis ; Chromatography, Liquid/methods ; Female ; Humans ; Lipid Metabolism ; Lipids/blood ; Male ; Middle Aged ; Plasma/chemistry ; Proteomics/*methods ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods ; Tandem Mass Spectrometry/methods ; },
abstract = {At present, Alzheimer's disease is detected mainly using psychological tests, which can only confirm the disease in its more advanced phases. Therefore, bioanalytical possibilities for detecting this disease earlier are being investigated. To date, the results of analyses, which focus mainly on the study of lipids and proteins either in cerebrospinal fluid or much less often in blood plasma, do not provide satisfactory results. In addition, cerebrospinal fluid sampling is uncomfortable for the patients and involves many health risks. In this work, we deal with proteomic analysis using Matrix-Assisted Laser Desorption/Ionisation-Time of Flight and Liquid Chromatography coupled to tandem Mass Spectrometry of blood plasma with a focus on various ways of preanalytical sample treatments. This should lead to results improvement and facilitate the subsequent evaluation using principal component analysis and partial least squares discriminant analysis. The obtained results indicate the direction of further research, namely the study of interactions between proteins and lipids contained in blood plasma. These substances may be regarded as potential biomarkers allowing for the diagnosis of Alzheimer´s disease even in its early stages.},
}
@article {pmid34545424,
year = {2021},
author = {Kanel, P and Bedard, MA and Aghourian, M and Rosa-Neto, P and Soucy, JP and Albin, RL and Bohnen, NI},
title = {Molecular Imaging of the Cholinergic System in Alzheimer and Lewy Body Dementias: Expanding Views.},
journal = {Current neurology and neuroscience reports},
volume = {21},
number = {10},
pages = {52},
pmid = {34545424},
issn = {1534-6293},
support = {R01 NS070856/NS/NINDS NIH HHS/United States ; P01 NS015655/NH/NIH HHS/United States ; P50 NS091856/NH/NIH HHS/United States ; P50 NS123067/NS/NINDS NIH HHS/United States ; I01 RX001631/RX/RRD VA/United States ; P01 NS015655/NS/NINDS NIH HHS/United States ; P50 NS091856/NS/NINDS NIH HHS/United States ; R01 NS070856/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/diagnostic imaging ; Brain ; Cholinergic Agents ; Humans ; *Lewy Body Disease/diagnostic imaging ; Molecular Imaging ; },
abstract = {PURPOSE OF REVIEW: Brain cholinergic denervation is a major feature of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). We reviewed the topography assessed by a cholinergic molecular imaging study in these two major types of dementia. A small meta-analysis directly comparing vesicular acetylcholine transporter (VAChT) PET scans of AD vs. DLB patients is presented.<br><br>RECENT FINDINGS: VAChT PET studies showed evidence of extensive cortical cholinergic denervation in both forms of dementia, while multiple subcortical structures were also in DLB. Novel analysis revealed evidence of metathalamic denervation in AD, and epithalamus, premotor/sensorimotor cortical, and striatal losses in DLB. Topographically distinct cortical and subcortical cholinergic lesions can distinguish AD and DLB, and new structures have been highlighted here. Differential vulnerability of specific cholinergic projections is likely associated with specific clinical features of these disorders. Improved understanding of the mechanisms and roles of cholinergic neurotransmission in regions with cholinergic deficits may lead to symptomatic therapies.},
}
@article {pmid34544751,
year = {2021},
author = {Arnaud, K and Oliveira Moreira, V and Vincent, J and Dallerac, G and Dubreuil, C and Dupont, E and Richter, M and Müller, UC and Rondi-Reig, L and Prochiantz, A and Di Nardo, AA},
title = {Choroid plexus APP regulates adult brain proliferation and animal behavior.},
journal = {Life science alliance},
volume = {4},
number = {11},
pages = {},
pmid = {34544751},
issn = {2575-1077},
mesh = {Alzheimer Disease/genetics/physiopathology ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/*genetics/*metabolism/physiology ; Animals ; Behavior, Animal ; Brain/metabolism ; Cell Proliferation ; Choroid Plexus/*metabolism ; Disease Models, Animal ; Hippocampus/metabolism ; Long-Term Potentiation ; Male ; Mice ; Mice, Inbred C57BL ; },
abstract = {Elevated amyloid precursor protein (APP) expression in the choroid plexus suggests an important role for extracellular APP metabolites such as sAPPα in cerebrospinal fluid. Despite widespread App brain expression, we hypothesized that specifically targeting choroid plexus expression could alter animal physiology. Through various genetic and viral approaches in the adult mouse, we show that choroid plexus APP levels significantly impact proliferation in both subventricular zone and hippocampus dentate gyrus neurogenic niches. Given the role of Aβ peptides in Alzheimer disease pathogenesis, we also tested whether favoring the production of Aβ in choroid plexus could negatively affect niche functions. After AAV5-mediated long-term expression of human mutated APP specifically in the choroid plexus of adult wild-type mice, we observe reduced niche proliferation, reduced hippocampus APP expression, behavioral defects in reversal learning, and deficits in hippocampal long-term potentiation. Our findings highlight the unique role played by the choroid plexus in regulating brain function and suggest that targeting APP in choroid plexus may provide a means to improve hippocampus function and alleviate disease-related burdens.},
}
@article {pmid34542571,
year = {2021},
author = {Janelidze, S and Teunissen, CE and Zetterberg, H and Allué, JA and Sarasa, L and Eichenlaub, U and Bittner, T and Ovod, V and Verberk, IMW and Toba, K and Nakamura, A and Bateman, RJ and Blennow, K and Hansson, O},
title = {Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease.},
journal = {JAMA neurology},
volume = {78},
number = {11},
pages = {1375-1382},
doi = {10.1001/jamaneurol.2021.3180},
pmid = {34542571},
issn = {2168-6157},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/*pathology ; Amyloid beta-Peptides/*analysis ; Biomarkers/analysis ; Brain/diagnostic imaging/*pathology ; Cross-Sectional Studies ; Female ; Humans ; Immunoassay/methods ; Male ; Mass Spectrometry/methods ; Middle Aged ; Peptide Fragments/*analysis ; Positron-Emission Tomography ; },
abstract = {Importance: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials.<br><br>Objective: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD.<br><br>This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.<br><br>Main Outcomes and Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status.<br><br>Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay.<br><br>Conclusions and Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.},
}
@article {pmid34542418,
year = {2021},
author = {Saredakis, D and Keage, HA and Corlis, M and Ghezzi, ES and Loffler, H and Loetscher, T},
title = {The Effect of Reminiscence Therapy Using Virtual Reality on Apathy in Residential Aged Care: Multisite Nonrandomized Controlled Trial.},
journal = {Journal of medical Internet research},
volume = {23},
number = {9},
pages = {e29210},
pmid = {34542418},
issn = {1438-8871},
mesh = {Aged ; *Apathy ; Australia ; Cognition ; Humans ; *Parkinson Disease ; *Virtual Reality ; },
abstract = {BACKGROUND: Apathy is a frequent and underrecognized neurological disorder symptom. Reduced goal-directed behavior caused by apathy is associated with poor outcomes for older adults in residential aged care. Recommended nonpharmacological treatments include person-centered therapy using information and communication technology. Virtual reality (VR) in the form of head-mounted displays (HMDs) is a fully immersive technology that provides access to a wide range of freely available content. The use of VR as a therapy tool has demonstrated promise in the treatment of posttraumatic stress disorder and anxiety. In addition, VR has been used to improve conditions including depression, anxiety, cognitive function, and balance in older adults with memory deficits, Alzheimer disease, and Parkinson disease. Research using VR for the symptoms of apathy in older adults living in residential aged care facilities is limited.<br><br>OBJECTIVE: This study aims to examine whether using HMDs as a tool for reminiscence therapy improves the symptoms of apathy compared with using a laptop computer and physical items with older adults living in residential aged care.<br><br>METHODS: In this multisite trial, 43 participants were allocated to one of three groups: reminiscence therapy intervention using VR in the form of HMDs, reminiscence therapy using a laptop computer supplemented by physical items if required (active control), and a usual care (passive control) group. The primary outcome was apathy, and the secondary outcomes included cognition and depression. The side effects of using HMDs were also measured in the VR group.<br><br>RESULTS: Mixed model analyses revealed no significant group interaction over time in outcomes between the VR and laptop groups (estimate=-2.24, SE 1.89; t40=-1.18; P=.24). Pooled apathy scores in the two intervention groups compared with the passive control group also revealed no significant group interaction over time (estimate=-0.26, SE 1.66; t40=-0.16; P=.88). There were no significant secondary outcomes. Most participants in the VR group stated that they would prefer to watch content in VR than on a flat screen (Χ22=11.2; P=.004), side effects from HMD use were negligible to minimal according to the Simulator Sickness Questionnaire cutoff scores.<br><br>CONCLUSIONS: Although there were no significant results in outcome measures, this study found that participants engaged in the research and enjoyed the process of reminiscing using both forms of technology. It was found that VR can be implemented in an aged care setting with correct protocols in place. Providing residents in aged care with a choice of technology may assist in increasing participation in activities. We cannot dismiss the importance of immediate effects while the therapy was in progress, and this is an avenue for future research.<br><br>TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001510134; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378564.<br><br>RR2-DOI: 10.1136/bmjopen-2020-046030.},
}
@article {pmid34541458,
year = {2021},
author = {Laudicella, R and Burger, IA and Panasiti, F and Longo, C and Scalisi, S and Minutoli, F and Baldari, S and Grimaldi, LME and Alongi, P},
title = {Subcutaneous Uptake on [18F]Florbetaben PET/CT: a Case Report of Possible Amyloid-Beta Immune-Reactivity After COVID-19 Vaccination.},
journal = {SN comprehensive clinical medicine},
volume = {3},
number = {12},
pages = {2626-2628},
doi = {10.1007/s42399-021-01058-0},
pmid = {34541458},
issn = {2523-8973},
abstract = {Introduction: Large-scale worldwide COVID-19 vaccination programs are being rapidly deployed, and high-risk patients with comorbidity are now receiving the first doses of the vaccine. Physicians should be, therefore, aware of new pitfalls associated with the current pandemic vaccination program, also in the case of [18F]Florbetaben PET/CT.Case PresentationWe described the first image of [18F]Florbetaben PET/CT in the evaluation of a 70-year-old male with suspicious Alzheimer disease and unclear history of heart disease. We detailed the diagnostic imaging PET/CT workup with different findings.<br><br>Conclusion: In this case, [18F]Florbetaben PET/CT can demonstrate potential beta-amyloid immune-reactivity and deposition associated with the current COVID-19 pandemic vaccination programs.},
}
@article {pmid34540049,
year = {2021},
author = {Xie, L and Pu, M and Liu, Y},
title = {The effect of individual nursing on improving the living ability and blood sugar control of Alzheimer disease patients with diabetes mellitus.},
journal = {American journal of translational research},
volume = {13},
number = {8},
pages = {9324-9331},
pmid = {34540049},
issn = {1943-8141},
abstract = {OBJECTIVE: To explore the effect of individual nursing on Alzheimer disease (AD) patients with diabetes mellitus.<br><br>METHODS: A total of 119 patients with AD complicated with diabetes admitted to our hospital from January 2017 to January 2019 were selected for prospective analysis, and 64 patients received individual nursing mode, which were regarded as the personality group (PG). Another 55 patients received routine nursing mode and were regarded as the regular group (RG). The curative effect of AD, blood glucose, living ability, cognitive function, self-care ability and nursing satisfaction of the two groups were investigated.<br><br>RESULTS: There was no difference between the two groups in AD curative effect and cognitive function (P > 0.05), and the blood sugar control, living ability, self-care ability and nursing satisfaction of the PG were higher than those of the RG (P < 0.05).<br><br>CONCLUSION: Individual nursing can effectively improve the ability of blood sugar control and daily life of AD patients with diabetes mellitus, and greatly enhance the patients' trust, dependence, and satisfaction with medical staff, which is worth popularizing in clinical practice.},
}
@article {pmid34539565,
year = {2021},
author = {Malek-Ahmadi, M and Su, Y and Jansen, WJ},
title = {Editorial: Vascular Factors and Vascular Lesions in Pre-clinical Alzheimer's Disease.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {738465},
pmid = {34539565},
issn = {1664-2295},
}
@article {pmid34539551,
year = {2021},
author = {Vaismoradi, M and Behboudi-Gandevani, S and Lorenzl, S and Weck, C and Paal, P},
title = {Needs Assessment of Safe Medicines Management for Older People With Cognitive Disorders in Home Care: An Integrative Systematic Review.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {694572},
pmid = {34539551},
issn = {1664-2295},
abstract = {Background and Objectives: The global trend of healthcare is to improve the quality and safety of care for older people with cognitive disorders in their own home. There is a need to identify how medicines management for these older people who are cared by their family caregivers can be safeguarded. This integrative systematic review aimed to perform the needs assessment of medicines management for older people with cognitive disorders who receive care from their family caregivers in their own home. Methods: An integrative systematic review of the international literature was conducted to retrieve all original qualitative and quantitative studies that involved the family caregivers of older people with cognitive disorders in medicines management in their own home. MeSH terms and relevant keywords were used to search four online databases of PubMed (including Medline), Scopus, CINAHL, and Web of Science and to retrieve studies published up to March 2021. Data were extracted by two independent researchers, and the review process was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Given that selected studies were heterogeneous in terms of the methodological structure and research outcomes, a meta-analysis could not be performed. Therefore, narrative data analysis and knowledge synthesis were performed to report the review results. Results: The search process led to retrieving 1,241 studies, of which 12 studies were selected for data analysis and knowledge synthesis. They involved 3,890 older people with cognitive disorders and 3,465 family caregivers. Their methodologies varied and included cohort, randomised controlled trial, cross-sectional studies, grounded theory, qualitative framework analysis, and thematic analysis. The pillars that supported safe medicines management with the participation of family caregivers in home care consisted of the interconnection between older people's needs, family caregivers' role, and collaboration of multidisciplinary healthcare professionals. Conclusion: Medicines management for older people with cognitive disorders is complex and multidimensional. This systematic review provides a comprehensive image of the interconnection between factors influencing the safety of medicines management in home care. Considering that home-based medicines management is accompanied with stress and burden in family caregivers, multidisciplinary collaboration between healthcare professionals is essential along with the empowerment of family caregivers through education and support.},
}
@article {pmid34539542,
year = {2021},
author = {Wu, D and Kumal, JPP and Lu, X and Li, Y and Mao, D and Tang, X and Nie, M and Liu, X and Sun, L and Liu, B and Zhang, Y},
title = {Traumatic Brain Injury Accelerates the Onset of Cognitive Dysfunction and Aggravates Alzheimer's-Like Pathology in the Hippocampus by Altering the Phenotype of Microglia in the APP/PS1 Mouse Model.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {666430},
pmid = {34539542},
issn = {1664-2295},
abstract = {An increasing number of studies have suggested that traumatic brain injury (TBI) is associated with some neurodegenerative diseases, including Alzheimer's disease (AD). Various aspects of the mechanism of TBI-induced AD have been elucidated. However, there are also studies opposing the view that TBI is one of the causes of AD. In the present study, we demonstrated that TBI exacerbated the disruption of hippocampal-dependent learning and memory, worsened the reductions in neuronal cell density and synapse formation, and aggravated the deposition of Aβ plaques in the hippocampi of APP/PS1 mice. We also found that TBI rapidly activated microglia in the central nervous system (CNS) and that this effect lasted for at least for 3 weeks. Furthermore, TBI boosted Aβ-related microglia-mediated neuroinflammation in the hippocampi of APP/PS1 mice and the transformation of microglia toward the proinflammatory phenotype. Therefore, our experiments suggest that TBI accelerates the onset of cognitive dysfunction and Alzheimer-like pathology in the APP/PS1 mouse model, at least partly by altering microglial reactions and polarization.},
}
@article {pmid34539382,
year = {2021},
author = {Li, B and Zhang, M and Jang, I and Ye, G and Zhou, L and He, G and Lin, X and Meng, H and Huang, X and Hai, W and Chen, S and Li, B and Liu, J},
title = {Amyloid-Beta Influences Memory via Functional Connectivity During Memory Retrieval in Alzheimer's Disease.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {721171},
pmid = {34539382},
issn = {1663-4365},
abstract = {Objective: Amnesia in Alzheimer's disease (AD) appears early and could be caused by encoding deficiency, consolidation dysfunction, and/or impairment in the retrieval of stored memory information. The relationship between AD pathology biomarker β-amyloid and memory dysfunction is unclear. Method: The memory task functional MRI and amyloid PET were simultaneously performed to investigate the relationship between memory performance, memory phase-related functional connectivity, and cortical β-amyloid deposition. We clustered functional networks during memory maintenance and compared network connectivity between groups in each memory phase. Mediation analysis was performed to investigate the mediator between β-amyloid and related cognitive performance. Results: Alzheimer's disease was primarily characterized by decreased functional connectivity in a data-driven network composed of an a priori default mode network, limbic network, and frontoparietal network during the memory maintenance (0.205 vs. 0.236, p = 0.04) and retrieval phase (0.159 vs. 0.183, p = 0.017). Within the network, AD had more regions with reduced connectivity during the retrieval than the maintenance and encoding phases (chi-square p = 0.01 and < 0.001). Furthermore, the global cortical β-amyloid negatively correlated with network connectivity during the memory retrieval phase (R = - 0.247, p = 0.032), with this relationship mediating the effect of cortical β-amyloid on memory performance (average causal mediation effect = - 0.05, p = 0.035). Conclusion: We demonstrated that AD had decreased connectivity in specific networks during the memory retrieval phase. Impaired functional connectivity during memory retrieval mediated the adverse effect of β-amyloid on memory. These findings help to elucidate the involvement of cortical β-amyloid (Aβ) in the memory performance in the early stages of AD.},
}
@article {pmid34538654,
year = {2021},
author = {Sáinz Pelayo, MDP and Pelayo Vergara, R and Albu, S and Figueira, C},
title = {[Experience with 4 clinical cases. Traumatic encephalopathy may be associated with a single traumatic brain injury?].},
journal = {Rehabilitacion},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.rh.2021.04.004},
pmid = {34538654},
issn = {1578-3278},
abstract = {Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that affects people who had repetitive head trauma. Also, in single traumatic brain injury (TBI), changes may be found during the follow-up visits. We present four clinical cases of patients visited at the Institut Guttmann clinic between 2017 and 2019. They were affected by mild sequelae of severe and unique TBI who have subsequently developed a neurodegenerative disease without a specific diagnosis, and who could meet clinical criteria for chronic traumatic encephalopathy syndrome. Rehabilitation doctors are the professionals with the greatest possibility of identifying a suggestive clinic of this pathology, they can order the appropriate studies and indicate the new rehabilitation goals according to the new neurological situation.},
}
@article {pmid34538105,
year = {2021},
author = {de Heus, RAA and Tzourio, C and Lee, EJL and Opozda, M and Vincent, AD and Anstey, KJ and Hofman, A and Kario, K and Lattanzi, S and Launer, LJ and Ma, Y and Mahajan, R and Mooijaart, SP and Nagai, M and Peters, R and Turnbull, D and Yano, Y and , and Claassen, JAHR and Tully, PJ},
title = {Association Between Blood Pressure Variability With Dementia and Cognitive Impairment: A Systematic Review and Meta-Analysis.},
journal = {Hypertension (Dallas, Tex. : 1979)},
volume = {78},
number = {5},
pages = {1478-1489},
pmid = {34538105},
issn = {1524-4563},
mesh = {Blood Pressure/*physiology ; Cognitive Dysfunction/*etiology ; Dementia/*etiology ; Humans ; Hypertension/*complications ; Risk ; },
abstract = {[Figure: see text].},
}
@article {pmid34537810,
year = {2021},
author = {Chen, SD and Lu, JY and Li, HQ and Yang, YX and Jiang, JH and Cui, M and Zuo, CT and Tan, L and Dong, Q and Yu, JT and , },
title = {Staging tau pathology with tau PET in Alzheimer's disease: a longitudinal study.},
journal = {Translational psychiatry},
volume = {11},
number = {1},
pages = {483},
pmid = {34537810},
issn = {2158-3188},
support = {P30 AG066512/AG/NIA NIH HHS/United States ; UL1 TR001422/TR/NCATS NIH HHS/United States ; //CIHR/Canada ; U01 AG024904/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides ; Biomarkers ; *Cognitive Dysfunction ; Female ; Humans ; Longitudinal Studies ; Male ; Positron-Emission Tomography ; tau Proteins ; },
abstract = {A biological research framework to define Alzheimer' disease with dichotomized biomarker measurement was proposed by National Institute on Aging-Alzheimer's Association (NIA-AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer's disease could be illustrated with biomarker measurement under NIA-AA framework. Clinical-neuroimaging-neuropathological studies in other cohorts are needed to validate these findings.},
}
@article {pmid34536437,
year = {2021},
author = {Naghibi, S and Shariatzadeh Joneydi, M and Barzegari, A and Davoodabadi, A and Ebrahimi, A and Eghdami, E and Fahimpour, N and Ghorbani, M and Mohammadikia, E and Rostami, M and Salari, AA},
title = {Treadmill exercise sex-dependently alters susceptibility to depression-like behaviour, cytokines and BDNF in the hippocampus and prefrontal cortex of rats with sporadic Alzheimer-like disease.},
journal = {Physiology &amp; behavior},
volume = {241},
number = {},
pages = {113595},
doi = {10.1016/j.physbeh.2021.113595},
pmid = {34536437},
issn = {1873-507X},
mesh = {*Alzheimer Disease ; Animals ; *Brain-Derived Neurotrophic Factor/metabolism ; Cytokines/metabolism ; Depression/etiology ; Disease Models, Animal ; Female ; Hippocampus/metabolism ; Male ; Prefrontal Cortex/metabolism ; Rats ; Rats, Wistar ; },
abstract = {Alzheimer's disease (AD) is associated with increased depression-related behaviours. Previous studies have reported a greater risk of AD and depression in women. In recent years, we and others have provided evidence that exercise during life could be used as a therapeutic strategy for stress-related disorders such as depression. The main goal of the current study was to determine whether treadmill exercise during life can reduce depression-related behaviours in male and female Wistar rats with sporadic Alzheimer-like disease (ALD). Animals were subjected to treadmill exercise eight weeks before and four weeks after ALD induction by streptozocin (STZ). We measured body weight, food intake, and depression-related symptoms in rats using five behavioural tests. We measured brain-derived-neurotrophic factor (BDNF), tumour-necrosis factor (TNF)-α, and interleukin (IL)-10 levels in the hippocampus and prefrontal cortex of animals. Our findings showed that exercise but not ALD induction decreased body weight and food intake in male and female rats. ALD induction increased depression-related symptoms and hippocampal TNF-α in male and female rats. Besides, treadmill exercise alone decreased depression-related behaviours and increased hippocampal BDNF in females but not males. We also found that treadmill exercise decreased depression-related behaviours and TNF-α in the hippocampus and prefrontal cortex, and increased IL-10 in the prefrontal cortex and BDNF in the hippocampus of female ALD-induced rats. However, treadmill exercise only reduced anhedonia-like behaviour and hippocampal TNF-α in male ALD-induced rats. Overall, the evidence from this study suggests that treadmill exercise alters depression-related behaviours, brain BDNF and cytokines in a sex-dependant manner in rats with sporadic Alzheimer-like disease.},
}
@article {pmid34535787,
year = {2021},
author = {Liu, KY and Howard, R},
title = {Can we learn lessons from the FDA's approval of aducanumab?.},
journal = {Nature reviews. Neurology},
volume = {17},
number = {11},
pages = {715-722},
pmid = {34535787},
issn = {1759-4766},
support = {MR/S021418/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/pharmacology/*therapeutic use ; Clinical Trials, Phase III as Topic ; *Drug Approval ; Humans ; Middle Aged ; Randomized Controlled Trials as Topic ; Treatment Outcome ; United States ; United States Food and Drug Administration/*organization &amp; administration ; },
abstract = {On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen's shared interpretation of clinical trial data - that high-dose aducanumab was substantially clinically effective - avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA's decision on 7 June 2021 and consider whether any lessons can be learned for the field.},
}
@article {pmid34532569,
year = {2021},
author = {Gerring, ZF and Gamazon, ER and White, A and Derks, EM},
title = {Integrative Network-Based Analysis Reveals Gene Networks and Novel Drug Repositioning Candidates for Alzheimer Disease.},
journal = {Neurology. Genetics},
volume = {7},
number = {5},
pages = {e622},
pmid = {34532569},
issn = {2376-7839},
support = {R01 HG011138/HG/NHGRI NIH HHS/United States ; R35 HG010718/HG/NHGRI NIH HHS/United States ; },
abstract = {BACKGROUND AND OBJECTIVES: To integrate genome-wide association study data with tissue-specific gene expression information to identify coexpression networks, biological pathways, and drug repositioning candidates for Alzheimer disease.<br><br>METHODS: We integrated genome-wide association summary statistics for Alzheimer disease with tissue-specific gene coexpression networks from brain tissue samples in the Genotype-Tissue Expression study. We identified gene coexpression networks enriched with genetic signals for Alzheimer disease and characterized the associated networks using biological pathway analysis. The disease-implicated modules were subsequently used as a molecular substrate for a computational drug repositioning analysis, in which we (1) imputed genetically regulated gene expression within Alzheimer disease implicated modules; (2) integrated the imputed gene expression levels with drug-gene signatures from the connectivity map to identify compounds that normalize dysregulated gene expression underlying Alzheimer disease; and (3) prioritized drug compounds and mechanisms of action based on the extent to which they normalize dysregulated expression signatures.<br><br>RESULTS: Genetic factors for Alzheimer disease are enriched in brain gene coexpression networks involved in the immune response. Computational drug repositioning analyses of expression changes within the disease-associated networks retrieved known Alzheimer disease drugs (e.g., memantine) as well as biologically meaningful drug categories (e.g., glutamate receptor antagonists).<br><br>DISCUSSION: Our results improve the biological interpretation of genetic data for Alzheimer disease and provide a list of potential antidementia drug repositioning candidates for which the efficacy should be investigated in functional validation studies.},
}
@article {pmid34532568,
year = {2021},
author = {Grangeon, L and Cassinari, K and Rousseau, S and Croisile, B and Formaglio, M and Moreaud, O and Boutonnat, J and Le Meur, N and Miné, M and Coste, T and Pipiras, E and Tournier-Lasserve, E and Rovelet-Lecrux, A and Campion, D and Wallon, D and Nicolas, G},
title = {Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication.},
journal = {Neurology. Genetics},
volume = {7},
number = {5},
pages = {e609},
pmid = {34532568},
issn = {2376-7839},
abstract = {BACKGROUND AND OBJECTIVE: To report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).<br><br>METHODS: Four copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.<br><br>RESULTS: Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.<br><br>DISCUSSION: Increased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.},
}
@article {pmid34531734,
year = {2021},
author = {Zecca, C and Pasculli, G and Tortelli, R and Dell'Abate, MT and Capozzo, R and Barulli, MR and Barone, R and Accogli, M and Arima, S and Pollice, A and Brescia, V and Logroscino, G},
title = {The Role of Age on Beta-Amyloid1-42 Plasma Levels in Healthy Subjects.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {698571},
pmid = {34531734},
issn = {1663-4365},
abstract = {Beta-amyloid (Aβ) plaques have been observed in the brain of healthy elderlies with frequencies strongly influenced by age. The aim of the study is to evaluate the role of age and other biochemical and hematological parameters on Aβ1-42 plasma levels in cognitively and neurologically normal individuals. Two-hundred and seventy-five normal subjects stratified by age groups (<35 years, 35-65 years, and >65 years) were included in the study. Aβ1-42 plasma levels significantly correlated with age (rs = 0.27; p < 0.0001) in the whole sample, inversely correlated with age in the first age group (rs = -0.25, p = 0.01), positively correlated in the second group (rs = 0.22, p = 0.03), while there was no significant correlation in the older group (rs = 0.02, p = 0.86). Both age (β-estimate = 0.08; p < 0.001) and cholesterol (β-estimate = 0.03; p = 0.009) were significantly associated with Aβ1-42 plasma level in multivariable analysis. However, only the association with age survived post hoc adjustment for multiple comparisons. The different effects of age on the Aβ level across age groups should be explored in further studies to better understand the age-dependent variability. This could better define the value of plasma Aβ as a biomarker of the Alzheimer neuropathology.},
}
@article {pmid34531308,
year = {2021},
author = {Lopez-Grancha, M and Bernardelli, P and Moindrot, N and Genet, E and Vincent, C and Roudieres, V and Krick, A and Sabuco, JF and Machnik, D and Ibghi, D and Pradier, L and Taupin, V},
title = {A Novel Selective PKR Inhibitor Restores Cognitive Deficits and Neurodegeneration in Alzheimer Disease Experimental Models.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {378},
number = {3},
pages = {262-275},
doi = {10.1124/jpet.121.000590},
pmid = {34531308},
issn = {1521-0103},
mesh = {*Alzheimer Disease ; Cognition Disorders ; Maze Learning ; Memory Disorders ; },
abstract = {In Alzheimer disease (AD), the double-strand RNA-dependent kinase protein kinase R (PKR)/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2α (eIF2α). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid-β oligomers (AβOs), have been associated with activation of PKR-dependent signaling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models. In ApoE4 human replacement male mice, 1-week oral treatment with SAR439883 rescued short-term memory impairment in the spatial object recognition test and dose-dependently reduced learning and memory deficits in the Barnes maze test. Moreover, in AβO-injected male mice, a 2-week administration of SAR439883 in diet dose-dependently ameliorated the AβO-induced cognitive impairment in both Y-maze and Morris Water Maze, prevented loss of synaptic proteins, and reduced levels of the proinflammatory cytokine interleukin-1β In both mouse models, these effects were associated with a dose-dependent inhibition of brain PKR activity as measured by both PKR occupancy and partial lowering of peIF2α levels. Our results provide evidence that selective pharmacological inhibition of PKR by a small selective molecule can rescue memory deficits and prevent neurodegeneration in animal models of AD-like pathology, suggesting that inhibition of PKR is a potential therapeutic approach for AD. SIGNIFICANCE STATEMENT: This study reports the identification of a new small molecule potent and selective protein kinase R (PKR) inhibitor that can prevent cognitive deficits and neurodegeneration in Alzheimer disease (AD) experimental models, including a mouse model expressing the most prevalent AD genetic risk factor ApoE4. With high potency and selectivity, this PKR inhibitor represents a unique tool for investigating the physiological role of PKR and a starting point for developing new drug candidates for AD.},
}
@article {pmid34531298,
year = {2021},
author = {Antolini, L and DiFrancesco, JC and Zedde, M and Basso, G and Arighi, A and Shima, A and Cagnin, A and Caulo, M and Carare, RO and Charidimou, A and Cirillo, M and Di Lazzaro, V and Ferrarese, C and Giossi, A and Inzitari, D and Marcon, M and Marconi, R and Ihara, M and Nitrini, R and Orlandi, B and Padovani, A and Pascarella, R and Perini, F and Perini, G and Sessa, M and Scarpini, E and Tagliavini, F and Valenti, R and Vázquez-Costa, JF and Villarejo-Galende, A and Hagiwara, Y and Ziliotto, N and Piazza, F},
title = {Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy-Related Inflammation: A Multicenter Prospective Longitudinal Cohort Study.},
journal = {Neurology},
volume = {97},
number = {18},
pages = {e1809-e1822},
pmid = {34531298},
issn = {1526-632X},
mesh = {Aged ; *Cerebral Amyloid Angiopathy/complications/diagnostic imaging ; Cerebral Hemorrhage ; Cohort Studies ; Female ; Humans ; Inflammation ; Longitudinal Studies ; Magnetic Resonance Imaging ; Prospective Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri).<br><br>METHODS: This was a multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria recruited through the Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease βiomarkers International Network from January 2013 to March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, gradient recalled echo-T2*, fluid-suppressed T2-weighted (fluid-attenuated inversion recovery), and T1 postgadolinium contrast-enhanced images acquired on 1.5T MRI, was used at the 3-, 6-, 12-, and 24-month follow-up. Centralized reads of MRIs were performed by investigators blinded to clinical, therapeutic, and time-point information. Main outcomes were survival, clinical and radiologic recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri.<br><br>RESULTS: The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri). Their mean age was 72.9 years; 43.4% were female; 37.1% were APOEε4 carriers; 36.3% had a history of Alzheimer disease; and 33.6% had a history of ICH. A history of ICH and the occurrence of new ICH at follow-up were more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%, p < 0.0001 and 19.3% vs 3.6%, p < 0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% confidence interval [CI] 61.6%-78.5%) and 84.1% (95% CI 76.2%-90.6%) clinically recovered within 3 and 12 months, followed by radiologic recovery in 45.1% (95% CI 36.4%-54.8%) and 77.4% (95% CI 67.7%-85.9%), respectively. After clinicoradiologic resolution of the first-ever episode, 38.3% (95% CI 22.9%-59.2%) had at least 1 recurrence within the following 24 months. Recurrence was more likely if IV high-dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering off (hazard ratio 4.68, 95% CI 1.57-13.93; p = 0.006).<br><br>DISCUSSION: These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiologic acute manifestations of the disease and the effectiveness of slow oral tapering off after IV corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in β-amyloid-driven diseases, including treatment-related ARIA in patients with Alzheimer disease exposed to immunotherapy drugs.},
}
@article {pmid34530925,
year = {2021},
author = {Marazuela, P and Solé, M and Bonaterra-Pastra, A and Pizarro, J and Camacho, J and Martínez-Sáez, E and Kuiperij, HB and Verbeek, MM and de Kort, AM and Schreuder, FHBM and Klijn, CJM and Castillo-Ribelles, L and Pancorbo, O and Rodríguez-Luna, D and Pujadas, F and Delgado, P and Hernández-Guillamon, M},
title = {MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.},
journal = {Acta neuropathologica communications},
volume = {9},
number = {1},
pages = {154},
pmid = {34530925},
issn = {2051-5960},
support = {R01 NS104147/NS/NINDS NIH HHS/United States ; },
mesh = {Aged ; Animals ; Antigens, Surface/*biosynthesis/genetics ; Biomarkers/metabolism ; Brain/*metabolism/*pathology ; Cells, Cultured ; Cerebral Amyloid Angiopathy/genetics/*metabolism/*pathology ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Milk Proteins/*biosynthesis/genetics ; },
abstract = {Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.},
}
@article {pmid34530113,
year = {2021},
author = {Gao, F and Liu, T and Tuo, M and Chi, S},
title = {The role of orexin in Alzheimer disease: From sleep-wake disturbance to therapeutic target.},
journal = {Neuroscience letters},
volume = {765},
number = {},
pages = {136247},
doi = {10.1016/j.neulet.2021.136247},
pmid = {34530113},
issn = {1872-7972},
mesh = {Alzheimer Disease/complications/*drug therapy/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Cognition/drug effects ; Cognitive Dysfunction/drug therapy/etiology ; Disease Models, Animal ; Humans ; Orexin Receptor Antagonists/pharmacology/*therapeutic use ; Orexins/antagonists &amp; inhibitors/*metabolism ; Sleep Wake Disorders/drug therapy/*etiology/pathology ; Sleep, REM/drug effects ; },
abstract = {Accumulating evidence has shown that sleep disturbance is a common symptom in Alzheimer's disease (AD), which is regarded as a modifiable risk factor for AD. Orexin is a key modulator of the sleep-wake cycle and has been found to be dysregulated in AD patients. The increased orexin in cerebrospinal fluid (CSF) is associated with decreased sleep efficiency and REM sleep, as well as cognitive impairment in AD patients. The orexin system has profuse projections to brain regions that are implicated in arousal and cognition and has been found to participate in the progression of AD pathology. Conversely the orexin receptor antagonists are able to consolidate sleep and reduce AD pathology. Therefore, improved understanding of the mechanisms linking orexin system, sleep disturbance and AD could make orexin receptor antagonists a promising target for the prevention or treatment of AD.},
}
@article {pmid34530075,
year = {2021},
author = {Barone, E and Di Domenico, F and Perluigi, M and Butterfield, DA},
title = {The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease.},
journal = {Free radical biology &amp; medicine},
volume = {176},
number = {},
pages = {16-33},
pmid = {34530075},
issn = {1873-4596},
support = {R01 AG060056/AG/NIA NIH HHS/United States ; },
mesh = {AMP-Activated Protein Kinases/genetics ; Aged ; *Alzheimer Disease ; Brain ; *Diabetes Mellitus, Type 2/complications ; Humans ; *Insulin Resistance ; Oxidative Stress ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resistance, as a risk factor for AD and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported in recent clinical and preclinical studies. Brain functions require continuous supply of glucose and oxygen and a tight regulation of metabolic processes. Loss of this metabolic regulation has been proposed to be a contributor to memory dysfunction associated with neurodegeneration. Within the above scenario, this review will focus on the interplay among oxidative stress (OS), insulin resistance and AMPK dysfunctions in the brain by highlighting how these neurotoxic events contribute to neurodegeneration. We provide an overview on the detrimental effects of OS on proteins regulating insulin signaling and how these alterations impact cell metabolic dysfunctions through AMPK dysregulation. Such processes, we assert, are critically involved in the molecular pathways that underlie AD.},
}
@article {pmid34529902,
year = {2021},
author = {Aleem, M},
title = {Phytochemistry and pharmacology of Celastrus paniculatus Wild.: a nootropic drug.},
journal = {Journal of complementary &amp; integrative medicine},
volume = {},
number = {},
pages = {},
doi = {10.1515/jcim-2021-0251},
pmid = {34529902},
issn = {1553-3840},
abstract = {OBJECTIVES: Celastrus paniculatus Wild is an evergreen climbing shrub. The plant is of great significance in the traditional Indian System of Medicine, such as Ayurveda, Unani, and Siddha. The seeds and their oil are extensively used to treat neurological disorders such as cognitive dysfunction, paralysis, epilepsy, insomnia, and other ailments like rheumatism, arthritis, sciatica, and leprosy. This paper aims to highlight the nootropic activity of C. paniculatus and explore its phytochemistry, traditional uses, and other pharmacological activities.<br><br>METHODS: All available information concerning C. paniculatus has been searched in the internationally accepted scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. Additional knowledge was gathered from the classical Textbooks and Unani Pharmacopoeia.<br><br>RESULTS: C. paniculatus is a rich source of several secondary metabolites, such as β-Dihydroagarofuranoids sesquiterpenes, alkaloids (Celastrine, Celapanin, Celapagin, and paniculatin), flavonoids, terpenoid (β-amyrin, Lupeol, Pristimerin), sterols (β-sitosterol, campesterol, stigmasterol, α-tocopherol, γ-Tocopherol), fatty acid (palmitic, stearic, oleic, linoleic, linolenic acids) and non-fatty acids (Benzoic acid, Cinnamic acid). The various study shows that the extracts and active constituent of this plant possess potent nootropic activity. Besides nootropic activity, it has also been reported for anti-Alzheimer, anticonvulsant, antidepressant, antioxidant, analgesic, anti-inflammatory, antiarthritic, gastroprotective, anti-psoriatic, wound healing, antibacterial, antimalarial, and several other properties.<br><br>CONCLUSIONS: Several in vitro and in vivo trials confirm the conventional use of C. paniculatus in cognitive dysfunction. However, the relations between the possible mechanisms of other activities and traditional uses of the C. paniculatus remain indistinct. Still, pharmacological studies also explored the effects of C. paniculatus, which were not recognized in ancient times, such as cytotoxic, ACE inhibitor, and antidiabetic activities. These discoveries are may be beneficial in the development of the new drug to treat various diseases. It is also confirmed that the β-dihydroagarofuranoids exhibit significant AChE inhibitory, cytotoxic, antibacterial, and insecticidal effects. This versatile medicine is truly a life elixir. Considering the therapeutic importance of the C. paniculatus and the absence of any reported clinical studies, extensive clinical trials are needed to explore its memory enhancing and other activities.},
}
@article {pmid34526539,
year = {2021},
author = {Benseny-Cases, N and Álvarez-Marimon, E and Aso, E and Carmona, M and Klementieva, O and Appelhans, D and Ferrer, I and Cladera, J},
title = {In situ identification and G4-PPI-His-Mal-dendrimer-induced reduction of early-stage amyloid aggregates in Alzheimer's disease transgenic mice using synchrotron-based infrared imaging.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {18368},
pmid = {34526539},
issn = {2045-2322},
mesh = {Alzheimer Disease/*drug therapy ; Amyloid beta-Peptides/genetics/metabolism ; Animals ; Cerebral Cortex/diagnostic imaging/drug effects/metabolism ; Dendrimers/administration &amp; dosage/*therapeutic use ; Histidine/chemistry ; Maltose/chemistry ; Mice ; Mice, Inbred C57BL ; Polypropylenes/administration &amp; dosage/*therapeutic use ; Spectroscopy, Fourier Transform Infrared ; },
abstract = {Amyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer Disease. In situ identification of early-stage amyloid aggregates in Alzheimer's disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months. A significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with poly(propylene imine) dendrimers with histidine-maltose shell (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating their putative therapeutic properties of in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. No less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques.},
}
@article {pmid34526343,
year = {2021},
author = {Bollinger, RM and Keleman, A and Thompson, R and Westerhaus, E and Fagan, AM and Benzinger, TL and Schindler, SE and Xiong, C and Balota, D and Morris, JC and Ances, BM and Stark, SL},
title = {Falls: a marker of preclinical Alzheimer disease: a cohort study protocol.},
journal = {BMJ open},
volume = {11},
number = {9},
pages = {e050820},
pmid = {34526343},
issn = {2044-6055},
support = {P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG057680/AG/NIA NIH HHS/United States ; S10 OD025214/OD/NIH HHS/United States ; },
mesh = {Accidental Falls ; *Alzheimer Disease/diagnosis ; Amyloid beta-Peptides ; Biomarkers ; Cohort Studies ; Humans ; Longitudinal Studies ; Positron-Emission Tomography ; tau Proteins ; },
abstract = {INTRODUCTION: Progression to symptomatic Alzheimer disease (AD) occurs slowly over a series of preclinical stages. Declining functional mobility may be an early indicator of loss of brain network integration and may lead to an increased risk of experiencing falls. It is unknown whether measures of functional mobility and falls are preclinical markers of AD. The purpose of this study is to examine (1) the relationship between falls and functional mobility with AD biomarkers to determine when falls occur within the temporal progression to symptomatic Alzheimer disease, and (2) the attentional compared with perceptual/motor systems that underlie falls and functional mobility changes seen with AD.<br><br>METHODS AND ANALYSIS: This longitudinal cohort study will be conducted at the Knight Alzheimer Disease Research Center. Approximately 350 cognitively normal participants (with and without preclinical AD) will complete an in-home visit every year for 4 years. During each yearly assessment, functional mobility will be assessed using the Performance Oriented Mobility Assessment, Timed Up and Go, and Timed Up and Go dual task. Data regarding falls (including number and severity) will be collected monthly by self-report and confirmed through interviews. This study will leverage ongoing neuropsychological assessments and neuroimaging (including molecular imaging using positron emission tomography and MRI) performed by the Knight Alzheimer Disease Research Center. Relationships between falls and biomarkers of amyloid, tau and neurodegeneration will be evaluated.<br><br>ETHICS AND DISSEMINATION: This study was approved by the Washington University in St. Louis Institutional Review Board (reference number 201807135). Written informed consent will be obtained in the home prior to the collection of any study data. Results will be published in peer-reviewed publications and presented at national and international conferences.<br><br>TRIAL REGISTRATION NUMBER: NCT04949529; Pre-results.},
}
@article {pmid34525960,
year = {2021},
author = {Khanassov, V and Rojas-Rozo, L and Sourial, R and Yang, XQ and Vedel, I},
title = {Needs of patients with dementia and their caregivers in primary care: lessons learned from the Alzheimer plan of Quebec.},
journal = {BMC family practice},
volume = {22},
number = {1},
pages = {186},
pmid = {34525960},
issn = {1471-2296},
support = {//CIHR/Canada ; },
mesh = {Aged ; *Alzheimer Disease/therapy ; Caregivers ; Cross-Sectional Studies ; *Dementia/therapy ; Humans ; Primary Health Care ; Quebec ; },
abstract = {BACKGROUND: Persons living with dementia have various health and social care needs and expectations, some which are not fully met by health providers, including primary care clinicians. The Quebec Alzheimer plan, implemented in 2014, aimed to cover these needs, but there is no research on the effect this plan had on the needs and expectations of persons living with dementia. The objective of this study is to identify persons living with dementia and caregivers' met and unmet needs and to describe their experience.<br><br>METHODS: This is a sequential mixed methods explanatory design: Phase 1: cross-sectional study to describe the met and unmet health and social care needs of community-dwelling persons living with dementia using Camberwell Assessment of Need of the Elderly and Carers' Assessment for Dementia tools. Phase 2: qualitative descriptive study to explore and understand the experiences of persons living with dementia and caregivers with the use of social and healthcare services, using semi-structured interviews. Data from phase 1 was analyzed with descriptive statistics, and from phase 2, with inductive thematic analysis. Results from phases 1 and 2 were compared, contrasted and interpreted together.<br><br>RESULTS: The mean total number of needs reported by the patients was 5.03 (4.48 and 0.55 met and unmet needs, respectively). Caregivers had 0.52 met needs (3.16 unmet needs). The main needs for both were memory, physical health, eyesight/hearing/communication, medication, looking after home, money/budgeting. Three categories were mentioned by the participants: Persons living with dementia and caregiver's attitude towards memory decline, their perception of community health services and of the family medicine practice.<br><br>CONCLUSIONS: Our study confirms the findings of other studies on the most common unmet needs of the patients and caregivers that are met partially or not at all. In addition, the participants were satisfied with access to care, and medical services in primary practices, being confident in their family. Our results indicate persons living with dementia and their caregivers need a contact person, a clear explanation of their dementia diagnosis, a care plan, written information on available services, and support for the caregivers.},
}
@article {pmid34525093,
year = {2021},
author = {Kauwe, G and Tracy, TE},
title = {Amyloid beta emerges from below the neck to disable the brain.},
journal = {PLoS biology},
volume = {19},
number = {9},
pages = {e3001388},
pmid = {34525093},
issn = {1545-7885},
support = {K01 AG057862/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Dendritic Spines/metabolism ; Humans ; },
abstract = {Accumulation of amyloid beta (Aβ) in the brain in Alzheimer disease drives pathophysiology. A study in this issue of PLOS Biology revealed that Aβ from the liver can promote brain pathology, supporting that peripheral Aβ can contribute to neurodegeneration.},
}
@article {pmid34524968,
year = {2021},
author = {Chiong, W and Tsou, AY and Simmons, Z and Bonnie, RJ and Russell, JA and , },
title = {Ethical Considerations in Dementia Diagnosis and Care: AAN Position Statement.},
journal = {Neurology},
volume = {97},
number = {2},
pages = {80-89},
doi = {10.1212/WNL.0000000000012079},
pmid = {34524968},
issn = {1526-632X},
mesh = {Dementia/*diagnosis/*therapy ; Humans ; Neurology/*ethics/*methods ; },
abstract = {Alzheimer disease and other dementias present unique practical challenges for patients, their families, clinicians, and health systems. These challenges reflect not only the growing public health effect of dementia in an aging global population, but also more specific ethical complexities including early loss of patients' capacity to make decisions regarding their own care, the stigma often associated with a dementia diagnosis, the difficulty of balancing concern for patients' welfare with respect for patients' remaining independence, and the effect on the physical, emotional, and financial well-being of family caregivers. Caring for patients with dementia requires respecting patient autonomy while acknowledging progressively diminishing decisional capacity and continuing to provide care in accordance with other core ethical principles (beneficence, justice, and nonmaleficence). Whereas these ethical principles remain unchanged, neurologists must reconsider how to apply them given changes across multiple domains including our understanding of disease, clinical and legal tools for addressing manifestations of illness, our expanding awareness of the crucial role of family caregivers in providing care and maintaining patient quality of life, and societal conceptions of dementia and individuals' personal expectations for aging. This revision to the American Academy of Neurology's 1996 position statement summarizes ethical considerations that often arise in caring for patients with dementia; although it addresses how such considerations influence patient management, it is not a clinical practice guideline.},
}
@article {pmid34524654,
year = {2022},
author = {Parker, K and Vincent, B and Rhee, Y and Choi, BJ and Robinson-Lane, SG and Hamm, JM and Klawitter, L and Jurivich, DA and McGrath, R},
title = {The estimated prevalence of no reported dementia-related diagnosis in older Americans living with possible dementia by healthcare utilization.},
journal = {Aging clinical and experimental research},
volume = {34},
number = {2},
pages = {359-365},
pmid = {34524654},
issn = {1720-8319},
support = {K01 AG065420/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Cognitive Dysfunction ; *Dementia/diagnosis/epidemiology ; *Home Care Services ; Humans ; Patient Acceptance of Health Care ; Prevalence ; United States/epidemiology ; },
abstract = {BACKGROUND: Screening for dementia in relevant healthcare settings may help in identifying low cognitive functioning for comprehensive cognitive assessments and subsequent dementia treatment after diagnosis.<br><br>AIMS: This study sought to estimate the prevalence of no reported dementia-related diagnosis in a nationally-representative sample of older Americans with a cognitive impairment consistent with dementia (CICD) by healthcare utilization.<br><br>METHODS: The unweighted analytical sample included 1514 Americans aged ≥ 65 years that were identified as having a CICD without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. An adapted Telephone Interview of Cognitive Status assessed cognitive functioning. Those with scores ≤ 6 had a CICD. Dementia-related diagnosis was self-reported. Respondents indicated if they visited a physician, received home healthcare, or experienced an overnight nursing home stay in the previous two years.<br><br>RESULTS: The prevalence of no reported dementia-related diagnosis in persons with a CICD who visited a physician was 89.9% (95% confidence interval (CI): 85.4%-93.1%). Likewise, the prevalence of no reported diagnosis in those with a CICD who received home healthcare was 84.3% (CI: 75.1-90.5%). For persons with a CICD that had an overnight nursing home stay, the prevalence of no reported dementia-related diagnosis was 83.0% (CI: 69.1-91.4%).<br><br>DISCUSSION: Although the prevalence of no reported dementia-related diagnosis in individuals with a CICD differed across healthcare settings, the prevalence was generally high nonetheless.<br><br>CONCLUSIONS: We recommend increased awareness and efforts be given to dementia screenings in various clinical settings.},
}
@article {pmid34522196,
year = {2021},
author = {Hassanzadeh, M and Hassanzadeh, F and Khodarahmi, GA and Rostami, M and Azimi, F and Nadri, H and Homayouni Moghadam, F},
title = {Design, synthesis, and bio-evaluation of new isoindoline-1,3-dione derivatives as possible inhibitors of acetylcholinesterase.},
journal = {Research in pharmaceutical sciences},
volume = {16},
number = {5},
pages = {482-492},
pmid = {34522196},
issn = {1735-5362},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease is considered one of the lead causes of elderly death around the world. A significant decrease in acetylcholine level in the brain is common in most patients with Alzheimer's disease, therefore acetylcholinesterase (AChE) inhibitors such as donepezil and rivastigmine are widely used for patients with limited therapeutic results and major side effects.<br><br>EXPERIMENTAL APPROACH: A series of isoindoline-1,3-dione -N-benzyl pyridinium hybrids were designed, synthesized and evaluated as anti-Alzheimer agents with cholinesterase inhibitory activities. The structure of the compounds were confirmed by various methods of analysis such as HNMR, CNMR, and FT-IR. Molecular modeling studies were also performed to identify the possible interactions between neprilysin and synthesized compounds.<br><br>FINDINGS/RESULTS: The biological screening results indicated that all synthesized compounds displayed potent inhibitory activity with IC50 values ranging from 2.1 to 7.4 μM. Among synthesized compounds, para-fluoro substituted compounds 7a and 7f exhibited the highest inhibitory potency against AChE (IC50 = 2.1 μM). Molecular modeling studies indicated that the most potent compounds were able to interact with both catalytic and peripheral active sites of the enzyme. Also, some of the most potent compounds (7a, 7c, and 7f) demonstrated a neuroprotective effect against H2O2-induced cell death in PC12 neurons.<br><br>CONCLUSION AND IMPLICATIONS: The synthesized compounds demonstrated moderate to good AChE inhibitory effect with results higher than rivastigmine.},
}
@article {pmid34522195,
year = {2021},
author = {Teymuori, M and Yegdaneh, A and Rabbani, M},
title = {Effects of Piper nigrum fruit and Cinnamum zeylanicum bark alcoholic extracts, alone and in combination, on scopolamine-induced memory impairment in mice.},
journal = {Research in pharmaceutical sciences},
volume = {16},
number = {5},
pages = {474-481},
pmid = {34522195},
issn = {1735-5362},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease is a progressive brain disorder that is thought to be triggered via disruption of cholinergic neurons and enhanced oxidative stress. Therefore, antioxidant phytochemicals with the ability to fortify cholinergic function should help in preventing the progress of the disease. This study aimed at evaluating the combinational effects of two popular herbs one with anticholinesterase activity namely Piper nigrum and the other with antioxidant capacity, Cinnamomum zeylanicum.<br><br>EXPERIMENTAL APPROACH: In this study, P. nigrum extract (PN) (50, 100 mg/kg, ip) and C. zeylanicum extract (CZ) (100, 200, 400 mg/kg, ip) and their combinations were administered for 8 days before the injection of scopolamine (1 mg/kg, ip). Mice were then tested for their memory using two behavioral models, namely the object recognition test and the passive avoidance task.<br><br>FINDINGS/RESULTS: Administration of scopolamine significantly impaired memory performance in both memory paradigms. In the passive avoidance test (PAT) model, PN at doses up to 100 mg/kg and CZ at doses up to 400 mg/kg did not significantly alter the memory impairment induced by scopolamine. The combination of these two plant extracts did not change the PAT parameters. In the object recognition test (ORT) model, however, administration of 100 mg/kg CZ alone and a combination of PN (50 mg/kg) with CZ (400 mg/kg), significantly increased the recognition index (P < 0.05).<br><br>CONCLUSION AND IMPLICATIONS: Two plant extracts when administered alone or in combinations affected the memory performance differently in two memory paradigms. In the PAT model, the extracts did not show any memory improvement, in ORT, however, some improvements were observed after plant extracts.},
}
@article {pmid34522039,
year = {2021},
author = {Bettcher, BM and Tansey, MG and Dorothée, G and Heneka, MT},
title = {Peripheral and central immune system crosstalk in Alzheimer disease - a research prospectus.},
journal = {Nature reviews. Neurology},
volume = {17},
number = {11},
pages = {689-701},
pmid = {34522039},
issn = {1759-4766},
support = {R01 AG058772/AG/NIA NIH HHS/United States ; R01 AG059752/AG/NIA NIH HHS/United States ; RF1 AG057247/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/*immunology/*physiopathology/therapy ; Animals ; Humans ; Immune System/*physiopathology ; Research ; },
abstract = {Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral-central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral-central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.},
}
@article {pmid34521342,
year = {2021},
author = {Wen, J and Zhao, M and Sun, W and Cheng, X and Yu, L and Cao, D and Li, P},
title = {Uptake of Aβ by OATPs might be a new pathophysiological mechanism of Alzheimer disease.},
journal = {BMC neuroscience},
volume = {22},
number = {1},
pages = {53},
pmid = {34521342},
issn = {1471-2202},
mesh = {Alzheimer Disease/chemically induced/*metabolism/*physiopathology ; Amyloid beta-Peptides/*metabolism/toxicity ; HEK293 Cells ; Humans ; Liver-Specific Organic Anion Transporter 1/*metabolism ; Peptide Fragments/*metabolism/toxicity ; },
abstract = {BACKGROUND: The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD), at the same time, it is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABC1B1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. In the preliminary study, we found that the protein expression of organic anion transporting Polypeptide 1a4 (OATP1B1) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp1a4 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD.<br><br>RESULTS: In this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport of Aβ1-42. Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK293T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATPs may act as an important "carrier" for the transport of Aβ1-42 from the blood to the tissues, including liver and brain.<br><br>CONCLUSIONS: This is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.},
}
@article {pmid34520451,
year = {2021},
author = {Lam, V and Takechi, R and Hackett, MJ and Francis, R and Bynevelt, M and Celliers, LM and Nesbit, M and Mamsa, S and Arfuso, F and Das, S and Koentgen, F and Hagan, M and Codd, L and Richardson, K and O'Mara, B and Scharli, RK and Morandeau, L and Gauntlett, J and Leatherday, C and Boucek, J and Mamo, JCL},
title = {Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.},
journal = {PLoS biology},
volume = {19},
number = {9},
pages = {e3001358},
pmid = {34520451},
issn = {1545-7885},
mesh = {*Alzheimer Disease ; Amyloid beta-Peptides/*biosynthesis/genetics ; Animals ; Blood-Brain Barrier/pathology ; Brain/blood supply ; Capillaries/pathology ; Disease Models, Animal ; Hepatocytes/*metabolism ; Humans ; Inflammation ; Learning ; Lipoproteins/metabolism ; Male ; Mice, Transgenic ; Nerve Degeneration ; },
abstract = {Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.},
}
@article {pmid34518345,
year = {2021},
author = {Watt, JA and Marple, R and Hemmelgarn, B and Straus, SE},
title = {Should Canadian patients look forward to aducanumab for Alzheimer disease?.},
journal = {CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne},
volume = {193},
number = {36},
pages = {E1430-E1431},
pmid = {34518345},
issn = {1488-2329},
mesh = {Alzheimer Disease/*drug therapy/prevention &amp; control ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Canada ; Dose-Response Relationship, Drug ; Humans ; Molecular Targeted Therapy/*standards ; Primary Health Care/*organization &amp; administration ; },
}
@article {pmid34517889,
year = {2021},
author = {Hassenstab, J and Nicosia, J and LaRose, M and Aschenbrenner, AJ and Gordon, BA and Benzinger, TLS and Xiong, C and Morris, JC},
title = {Is comprehensiveness critical? Comparing short and long format cognitive assessments in preclinical Alzheimer disease.},
journal = {Alzheimer's research &amp; therapy},
volume = {13},
number = {1},
pages = {153},
pmid = {34517889},
issn = {1758-9193},
support = {P01AG03991/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; K01 AG 053474/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease/diagnostic imaging ; Amyloid beta-Peptides ; Biomarkers ; Cognition ; *Cognitive Dysfunction/diagnostic imaging ; Disease Progression ; Humans ; Mental Status and Dementia Tests ; Positron-Emission Tomography ; tau Proteins ; },
abstract = {BACKGROUND: Comprehensive testing of cognitive functioning is standard practice in studies of Alzheimer disease (AD). Short-form tests like the Montreal Cognitive Assessment (MoCA) use a "sampling" of measures, administering key items in a shortened format to efficiently assess cognition while reducing time requirements, participant burden, and administrative costs. We compared the MoCA to a commonly used long-form cognitive battery in predicting AD symptom onset and sensitivity to AD neuroimaging biomarkers.<br><br>METHODS: Survival, area under the receiver operating characteristic (ROC) curve (AUC), and multiple regression analyses compared the MoCA and long-form measures in predicting time to symptom onset in cognitively normal older adults (n = 6230) from the National Alzheimer's Coordinating Center (NACC) cohort who had, on average, 2.3 ± 1.2 annual assessments. Multiple regression models in a separate sample (n = 416) from the Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC) compared the sensitivity of the MoCA and long-form measures to neuroimaging biomarkers including amyloid PET, tau PET, and cortical thickness.<br><br>RESULTS: Hazard ratios suggested that both the MoCA and the long-form measures are similarly and modestly efficacious in predicting symptomatic conversion, although model comparison analyses indicated that the long-form measures slightly outperformed the MoCA (HRs > 1.57). AUC analyses indicated no difference between the measures in predicting conversion (DeLong's test, Z = 1.48, p = 0.13). Sensitivity to AD neuroimaging biomarkers was similar for the two measures though there were only modest associations with tau PET (rs = - 0.13, ps < 0.02) and cortical thickness in cognitively normal participants (rs = 0.15-0.16, ps < 0.007).<br><br>CONCLUSIONS: Both test formats showed weak associations with symptom onset, AUC analyses indicated low diagnostic accuracy, and biomarker correlations were modest in cognitively normal participants. Alternative assessment approaches are needed to improve how clinicians and researchers monitor cognitive changes and disease progression prior to symptom onset.},
}
@article {pmid34516970,
year = {2022},
author = {Di Lauro, C and Bianchi, C and Sebastián-Serrano, Á and Soria-Tobar, L and Alvarez-Castelao, B and Nicke, A and Díaz-Hernández, M},
title = {P2X7 receptor blockade reduces tau induced toxicity, therapeutic implications in tauopathies.},
journal = {Progress in neurobiology},
volume = {208},
number = {},
pages = {102173},
doi = {10.1016/j.pneurobio.2021.102173},
pmid = {34516970},
issn = {1873-5118},
mesh = {Animals ; Disease Models, Animal ; Glycogen Synthase Kinase 3/metabolism/therapeutic use ; Humans ; Mice ; Mice, Transgenic ; *Receptors, Purinergic P2X7/therapeutic use ; *Tauopathies/drug therapy/metabolism ; tau Proteins/metabolism ; },
abstract = {Tauopathies are neurodegenerative diseases characterized by the presence of aberrant intraneuronal aggregates of hyperphosphorylated Tau protein. Recent studies suggest that associated chronic neuroinflammation may contribute to the pathological Tau dissemination. However, the underlying molecular mechanisms remain unknown. Since purinergic P2X7 receptors (P2X7) can sense the rise of extracellular ATP levels associated with neuroinflammation, its involvement in neurodegeneration-associated inflammation was suggested. We found a P2X7 upregulation in patients diagnosed with different tauopathies and in a tauopathy mouse model, P301S mice. In vivo pharmacological or genetic blockade of P2X7 reverted microglial activation in P301S mice leading to a reduction in microglial migratory, secretory, and proliferative capacities, and promoting phagocytic function. Furthermore, it reduced the intraneuronal phosphorylated Tau levels in a GSK3-dependent way and increased extracellular phosphorylated Tau levels by reducing the expression of ectoenzyme TNAP. Accordingly, pharmacological or genetic blockade of P2X7 improved the cellular survival, motor and memory deficits and anxiolytic profile in P301S mice. Contrary, P2X7 overexpression caused a significant worsening of Tau-induced toxicity and aggravated the deteriorated motor and memory deficits in P301S mice. Our results indicate that P2X7 plays a deleterious role in tauopathies and suggest that its blockade may be a promising approach to treat Tauopathies.},
}
@article {pmid34515788,
year = {2021},
author = {Schwartz, JB and Weintraub, S},
title = {Treatment for Alzheimer Disease-Sex and Gender Effects Need to Be Explicitly Analyzed and Reported in Clinical Trials.},
journal = {JAMA network open},
volume = {4},
number = {9},
pages = {e2124386},
doi = {10.1001/jamanetworkopen.2021.24386},
pmid = {34515788},
issn = {2574-3805},
mesh = {*Alzheimer Disease/drug therapy/epidemiology ; Gender Identity ; Humans ; Sex Factors ; },
}
@article {pmid34515784,
year = {2021},
author = {Martinkova, J and Quevenco, FC and Karcher, H and Ferrari, A and Sandset, EC and Szoeke, C and Hort, J and Schmidt, R and Chadha, AS and Ferretti, MT},
title = {Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease: A Systematic Review and Meta-analysis.},
journal = {JAMA network open},
volume = {4},
number = {9},
pages = {e2124124},
doi = {10.1001/jamanetworkopen.2021.24124},
pmid = {34515784},
issn = {2574-3805},
mesh = {Alzheimer Disease/*epidemiology/etiology ; Europe/epidemiology ; Female ; *Gender Identity ; Humans ; Male ; *Patient Selection ; Randomized Controlled Trials as Topic ; *Severity of Illness Index ; United States/epidemiology ; },
abstract = {Importance: Women represent two-thirds of patients with Alzheimer disease (AD), and sex differences might affect results of randomized clinical trials (RCTs). However, little information exists on differences in sex as reported in RCTs for AD.<br><br>Objective: To assess the ratio of females to males and the reporting of sex-stratified data in large pharmaceutical RCTs for AD.<br><br>Data Sources: A search for pharmaceutical RCTs for AD was conducted on September 4, 2019, using ClinicalTrials.gov with the key word Alzheimer disease, and articles related to those trials were identified using the PubMed, Scopus, and Google Scholar databases. Searches were conducted between September 4 and October 31, 2019, and between April 15 and May 31, 2020.<br><br>Study Selection: Controlled RCTs that had more than 100 participants and tested the efficacy of drugs or herbal extracts were included. Of 1047 RCTs identified, 409 were published and therefore screened. A total of 77 articles were included in the final analysis, including 56 primary articles on AD, 13 secondary articles on AD, and 8 articles on mild cognitive impairment.<br><br>Data Extraction and Synthesis: The location and date of publication; number, sex, and age of patients enrolled; disease severity; experimental or approved status of the drug; and whether the study included a sex-stratified analysis in the protocol, methods, or results were extracted by 1 reviewer for each article, and the meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Data were analyzed using a mixed-effects model.<br><br>Main Outcomes and Measures: The mean proportion of women enrolled in the trials and the associations between prespecified variables were analyzed. The proportion of articles that included sex-stratified results and the temporal trends in the reporting of these results were also studied.<br><br>Results: In this review of 56 RCTs for AD involving 39 575 participants, 23 348 women (59.0%) were included. The mean (SD) proportion of women in RCTs of approved drugs was 67.3% (6.9%), and in RCTs of experimental drugs was 57.9% (5.9%). The proportion of women in RCTs of experimental drugs was significantly lower than the proportion of women in the general population with AD in the US (62.1%; difference, -4.56% [95% CI, -6.29% to -2.87%]; P < .001) and Europe (68.2%; difference, -10.67% [95% CI, -12.39% to -8.97%]; P < .001). Trials of approved drugs had a higher probability of including women than trials of experimental drugs (odds ratio [OR], 1.26; 95% CI, 1.05-1.52; P = .02). Both the severity of AD at baseline and the trial location were associated with the probability of women being enrolled in trials (severity: OR, 0.98; 95% CI, 0.97-1.00; P = .02; location in Europe: OR, 1.26; 95% CI, 1.05-1.52; P = .01; location in North America: OR, 0.81; 95% CI, 0.71-0.93; P = .002). Only 7 articles (12.5%) reported sex-stratified results, with an increasing temporal trend (R, 0.30; 95% CI, 0.05-0.59; P = .03).<br><br>Conclusions and Relevance: In this systematic review and meta-analysis, the proportion of women in RCTs for AD, although higher than the proportion of men, was significantly lower than that in the general population. Only a small proportion of trials reported sex-stratified results. These findings support strategies to improve diversity in enrollment and data reporting in RCTs for AD.},
}
@article {pmid34515750,
year = {2021},
author = {Planche, V and Villain, N},
title = {US Food and Drug Administration Approval of Aducanumab-Is Amyloid Load a Valid Surrogate End Point for Alzheimer Disease Clinical Trials?.},
journal = {JAMA neurology},
volume = {78},
number = {11},
pages = {1307-1308},
doi = {10.1001/jamaneurol.2021.3126},
pmid = {34515750},
issn = {2168-6157},
mesh = {Alzheimer Disease/*drug therapy ; Amyloid beta-Peptides/*drug effects ; Antibodies, Monoclonal, Humanized/*therapeutic use ; *Biomarkers ; Clinical Trials as Topic/*standards ; *Drug Approval ; Humans ; United States ; United States Food and Drug Administration ; },
}
@article {pmid34513285,
year = {2021},
author = {Ford, JN and Sweeney, EM and Skafida, M and Glynn, S and Amoashiy, M and Lange, DJ and Lin, E and Chiang, GC and Osborne, JR and Pahlajani, S and de Leon, MJ and Ivanidze, J},
title = {Heuristic scoring method utilizing FDG-PET statistical parametric mapping in the evaluation of suspected Alzheimer disease and frontotemporal lobar degeneration.},
journal = {American journal of nuclear medicine and molecular imaging},
volume = {11},
number = {4},
pages = {313-326},
pmid = {34513285},
issn = {2160-8407},
support = {P30 AG066512/AG/NIA NIH HHS/United States ; R01 AG068398/AG/NIA NIH HHS/United States ; },
abstract = {Distinguishing frontotemporal lobar degeneration (FTLD) and Alzheimer Disease (AD) on FDG-PET based on qualitative review alone can pose a diagnostic challenge. SPM has been shown to improve diagnostic performance in research settings, but translation to clinical practice has been lacking. Our purpose was to create a heuristic scoring method based on statistical parametric mapping z-scores. We aimed to compare the performance of the scoring method to the initial qualitative read and a machine learning (ML)-based method as benchmarks. FDG-PET/CT or PET/MRI of 65 patients with suspected dementia were processed using SPM software, yielding z-scores from either whole brain (W) or cerebellar (C) normalization relative to a healthy cohort. A non-ML, heuristic scoring system was applied using region counts below a preset z-score cutoff. W z-scores, C z-scores, or WC z-scores (z-scores from both W and C normalization) served as features to build random forest models. The neurological diagnosis was used as the gold standard. The sensitivity of the non-ML scoring system and the random forest models to detect AD was higher than the initial qualitative read of the standard FDG-PET [0.89-1.00 vs. 0.22 (95% CI, 0-0.33)]. A categorical random forest model to distinguish AD, FTLD, and normal cases had similar accuracy than the non-ML scoring model (0.63 vs. 0.61). Our non-ML-based scoring system of SPM z-scores approximated the diagnostic performance of a ML-based method and demonstrated higher sensitivity in the detection of AD compared to qualitative reads. This approach may improve the diagnostic performance.},
}
@article {pmid34512509,
year = {2021},
author = {Finneran, DJ and Njoku, IP and Flores-Pazarin, D and Ranabothu, MR and Nash, KR and Morgan, D and Gordon, MN},
title = {Toward Development of Neuron Specific Transduction After Systemic Delivery of Viral Vectors.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {685802},
pmid = {34512509},
issn = {1664-2295},
support = {R01 AG062217/AG/NIA NIH HHS/United States ; },
abstract = {Widespread transduction of the CNS with a single, non-invasive systemic injection of adeno-associated virus is now possible due to the creation of blood-brain barrier-permeable capsids. However, as these capsids are mutants of AAV9, they do not have specific neuronal tropism. Therefore, it is necessary to use genetic tools to restrict expression of the transgene to neuronal tissues. Here we compare the strength and specificity of two neuron-specific promoters, human synapsin 1 and mouse calmodulin/calcium dependent kinase II, to the ubiquitous CAG promoter. Administration of a high titer of virus is necessary for widespread CNS transduction. We observed the neuron-specific promoters drive comparable overall expression in the brain to the CAG promoter. Furthermore, the neuron-specific promoters confer significantly less transgene expression in peripheral tissues compared with the CAG promoter. Future experiments will utilize these delivery platforms to over-express the Alzheimer-associated pathological proteins amyloid-beta and tau to create mouse models without transgenesis.},
}
@article {pmid34512506,
year = {2021},
author = {Tsolaki, M and Tsatali, M and Gkioka, M and Poptsi, E and Tsolaki, A and Papaliagkas, V and Tabakis, IM and Lazarou, I and Makri, M and Kazis, D and Papagiannopoulos, S and Kiryttopoulos, A and Koutsouraki, E and Tegos, T},
title = {Memory Clinics and Day Care Centers in Thessaloniki, Northern Greece: 30 Years of Clinical Practice and Experience.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {683131},
pmid = {34512506},
issn = {1664-2295},
abstract = {Background: This review describes the diagnostic and interventional procedures conducted in two university memory clinics (established network of G. Papanikolaou Hospital: 1988-2017 and AHEPA hospital: 2017-today) and 2 day care centers (established network of DCCs: 2005-today) in North Greece and their contribution in the scientific field of dementia. The aims of this work are (1) to provide a diagnosis and treatment protocol established in the network of memory clinics and DCCs and (2) to present further research conducted in the aforementioned network during the last 30 years of clinical practice. Methods: The guidelines to set a protocol demand a series of actions as follows: (1) set the diagnosis criteria, neuropsychological assessment, laboratory examinations, and examination of neurophysiological, neuroimaging, cerebrospinal fluid, blood, and genetic markers; and (2) apply non-pharmacological interventions according to the needs and specialized psychosocial interventions of the patient to the caregivers of the patient. Results: In addition to the guidelines followed in memory clinics at the 1st and 3rd Department of Neurology and two DCCs, a database of patients, educational programs, and further participation in international research programs, including clinical trials, make our contribution in the dementia field strong. Conclusion: In the current paper, we provide useful guidelines on how major and minor neurocognitive disorders are being treated in Thessaloniki, Greece, describing successful practices which have been adapted in the last 30 years.},
}
@article {pmid34512305,
year = {2021},
author = {Sevinc, G and Rusche, J and Wong, B and Datta, T and Kaufman, R and Gutz, SE and Schneider, M and Todorova, N and Gaser, C and Thomalla, G and Rentz, D and Dickerson, BD and Lazar, SW},
title = {Mindfulness Training Improves Cognition and Strengthens Intrinsic Connectivity Between the Hippocampus and Posteromedial Cortex in Healthy Older Adults.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {702796},
pmid = {34512305},
issn = {1663-4365},
support = {P30 AG062421/AG/NIA NIH HHS/United States ; },
abstract = {Maintaining optimal cognitive functioning throughout the lifespan is a public health priority. Evaluation of cognitive outcomes following interventions to promote and preserve brain structure and function in older adults, and associated neural mechanisms, are therefore of critical importance. In this randomized controlled trial, we examined the behavioral and neural outcomes following mindfulness training (n = 72), compared to a cognitive fitness program (n = 74) in healthy, cognitively normal, older adults (65-80 years old). To assess cognitive functioning, we used the Preclinical Alzheimer Cognitive Composite (PACC), which combines measures of episodic memory, executive function, and global cognition. We hypothesized that mindfulness training would enhance cognition, increase intrinsic functional connectivity measured with magnetic resonance imaging (MRI) between the hippocampus and posteromedial cortex, as well as promote increased gray matter volume within those regions. Following the 8-week intervention, the mindfulness training group showed improved performance on the PACC, while the control group did not. Furthermore, following mindfulness training, greater improvement on the PACC was associated with a larger increase in intrinsic connectivity within the default mode network, particularly between the right hippocampus and posteromedial cortex and between the left hippocampus and lateral parietal cortex. The cognitive fitness training group did not show such effects. These findings demonstrate that mindfulness training improves cognitive performance in cognitively intact older individuals and strengthens connectivity within the default mode network, which is particularly vulnerable to aging affects. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT02628548], identifier [NCT02628548].},
}
@article {pmid34511072,
year = {2021},
author = {Islam, MS and Mia, MAK and Rahman, MS and Arefin, MS and Dhar, PK and Koshiba, T},
title = {Frequent contiguous pattern mining over biological sequences of protein misfolded diseases.},
journal = {BMC bioinformatics},
volume = {22},
number = {1},
pages = {435},
pmid = {34511072},
issn = {1471-2105},
mesh = {Amino Acid Sequence ; Amino Acids ; Humans ; *Retinitis Pigmentosa ; Rhodopsin ; },
abstract = {BACKGROUND: Proteins are integral part of all living beings, which are building blocks of many amino acids. To be functionally active, amino acids chain folds up in a complex way to give each protein a unique 3D shape, where a minor error may cause misfolded structure. Genetic disorder diseases i.e. Alzheimer, Parkinson, etc. arise due to misfolding in protein sequences. Thus, identifying patterns of amino acids is important for inferring protein associated genetic diseases. Recent studies in predicting amino acids patterns focused on only simple protein misfolded disease i.e. Chromaffin Tumor, by association rule mining. However, more complex diseases are yet to be attempted. Moreover, association rules obtained by these studies were not verified by usefulness measuring tools.<br><br>RESULTS: In this work, we analyzed protein sequences associated with complex protein misfolded diseases (i.e. Sickle Cell Anemia, Breast Cancer, Cystic Fibrosis, Nephrogenic Diabetes Insipidus, and Retinitis Pigmentosa 4) by association rule mining technique and objective interestingness measuring tools. Experimental results show the effectiveness of our method.<br><br>CONCLUSION: Adopting quantitative experimental methods, this work can form more reliable, useful and strong association rules i. e. dominating patterns of amino acid of complex protein misfolded diseases. Thus, in addition to usual applications, the identified patterns can be more useful in discovering medicines for protein misfolded diseases and thereby may open up new opportunities in medical science to handle genetic disorder diseases.},
}
@article {pmid34509621,
year = {2021},
author = {George, KM and Peterson, RL and Gilsanz, P and Barnes, LL and Mayeda, ER and Glymour, MM and Mungas, DM and DeCarli, CS and Whitmer, RA},
title = {Stroke Belt birth state and late-life cognition in the Study of Healthy Aging in African Americans (STAR).},
journal = {Annals of epidemiology},
volume = {64},
number = {},
pages = {26-32},
pmid = {34509621},
issn = {1873-2585},
support = {P30 AG010129/AG/NIA NIH HHS/United States ; R00 AG053410/AG/NIA NIH HHS/United States ; RF1 AG050782/AG/NIA NIH HHS/United States ; T32 AG050061/AG/NIA NIH HHS/United States ; },
mesh = {African Americans ; Aged ; Cognition ; Executive Function ; *Healthy Aging ; Humans ; Middle Aged ; *Stroke/epidemiology ; },
abstract = {PURPOSE: We examined the association of Stroke Belt birth state with late-life cognition in The Study of Healthy Aging in African Americans (STAR).<br><br>METHODS: STAR enrolled 764 Black Americans ages 50+ who were long-term Kaiser Permanente Northern California members. Participants completed Multiphasic Health Check-ups (MHC; 1964-1985) where early-life overweight/obesity, hypertension, diabetes, and hyperlipidemia were measured. At STAR (2018), birth state, self-reported early-life socioeconomic status (SES), and executive function, verbal episodic memory, and semantic memory scores were collected. We used linear regression to examine the association between Stroke Belt birth and late-life cognition adjusting for birth year, gender, and parental education. We evaluated early-life SES and cardiovascular risk factors (CVRF) as potential mechanisms.<br><br>RESULTS: Twenty-seven percent of participants were born in the Stroke Belt with a mean age of 69 (standard deviation = 9) at STAR. Stroke Belt birth was associated with worse late-life executive function (β [95% confidence interval]: -0.18 [-0.33, -0.02]) and semantic memory (-0.37 [-0.53, -0.21]), but not verbal episodic memory (-0.04 [-0.20, 0.12]). Adjustment for SES and CVRF attenuated associations of Stroke Belt birth with cognition (executive function [-0.05 {-0.25, 0.14}
]; semantic memory [-0.28 {-0.49, -0.07}
]).<br><br>CONCLUSIONS: Black Americans born in the Stroke Belt had worse late-life cognition than those born elsewhere, underscoring the importance of early-life exposures on brain health.},
}
@article {pmid34509401,
year = {2021},
author = {Bello-Medina, PC and González-Franco, DA and Vargas-Rodríguez, I and Díaz-Cintra, S},
title = {Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease.},
journal = {Neurologia (Barcelona, Spain)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.nrleng.2019.06.008},
pmid = {34509401},
issn = {2173-5808},
abstract = {INTRODUCTION: Worldwide, approximately 50 million people have dementia, with Alzheimer disease (AD) being the most common type, accounting for 60%-70% of cases. Given its high incidence, it is imperative to design studies to expand our knowledge about its onset and development, and to develop early diagnosis strategies and/or possible treatments. One methodological strategy is the use of transgenic mouse models for the study of the factors involved in AD aetiology, which include oxidative stress and the immune response.<br><br>DEVELOPMENT: We searched the PubMed, Scopus, and Google Scholar databases for original articles and reviews published between 2013 and 2019. In this review, we address 2 factors that have been studied independently, oxidative stress and the immune response, in transgenic models of AD, and discuss the relationship between these factors and their impact on the loss of synaptic and structural plasticity, resulting in cognitive impairment.<br><br>CONCLUSION: This review describes possible mechanisms by which oxidative stress and the immune response participate in the molecular, cellular, and behavioural effects of AD, observing a close relationship between these factors, which lead to cognitive impairment.},
}
@article {pmid34508753,
year = {2021},
author = {Baldinotti, R and Fronza, MG and Fetter, J and Silva, L and Bender, CB and Lüdtke, DS and Seixas, FK and Collares, T and Alves, D and Savegnago, L},
title = {Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {910},
number = {},
pages = {174499},
doi = {10.1016/j.ejphar.2021.174499},
pmid = {34508753},
issn = {1879-0712},
mesh = {Alzheimer Disease/chemically induced/pathology/*prevention &amp; control ; Animals ; Cerebral Cortex/drug effects/pathology ; Disease Models, Animal ; Glycosides/*pharmacology/therapeutic use ; Hippocampus/drug effects/pathology ; Humans ; Infusions, Intraventricular ; Lipid Peroxidation/drug effects ; Male ; Mice ; Organoselenium Compounds/*pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Streptozocin/administration &amp; dosage/toxicity ; },
abstract = {Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of streptozotocin (STZ). To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated intracerebroventricular infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.},
}
@article {pmid34507318,
year = {2021},
author = {Brenowitz, WD and Xiang, Y and McEvoy, CT and Yang, C and Yaffe, K and Le, WD and Leng, Y},
title = {Current Alzheimer disease research highlights: evidence for novel risk factors.},
journal = {Chinese medical journal},
volume = {134},
number = {18},
pages = {2150-2159},
pmid = {34507318},
issn = {2542-5641},
support = {K01 AG062722/AG/NIA NIH HHS/United States ; R00 AG056598/AG/NIA NIH HHS/United States ; },
mesh = {*Alzheimer Disease/epidemiology/etiology ; Amyloid ; Amyloid beta-Peptides ; Humans ; Risk Factors ; tau Proteins ; },
abstract = {ABSTRACT: Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.},
}
@article {pmid34506904,
year = {2022},
author = {Sanders, OD and Rajagopal, L and Rajagopal, JA},
title = {The oxidatively damaged DNA and amyloid-β oligomer hypothesis of Alzheimer's disease.},
journal = {Free radical biology &amp; medicine},
volume = {179},
number = {},
pages = {403-412},
doi = {10.1016/j.freeradbiomed.2021.08.019},
pmid = {34506904},
issn = {1873-4596},
mesh = {*Alzheimer Disease/drug therapy ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism ; DNA ; Hippocampus/metabolism ; Humans ; Peptide Fragments ; },
abstract = {The amyloid-β (Aβ) oligomer hypothesis of Alzheimer's disease (AD) still dominates the field, yet the clinical trial evidence does not robustly support it. A falsifiable prediction of the hypothesis is that Aβ oligomer levels should be elevated in the brain regions and at the disease stages where and when neuron death and synaptic protein loss begin and are the most severe, but we review previous evidence to demonstrate that this is not consistently the case. To rescue the Aβ oligomer hypothesis from falsification, we propose the novel ad-hoc hypothesis that the exceptionally vulnerable hippocampus may normally produce Aβ peptides even in healthily aging individuals, and hippocampal oxidatively damaged DNA, pathogen DNA, and metal ions such as zinc may initiate and drive Aβ peptide aggregation into oligomers and spreading, neuron death, synaptic dysfunction, and other aspects of AD neurodegeneration. We highlight additional evidence consistent with the underwhelming efficacy of Aβ oligomer-lowering agents, such as aducanumab, and of antioxidants, such as vitamin E, versus the so far isolated case report that DNase-I treatment for 2 months resulted in a severe AD patient's Mini-Mental State Exam score increasing from 3 to 18, reversing his diagnosis to moderate AD, according to the Mini-Mental State Exam.},
}
@article {pmid34506082,
year = {2021},
author = {Xiromerisiou, G and Bourinaris, T and Houlden, H and Lewis, PA and Senkevich, K and Hammer, M and Federoff, M and Khan, A and Spanaki, C and Hadjigeorgiou, GM and Bonstanjopoulou, S and Fidani, L and Ermolaev, A and Gan-Or, Z and Singleton, A and Vandrovcova, J and Hardy, J},
title = {SORL1 mutation in a Greek family with Parkinson's disease and dementia.},
journal = {Annals of clinical and translational neurology},
volume = {8},
number = {10},
pages = {1961-1969},
pmid = {34506082},
issn = {2328-9503},
support = {MR/K01417X/1/MRC_/Medical Research Council/United Kingdom ; G1001253/MRC_/Medical Research Council/United Kingdom ; MR/L501542/1/MRC_/Medical Research Council/United Kingdom ; G-0907/PUK_/Parkinson's UK/United Kingdom ; MR/J004758/1/MRC_/Medical Research Council/United Kingdom ; PDF-IRGP-1102/PDF/Parkinson's Disease Foundation/United States ; G0701075/MRC_/Medical Research Council/United Kingdom ; G0901254/MRC_/Medical Research Council/United Kingdom ; MR/N026004/1/MRC_/Medical Research Council/United Kingdom ; G-1307/PUK_/Parkinson's UK/United Kingdom ; },
mesh = {Aged ; Aged, 80 and over ; Dementia/*genetics/physiopathology ; Female ; Greece ; Humans ; LDL-Receptor Related Proteins/*genetics ; Male ; Membrane Transport Proteins/*genetics ; Parkinson Disease/*genetics/physiopathology ; Pedigree ; },
abstract = {Whole exome sequencing and linkage analysis were performed in a three generational pedigree of Greek origin with a broad phenotypic spectrum spanning from Parkinson's disease and Parkinson's disease dementia to dementia of mixed type (Alzheimer disease and vascular dementia). We identified a novel heterozygous c.G1135T (p.G379W) variant in SORL1 which segregated with the disease in the family. Mutation screening in sporadic Greek PD cases identified one additional individual with the mutation, sharing the same 12.8Mb haplotype. Our findings provide support for SORL1 mutations resulting in a broad range of additional phenotypes and warrants further studies in neurodegenerative diseases beyond AD.},
}
@article {pmid34505007,
year = {2021},
author = {Aguilar-Pineda, JA and Vera-Lopez, KJ and Shrivastava, P and Chávez-Fumagalli, MA and Nieto-Montesinos, R and Alvarez-Fernandez, KL and Goyzueta Mamani, LD and Davila Del-Carpio, G and Gomez-Valdez, B and Miller, CL and Malhotra, R and Lindsay, ME and Lino Cardenas, CL},
title = {Vascular smooth muscle cell dysfunction contribute to neuroinflammation and Tau hyperphosphorylation in Alzheimer disease.},
journal = {iScience},
volume = {24},
number = {9},
pages = {102993},
pmid = {34505007},
issn = {2589-0042},
support = {R01 HL148239/HL/NHLBI NIH HHS/United States ; T32 HL007208/HL/NHLBI NIH HHS/United States ; },
abstract = {Despite the emerging evidence implying early vascular contributions to neurodegenerative syndromes, the role of vascular smooth muscle cells (VSMCs) in the pathogenesis of Alzheimer disease (AD) is still not well understood. Herein, we show that VSMCs in brains of patients with AD and animal models of the disease are deficient in multiple VSMC contractile markers which correlated with Tau accumulation in brain arterioles. Ex vivo and in vitro experiments demonstrated that VSMCs undergo dramatic phenotypic transitions under AD-like conditions, adopting pro-inflammatory phenotypes. Notably, these changes coincided with Tau hyperphosphorylation at residues Y18, T205, and S262. We also observed that VSMC dysfunction occurred in an age-dependent manner and that expression of Sm22α protein was inversely correlated with CD68 and Tau expression in brain arterioles of the 3xTg-AD and 5xFAD mice. Together, these findings further support the contribution of dysfunctional VSMCs in AD pathogenesis and nominate VSMCs as a potential therapeutic target in AD.},
}
@article {pmid34504414,
year = {2021},
author = {Nascimento, FP and Macedo-Júnior, SJ and Lapa-Costa, FR and Cezar-Dos-Santos, F and Santos, ARS},
title = {Inosine as a Tool to Understand and Treat Central Nervous System Disorders: A Neglected Actor?.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {703783},
pmid = {34504414},
issn = {1662-4548},
abstract = {Since the 1970s, when ATP was identified as a co-transmitter in sympathetic and parasympathetic nerves, it and its active metabolite adenosine have been considered relevant signaling molecules in biological and pathological processes in the central nervous system (CNS). Meanwhile, inosine, a naturally occurring purine nucleoside formed by adenosine breakdown, was considered an inert adenosine metabolite and remained a neglected actor on the purinergic signaling scene in the CNS. However, this scenario began to change in the 1980s. In the last four decades, an extensive group of shreds of evidence has supported the importance of mediated effects by inosine in the CNS. Also, inosine was identified as a natural trigger of adenosine receptors. This evidence has shed light on the therapeutic potential of inosine on disease processes involved in neurological and psychiatric disorders. Here, we highlight the clinical and preclinical studies investigating the involvement of inosine in chronic pain, schizophrenia, epilepsy, depression, anxiety, and in neural regeneration and neurodegenerative diseases, such as Parkinson and Alzheimer. Thus, we hope that this review will strengthen the knowledge and stimulate more studies about the effects promoted by inosine in neurological and psychiatric disorders.},
}
@article {pmid34504031,
year = {2021},
author = {Poletti, B and Solca, F and Carelli, L and Diena, A and Colombo, E and Torre, S and Maranzano, A and Greco, L and Cozza, F and Lizio, A and Ferrucci, R and Girotti, F and Verde, F and Morelli, C and Lunetta, C and Silani, V and Ticozzi, N},
title = {Association of Clinically Evident Eye Movement Abnormalities With Motor and Cognitive Features in Patients With Motor Neuron Disorders.},
journal = {Neurology},
volume = {97},
number = {18},
pages = {e1835-e1846},
doi = {10.1212/WNL.0000000000012774},
pmid = {34504031},
issn = {1526-632X},
mesh = {*Amyotrophic Lateral Sclerosis/diagnosis ; Cognition/physiology ; *Cognition Disorders/complications ; Eye Movements ; Humans ; Motor Neurons ; Neuropsychological Tests ; Retrospective Studies ; },
abstract = {BACKGROUND AND OBJECTIVES: Although oculomotor abnormalities (OMAs) are not usually considered prominent features of amyotrophic lateral sclerosis (ALS), they may represent potential clinical markers of neurodegeneration, especially when investigated together with cognitive and behavioral alterations. The aim of our study was to identify patterns of clinically evident OMAs in patients with ALS and to correlate such findings with cognitive-behavioral data.<br><br>METHODS: Three consecutive inpatient cohorts of Italian patients with ALS and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided into a discovery cohort and a replication cohort. Controls included a cohort of cognitively impaired individuals and patients with Alzheimer disease (AD). Participants underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed with a standard neuropsychological battery (discovery ALS cohort and AD cohort) and the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS) (replication ALS cohort).<br><br>RESULTS: We recruited 864 individuals with ALS (635 discovery, 229 replication), 798 who were cognitively unimpaired and 171 with AD. OMAs were detected in 10.5% of our ALS cohort vs 1.6% of cognitively unimpaired controls (p = 1.2 × 10-14) and 11.4% of patients with AD (p = NS). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMA frequency was higher in patients with bulbar onset, prominent upper motor neuron signs, and advanced disease stages. Cognitive dysfunction was significantly more frequent in patients with OMAs in both ALS cohorts (p = 1.1 × 10-25). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathologic scores at the ECAS ALS-specific domains. Last, OMAs could be observed in 35.0% of cognitively impaired patients with ALS vs 11.4% of patients with AD (p = 6.4 × 10-7), suggesting a possible involvement of frontal oculomotor areas in ALS.<br><br>CONCLUSION: Patients with ALS showed a range of clinically evident OMAs, and these alterations were significantly correlated with cognitive, but not behavioral, changes. OMAs may be a marker of neurodegeneration, and bedside assessment represents a rapid, highly specific tool for detecting cognitive impairment in ALS.},
}
@article {pmid34504028,
year = {2021},
author = {Schindler, SE and Li, Y and Buckles, VD and Gordon, BA and Benzinger, TLS and Wang, G and Coble, D and Klunk, WE and Fagan, AM and Holtzman, DM and Bateman, RJ and Morris, JC and Xiong, C},
title = {Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET.},
journal = {Neurology},
volume = {97},
number = {18},
pages = {e1823-e1834},
pmid = {34504028},
issn = {1526-632X},
support = {P30 AG066444/AG/NIA NIH HHS/United States ; R03 AG050921/AG/NIA NIH HHS/United States ; K01 AG053474/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; K23 AG053426/AG/NIA NIH HHS/United States ; R01 AG025350/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease/diagnostic imaging ; Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; *Amyloidosis/diagnostic imaging ; Aniline Compounds ; Brain/diagnostic imaging/metabolism ; *Cognitive Dysfunction/diagnostic imaging ; Humans ; Middle Aged ; Positron-Emission Tomography ; },
abstract = {BACKGROUND AND OBJECTIVES: To predict when cognitively normal individuals with brain amyloidosis will develop symptoms of Alzheimer disease (AD).<br><br>METHODS: Brain amyloid burden was measured by amyloid PET with Pittsburgh compound B. The mean cortical standardized uptake value ratio (SUVR) was transformed into a timescale with the use of longitudinal data.<br><br>RESULTS: Amyloid accumulation was evaluated in 236 individuals who underwent >1 amyloid PET scan. The average age was 66.5 ± 9.2 years, and 12 individuals (5%) had cognitive impairment at their baseline amyloid PET scan. A tipping point in amyloid accumulation was identified at a low level of amyloid burden (SUVR 1.2), after which nearly all individuals accumulated amyloid at a relatively consistent rate until reaching a high level of amyloid burden (SUVR 3.0). The average time between levels of amyloid burden was used to estimate the age at which an individual reached SUVR 1.2. Longitudinal clinical diagnoses for 180 individuals were aligned by the estimated age at SUVR 1.2. In the 22 individuals who progressed from cognitively normal to a typical AD dementia syndrome, the estimated age at which an individual reached SUVR 1.2 predicted the age at symptom onset (R 2 = 0.54, p < 0.0001, root mean square error [RMSE] 4.5 years); the model was more accurate after exclusion of 3 likely misdiagnoses (R 2 = 0.84, p < 0.0001, RMSE 2.8 years).<br><br>CONCLUSION: The age at symptom onset in sporadic AD is strongly correlated with the age at which an individual reaches a tipping point in amyloid accumulation.},
}
@article {pmid34504027,
year = {2021},
author = {Buciuc, M and Josephs, KA and Jones, DT and Whitwell, JL and Graff-Radford, J},
title = {Progressive Auditory Verbal Agnosia Secondary to Alzheimer Disease.},
journal = {Neurology},
volume = {97},
number = {19},
pages = {908-909},
pmid = {34504027},
issn = {1526-632X},
support = {R01 AG050603/AG/NIA NIH HHS/United States ; },
mesh = {*Agnosia/etiology ; *Alzheimer Disease/complications ; Auditory Perception ; Humans ; },
}
@article {pmid34504022,
year = {2021},
author = {McCarter, SJ and Lesnick, TG and Lowe, V and Mielke, MM and Constantopoulos, E and Rabinstein, AA and Przybelski, SA and Botha, H and Jones, DT and Ramanan, VK and Jack, CR and Petersen, RC and Knopman, D and Boeve, BF and Murray, ME and Dickson, DW and Vemuri, P and Kantarci, K and Reichard, RR and Graff-Radford, J},
title = {Cerebral Amyloid Angiopathy Pathology and Its Association With Amyloid-β PET Signal.},
journal = {Neurology},
volume = {97},
number = {18},
pages = {e1799-e1808},
pmid = {34504022},
issn = {1526-632X},
support = {R01 AG034676/AG/NIA NIH HHS/United States ; R01 AG041851/AG/NIA NIH HHS/United States ; R01 AG011378/AG/NIA NIH HHS/United States ; R01 AG054449/AG/NIA NIH HHS/United States ; R33 AG058738/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; R01 NS097495/NS/NINDS NIH HHS/United States ; U01 NS100620/NS/NINDS NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides ; Aniline Compounds ; *Cerebral Amyloid Angiopathy/complications/diagnostic imaging ; Female ; Humans ; Male ; Plaque, Amyloid/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; },
abstract = {BACKGROUND AND OBJECTIVES: To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention.<br><br>METHODS: Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR.<br><br>RESULTS: Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all p < 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region.<br><br>DISCUSSION: We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.},
}
@article {pmid34501947,
year = {2021},
author = {Lee, YY and Chen, CL and Lee, IC and Lee, IC and Chen, NC},
title = {History of Falls, Dementia, Lower Education Levels, Mobility Limitations, and Aging Are Risk Factors for Falls among the Community-Dwelling Elderly: A Cohort Study.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {17},
pages = {},
pmid = {34501947},
issn = {1660-4601},
mesh = {*Accidental Falls ; Aged ; Aging ; Cohort Studies ; *Dementia/epidemiology ; Humans ; Independent Living ; Mobility Limitation ; Risk Factors ; },
abstract = {BACKGROUND: Falling is a serious issue among elderly community dwellers, often resulting in disability. We aimed to investigate the risk factors for falls among elderly community dwellers.<br><br>METHODS: We recruited 232 participants from multiple community learning and care centers, who provided their information through questionnaires. They were divided into two groups, according to their falling events after a 1-year follow-up. Univariate and multivariate logistic regressions were used for statistical analysis.<br><br>RESULTS: A total of 64 participants reported a fall at the 1-year follow-up. The falling group comprised older and single people with lower education levels, higher rates of dementia, a history of falls, lower scores on the Mini-Mental State Examination, and more disability functions when compared to the non-falling group (all p < 0.05). The regression model showed that a history of falls (OR: 62.011; p < 0.0001), lower education levels (OR: 4.088; p = 0.039), mild dementia (OR: 20.729; p = 0.028), older age (OR: 1.176; p < 0.0001), walking for 300 m (OR: 4.153; p = 0.030), and running for 30 m (OR: 3.402; p = 0.015) were 1-year risk factors for falls.<br><br>CONCLUSION: A history of falling, low education levels, aging, mild dementia, and certain mobility limitations were strong risk factors for future falling accidents in elderly Taiwanese community dwellers.},
}
@article {pmid34500640,
year = {2021},
author = {Purgatorio, R and Gambacorta, N and de Candia, M and Catto, M and Rullo, M and Pisani, L and Nicolotti, O and Altomare, CD},
title = {First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {17},
pages = {},
pmid = {34500640},
issn = {1420-3049},
support = {PRIN, Grant 201744BN5T_004//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; PRIN, Grant 2017RPHBCW_002//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
mesh = {Acetylcholinesterase/metabolism ; Alzheimer Disease/*drug therapy/metabolism ; Animals ; Butyrylcholinesterase/metabolism ; Cattle ; Cholinesterase Inhibitors/*pharmacology ; Factor Xa/metabolism ; Factor Xa Inhibitors/pharmacology ; Humans ; Molecular Docking Simulation ; Piperidines/pharmacology ; Structure-Activity Relationship ; Thrombin/*metabolism ; },
abstract = {Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 μM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.},
}
@article {pmid34499725,
year = {2021},
author = {Anderson, TS and Ayanian, JZ and Souza, J and Landon, BE},
title = {Representativeness of Participants Eligible to Be Enrolled in Clinical Trials of Aducanumab for Alzheimer Disease Compared With Medicare Beneficiaries With Alzheimer Disease and Mild Cognitive Impairment.},
journal = {JAMA},
volume = {326},
number = {16},
pages = {1627-1629},
doi = {10.1001/jama.2021.15286},
pmid = {34499725},
issn = {1538-3598},
support = {P01 AG032952/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/adverse effects/*therapeutic use ; Clinical Trials, Phase III as Topic ; Cognitive Dysfunction/*drug therapy ; Contraindications, Drug ; Drug Approval ; *Early Termination of Clinical Trials ; Female ; Humans ; Insurance Claim Review/statistics &amp; numerical data ; Male ; Medicare/*statistics &amp; numerical data ; Middle Aged ; Patient Selection ; United States ; United States Food and Drug Administration ; },
}
@article {pmid34499406,
year = {2021},
author = {Ryan, KC and Ashkavand, Z and Sarasija, S and Laboy, JT and Samarakoon, R and Norman, KR},
title = {Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.},
journal = {Aging cell},
volume = {20},
number = {10},
pages = {e13472},
pmid = {34499406},
issn = {1474-9726},
support = {RF1 AG064175/AG/NIA NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R01 GM088213/GM/NIGMS NIH HHS/United States ; },
mesh = {Alzheimer Disease/*genetics ; Animals ; Caenorhabditis elegans/*genetics ; Caenorhabditis elegans Proteins/*metabolism ; Calcium/*metabolism ; Mechanistic Target of Rapamycin Complex 1/*metabolism ; Mitochondria/*metabolism ; Neurodegenerative Diseases/*genetics/pathology ; Presenilins/*metabolism ; Signal Transduction ; },
abstract = {Metabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease. However, the mechanisms underlying these abnormalities remain poorly understood. We have found that mutations in the gene encoding presenilin in Caenorhabditis elegans, sel-12, results in elevated mitochondrial activity that drives oxidative stress and neuronal dysfunction. Mutations in the human presenilin genes are the primary cause of familial Alzheimer's disease. Here, we demonstrate that loss of SEL-12/presenilin results in the hyperactivation of the mTORC1 pathway. This hyperactivation is caused by elevated mitochondrial calcium influx and, likely, the associated increase in mitochondrial activity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagosome formation, and this reduction is prevented by limiting mitochondrial calcium uptake. Moreover, the improvements of proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. These results indicate that mTORC1 hyperactivation exacerbates the defects in proteostasis and neuronal function in sel-12 mutants and demonstrate a critical role of presenilin in promoting neuronal health.},
}
@article {pmid34498439,
year = {2021},
author = {Heger, I and Köhler, S and Boxtel, MV and Vugt, M and Hajema, K and Verhey, F and Deckers, K},
title = {[Raising awareness for dementia risk reduction through a public health campaign: a pre-post study].},
journal = {Tijdschrift voor gerontologie en geriatrie},
volume = {52},
number = {2},
pages = {},
doi = {10.36613/tgg.1875-6832/2021.02.01},
pmid = {34498439},
issn = {0167-9228},
mesh = {*Dementia/prevention &amp; control ; Health Knowledge, Attitudes, Practice ; *Health Promotion ; Humans ; Mass Media ; Risk Reduction Behavior ; },
abstract = {This study evaluates a public health campaign initiated by the Alzheimer Center Limburg of Maastricht University. The aim was to increase awareness of the influence of a healthy lifestyle on lowering the risk of dementia in community-dwelling inhabitants of the Province of Limburg (aged 40 - 75 years). The campaign used mass media and public events, supported by a campaign website and mobile application (MijnBreincoach app). An additional district-oriented approach was chosen in the municipalities of Roermond, Landgraaf and Brunssum, in which local stakeholders were involved in the design and execution of campaign-related events. Population-level difference in awareness before and after the campaign was assessed in two independent samples. No pre-post difference was observed in the level of awareness of dementia risk reduction. An additional analyses in the post-campaign sample revealed that the group that reported to have heard of the campaign, was more often aware of dementia risk reduction and reported higher motivation for behavioural change than the group that had not heard of the campaign. The district-oriented approach resulted in better recognition of campaign-material and the mobile application. With regard to the individual lifestyle factors, healthy diet and physical activity were identified more often post-campaign. Cognitive activity was identified most often at both pre- and post-assessment, but there was no increase in awareness after the campaign.},
}
@article {pmid34498073,
year = {2021},
author = {Fernandes, AR and Dujardin, S and Maté de Gérando, A and Hyman, BT and Frosch, MP},
title = {Impact of Sterilization Methods on the Seeding Ability of Human Tau Proteopathic Seeds.},
journal = {Journal of neuropathology and experimental neurology},
volume = {80},
number = {10},
pages = {912-921},
doi = {10.1093/jnen/nlab087},
pmid = {34498073},
issn = {1554-6578},
mesh = {Alzheimer Disease/*pathology ; Animals ; Brain/drug effects/*pathology ; Chromatography, Gel/methods ; Formates/pharmacology ; HEK293 Cells ; Humans ; Mice ; Mice, Transgenic ; Sterilization/*methods ; Tauopathies/pathology ; tau Proteins/antagonists &amp; inhibitors/*isolation &amp; purification ; },
abstract = {The protein tau, when misfolded in neurodegenerative diseases, has several prion-like properties including being able to spread by cell-to-cell transfer, induce templated seeding, and exist in distinct conformational strains. These properties of transmission may present health hazards when lesion-containing biospecimens are used in research and neuropathology laboratories. We evaluated the impact standard sterilization and cleaning methods have on the capacity of tau seeds to induce aggregation. We employed a previously developed, highly sensitive FRET-based biosensor assay to assess remnant tau seeding after exposure to these procedures. For tau species derived from human Alzheimer disease tissue (brain homogenate and sarkosyl-insoluble fibrils), both autoclaving and incubation in 90.6% formic acid were sufficient to reduce tau bioactivity. By contrast, boiling was not always effective in completely blocking bioactivity in the seeding assay. Notably, only formic acid incubation was able to produce a similar reduction in tissue from a P301L mutant tau mouse model of tauopathy. Our study highlights nuances in methods for inactivation of tau seeding which may support adapted tissue processing procedures, especially in research settings. These findings also highlight the importance of universal precautions when handling human neuropathological and research laboratory materials.},
}
@article {pmid34496627,
year = {2021},
author = {Lee, SR and Choi, EK and Park, SH and Jung, JH and Han, KD and Oh, S and Lip, GYH},
title = {Comparing Warfarin and 4 Direct Oral Anticoagulants for the Risk of Dementia in Patients With Atrial Fibrillation.},
journal = {Stroke},
volume = {52},
number = {11},
pages = {3459-3468},
doi = {10.1161/STROKEAHA.120.033338},
pmid = {34496627},
issn = {1524-4628},
mesh = {Aged ; Anticoagulants/*therapeutic use ; Atrial Fibrillation/complications/*drug therapy ; Cardiovascular Diseases/etiology/prevention &amp; control ; Cerebrovascular Disorders/etiology/prevention &amp; control ; Dementia/*epidemiology ; Factor Xa Inhibitors/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; Warfarin/*therapeutic use ; },
abstract = {Background and Purpose: Atrial fibrillation is a risk factor for dementia, and oral anticoagulant use is associated with a decreased risk of dementia in patients with atrial fibrillation. We aimed to investigate whether the risk of dementia would be different between patients treated with direct oral anticoagulants (DOACs) compared with those with warfarin.<br><br>Methods: Using the Korean nationwide claims database from January 2014 to December 2017, we identified oral anticoagulant–naive nonvalvular atrial fibrillation patients aged ≥40 years. For the comparisons, warfarin and DOAC groups were balanced using the inverse probability of treatment weighting method. The primary outcome was incident dementia.<br><br>Results: Among 72 846 of total study patients, 25 948 were treated with warfarin, and 46 898 were treated with DOAC (17 193 with rivaroxaban, 9882 with dabigatran, 11 992 with apixaban, and 7831 with edoxaban). During mean 1.3±1.1 years of follow-up, crude incidence of dementia was 4.87 per 100 person-years (1.20 per 100 person-years for vascular dementia and 3.30 per 100 person-years for Alzheimer dementia). Compared with warfarin, DOAC showed a comparable risks of dementia, vascular dementia, and Alzheimer dementia. In subgroup analyses, DOAC was associated with a lower risk of dementia than warfarin, particularly in patients aged 65 to 74 years (hazard ratio, 0.815 [95% CI, 0.709–0.936]) and in patients with prior stroke (hazard ratio, 0.891 [95% CI, 0.820–0.968]). When comparing individual DOACs with warfarin, edoxaban was associated with a lower risk of dementia (hazard ratio, 0.830 [95% CI, 0.740–0.931]).<br><br>Conclusions: In this large Asian population with atrial fibrillation, DOAC showed a comparable risk of dementia with warfarin overall. DOACs appeared more beneficial than warfarin, in those aged 65 to 74 years or with a history of stroke. For specific DOACs, only edoxaban was associated with a lower risk of dementia than warfarin.},
}
@article {pmid34496377,
year = {2021},
author = {Sternin, A and McGarry, LM and Owen, AM and Grahn, JA},
title = {The Effect of Familiarity on Neural Representations of Music and Language.},
journal = {Journal of cognitive neuroscience},
volume = {33},
number = {8},
pages = {1595-1611},
doi = {10.1162/jocn_a_01737},
pmid = {34496377},
issn = {1530-8898},
support = {300292//CIHR/Canada ; },
mesh = {Auditory Perception ; Humans ; Language ; *Music ; Recognition, Psychology ; Temporal Lobe ; },
abstract = {We investigated how familiarity alters music and language processing in the brain. We used fMRI to measure brain responses before and after participants were familiarized with novel music and language stimuli. To manipulate the presence of language and music in the stimuli, there were four conditions: (1) whole music (music and words together), (2) instrumental music (no words), (3) a capella music (sung words, no instruments), and (4) spoken words. To manipulate participants' familiarity with the stimuli, we used novel stimuli and a familiarization paradigm designed to mimic "natural" exposure, while controlling for autobiographical memory confounds. Participants completed two fMRI scans that were separated by a stimulus training period. Behaviorally, participants learned the stimuli over the training period. However, there were no significant neural differences between the familiar and unfamiliar stimuli in either univariate or multivariate analyses. There were differences in neural activity in frontal and temporal regions based on the presence of language in the stimuli, and these differences replicated across the two scanning sessions. These results indicate that the way we engage with music is important for creating a memory of that music, and these aspects, over and above familiarity on its own, may be responsible for the robust nature of musical memory in the presence of neurodegenerative disorders such as Alzheimer disease.},
}
@article {pmid34496036,
year = {2022},
author = {Mahmoudi, E and Lin, P and Kamdar, N and Gonzales, G and Norcott, A and Peterson, MD},
title = {Risk of early- and late-onset Alzheimer disease and related dementia in adults with cerebral palsy.},
journal = {Developmental medicine and child neurology},
volume = {64},
number = {3},
pages = {372-378},
doi = {10.1111/dmcn.15044},
pmid = {34496036},
issn = {1469-8749},
mesh = {Aged ; Alzheimer Disease/epidemiology ; Cerebral Palsy/*epidemiology ; Comorbidity ; Dementia/*epidemiology ; Female ; Humans ; Male ; Middle Aged ; Proportional Hazards Models ; United States/epidemiology ; },
abstract = {AIM: To examine the risk of Alzheimer disease and related dementia (ADRD) among adults with cerebral palsy (CP).<br><br>METHOD: Using administrative insurance claims data for 2007 to 2017 in the USA, we identified adults (45y or older) with a diagnosis of CP (n=5176). Adults without a diagnosis of CP were included as a typically developing comparison group (n=1 119 131). Using age, sex, ethnicity, other demographic variables, and a set of chronic morbidities, we propensity-matched individuals with and without CP (n=5038). Cox survival models were used to estimate ADRD risk within a 3-year follow up.<br><br>RESULTS: The unadjusted incidence of ADRD was 9 and 2.4 times higher among cohorts of adults 45 to 64 years (1.8%) and 65 years and older (4.8%) with CP than the respective unmatched individuals without CP (0.2% and 2.0% among 45-64y and 65y or older respectively). Fully adjusted survival models indicated that adults with CP had a greater hazard for ADRD (among 45-64y: unmatched hazard ratio 7.48 [95% confidence interval {CI}
6.05-9.25], matched hazard ratio 4.73 [95% CI 2.72-8.29]; among 65y or older: unmatched hazard ratio 2.21 [95% CI 1.95-2.51], matched hazard ratio 1.73 [1.39-2.15]).<br><br>INTERPRETATION: Clinical guidelines for early screening of cognitive function among individuals with CP need updating, and preventative and/or therapeutic services should be used to reduce the risk of ADRD.},
}
@article {pmid34493618,
year = {2021},
author = {Li, X and Song, R and Qi, X and Xu, H and Yang, W and Kivipelto, M and Bennett, DA and Xu, W},
title = {Influence of Cognitive Reserve on Cognitive Trajectories: Role of Brain Pathologies.},
journal = {Neurology},
volume = {97},
number = {17},
pages = {e1695-e1706},
pmid = {34493618},
issn = {1526-632X},
support = {UH2 NS100599/NS/NINDS NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Brain/*pathology ; Cognitive Dysfunction/*physiopathology ; Cognitive Reserve/*physiology ; Educational Status ; Female ; Humans ; Male ; Middle Aged ; Social Behavior ; },
abstract = {BACKGROUND AND OBJECTIVES: Evidence on the association of cognitive reserve (CR) with the cognitive trajectories is limited. We aimed to examine the influence of CR indicator on domain-specific cognitive trajectories taking brain pathologies into account.<br><br>METHODS: Within the Rush Memory and Aging Project, 1,697 participants without dementia (mean age 79.6 years) were followed up to 21 years. CR indicator encompassing education, early-life, mid-life, and late-life cognitive activities and late-life social activity was ascertained at baseline and categorized as tertiles (lowest, middle, and highest). Global cognition, episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with 19 tests, from which composite scores were derived. During the follow-up, 648 participants died and underwent autopsies to evaluate brain pathologies. Data were analyzed using linear mixed-effect models.<br><br>RESULTS: Among the participants, the score of the CR indicator ranged from -8.00 to 5.74 (mean 0.00 ± 2.23). In multi-adjusted mixed-effect models, compared to the lowest CR, the highest was related to a slower decline in global cognition (β = 0.028, 95% confidence interval [CI] 0.012-0.043), episodic memory (β = 0.028, 95% CI 0.010-0.047), and working memory (β = 0.019, 95% CI 0.005-0.033) during the follow-up. In brain pathologic data analysis, the association of the highest CR with cognitive function changes remained significant among participants with high Alzheimer disease pathology or gross infarcts.<br><br>DISCUSSION: High CR indicator is associated with preserved global cognitive function, episodic memory, and working memory, even in the presence of brain pathologies. Our findings highlight the important role of high CR accumulation in the prevention of cognitive decline.},
}
@article {pmid34493616,
year = {2021},
author = {Leuzy, A and Janelidze, S and Mattsson-Carlgren, N and Palmqvist, S and Jacobs, D and Cicognola, C and Stomrud, E and Vanmechelen, E and Dage, JL and Hansson, O},
title = {Comparing the Clinical Utility and Diagnostic Performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays.},
journal = {Neurology},
volume = {97},
number = {17},
pages = {e1681-e1694},
pmid = {34493616},
issn = {1526-632X},
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*cerebrospinal fluid/*diagnosis ; Biomarkers/*cerebrospinal fluid ; Female ; Humans ; Immunoassay/methods ; Male ; Middle Aged ; Protein Isoforms/cerebrospinal fluid ; Sensitivity and Specificity ; Sweden ; tau Proteins/*cerebrospinal fluid ; },
abstract = {BACKGROUND AND OBJECTIVES: Phosphorylated tau (p-tau) in CSF is considered an important biomarker in Alzheimer disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including p-tau at threonines 181 (p-tau181), 217 (p-tau217), and 231 (p-tau231). However, no studies have compared their diagnostic performance or association to β-amyloid (Aβ) and tau-PET. Understanding which p-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of p-tau181, p-tau217, and p-tau231 in CSF for AD and their association with Aβ and tau-PET.<br><br>METHODS: A total of 629 participants in the Swedish BioFINDER-2 study were included (cognitively unimpaired, n = 334; Aβ-positive mild cognitive impairment, n = 84; AD dementia, n = 119; and non-AD disorders, n = 92). In addition to p-tau181 and p-tau217 measured using assays with the same detector antibodies from Eli Lilly (p-tau181Lilly, p-tau217Lilly) and p-tau231, we also included p-tau181 measurements from 2 commonly used assays (Innotest and Elecsys).<br><br>RESULTS: Although all p-tau variants increased across the AD continuum, p-tau217Lilly showed the greatest dynamic range (13-fold increase vs 1.9-5.4-fold increase for other p-tau variants for AD dementia vs non-AD). P-Tau217Lilly showed stronger correlations with Aβ- and tau-PET (p < 0.0001). P-Tau217Lilly exhibited higher accuracy than other p-tau variants for separating AD dementia from non-AD (area under the curve [AUC], 0.98 vs 0.88 [p < 0.0001] - 0.96 [p < 0.05]) and for identifying Aβ-PET (AUC, 0.86 vs 0.74 [p < 0.0001] and 0.83 [p < 0.001]) and tau-PET positivity (AUC, 0.94 vs 0.80-0.92, p < 0.0001). Finally, p-Tau181Lilly generally performed better than the other p-tau181 assays (e.g., AD dementia vs non-AD, AUC, 0.96 vs 0.88 [p-tau181Innotest] and 0.89 [p-tau181Elecsys]; p < 0.0001).<br><br>DISCUSSION: CSF p-tau217Lilly seems to be more useful than other included p-tau assays in the workup of AD. Varied results across p-tau181 assays highlights the importance of anti-tau antibodies for biomarker performance.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that p-tau217 provides higher diagnostic accuracy for diagnosis of AD dementia than p-tau181 or p-tau231.},
}
@article {pmid34491277,
year = {2021},
author = {Elliott, CL and Ryan, L and Silverberg, N},
title = {Building Inclusive and Open Alzheimer Disease and Alzheimer Disease-Related Dementias Research Programs.},
journal = {JAMA neurology},
volume = {78},
number = {10},
pages = {1177-1178},
doi = {10.1001/jamaneurol.2021.2941},
pmid = {34491277},
issn = {2168-6157},
mesh = {*Alzheimer Disease ; *Dementia/epidemiology ; Humans ; },
}
@article {pmid34489759,
year = {2021},
author = {Wang, Y and Chi, I and Zhan, Y and Chen, W and Li, T},
title = {Effectiveness of Resilience Interventions on Psychosocial Outcomes for Persons With Neurocognitive Disorders: A Systematic Review and Meta-Analysis.},
journal = {Frontiers in psychiatry},
volume = {12},
number = {},
pages = {709860},
pmid = {34489759},
issn = {1664-0640},
abstract = {Background: Neurocognitive disorders, such as mild cognitive impairment (MCI), dementia, and Alzheimer's disease, not only harm people's cognitive function but also lead to negative emotions, poor quality of life (QOL), and unsatisfactory level of well-being. Resilience can be defined as a dynamic and amendable process, which maintains or improves life satisfaction and quick recovery from own dilemma. However, no meta-analysis of randomized controlled trials (RCTs) has thus far examined the effectiveness of resilience interventions among persons with neurocognitive disorders, and the results of RCTs were inconsistent. This systematic review aimed to assess the effectiveness of resilience interventions on psychosocial outcomes among persons with neurocognitive disorders. Methods: Nine electronic Chinese and English databases (the Cochrane Library, PsycINFO, Web of Science, PubMed, Medline, Eric, JSTOR, CNKI, and WANGFANG) were searched through April 2021. Only RCTs were included, and the quality of the included studies was assessed by the Cochrane "Risk of Bias" tool. Meta-analysis was carried out on psychosocial outcomes, and heterogeneity was investigated by subgroup and sensitivity analysis. RevMan 5.4 was used for meta-analysis. Results: Fourteen RCT studies were identified, representing a total of 2,442 participants with neurocognitive disorders. The risk of bias was high or unclear for most included studies in the domains of allocation concealment, blinding participants, and interventionists. Meta-analysis showed that heterogeneity was low or moderate. There were significant differences in favor of resilience interventions compared with control on the outcome of QOL, using the Quality of Life-Alzheimer Disease scale (QOL-AD) [I 2 = 36%, standardized mean difference (SMD) = 0.14, 95% CI (0.02, 0.26), p = 0.02], and no significant differences on depression, using the Cornell Scale for Depression in Dementia (CSDD) [I 2 = 41%, SMD = -0.14, 95% CI (-0.34, 0.05), p = 0.16], and neuropsychiatric symptoms using the Neuropsychiatric Inventory Questionnaire (NPI-Q) [I 2 = 62%, SMD = -0.10, 95% CI (-0.37, -0.16), p ≤ 0.46]. Conclusions: Resilience interventions had a significant benefit on QOL but no significant benefit on depression and neuropsychiatric behavioral symptoms. More evidence is needed to answer questions about how to implement resilience interventions and how to evaluate their effectiveness.},
}
@article {pmid34489674,
year = {2021},
author = {Ou, H and Chien, WC and Chung, CH and Chang, HA and Kao, YC and Wu, PC and Tzeng, NS},
title = {Association Between Antibiotic Treatment of Chlamydia pneumoniae and Reduced Risk of Alzheimer Dementia: A Nationwide Cohort Study in Taiwan.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {701899},
pmid = {34489674},
issn = {1663-4365},
abstract = {Background: Chlamydia pneumoniae (CPn) is a common community-acquired pneumonia. In the literature, CPn infection is demonstrated to exhibit an association with Alzheimer dementia (AD). We executed the present nationwide, population-based research with the goal of probing the association of CPn infection and antibiotic therapy with AD risk. Methods: We conducted a cohort study using a database extracted from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each enrolled individuals were categorized using the International Classification of Diseases, ninth Revision classifications. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CPn pneumonia-associated hospitalizations and AD were estimated using Fine and Gray's survival analysis and adjusted for comorbidities. The effects of the antibiotics on the HRs for AD in the patients with CPn pneumonia-associated hospitalization were also analyzed. Results: Our analyses included 6,628 individuals, including 1,657 CPn-infected patients, as well as 4,971 controls matched by age, index date, and sex (1:3). In this study, patients hospitalized for CPn pneumonia exhibited a significantly higher AD risk (adjusted HR = 1.599, 95% CI = 1.284-1.971, p < 0.001). We also noted an association of macrolide use (≥15 days) and fluoroquinolone use (≥15 days) with decreased AD risk. Conclusions: We determined CPn pneumonia to be associated with a relatively high AD risk. The result in this study confirmed the findings from previous literatures, by using a large, nationwide, population-based database. Appropriate macrolide and fluoroquinolone treatment may attenuate this risk.},
}
@article {pmid34489627,
year = {2021},
author = {Sim, AY and Barua, S and Kim, JY and Lee, YH and Lee, JE},
title = {Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {708547},
pmid = {34489627},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.},
}
@article {pmid34488782,
year = {2021},
author = {Shafiezadeh, A and Heravi-Karimooi, M and Mirzaee, A and Rejeh, N and Nia, HS and Montazeri, A},
title = {Correction to: Psychometric characteristics of the Iranian Caregiver Burden Inventory (CBI) in caregivers of elderly patients with Alzheimer.},
journal = {Health and quality of life outcomes},
volume = {19},
number = {1},
pages = {215},
pmid = {34488782},
issn = {1477-7525},
}
@article {pmid34488612,
year = {2021},
author = {Nezhadmoghadam, F and Martinez-Torteya, A and Treviño, V and Martínez, E and Santos, A and Tamez-Peña, J and Alzheimer's Disease Neuroimaging Initiative, },
title = {Robust Discovery of Mild Cognitive Impairment Subtypes and Their Risk of Alzheimer's Disease Conversion Using Unsupervised Machine Learning and Gaussian Mixture Modeling.},
journal = {Current Alzheimer research},
volume = {18},
number = {7},
pages = {595-606},
doi = {10.2174/1567205018666210831145825},
pmid = {34488612},
issn = {1875-5828},
mesh = {*Alzheimer Disease/complications ; Brain ; *Cognitive Dysfunction/psychology ; Disease Progression ; Humans ; Unsupervised Machine Learning ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills. The ability to correctly predict the diagnosis of Alzheimer's disease in its earliest stages can help physicians make more informed clinical decisions on therapy plans.<br><br>OBJECTIVE: This study aimed to determine whether the unsupervised discovering of latent classes of subjects with Mild Cognitive Impairment (MCI) may be useful in finding different prodromal AD stages and/or subjects with a low MCI to AD conversion risk.<br><br>METHODS: Total 18 features relevant to the MCI to AD conversion process led to the identification of 681 subjects with early MCI. Subjects were divided into training (70%) and validation (30%) sets. Subjects from the training set were analyzed using consensus clustering, and Gaussian Mixture Models (GMM) were used to describe the latent classes. The discovered GMM predicted the latent class of the validation set. Finally, descriptive statistics, rates of conversion, and Odds Ratios (OR) were computed for each discovered class.<br><br>RESULTS: Through consensus clustering, we discovered three different clusters among MCI subjects. The three clusters were associated with low-risk (OR = 0.12, 95%CI = 0.04 to 0.3|), medium-risk (OR = 1.33, 95%CI = 0.75 to 2.37), and high-risk (OR = 3.02, 95%CI = 1.64 to 5.57) of converting from MCI to AD, with the high-risk and low-risk groups highly contrasting. Hence, prodromal AD subjects were present in only two clusters.<br><br>CONCLUSION: We successfully discovered three different latent classes among MCI subjects with varied risks of MCI-to-AD conversion through consensus clustering. Two of the discovered classes may represent two different prodromal presentations of Alzheimer´s disease.},
}
@article {pmid34486652,
year = {2021},
author = {Kloske, CM and Dugan, AJ and Weekman, EM and Winder, Z and Patel, E and Nelson, PT and Fardo, DW and Wilcock, DM},
title = {Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status.},
journal = {Journal of neuropathology and experimental neurology},
volume = {80},
number = {10},
pages = {922-932},
pmid = {34486652},
issn = {1554-6578},
support = {P30 AG072946/AG/NIA NIH HHS/United States ; T32 AG057461/AG/NIA NIH HHS/United States ; P30-AG028383/AG/NIA NIH HHS/United States ; F31 AG069372/AG/NIA NIH HHS/United States ; RF1 AG057754/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/genetics/*metabolism/*pathology ; Apolipoproteins E/genetics/*metabolism ; Cohort Studies ; Female ; Humans ; Inflammation Mediators/*metabolism ; Male ; Microglia/pathology ; Protein Isoforms/genetics/metabolism ; Temporal Lobe/*metabolism/*pathology ; },
abstract = {Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.},
}
@article {pmid34484988,
year = {2021},
author = {Cardona, K and Medina, J and Orrego-Cardozo, M and Restrepo de Mejía, F and Elcoroaristizabal, X and Naranjo Galvis, CA},
title = {Inflammatory gene expression profiling in peripheral blood from patients with Alzheimer's disease reveals key pathways and hub genes with potential diagnostic utility: a preliminary study.},
journal = {PeerJ},
volume = {9},
number = {},
pages = {e12016},
pmid = {34484988},
issn = {2167-8359},
abstract = {BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disease caused by central nervous system disorders. Late-onset Alzheimer disease (LOAD) is the most common neurodegenerative disorder worldwide. Differences at the expression level of certain genes, resulting from either genetic variations or environmental interactions, might be one of the mechanisms underlying differential risks for developing AD. Peripheral blood genome transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tau for AD research.<br><br>METHODS: This preliminary study explores molecular pathogenesis of LOAD-related inflammation through next generation sequencing, to assess RNA expression profiles in peripheral blood from five patients with LOAD and 10 healthy controls.<br><br>RESULTS: The analysis of RNA expression profiles revealed 94 genes up-regulated and 147 down-regulated. Gene function analysis, including Gene Ontology (GO) and KOBAS-Kyoto Encyclopedia of DEGs and Genomes (KEGG) pathways indicated upregulation of interferon family (INF) signaling, while the down-regulated genes were mainly associated with the cell cycle process. KEGG metabolic pathways mapping showed gene expression alterations in the signaling pathways of JAK/STAT, chemokines, MAP kinases and Alzheimer disease. The results of this preliminary study provided not only a comprehensive picture of gene expression, but also the key processes associated with pathology for the regulation of neuroinflammation, to improve the current mechanisms to treat LOAD.},
}
@article {pmid34484963,
year = {2021},
author = {Venditto, JG and Bender, E and Lichtenstein, ML},
title = {Psychosis in a Middle-aged Woman: A Case of Presenilin-1 p.Gly206Ala Alzheimer Disease.},
journal = {Neurology. Clinical practice},
volume = {11},
number = {4},
pages = {e573-e575},
pmid = {34484963},
issn = {2163-0402},
}
@article {pmid34484950,
year = {2021},
author = {Moinuddin, O and Khandwala, NS and Young, KZ and Sathrasala, SK and Barmada, SJ and Albin, RL and Besirli, CG},
title = {Role of Optical Coherence Tomography in Identifying Retinal Biomarkers in Frontotemporal Dementia: A Review.},
journal = {Neurology. Clinical practice},
volume = {11},
number = {4},
pages = {e516-e523},
pmid = {34484950},
issn = {2163-0402},
support = {P30 AG072931/AG/NIA NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; },
abstract = {PURPOSE OF REVIEW: Frontotemporal dementia (FTD) is often misdiagnosed or recognized late. Clinical heterogeneity and overlap with other dementias impede accurate diagnosis. FTD biomarkers are limited, expensive, and invasive. We present a narrative review of the current literature focused on optical coherence tomography (OCT) to identify retinal biomarkers of dementia, discuss OCT findings in FTD, and explore the implications of an FTD-specific ocular biomarker for research and patient care.<br><br>RECENT FINDINGS: Recent studies suggest that outer retinal thinning detected via OCT may function as a novel ocular biomarker of FTD. The degree and rate of inner retinal thinning may correlate with disease severity and progression. In Alzheimer disease (AD), OCT demonstrates thinning of the inner retina, which may differentiate this condition from FTD. We conducted a comprehensive search of the literature and reviewed published OCT findings in FTD, AD, and mild cognitive impairment, as well as reports on biomarkers of FTD and AD used in the research and patient care settings. Three of the authors (O.M., N.S.K., and K.Z.Y.) independently conducted literature searches using PubMed to identify studies published before May 1, 2020, using the following search terminology: "Alzheimer's disease," "Alzheimer's dementia," "frontotemporal dementia," "FTD," "mild cognitive impairment," "dementia biomarkers," and "neurodegeneration biomarkers." Search results were then refined using one or more of the following keywords: "optical coherence tomography," "optical coherence tomography angiography," "retinal imaging," and "retinal thinning." The selection of published works for inclusion in this narrative review was then limited to full-text articles written in English based on consensus agreement of the authors.<br><br>SUMMARY: FTD diagnosis is imprecise, emphasizing the need for improved state and trait biomarkers. OCT imaging of the retina holds considerable potential for establishing effective ocular biomarkers for FTD.},
}
@article {pmid34484904,
year = {2021},
author = {Mahdavi, KD and Jordan, SE and Barrows, HR and Pravdic, M and Habelhah, B and Evans, NE and Blades, RB and Iovine, JJ and Becerra, SA and Steiner, RA and Chang, M and Kesari, S and Bystritsky, A and O'Connor, E and Gross, H and Pereles, FS and Whitney, M and Kuhn, T},
title = {Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor.},
journal = {Neurology. Clinical practice},
volume = {11},
number = {3},
pages = {e294-e302},
pmid = {34484904},
issn = {2163-0402},
abstract = {OBJECTIVE: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib.<br><br>METHODS: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline.<br><br>RESULTS: The present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances.<br><br>CONCLUSIONS: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.},
}
@article {pmid34484498,
year = {2021},
author = {Kaasalainen, S and Mccleary, L and Vellani, S and Pereira, J},
title = {Improving End-of-Life Care for People with Dementia in LTC Homes During the COVID-19 Pandemic and Beyond.},
journal = {Canadian geriatrics journal : CGJ},
volume = {24},
number = {3},
pages = {164-169},
pmid = {34484498},
issn = {1925-8348},
abstract = {COVID-19 pandemic has resulted in a significant increase in deaths in long-term care homes (LTCH). People with dementia living in LTCHs represent one of the most frail and marginalized populations in Canada. The surge of COVID-19 cases in LTCHs and rationing of health-care resources during the pandemic have amplified the pre-existing need for improvements in palliative and end-of-life care in LTCHs. This position statement, created by a task force commissioned by the Alzheimer Society of Canada, provides recommendations for a multipronged coordinated approach to improving palliative and end-of-life care of people with dementia living in LTCHs during the COVID-19 pandemic and beyond.},
}
@article {pmid34484054,
year = {2021},
author = {Wynn, MJ and Ju, CH and Hill, PL},
title = {Sense of Purpose Following a Dementia Diagnostic Appointment: Comparing Self- and Other-Reports of Care Recipients and Care Partners.},
journal = {Frontiers in psychology},
volume = {12},
number = {},
pages = {703478},
pmid = {34484054},
issn = {1664-1078},
abstract = {Objective: Purpose in life tends to decline in older adulthood and it is thought that intact cognitive functioning is required for purposeful living. Thus, it is likely that individuals may perceive older adults who are experiencing cognitive declines associated with dementia as having a reduced sense of purpose. Biases such as these may influence how individuals, especially care partners, interact with those with dementia. Method: This study examined how sense of purpose changed following a dementia diagnostic appointment for both the person receiving a diagnosis and their care partner. This study also explored how each individual perceived the other member of the dyad's sense of purpose. Older adults (47 care recipients and 75 care partners, 57% female; Mage = 68.5 years, SDage = 12.0 years) provided self- and other-report ratings of sense of purpose before and after their appointment at a specialized memory clinic. Results: Overall, both care recipients and care partners' sense of purpose declined following a dementia diagnostic appointment [t(85) = 7.01, p < 0.001]. However, when comparing self-reports and other-reports of purpose, care partners reported that care recipients experienced a lower sense of purpose in life than the care recipients reported about themselves. Conclusions: Care recipients and partners reported less purpose in life following their dementia diagnostic appointment. Care partners may hold certain biases regarding sense of purpose toward care recipients. These findings can inform future work regarding how care recipients and care partners can plan purposeful lives following a dementia diagnosis.},
}
@article {pmid34483835,
year = {2021},
author = {Contini, C and Olianas, A and Serrao, S and Deriu, C and Iavarone, F and Boroumand, M and Bizzarro, A and Lauria, A and Faa, G and Castagnola, M and Messana, I and Manconi, B and Masullo, C and Cabras, T},
title = {Corrigendum: Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {743596},
doi = {10.3389/fnins.2021.743596},
pmid = {34483835},
issn = {1662-4548},
abstract = {[This corrects the article DOI: 10.3389/fnins.2021.668852.].},
}
@article {pmid34482637,
year = {2021},
author = {Sanz-Blasco, R and Ruiz-Sánchez de León, JM and Ávila-Villanueva, M and Valentí-Soler, M and Gómez-Ramírez, J and Fernández-Blázquez, MA},
title = {Transition from mild cognitive impairment to normal cognition: Determining the predictors of reversion with multi-state Markov models.},
journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association},
volume = {},
number = {},
pages = {},
doi = {10.1002/alz.12448},
pmid = {34482637},
issn = {1552-5279},
support = {//Alzheimer's Disease Research Unit in Madrid/ ; //Spanish Ministry of Science, Innovation, and Universities/ ; //European Regional Development Fund/ ; //Fundación General de la Universidad de Salamanca (FGUSAL)/ ; //Centro Internacional sobre el Envejecimiento/ ; //Interreg V-A Programme, Spain-Portugal/ ; },
abstract = {INTRODUCTION: The theoretical framework of the Alzheimer's disease continuum considers transition between stages in a unidirectional manner. Here we examine the rate of reversion from mild cognitive impairment (MCI) to normal cognition (NC) and explore a set of potential variables associated with this phenomenon.<br><br>METHODS: A total of 985 Spanish community-dwelling individuals aged 70 years and over at baseline were monitored for 5 years. During this time, 173 MCI and 36 dementia cases were identified. Multi-state Markov models were performed to characterize transitions between states through the dementia continuum.<br><br>RESULTS: The rate of reversion from MCI to NC was 11%. There were significant non-modifiable (age, socioeconomic status, or apolipoprotein E) and modifiable factors (cognitive training or absence of affective symptoms) associated with reversion.<br><br>DISCUSSION: Overall, our results highlight that the likelihood of progression from MCI to dementia is very similar to that of reversion from MCI to NC.},
}
@article {pmid34480901,
year = {2021},
author = {Nies, SH and Takahashi, H and Herber, CS and Huttner, A and Chase, A and Strittmatter, SM},
title = {Spreading of Alzheimer tau seeds is enhanced by aging and template matching with limited impact of amyloid-β.},
journal = {The Journal of biological chemistry},
volume = {297},
number = {4},
pages = {101159},
doi = {10.1016/j.jbc.2021.101159},
pmid = {34480901},
issn = {1083-351X},
support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG034924/AG/NIA NIH HHS/United States ; R01 AG066165/AG/NIA NIH HHS/United States ; RF1 AG053000/AG/NIA NIH HHS/United States ; },
mesh = {Aging/genetics/*metabolism ; Alzheimer Disease/genetics/*metabolism ; Amyloid beta-Peptides/genetics/*metabolism ; Animals ; Cerebral Cortex/*metabolism ; Hippocampus/*metabolism ; Mice ; Mice, Knockout ; Neurites/*metabolism ; tau Proteins/genetics/*metabolism ; },
abstract = {In Alzheimer's disease (AD), deposition of pathological tau and amyloid-β (Aβ) drive synaptic loss and cognitive decline. The injection of misfolded tau aggregates extracted from human AD brains drives templated spreading of tau pathology within WT mouse brain. Here, we assessed the impact of Aβ copathology, of deleting loci known to modify AD risk (Ptk2b, Grn, and Tmem106b) and of pharmacological intervention with an Fyn kinase inhibitor on tau spreading after injection of AD tau extracts. The density and spreading of tau inclusions triggered by human tau seed were unaltered in the hippocampus and cortex of APPswe/PSEN1ΔE9 transgenic and AppNL-F/NL-F knock-in mice. In mice with human tau sequence replacing mouse tau, template matching enhanced neuritic tau burden. Human AD brain tau-enriched preparations contained aggregated Aβ, and the Aβ coinjection caused a redistribution of Aβ aggregates in mutant AD model mice. The injection-induced Aβ phenotype was spatially distinct from tau accumulation and could be ameliorated by depleting Aβ from tau extracts. These data suggest that Aβ and tau pathologies propagate by largely independent mechanisms after their initial formation. Altering the activity of the Fyn and Pyk2 (Ptk2b) kinases involved in Aβ-oligomer-induced signaling, or deleting expression of the progranulin and TMEM106B lysosomal proteins, did not alter the somatic tau inclusion burden or spreading. However, mouse aging had a prominent effect to increase the accumulation of neuritic tau after injection of human AD tau seeds i