@article {pmid34856171,
year = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.jamda.2021.10.018},
pmid = {34856171},
issn = {1538-9375},
abstract = {OBJECTIVES: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer 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: Mild to moderate probable AD patients 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},
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 = {2021},
author = {Chen, SX and Xiang, JY and Han, JX and Feng, Y 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 = {},
number = {},
pages = {},
doi = {10.1002/cbdv.202100443},
pmid = {34855291},
issn = {1612-1880},
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 IC 50 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 IC 50 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 (AlCl 3).},
}
@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},
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},
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},
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 = {},
number = {},
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},
doi = {10.1016/j.jcte.2021.100274},
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 = {},
doi = {10.1212/NXI.0000000000001106},
pmid = {34848502},
issn = {2332-7812},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.regg.2021.10.002},
pmid = {34848100},
issn = {1578-1747},
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 {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 AG055581/NH/NIH HHS/United States ; R01 AG056622/NH/NIH HHS/United States ; R01 AG073823/NH/NIH HHS/United States ; NIRG-15-362799/ALZ/Alzheimer's Association/United States ; A2017457S//BrightFocus Foundation/ ; },
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 {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},
doi = {10.1371/journal.pone.0260384},
pmid = {34847159},
issn = {1932-6203},
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34846582},
issn = {1590-3478},
support = {NRF-2018M3C7A1056571//National Research Foundation/ ; },
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 = {},
number = {},
pages = {},
doi = {10.1042/EBC20210025},
pmid = {34846514},
issn = {1744-1358},
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 = {2021},
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 = {},
number = {},
pages = {462612},
doi = {10.1016/j.chroma.2021.462612},
pmid = {34844738},
issn = {1873-3778},
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},
}
@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) 2021 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 = {},
doi = {10.3390/pharmacy9040189},
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},
doi = {10.1212/CPJ.0000000000001060},
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},
doi = {10.1212/CPJ.0000000000001102},
pmid = {34840862},
issn = {2163-0402},
}
@article {pmid34839903,
year = {2021},
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 = {},
number = {},
pages = {105056},
doi = {10.1016/j.compbiomed.2021.105056},
pmid = {34839903},
issn = {1879-0534},
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},
doi = {10.1080/21655979.2021.1989261},
pmid = {34839794},
issn = {2165-5987},
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},
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 = {},
doi = {10.3390/nu13114080},
pmid = {34836334},
issn = {2072-6643},
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 = {},
doi = {10.3390/molecules26226975},
pmid = {34834067},
issn = {1420-3049},
support = {PN-II-ID-PCE-2011-3-0300//National Council for Development and Innovation/ ; },
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 = {},
doi = {10.3390/medicina57111164},
pmid = {34833381},
issn = {1648-9144},
support = {80623//General Secretariat for Research and Technology/ ; 80623//ERGO AEBE INC, GR/ ; },
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 = {},
doi = {10.3390/ph14111136},
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 = {},
doi = {10.3390/cells10113064},
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/ ; },
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 = {},
doi = {10.3390/cells10112941},
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/ ; },
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 = {},
doi = {10.3390/ijms222212282},
pmid = {34830164},
issn = {1422-0067},
support = {2019/33/B/NZ7/02699//National Science Center/ ; DIR/WK/2017/01//Ministry of Science and Higher Education/ ; },
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 = {},
doi = {10.3390/ijms222212181},
pmid = {34830060},
issn = {1422-0067},
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 = {},
doi = {10.3390/antiox10111806},
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 = {},
doi = {10.3390/biom11111652},
pmid = {34827650},
issn = {2218-273X},
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 {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},
}
@article {pmid34825396,
year = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1111/nan.12781},
pmid = {34825396},
issn = {1365-2990},
}
@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},
doi = {10.1039/d1md00030f},
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 = {},
doi = {10.24966/and-9608/100055},
pmid = {34825129},
issn = {2572-9608},
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 {pmid34824471,
year = {2021},
author = {Cummings, J},
title = {Disease modification is not all - we need symptomatic therapies for Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34824471},
issn = {1759-4766},
}
@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/ ; },
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},
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/ ; },
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 {pmid34823269,
year = {2021},
author = {Kurz, C and Walker, L and Rauchmann, BS and Perneczky, R},
title = {Dysfunction of the blood-brain barrier in Alzheimer's disease: evidence from human studies.},
journal = {Neuropathology and applied neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1111/nan.12782},
pmid = {34823269},
issn = {1365-2990},
abstract = {The pathological processes leading to synapse loss, neuronal loss, brain atrophy and gliosis in Alzheimer´s disease (AD) and their relation to vascular disease and immunological changes are yet to be fully explored. Amyloid-β (Aβ) aggregation, vascular damage and altered immune response interact at the blood-brain-barrier (BBB), affecting the brain endothelium and fuelling neurodegeneration. The aim of the present systematic literature review was to critically appraise and to summarise the published evidence on the clinical correlations and pathophysiological concepts of BBB damage in AD, focusing on human data. The PubMed, Cochrane, Medline and Embase databases were searched for original research articles, systematic reviews and meta-analyses, published in English language from 01/2000 to 07/2021, using the keywords Alzheimer*, amyloid-β or β-amyloid or abeta and brain-blood barrier or BBB. This review shows that specific changes of intercellular structures, reduced expression of transendothelial carriers, induction of vasoactive mediators and activation of both astroglia and monocytes/macrophages characterise blood-brain barrier damage in human AD and AD models. BBB dysfunction on magnetic resonance imaging takes place early in the disease course in AD-specific brain regions. The toxic effects of Aβ and apolipoprotein E (ApoE) are likely to induce a non-cerebral-amyloid-angiopathy-related degeneration of endothelial cells, independently of cerebrovascular disease; however, some of the observed structural changes may just arise with age. Small vessel disease, ApoE, loss of pericytes, pro-inflammatory signalling and cerebral amyloid angiopathy enhance blood-brain-barrier damage. Novel therapeutic approaches for AD, including magnetic resonance-guided focused ultrasound, aim to open the BBB, potentially leading to an improved drainage of Aβ along perivascular channels and increased elimination from the brain. In vitro treatments with ApoE-modifying agents yielded promising effects on modulating BBB function. Reducing cardiovascular risk factors represents one of the most promising interventions for dementia prevention at present. However, further research is needed to elucidate the connection of BBB damage and tau pathology, the role of pro-inflammatory mediators in draining macromolecules and cells from the cerebral parenchyma, including their contribution to cerebral amyloid angiopathy. Improved insight into these pathomechanisms may allow to shed light on the role of Aβ deposition as a primary vs. a secondary event in the complex pathogenesis of AD.},
}
@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},
doi = {10.1001/jamanetworkopen.2021.36008},
pmid = {34817582},
issn = {2574-3805},
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},
doi = {10.1016/j.xpro.2021.100877},
pmid = {34816125},
issn = {2666-1667},
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34815562},
issn = {1471-0048},
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 {pmid34813500,
year = {2021},
author = {Wang, X and Allen, M and İş, Ö and Reddy, JS and Tutor-New, FQ and Castanedes Casey, M and Carrasquillo, MM and Oatman, SR and Min, Y and Asmann, YW and Funk, C and Nguyen, T and Ho, CC and Malphrus, KG and Seyfried, NT and Levey, AI and Younkin, SG and Murray, ME and Dickson, DW and Price, ND and Golde, TE and Ertekin-Taner, N},
title = {Alzheimer's disease and progressive supranuclear palsy share similar transcriptomic changes in distinct brain regions.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI149904},
pmid = {34813500},
issn = {1558-8238},
abstract = {Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer's disease (AD), however neither disease- nor brain region-specificity of these transcriptome alterations have been explored. Using RNA sequencing data from 231 temporal cortex and 224 cerebellum samples of patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identify a striking correlation in the directionality and magnitude of gene expression changes between these two neurodegenerative proteinopathies. Further, the transcriptome changes in AD and PSP are highly conserved between the temporal and cerebellar cortices, indicating highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or down-regulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of two distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex and ubiquitous molecular alterations in neurodegenerative diseases.},
}
@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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1111/nuf.12674},
pmid = {34812493},
issn = {1744-6198},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000013107},
pmid = {34810247},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVE: Patients with earlier age at onset of sporadic Alzheimer's Disease (AD) are more likely than those with later onset to present with atypical clinical and cognitive features. We sought to determine if this age-related clinical and cognitive heterogeneity is mediated by different topographical 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, TDP-43, and microvascular co-pathologies 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 pathological 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 non-memory complaints (OR=0.46 per decade, 95%CI: 0.22 - 0.88), psychiatric symptoms (β=-0.66, 95%CI: -1.15 - -0.17), and functional impairment (β=-1.25, 95%CI: -2.34 - -0.16). TDP-43 (OR = 2.00, 95%CI: 1.23 - 3.35) and microvascular co-pathology (OR = 2.02, 95%CI: 1.24 - 3.40) were more common in later onset AD, and α-synuclein co-pathology was not related to age at onset. NFT density in Midfrontal cortex (β = -0.51, 95% CI: -0.72 - -0.31) and Midfrontal/Hippocampal NFT ratio (β = -0.18, 95% CI: -0.26 - -0.10) were lower in those with later age at onset. Executive function (β = 0.48, 95% CI: 0.09 - 0.90) and visuospatial (β = 0.97, 95% CI: 0.46 - 1.46) cognitive deficits 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 {pmid34810241,
year = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000013109},
pmid = {34810241},
issn = {1526-632X},
abstract = {A physician's reflection upon caring for a patient with the medical complexities of Trisomy 21 and Alzheimer's disease, whom she diagnosed with epilepsy, and navigating that care after he contracted COVID-19.},
}
@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},
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},
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 = {2021},
author = {George, B and Gokhale, SD 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 = {},
number = {},
pages = {136357},
doi = {10.1016/j.neulet.2021.136357},
pmid = {34808269},
issn = {1872-7972},
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,GEOarchive 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 {pmid34807243,
year = {2021},
author = {Salloway, S and Chalkias, S and Barkhof, F and Burkett, P and Barakos, J and Purcell, D and Suhy, J and Forrestal, F and Tian, Y and Umans, K and Wang, G and Singhal, P and Budd Haeberlein, S and Smirnakis, K},
title = {Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.4161},
pmid = {34807243},
issn = {2168-6157},
abstract = {Importance: The EMERGE and ENGAGE phase 3 randomized clinical trials of aducanumab provide a robust data set to characterize amyloid-related imaging abnormalities (ARIA) that occur with treatment with aducanumab, an amyloid-β (Aβ)-targeting monoclonal antibody, in patients with mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease dementia.<br><br>Objective: To describe the radiographic and clinical characteristics of ARIA that occurred in EMERGE and ENGAGE.<br><br>Secondary analysis of data from the EMERGE and ENGAGE trials, which were 2 double-blind, placebo-controlled, parallel-group, phase 3 randomized clinical trials that compared low-dose and high-dose aducanumab treatment with placebo among participants at 348 sites across 20 countries. Enrollment occurred from August 2015 to July 2018, and the trials were terminated early (March 21, 2019) based on a futility analysis. The combined studies consisted of a total of 3285 participants with Alzheimer disease who received 1 or more doses of placebo (n = 1087) or aducanumab (n = 2198; 2752 total person-years of exposure) during the placebo-controlled period. Primary data analyses were performed from November 2019 to July 2020, with additional analyses performed through July 2021.<br><br>Interventions: Participants were randomly assigned 1:1:1 to high-dose or low-dose intravenous aducanumab or placebo once every 4 weeks. Dose titration was used as a risk-minimization strategy.<br><br>Main Outcomes and Measures: Brain magnetic resonance imaging was used to monitor patients for ARIA; associated symptoms were reported as adverse events.<br><br>Results: Of 3285 included participants, the mean (SD) age was 70.4 (7.45) years; 1706 participants (52%) were female, 2661 (81%) had mild cognitive impairment due to Alzheimer disease, and 1777 (54%) used symptomatic medications for Alzheimer disease. A total of 764 participants from EMERGE and 709 participants from ENGAGE were categorized as withdrawn before study completion, most often owing to early termination of the study by the sponsor. Unless otherwise specified, all results represent analyses from the 10-mg/kg group. During the placebo-controlled period, 425 of 1029 patients (41.3%) experienced ARIA, with serious cases occurring in 14 patients (1.4%). ARIA-edema (ARIA-E) was the most common adverse event (362 of 1029 [35.2%]), and 263 initial events (72.7%) occurred within the first 8 doses of aducanumab; 94 participants (26.0%) with an event exhibited symptoms. Common associated symptoms among 103 patients with symptomatic ARIA-E or ARIA-H were headache (48 [46.6%]), confusion (15 [14.6%]), dizziness (11 [10.7%]), and nausea (8 [7.8%]). Incidence of ARIA-E was highest in aducanumab-treated participants who were apolipoprotein E ε4 allele carriers. Most events (479 of 488 [98.2%]) among those with ARIA-E resolved radiographically; 404 of 488 (82.8%) resolved within 16 weeks. In the placebo group, 29 of 1076 participants (2.7%) had ARIA-E (apolipoprotein E ε4 carriers: 16 of 742 [2.2%]; noncarriers, 13 of 334 [3.9%]). ARIA-microhemorrhage and ARIA-superficial siderosis occurred in 197 participants (19.1%) and 151 participants (14.7%), respectively.<br><br>Conclusions and Relevance: In this integrated safety data set from EMERGE and ENGAGE, the most common adverse event in the 10-mg/kg group was ARIA-E, which occurred in 362 of the 1029 patients (35.2%) in the 10-mg/kg group with at least 1 postbaseline MRI scan, with 94 patients (26.0%) experiencing associated symptoms. The most common associated symptom was headache.<br><br>Trial Registrations: ClinicalTrials.gov Identifiers: NCT02484547, NCT02477800.},
}
@article {pmid34807233,
year = {2021},
author = {Gonzalez, MC and Ashton, NJ and Gomes, BF and Tovar-Rios, DA and Blanc, F and Karikari, TK and Mollenhauer, B and Pilotto, A and Lemstra, A and Paquet, C and Abdelnour, C and Kramberger, MG and Bonanni, L and Vandenberghe, R and Hye, A and Blennow, K and Zetterberg, H and Aarsland, D and , },
title = {Association of Plasma p-tau181 and p-tau231 Concentrations With Cognitive Decline in Patients With Probable Dementia With Lewy Bodies.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.4222},
pmid = {34807233},
issn = {2168-6157},
abstract = {Importance: Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder.<br><br>Objective: To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB.<br><br>This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205).<br><br>Main Outcomes and Measures: The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition.<br><br>Results: Among this cohort of 987 patients (512 men [51.9%]; mean [SD] age, 70.0 [8.8] years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, -3.61 pg/mL; 95% CI, -5.43 to -1.79 pg/mL; P = .049; difference in the groups in p-tau231, -2.51 pg/mL; 95% CI, -3.63 to -1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, -0.092 MMSE points; 95% CI, -0.12 to -0.06 MMSE points; P = .001; for p-tau231, -0.16 MMSE points; 95% CI, -0.21 to -0.12 MMSE points; P < .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of -0.094 MMSE points per year (95% CI, -0.144 to -0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of -0.130 MMSE points (95% CI, -0.201 to -0.071 MMSE points; P = .02), after adjusting for sex and age.<br><br>Conclusions and Relevance: This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.},
}
@article {pmid34806610,
year = {2021},
author = {Ruiz-Adame, M},
title = {A Systematic Review of the Indirect and Social Costs for Early and Young Onset Dementias.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-215204},
pmid = {34806610},
issn = {1875-8908},
abstract = {BACKGROUND: The World Health Organization has estimated that worldwide around 50 million people have dementia. The World Alzheimer Report estimated that between 2 and 10% of all cases of dementia begin before the age of 65. Early and young onset dementias (EYOD) provoke more working, social, family, and economic consequences than late onset dementias. All general studies about costs of dementias show that most of them are indirect or social costs. Despite that, very few studies have been performed in EYOD.<br><br>OBJECTIVE: To do a systematic review of literature about indirect or social costs in EYOD to know the state of knowledge and to discover gaps that should be filled.<br><br>METHODS: A systematic review was performed in the main database: Scopus, PsychInfo, Web of Science (Web of Science Core Collection, Medline and SciELO), and CINAHL. Additionally, we looked for reviews in Cochrane and in the International Prospective Register Of Systematic Reviews (PROSPERO).<br><br>RESULTS: Most of the studies are about costs of dementias in general, but they do no differentiate costs for the case of EYOD. Many studies highlight the increased costs for EYOD but very little included evidence of that. 135 papers were selected. Finally, only two were studies providing data. EYOD reduce the odds to get or maintain a job. Most of the care is provided by informal caregivers. The costs in EYOD are 39.26% higher among EYOD than in late onset.<br><br>CONCLUSION: There is a lack of studies about social and indirect costs in EYOD. More evidence is needed.},
}
@article {pmid34801832,
year = {2021},
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},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1111/ene.15190},
pmid = {34797599},
issn = {1468-1331},
abstract = {BACKGROUND: The causal effect of insulin resistance on small vessel stroke and Alzheimer Disease was controversial in previous studies. We therefore applied Mendelian randomization (MR) analyses to identify causal effect of insulin resistance on small vessel stroke and Alzheimer's disease (AD).<br><br>METHODS: We selected 12 single-nucleotide polymorphisms (SNPs) associated with fasting insulin levels and 5 SNPs associated with gold standard measures of insulin resistance as instrumental variables in MR analyses. Summary statistical data of SNP-small vessel stroke and of SNP-AD associations were derived from the MEGASTROKE and PGC-ALZ of 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 methods.<br><br>RESULTS: Genetically predicted higher insulin resistance had a higher odds ratio (OR) of small vessel stroke [OR 1.23; 95% confidence intervals (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 measure 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 a genetic support for 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},
doi = {10.1097/MD.0000000000027686},
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/ ; },
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 {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},
doi = {10.1001/jamanetworkopen.2021.35168},
pmid = {34792590},
issn = {2574-3805},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1002/mrm.29088},
pmid = {34792198},
issn = {1522-2594},
support = {ACI- 1550405//National Science Foundation/ ; MRP17454755//University of California MPRI/ ; DGE-1650112//National Science Foundation Graduate Research Fellowship Program/ ; DGE-2038238//National Science Foundation Graduate Research Fellowship Program/ ; R01 AR070830/AR/NIAMS NIH HHS/United States ; RO1 AG054049//National Institute of Health/ ; RO1 HD088437//National Institute of Health/ ; },
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 Ricard, A and Henry, E and Silvia, V},
title = {Connectivity and Patterns of Regional Cerebral Blood Flow, Cerebral Glu- cose Uptake, and Aβ-Amyloid Deposition in Alzheimer's Disease (Early and Late-Onset) Compared to Normal Ageing.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/1567205018666211116095035},
pmid = {34784866},
issn = {1875-5828},
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 im- ages 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 in- creased at the mesial frontal and temporal cortex. There was a mild increase in an amyloid deposi- tion 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 be- tween 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-beta and cognition.},
journal = {JCI insight},
volume = {},
number = {},
pages = {},
doi = {10.1172/jci.insight.152858},
pmid = {34784296},
issn = {2379-3708},
abstract = {BACKGROUND: Tight relationships between sleep quality, cognition and amyloid-beta (Aβ) accumulation, a hallmark of Alzheimer's disease (AD) neuropathology, emerge in the literature. Sleep arousals become more prevalent with ageing and are considered to reflect poorer sleep quality. Yet, heterogeneity in arousals has been suggested while their associations with Aβ and cognition are not established.<br><br>METHODS: We recorded undisturbed night-time sleep with EEG in 101 healthy individuals in late midlife (50-70y), 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 cognition via extensive neuropsychological testing.<br><br>RESULTS: Arousal types differed in their oscillatory composition in theta and beta EEG bands. Furthermore, T+M- arousals, which interrupt sleep continuity, were positively linked to Aβ burden (p=.0053, R²β*=0.08). By contrast, more prevalent T-M+ arousals, upholding sleep continuity, were associated with lower Aβ burden (p=.0003, R²β*=0.13), and better cognition, particularly over the attentional domain (p<.05, R²β*≥0.04).<br><br>CONCLUSION: Contrasting 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. This warrants re-evaluation of age-related sleep changes and suggests that spontaneous arousals could constitute a marker of favourable brain and cognitive health trajectories.<br><br>TRIAL REGISTRATION: EudraCT 2016-001436-35.<br><br>FUNDING: This work was supported by Fonds National de la Recherche Scientifique (FRS-FNRS, FRSM 3.4516.11, Belgium), Actions de Recherche Concertées (ARC SLEEPDEM 17/27-09) of the Fédération Wallonie-Bruxelles, University of Liège (ULiège), Fondation Simone et Pierre Clerdent, European Regional Development Fund (ERDF, Radiomed Project). [18F]Flutemetamol doses were provided and cost covered by GE Healthcare Ltd (Little Chalfont, UK) as part of an investigator sponsored study (ISS290) agreement. This agreement had no influence on the protocol and results of the study reported here. M.V.E., C.B., F.C., C.P., and G.V. are/were supported by the F.R.S.-FNRS Belgium. C. B., P. B. and M. B. are owners of Physip, the company that analysed the EEG data as part of a collaboration. This ownership and the collaboration had no impact on the design, data acquisition and interpretations of the findings.},
}
@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},
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 = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.1c01318},
pmid = {34779640},
issn = {1520-4804},
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 {pmid34779370,
year = {2021},
author = {Singh, B and Singh, H and Singh, B and Kumar, N and Rajput, A and Sidhu, D and Kaur, A and Arora, S and Kaur, S},
title = {A comprehensive review on medicinal herbs and novel formulations for the prevention of Alzheimer's disease.},
journal = {Current drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.2174/1567201818666211015152733},
pmid = {34779370},
issn = {1875-5704},
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases reported in the aging population across the globe. About 46.8 million people are reported to have dementia, and AD is mainly responsible for dementia in aged people. Alzheimer's disease (AD) is thought to occur due to the accumulation of β-amyloid (Aβ) in the neocortex portion of the brain, nitric oxide mediated dysfunctioning of blood-brain barrier, reduced activity of serine racemase enzyme, cell cycle disturbances, damage of N-methyl-D-aspartate (NMDA) receptors and glutamatergic neurotransmission. Modern treatment methods target the pathways responsible for the disease. To date, solely symptomatic treatments exist for this disease, all making an attempt to counterbalance the neurotransmitter disturbance. Treatments able to prevent or at least effectively modifying the course of AD, referred to as 'disease-modifying' drugs, are still under extensive research. Effective treatments entail a better indulgence of the herbal bioactives by novel drug delivery systems. The herbal bioactive administered by novel drug delivery systems have proved beneficial in treating this disease. This review provides detailed information about the role of medicinal plants and their formulations in treating Alzheimer disease which will be highly beneficial for the researchers working in this area.},
}
@article {pmid34775786,
year = {2021},
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 = {},
number = {},
pages = {HYPERTENSIONAHA12117283},
doi = {10.1161/HYPERTENSIONAHA.121.17283},
pmid = {34775786},
issn = {1524-4563},
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 = {},
number = {},
pages = {e13514},
doi = {10.1111/acel.13514},
pmid = {34775673},
issn = {1474-9726},
support = {81673134//National Natural Science Foundation of China/ ; 81171191//National Natural Science Foundation of China/ ; 2018B030336001//Guangdong Provincial Key S&amp;T Program/ ; JCYJ20170810163329510//Grants Science and Technology Innovation Committee of Shenzhen/ ; JCYJ20180507182417779//Grants Science and Technology Innovation Committee of Shenzhen/ ; 2019SHIBS0004//Shenzhen-Hong Kong Institute of Brain Science/ ; SZSM201911003//Sanming Project of Medicine in Shenzhen/ ; SZXK06162//Shenzhen Key Medical Discipline Construction Fund/ ; SZBL20190 62801003//Shenzhen bay laboratory/ ; },
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 = {2021},
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},
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 = {},
doi = {10.3390/ma14216291},
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 = {},
doi = {10.3390/molecules26216531},
pmid = {34770940},
issn = {1420-3049},
support = {AFB-170005//Agencia Nacional de Investigación y Desarrollo/ ; },
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 = {},
doi = {10.3390/ijerph182111568},
pmid = {34770082},
issn = {1660-4601},
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 = {},
doi = {10.3390/ijms222111550},
pmid = {34768981},
issn = {1422-0067},
support = {//H2020 SME Phase 1/ ; },
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 = {},
doi = {10.3390/jcm10214932},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2021.10.009},
pmid = {34767756},
issn = {1537-6605},
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 {pmid34766515,
year = {2021},
author = {Gu, Q and Xu, F and Orgil, BO and Khuchua, Z and Munkhsaikhan, U and Johnson, JN and Alberson, NR and Pierre, JF and Black, DD and Dong, D and Brennan, JA and Cathey, BM and Efimov, IR and Towbin, JA and Purevjav, E and Lu, L},
title = {Systems Genetics Analysis Defines Importance Of TMEM43/LUMA For Cardiac And Metabolic Related Pathways.},
journal = {Physiological genomics},
volume = {},
number = {},
pages = {},
doi = {10.1152/physiolgenomics.00066.2021},
pmid = {34766515},
issn = {1531-2267},
support = {HL128350//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HL151438//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; CORNET//UTHSC/ ; },
abstract = {BACKGROUND: Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/LUMA).<br><br>OBJECTIVE: The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes and up- or down-stream regulators.<br><br>METHODS: Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) was applied for genetic correlation, functional enrichment and co-expression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans.<br><br>RESULTS: We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, while levels of Tmem43 highly positively correlated with plasma high density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, Hypertrophic cardiomyopathy, Dilated cardiomyopathy, Non-alcoholic fatty liver disease, Alzheimer disease, Parkinson disease and Huntington disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6 and Uqcrc2 were significantly altered in Tmem43S358L mice vs Tmem43WT controls.<br><br>CONCLUSIONS: Our study defined the importance of Tmem43 for cardiac and metabolism related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.},
}
@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},
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 = {2021},
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 = {},
number = {},
pages = {appineuropsych21040114},
doi = {10.1176/appi.neuropsych.21040114},
pmid = {34763525},
issn = {1545-7222},
}
@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 = {},
number = {},
pages = {105973},
doi = {10.1016/j.phrs.2021.105973},
pmid = {34763094},
issn = {1096-1186},
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 = {2021},
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 = {},
number = {},
pages = {},
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/ ; },
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 = {2021},
author = {Nassan, M and Videnovic, A},
title = {Circadian rhythms in neurodegenerative disorders.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34759373},
issn = {1759-4766},
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 = {},
doi = {10.1212/NXI.0000000000001103},
pmid = {34759019},
issn = {2332-7812},
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 {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 {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 = {2021},
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 = {},
number = {},
pages = {e22953},
doi = {10.1002/jbt.22953},
pmid = {34757642},
issn = {1099-0461},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1089/met.2021.0046},
pmid = {34756135},
issn = {1557-8518},
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 Ravichandran, 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 = {},
number = {},
pages = {},
doi = {10.1080/14737175.2021.2003705},
pmid = {34756134},
issn = {1744-8360},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1111/ggi.14304},
pmid = {34755432},
issn = {1447-0594},
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 2021; ••: ••-••.},
}
@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},
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},
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},
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34750588},
issn = {1759-4766},
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 {pmid34748685,
year = {2021},
author = {Xiang, S and Wagner, J and Lückerath, T and Müllen, K and Ng, DYW and Hedrich, J and Weil, T},
title = {Reversing Aβ Fibrillation and Inhibiting Aβ Primary Neuronal Cell Toxicity using Amphiphilic Polyphenylene Dendrons.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e2101854},
doi = {10.1002/adhm.202101854},
pmid = {34748685},
issn = {2192-2659},
abstract = {xxxx. This article is protected by copyright. All rights reserved.},
}
@article {pmid34740867,
year = {2021},
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 = {},
number = {},
pages = {101508},
doi = {10.1016/j.arr.2021.101508},
pmid = {34740867},
issn = {1872-9649},
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 be considered for a preventive intervention.},
}
@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},
support = {2016M3C7A1914123//ministry of education, science and technology/ ; },
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 {pmid34739400,
year = {2021},
author = {Rudolphi-Solero, T and Triviño Ibáñez, EM and Aroui, T and Navidad, RH and Gómez-Río, M},
title = {Dual-Phase 18F-Florbetaben PET/CT: Unsuspected Thalamic Infarction Mimicking Alzheimer Disease.},
journal = {Clinical nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/RLU.0000000000003955},
pmid = {34739400},
issn = {1536-0229},
abstract = {ABSTRACT: Dual-phase amyloid PET is considered a useful protocol to study patients with cognitive impairment. Early-phase 18F-florbetaben PET/CT has been proposed as a surrogate of 18F-FDG PET/CT providing information related to regional brain perfusion. We report the case of a 61-year-old woman referred to the cognitive impairment unit for study, preliminary diagnosed as probable Alzheimer disease. The dual-phase 18F-florbetaben PET/CT was shown as the main finding, no uptake in the left anterior thalamus. Memory and language symptoms have been described as primary clinical features of anterior thalamic infarctions that could be confused with the main manifestations of Alzheimer disease.},
}
@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 = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2021.10.036},
pmid = {34737037},
issn = {1873-4596},
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 = {2021},
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},
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},
doi = {10.12788/fp.0159},
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},
doi = {10.1177/09727531211046369},
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 {pmid34729858,
year = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1002/hbm.25605},
pmid = {34729858},
issn = {1097-0193},
support = {Ricerca Finalizzata Progetto Reti Nazionale AD NET-2011-02346784//Italian Ministry of Health/ ; 320030_169876/SNSF_/Swiss National Science Foundation/Switzerland ; 320030_185028/SNSF_/Swiss National Science Foundation/Switzerland ; 1123//Velux foundation/ ; },
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 {pmid34728295,
year = {2021},
author = {Knorr, U and Simonsen, AH and Jensen, CS and Zetterberg, H and Blennow, K and Akhøj, M and Forman, J and Hasselbalch, SG and Kessing, LV},
title = {Alzheimer´s disease related biomarkers in bipolar disorder - a longitudinal one-year case-control study.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jad.2021.10.074},
pmid = {34728295},
issn = {1573-2517},
abstract = {INTRODUCTION: Bipolar disorder (BD) is a heterogeneous mental disorder characterized by recurrent relapses of affective episodes: Subgroups of patients with BD have cognitive deficits, and an increased risk of dementia.<br><br>METHODS: This prospective, longitudinal, one-year follow-up, case-control study investigated biomarkers for AD and neurodegenerative diseases, namely: cerebrospinal fluid (CSF) amyloid beta (Aβ) isoforms and ratios (Aβ42, Aβ40, Aβ38), CSF soluble amyloid precursor protein (sAPP) α and β, CSF total (t-tau) and phosphorylated tau (p-tau), CSF neurofilament-light (NF-L), CSF neurogranin (NG), plasma-isoforms Aβ42 and Aβ40, plasma-tau, plasma-NF-L, and serum S100B, in patients with BD (N = 62, aged 18-60) and gender-and-age-matched healthy control individuals (N = 40). CSF and plasma/serum samples were collected at baseline, during and after an affective episode, if it occurred, and after a year. Data were analyzed in mixed models.<br><br>RESULTS: Levels of CSF Aβ42 decreased in patients with BD who had an episode during follow-up (BD-E) (N = 22) compared to patients without an episode (BD-NE) (N = 25) during follow-up (P = 0.002). Stable levels were seen for all other markers in BD-E compared to BD-NE during the one-year follow-up. We found no statistically significant differences between patients with BD and HC at T0 and T3 for Aβ42, Aβ40, Aβ38, Aβ42/38, Aβ42/40, sAPPα, sAPPβ, t-tau, p-tau, p-tau /t-tau, NF-L, NG in CSF and further Aβ40, Aβ42, Aβ42/40, t-tau, NF-L in plasma, S100B in serum, and APOE-status. Furthermore, all 18 biomarkers were stable in HC during the one-year follow-up from T0 to T3.<br><br>CONCLUSION: A panel of biomarkers of Alzheimer's and neurodegeneration show no differences between patients with BD and HC. There were abnormalities of amyloid production/clearance during an acute BD episode. The abnormalities mimic the pattern seen in AD namely decreasing CSF Aβ42 and may suggest an association with brain amyloidosis.},
}
@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 {pmid34725788,
year = {2021},
author = {Xu, X and Sun, Y and Cen, X and Shan, B and Zhao, Q and Xie, T and Wang, Z and Hou, T and Xue, Y and Zhang, M and Peng, D and Sun, Q and Yi, C and Najafov, A and Xia, H},
title = {Correction to: Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model.},
journal = {Protein &amp; cell},
volume = {},
number = {},
pages = {},
doi = {10.1007/s13238-021-00873-4},
pmid = {34725788},
issn = {1674-8018},
}
@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 = {},
number = {},
pages = {},
pmid = {34725519},
issn = {1471-0048},
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 = {},
number = {},
pages = {},
doi = {10.30802/AALAS-JAALAS-21-000011},
pmid = {34725027},
issn = {1559-6109},
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 {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},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1515/hsz-2021-0330},
pmid = {34619027},
issn = {1437-4315},
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 {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},
doi = {10.3389/fcell.2021.737426},
pmid = {34722519},
issn = {2296-634X},
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},
doi = {10.1159/000518922},
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34719771},
issn = {1573-7365},
support = {SWU Grant 5330500183//Southwest University/ ; },
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34719765},
issn = {1432-0533},
support = {R01 AG054008/NH/NIH HHS/United States ; R01 NS095252/NH/NIH HHS/United States ; R01 AG060961/NH/NIH HHS/United States ; R01 NS086736/NH/NIH HHS/United States ; F32 AG056098/NH/NIH HHS/United States ; P30 AG066514/NH/NIH HHS/United States ; P50 AG005138/NH/NIH HHS/United States ; P30 AG066514/NH/NIH HHS/United States ; 75N95019C00049/NH/NIH HHS/United States ; K99 AG070109/NH/NIH HHS/United States ; R01 AG062348/NH/NIH HHS/United States ; P50 AG008702/NH/NIH HHS/United States ; U54 NS115266/NH/NIH HHS/United States ; R01 CA079830/NH/NIH HHS/United States ; P30 AG010124/NH/NIH HHS/United States ; P01 AG017586/NH/NIH HHS/United States ; U19 AG062418/NH/NIH HHS/United States ; P30 AG072979/NH/NIH HHS/United States ; P01 AG066597/NH/NIH HHS/United States ; R01 AG066152/NH/NIH HHS/United States ; R01 AG066152/NH/NIH HHS/United States ; P30 AG066468/NH/NIH HHS/United States ; U24 NS072026/NH/NIH HHS/United States ; P30 AG019610/NH/NIH HHS/United States ; P30 AG013854/NH/NIH HHS/United States ; P30 NS055077/NH/NIH HHS/United States ; P50 AG025688/NH/NIH HHS/United States ; P30 AG08017/NH/NIH HHS/United States ; R01 AG059848/NH/NIH HHS/United States ; P50 AG05134/NH/NIH HHS/United States ; AG10161/NH/NIH HHS/United States ; R01 AG021055/NH/NIH HHS/United States ; P50 AG016573/NH/NIH HHS/United States ; P01 AG000538/NH/NIH HHS/United States ; P30 AG062429/NH/NIH HHS/United States ; P50 AG005131/NH/NIH HHS/United States ; P30 AG028383/NH/NIH HHS/United States ; P50 AG005136/NH/NIH HHS/United States ; P30 AG066509/NH/NIH HHS/United States ; U01 AG006781/NH/NIH HHS/United States ; U19 066567/NH/NIH HHS/United States ; P30 AG066444/NH/NIH HHS/United States ; P01 AG003991/NH/NIH HHS/United States ; P01 AG026276/NH/NIH HHS/United States ; P01AG000538/NH/NIH HHS/United States ; G0400074//UK Medical Research Council/ ; },
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},
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},
doi = {10.3389/fdgth.2021.686068},
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 {pmid34713027,
year = {2020},
author = {Baker, E and Escott-Price, V},
title = {Polygenic Risk Scores in Alzheimer's Disease: Current Applications and Future Directions.},
journal = {Frontiers in digital health},
volume = {2},
number = {},
pages = {14},
doi = {10.3389/fdgth.2020.00014},
pmid = {34713027},
issn = {2673-253X},
abstract = {Genome-wide association studies have identified nearly 40 genome-wide significant single nucleotide polymorphisms (SNPs) which are associated with Alzheimer's Disease (AD). Due to the polygenicity of AD, polygenic risk scores (PRS) have shown high potential for AD risk prediction. PRSs have been shown to successfully discriminate between AD cases and controls achieving a prediction accuracy of up to 84% based on area under the receiver operating curve. The prediction accuracy in AD is higher compared with other complex genetic disorders. PRS can be restricted to SNPs which reside in biologically relevant gene-sets; the predictive value of these gene-sets in the general population is not as high as genome-wide PRS, but they may play an important role to identify mechanisms of disease development and inform biological experiments. Multiple methods are available to derive PRSs, such as selecting SNPs based on statistical evidence of association with the disease or using prior evidence for SNP selection. All methods have advantages, but PRS produced using different methodologies are often not comparable, and results should be interpreted with care. Similarly, this is true when PRS is based on different background populations. With the exponential growth in development of digital electronic devices it is easy to calculate an individual's disease risk using public databases. A major limitation for the utility of PRSs is that the risk score is sample and method dependent. Therefore, replicability and interpretability of PRS is an important issue. PRS can be used to determine the probability of developing disease which incorporates information about disease risk in the general population or in a specific AD risk group. It is essential to consult with genetic counselors to ensure genetic risk is communicated appropriately.},
}
@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 = {},
number = {},
pages = {ATVBAHA121316477},
doi = {10.1161/ATVBAHA.121.316477},
pmid = {34706559},
issn = {1524-4636},
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 = {2021},
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},
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 = {undefined},
pages = {},
doi = {10.18632/aging.203652},
pmid = {34705667},
issn = {1945-4589},
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},
doi = {10.1093/braincomms/fcab144},
pmid = {34704025},
issn = {2632-1297},
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},
doi = {10.17245/jdapm.2021.21.5.461},
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},
doi = {10.1159/000518469},
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34703027},
issn = {1759-5037},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.amepre.2021.07.020},
pmid = {34702606},
issn = {1873-2607},
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 = {2021},
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},
doi = {10.1016/j.neurobiolaging.2021.09.015},
pmid = {34700200},
issn = {1558-1497},
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 {pmid34699606,
year = {2021},
author = {Zhang, H and Yang, M and Wang, X and Wei, H and Du, M and Wang, M and Wang, J and Chen, Z and Peng, C and Liu, R},
title = {Zinc induces reactive astrogliosis through ERK dependent activation of Stat3 and promotes synaptic degeneration.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.15531},
pmid = {34699606},
issn = {1471-4159},
abstract = {Reactive astrogliosis is an early event in Alzheimer disease (AD) brain and play a key role in synaptic degeneration in AD development. Zinc accumulates in extracellular fraction and synaptosomes in AD human brains with its effect on reactive astrocytes remaining unknown. Through Western blotting, Quantitative polymerase chain reaction (qPCR) and immunofluorescence detection on primary astrocytes treated by zinc and/or zinc chelator, we revealed that zinc induced harmful A1 type reactive astrogliosis in cultured primary astrocytes; the latter, promoted synaptic degeneration in primary neurons. The mechanism investigation showed that zinc induced activation of extracellular regulated protein kinases (ERK) and Janus kinase 2 (JAK2), which phosphorylated signal transduction and transcription activator 3 (Stat3) at serine 727 (S727-Stat3) and tyrosine 705 (Y705-Stat3) respectively, resulting in activation of Stat3. Stat3 phosphorylation at S727 by ERK plays a key role in zinc-induced astrogliosis. These data imply a new molecular mechanism of reactive astrogliosis in AD in which excessive zinc activates Stat3 through upregulating ERK signaling pathway.},
}
@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},
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 {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 = {},
number = {},
pages = {108208},
doi = {10.1016/j.biopsycho.2021.108208},
pmid = {34688826},
issn = {1873-6246},
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 {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 = {1R21AG066012-01A11//National Institute on Aging/ ; R01AG059689-01A1//National Institute on Aging/ ; 2020-28-25-II//Texas Alzheimer's Research and Care Consortium/ ; 2018-191983//Chan Zuckerburg Initiative/ ; },
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 {pmid34695453,
year = {2021},
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 = {},
number = {},
pages = {136303},
doi = {10.1016/j.neulet.2021.136303},
pmid = {34695453},
issn = {1872-7972},
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 = {},
number = {},
pages = {147701},
doi = {10.1016/j.brainres.2021.147701},
pmid = {34695393},
issn = {1872-6240},
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 = {},
number = {},
pages = {},
doi = {10.1021/acs.langmuir.1c02407},
pmid = {34694126},
issn = {1520-5827},
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},
doi = {10.9758/cpn.2021.19.4.640},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1111/acps.13380},
pmid = {34689322},
issn = {1600-0447},
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 three 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 three years, ever use of SGA and SGA treatments of more than three 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 {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},
}
@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},
doi = {10.1001/jamanetworkopen.2021.29392},
pmid = {34677596},
issn = {2574-3805},
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 {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 = {},
number = {},
pages = {},
doi = {10.1002/jdn.10153},
pmid = {34687079},
issn = {1873-474X},
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 = {},
doi = {10.3390/cells10102748},
pmid = {34685728},
issn = {2073-4409},
support = {386893015//Deutsche Forschungsgemeinschaft/ ; VH-NG-1021//German Center for Neurodegenerative Diseases/ ; Schaefer Research Scholars Awards//Columbia University Medical Center/ ; R56AG069118//National Institute of Health/ ; R56AG066889//National Institute of Health/ ; R56AG051876//National Institute of Health/ ; R01AG067501//National Institute of Health/ ; },
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 = {},
doi = {10.3390/nano11102658},
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 = {},
doi = {10.3390/pharmaceutics13101635},
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 = {},
doi = {10.3390/pharmaceutics13101555},
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 = {},
doi = {10.3390/jpm11100990},
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 = {},
doi = {10.3390/ijerph182010707},
pmid = {34682452},
issn = {1660-4601},
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 = {},
doi = {10.3390/ijms222011106},
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/ ; },
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 = {},
doi = {10.3390/ijms222010907},
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/ ; },
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 = {},
doi = {10.3390/diagnostics11101888},
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 {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 = {},
number = {},
pages = {},
doi = {10.1093/brain/awab272},
pmid = {34668959},
issn = {1460-2156},
support = {P01 AG03991, P01 AG026276, P30 AG066444, K76 AG054863, UL1 TR000448, KL2 TR000450, R01 AG052550, and R01 AG057680/NH/NIH HHS/United States ; //A Physician Scientist Training Award from the American Sleep Medicine Foundation and support from the Roger and Paula Riney Fund and the Daniel J. Brennan, MD Fund/ ; },
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34668150},
issn = {1559-1166},
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 {pmid34654271,
year = {2018},
author = {Houston, A and Mulkerrin, EC and O'Keeffe, ST},
title = {The de-alzheimerisation of dementia? An analysis of internet searches.},
journal = {European geriatric medicine},
volume = {9},
number = {1},
pages = {117-120},
pmid = {34654271},
issn = {1878-7649},
abstract = {PURPOSE: Alzheimer's disease is often seen by the public as synonymous with dementia but this may have changed in recent years.<br><br>METHODS: We used Google Trends to examine the relative volume of internet searches from 2004 to July 2017 for the terms 'dementia' and 'Alzheimer' in English-speaking countries. For each country, a linear regression model was fitted for each search term and the slopes of the lines were compared.<br><br>RESULTS: The slopes (standard error) for 'dementia' and 'Alzheimer', respectively, were: Australia-0.26 (0.02) and - 001 (0.002); Canada-0.23 (0.01) and 0.004 (0.01); Ireland: 0.33 (0.02) and - 0.04 (0.01); United Kingdom-0.36 (0.01) and 0.01 (0.001); and United States-0.23 (0.01) and - 0.01 (0.004). Differences between slopes were all significant at p < 0.001.<br><br>CONCLUSIONS: In all countries, there was a large increase over time in relative search volumes for 'dementia' and a flat or negative trend in searches for 'Alzheimer'.},
}
@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},
support = {2018-02181//Swedish Research Council/Vetenskapsrådet/ ; AF-939767//Swedish Alzheimer Foundation/ ; },
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},
doi = {10.1097/MD.0000000000027218},
pmid = {34664858},
issn = {1536-5964},
support = {KSN2021240, HB16C0044//Korea National Institute of Health/ ; },
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.biopsych.2021.08.021},
pmid = {34663503},
issn = {1873-2402},
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% confidence interval 1.20-2.34), and conscientiousness was associated with lower cortical amyloid burden (odds ratio 0.61, 95% confidence interval 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 = {},
number = {},
pages = {},
doi = {10.1093/clinchem/hvab192},
pmid = {34662373},
issn = {1530-8561},
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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3671},
pmid = {34661615},
issn = {2168-6157},
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},
doi = {10.1155/2021/3928060},
pmid = {34660786},
issn = {2314-6141},
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},
doi = {10.3389/fnagi.2021.738244},
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 = {},
number = {},
pages = {},
doi = {10.3233/JAD-215275},
pmid = {34657891},
issn = {1875-8908},
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 = {2021},
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},
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 = {2021},
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},
doi = {10.1016/j.neurobiolaging.2021.09.010},
pmid = {34655980},
issn = {1558-1497},
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},
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},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1002/mrm.29041},
pmid = {34655092},
issn = {1522-2594},
support = {0.16.Veni.188.040//Netherlands Organization for Scientific Research/ ; },
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 ; W81XWH-12-2-0012//DoD Alzheimer's Disease Neuroimaging Initiative (US)/ ; },
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 = {NIA U01AG066623-01/AG/NIA NIH HHS/United States ; },
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 {pmid34629042,
year = {2021},
author = {Anjireddy, K and Subramanian, K},
title = {A new mode of Thinfilm and Nanofiber for burst release of the drug for Alzheimer disease; A complete scenario from dispersible polymer to formulation methodology.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/1389557521666211008152446},
pmid = {34629042},
issn = {1875-5607},
abstract = {Alzheimer's disease (AD) is usually caused intellectual deterioration which happened due to the degeneration of cholinergic neurons. Donepezil is employed for cholinesterase enzyme Inhibition (ChEI) to treat AD in a wider population. Over the years, researchers finding difficulties prompted through traditional dosage forms particularly in geriatric patience. To avoid swallowing difficulties brought about with the aid of the AD population, researchers majorly focused on oral thin-film technology (OTF). This technology strongly eliminates issues caused by solid oral dosage forms. It is one of the quality strategies to an alternate drug that is used in the first-pass metabolism or pre systematic metabolism. The solubility of the drug is a higher trouble and it can expand by way of lowering particle size. Nanofibers are the excellent desire to minimize the drug particles to the submicron stage and can increase the drug release rate drastically. It can be prepared by Electrospinning technology by incorporating polymeric material into poorly soluble drugs. Mostly natural and biodegradable polymers prefer in all pharmaceutical preparations. Polymers employed for oral delivery should be stable, possess mucoadhesive property, and should release the drug by diffusion, degradation, and swelling mechanism. The objective of the present review explains various thin-film and nanofiber formulations used for faster drug release in the treatment of Alzheimer's disease.},
}
@article {pmid34654043,
year = {2021},
author = {Fu, J and Ji, X and Liu, J and Chen, X and Shang, H},
title = {Meta-analysis of the Connection Between Alzheimer Disease and Telomeres.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000468},
pmid = {34654043},
issn = {1546-4156},
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common neurodegenerative disease of the central nervous system. The stability of the telomere-telomerase system is closely related to AD. A previous meta-analysis indicated that AD patients had shorter telomere length (TL) than control subjects. However, there are no consistent telomerase activity findings in AD patients, and the published telomerase studies were not meta-analyzed yet.<br><br>METHODS: We searched all the related studies that probed into TL and/or telomerase activity in AD patients based on PubMed and Embase database from the establishment to September 2020. The Chinese National Knowledge Infrastructure, Wanfang and China Science and Technology Journal Database were also utilized. The quality of the included studies was evaluated by using Newcastle-Ottawa Scale. All the statistical analyses of this meta-analysis were performed using Stata version 15.0.<br><br>RESULTS: Analyzing 30 TL data from 2248 AD patients and 4865 controls, AD patients had a significantly shorter TL than the controls, with a standardized mean difference of -0.70 (confidence interval: -0.95 to -0.46; P<0.05). The meta-analysis included 3 primary studies and did not find a significant difference in the telomerase activity between 233 AD patients and 132 controls, but AD patients had a trend of increased telomerase activity compared with controls (standardized mean difference: 0.47; confidence interval: -0.29 to 1.23; P>0.05).<br><br>CONCLUSION: Our results showed that compared with the control group, the AD group had a shorter TL and may have higher telomerase activity.},
}
@article {pmid34653052,
year = {2021},
author = {Tsiouris, S and Bougias, C and Konitsiotis, S and Papadopoulos, A and Fotopoulos, A},
title = {Early-Onset Frontotemporal Dementia-Related Semantic Variant of Primary Progressive Aphasia: Multimodal Evaluation With Brain Perfusion SPECT, SPECT/MRI Coregistration, and MRI Volumetry.},
journal = {Clinical nuclear medicine},
volume = {},
number = {},
pages = {},
doi = {10.1097/RLU.0000000000003934},
pmid = {34653052},
issn = {1536-0229},
abstract = {ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by cortical and subcortical atrophies, with early involvement of the hippocampus and amygdala. A 58-year-old man with clinical presentation of primary progressive aphasia-particularly its svPPA (semantic variant)-and bilateral asymmetric (left-predominant) anterior temporal lobe atrophy on MRI was referred for brain perfusion SPECT. This revealed bilateral hypoperfusion of the anterior temporal lobe (sustained by software-fused SPECT/MRI), pointing toward FTD rather than Alzheimer disease. Furthermore, voxel-based MRI volumetric analysis confirmed bilateral atrophy affecting the hippocampus and amygdala. Combining SPECT with MRI was supportive of the early-onset FTD-related svPPA diagnosis.},
}
@article {pmid34652786,
year = {2019},
author = {Herrera-Landero, A and Amaya-Sánchez, LE and D Hyver de Las-Deses, C and Solórzano-Santos, F and Gordillo-Pérez, MG},
title = {Borrelia burgdorferi as a risk factor for Alzheimer's dementia and mild cognitive impairment.},
journal = {European geriatric medicine},
volume = {10},
number = {3},
pages = {493-500},
pmid = {34652786},
issn = {1878-7649},
support = {Support Program for Graduate Studies 2017//Universidad Nacional Autónoma de México/ ; FIS/IMSS Prot MD17/1688//Instituto Mexicano del Seguro Social/ ; },
abstract = {OBJECTIVE: To determine the association of Borrelia burgdorferi infection with Alzheimer's disease or mild cognitive impairment (MCI) in older adults.<br><br>METHODS: Case-control study. Patients older than 60 years, both sexes, were included. Three groups were created: with probable Alzheimer's disease cases with NINCDS-ADRDA criteria, MCI cases in those not meeting NINCDS-ADRDA criteria for dementia, but who had an abnormal cognitive evaluation and independence in instrumental activities of daily living (IADL), cognitively healthy controls were diagnosed with normal cognitive evaluation and independence in IADL were identified in the community. Western blot IgG against B. burgdorferi in serum was done in all the participants. Non-conditional logistic regression was applied to estimate the association of Alzheimer's disease or MCI and seropositive to B. burgdorferi.<br><br>RESULTS: Thirty-eight patients with Alzheimer's disease, mean age of 75.6 ± 3.4 years, 69% were females, education 8.3 ± 4.8 years. 39 patients with MCI, mean age of 72.2 ± 6.8 years, 85% were females, education 11.2 ± 4.2 years. A total of 11/38 (29%) were positive to B. burgdorferi with Alzheimer's disease, 9/39 (23%) with MCI, and 11/108 (10%) of controls. In patients with Alzheimer's disease, an adjusted odds ratio (aOR) = 3.65 (95% CI 1.2-11.1) adjusted for education and a history of cerebrovascular disease (CVD) was estimated, and in patients with MCI an aOR = 3.2 (95% CI 1.1-9.1) for a history of diabetes mellitus and CVD was estimated.<br><br>CONCLUSIONS: In our study, there was an increased risk of Alzheimer's disease and MCI in seropositive IgG patients to B. burgdorferi.},
}
@article {pmid34652580,
year = {2021},
author = {Taché, Y and Saavedra, JM},
title = {Introduction to the Special Issue "The Brain-Gut Axis".},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {34652580},
issn = {1573-6830},
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},
doi = {10.1093/arclin/acab052},
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 = {},
doi = {10.1172/JCI154889},
pmid = {34651585},
issn = {1558-8238},
}
@article {pmid34647974,
year = {2021},
author = {Mohammed, A and Gibbons, LE and Gates, G and Anderson, ML and McCurry, SM and McCormick, W and Bowen, JD and Grabowski, TJ and Crane, PK and Larson, EB},
title = {Association of Performance on Dichotic Auditory Tests With Risk for Incident Dementia and Alzheimer Dementia.},
journal = {JAMA otolaryngology-- head &amp; neck surgery},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoto.2021.2716},
pmid = {34647974},
issn = {2168-619X},
abstract = {Importance: Age-related hearing difficulties can include problems with signal audibility and central auditory processing. Studies have demonstrated associations between audibility and dementia risk. To our knowledge, limited data exist to determine whether audibility, central processing, or both drive these associations.<br><br>Objective: To determine the associations between signal sensitivity, central auditory processing, and dementia and Alzheimer dementia (AD) risk.<br><br>This follow-up observational study of a sample from the prospective Adult Changes in Thought study of dementia risk was conducted at Kaiser Permanente Washington, a western Washington health care delivery system, and included 280 volunteer participants without dementia who were evaluated from October 2003 to February 2006 with follow-up through September 2018. Analyses began in 2019 and continued through 2021.<br><br>Exposures: Hearing tests included pure tone signal audibility, a monaural word recognition test, and 2 dichotic tests: the Dichotic Sentence Identification (DSI) test and the Dichotic Digits test (DDT).<br><br>Main Outcomes and Measures: Cognition was assessed biennially with the Cognitive Abilities Screening Instrument (range, 1-100; higher scores are better), and scores of less than 86 prompted clinical and neuropsychological evaluations. All data were reviewed at multidisciplinary consensus conferences, and standardized criteria were used to define incident cases of dementia and probable or possible AD. Cox proportional hazard models were used to determine associations with hearing test performance.<br><br>Results: A total of 280 participants (177 women [63%]; mean [SD] age, 79.5 [5.2] years). As of September 2018, there were 2196 person-years of follow-up (mean, 7.8 years) and 89 incident cases of dementia (66 not previously analyzed), of which 84 (94.4%) were AD (63 not previously analyzed). Compared with people with DSI scores of more than 80, the dementia adjusted hazard ratio (aHR) for DSI scores of less than 50 was 4.18 (95% CI, 2.37-7.38; P < .001); for a DSI score of 50 to 80, it was 1.82 (95% CI, 1.10-3.04; P = .02). Compared with people with DDT scores of more than 80, the dementia aHR for DDT scores of less than 50 was 2.66 (95% CI, 1.31-5.42; P = .01); for a DDT score of 50 to 80, it was 2.40 (95% CI, 1.45-3.98; P = .001). The AD results were similar. Pure tone averages were weakly and insignificantly associated with dementia and AD, and associations were null when controlling for DSI scores.<br><br>Conclusions and Relevance: In this cohort study, abnormal central auditory processing as measured by dichotic tests was independently associated with dementia and AD risk.},
}
@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 = {},
doi = {10.1002/alz.12480},
pmid = {34647694},
issn = {1552-5279},
support = {U01 AG024904/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; U19 AG062418.//National Institutes of Health Grants/ ; },
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},
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 = {undefined},
pages = {},
doi = {10.18632/aging.203634},
pmid = {34644262},
issn = {1945-4589},
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},
support = {InductAlz//Association France Alzheimer/ ; NeurATRIS - ANR-11-INBS-0011//agence nationale de la recherche/ ; PhD grant//fondation pour la recherche médicale/ ; PhD grant//Ministère de l'Enseignement Supérieur, de la Recherche Scientifique et des Technologies de l'Information et de la Communication/ ; },
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 = {},
doi = {10.3390/jcm10194582},
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 = {},
doi = {10.3390/ijms221910425},
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/ ; },
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 = {},
doi = {10.3390/ijms221910283},
pmid = {34638632},
issn = {1422-0067},
support = {1.010.924.//Fundación Banco Santander/ ; },
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 = {2021},
author = {McEvoy, LK},
title = {Disruption of White Matter Connectivity Precedes Development of Dementia in Alzheimer Disease.},
journal = {Radiology},
volume = {},
number = {},
pages = {212097},
doi = {10.1148/radiol.2021212097},
pmid = {34636642},
issn = {1527-1315},
}
@article {pmid34636637,
year = {2021},
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 = {},
number = {},
pages = {210383},
doi = {10.1148/radiol.2021210383},
pmid = {34636637},
issn = {1527-1315},
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 = {},
number = {},
pages = {},
pmid = {34635841},
issn = {1759-4766},
}
@article {pmid34634492,
year = {2021},
author = {Zakusilo, FT and Gelbard, HA and Seluanov, A and Kerry O'Banion, M and Gorbunova, V},
title = {Matters of size: Roles of hyaluronan in CNS aging and disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {101485},
doi = {10.1016/j.arr.2021.101485},
pmid = {34634492},
issn = {1872-9649},
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 Kerimolgu, 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 = {},
number = {},
pages = {e13659},
doi = {10.15252/emmm.202013659},
pmid = {34633146},
issn = {1757-4684},
support = {DEPICODE 648898//EC|H2020|H2020 Priority Excellent Science|H2020 European Research Council (ERC)/ ; SPP1738//Deutsche Forschungsgemeinschaft (DFG)/ ; SCHU1603/4-1 5-1 71//Deutsche Forschungsgemeinschaft (DFG)/ ; KFO241/PsyCourse FA241/16-1//Deutsche Forschungsgemeinschaft (DFG)/ ; SA1005/2//Deutsche Forschungsgemeinschaft (DFG)/ ; EXC 2067/1 390729940//Deutsche Forschungsgemeinschaft (DFG)/ ; SFB1286//Deutsche Forschungsgemeinschaft (DFG)/ ; KFO241/PsyCourse,FI981-4,11-1//Deutsche Forschungsgemeinschaft (DFG)/ ; FI981-4,15-1//Deutsche Forschungsgemeinschaft (DFG)/ ; Integrament,01ZX1314D//Bundesministerium für Bildung und Forschung (BMBF)/ ; 01EE1404H//Bundesministerium für Bildung und Forschung (BMBF)/ ; 01ZX1614K//Bundesministerium für Bildung und Forschung (BMBF)/ ; ENERGI,01GQ1421A//Bundesministerium für Bildung und Forschung (BMBF)/ ; GMP LiPSC-GR1.1//HHS|NIH|OSC|Common Fund (NIH Common Fund)/ ; },
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 = {2021},
author = {Engelborghs, S},
title = {Adults with cerebral palsy and Alzheimer disease: a missing link?.},
journal = {Developmental medicine and child neurology},
volume = {},
number = {},
pages = {},
doi = {10.1111/dmcn.15080},
pmid = {34632577},
issn = {1469-8749},
}
@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},
doi = {10.1590/1980-57642021dn15-030003},
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},
doi = {10.3389/fnins.2021.742065},
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 = {},
number = {},
pages = {},
doi = {10.1515/bmt-2021-0070},
pmid = {34626530},
issn = {1862-278X},
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 = {},
number = {},
pages = {},
doi = {10.1038/s41582-021-00579-5},
pmid = {34625724},
issn = {1759-4766},
}
@article {pmid34625662,
year = {2021},
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 = {},
number = {},
pages = {},
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)/ ; },
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},
doi = {10.1016/j.metop.2021.100125},
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 = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A7294},
pmid = {34620589},
issn = {1936-959X},
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 {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},
doi = {10.1371/journal.pbio.3001412},
pmid = {34613972},
issn = {1545-7885},
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 {pmid34613338,
year = {2021},
author = {Nordestgaard, LT and Christoffersen, M and Lauridsen, BK and Afzal, S and Nordestgaard, BG and Frikke-Schmidt, R and Tybjærg-Hansen, A},
title = {Long-term Benefits and Harms Associated With Genetic Cholesteryl Ester Transfer Protein Deficiency in the General Population.},
journal = {JAMA cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamacardio.2021.3728},
pmid = {34613338},
issn = {2380-6591},
abstract = {Importance: The balance between the potential long-term clinical benefits and harms associated with genetic cholesteryl ester transfer protein (CETP) deficiency, mimicking pharmacologic CETP inhibition, is unknown.<br><br>Objective: To assess the relative benefits and harms associated with genetic CETP deficiency.<br><br>This study examined 2 similar prospective cohorts of the Danish general population, with data on a total of 102 607 participants collected from October 10, 1991, through December 7, 2018.<br><br>Exposures: Weighted CETP allele scores.<br><br>Main Outcomes and Measures: Incident cardiovascular mortality, ischemic heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, vascular dementia, Alzheimer disease, all-cause mortality, and age-related macular degeneration (AMD). The study first tested whether a CETP allele score was associated with morbidity and mortality, when scaled to genetically lower levels of non-high-density lipoprotein (HDL) cholesterol (ie, 17 mg/dL), corresponding to the reduction observed for anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the study assessed how much of the change in morbidity and mortality was associated with genetically lower levels of non-HDL cholesterol. Finally, the balance between the potential long-term clinical benefits and harms associated with genetic CETP deficiency was quantified. For AMD, the analyses also included higher levels of HDL cholesterol associated with genetic CETP deficiency.<br><br>Results: Of 102 607 individuals in the study, 56 559 (55%) were women (median age, 58 years [IQR, 47-67 years]). Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77 [95% CI, 0.62-0.95]), ischemic heart disease (HR, 0.80 [95% CI, 0.68-0.95]), myocardial infarction (HR, 0.72 [95% CI, 0.55-0.93]), peripheral arterial disease (HR, 0.80 [95% CI, 0.63-1.02]), and vascular dementia (HR, 0.38 [95% CI, 0.18-0.80]) and an increased risk of AMD (HR, 2.33 [95% CI, 1.63-3.30]) but was not associated with all-cause mortality (HR, 0.91 [95% CI, 0.81-1.02]), ischemic stroke (HR, 1.05 [95% CI, 0.81-1.36]), or Alzheimer disease (HR, 1.25 [95% CI, 0.89-1.76]). When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger. A considerable fraction of the lower risk of cardiovascular end points was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol. Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol.<br><br>Conclusions and Relevance: This study suggests that genetic CETP deficiency, mimicking pharmacologic CETP inhibition, was associated with a lower risk of cardiovascular morbidity and mortality, but with a markedly higher risk of AMD.},
}
@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},
doi = {10.4235/agmr.21.0079},
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},
doi = {10.1001/jamanetworkopen.2021.25166},
pmid = {34609497},
issn = {2574-3805},
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},
doi = {10.1001/jamanetworkopen.2021.28225},
pmid = {34609493},
issn = {2574-3805},
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 de González, AB},
title = {Racial and Ethnic Disparities in Excess Deaths During the COVID-19 Pandemic, March to December 2020.},
journal = {Annals of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.7326/M21-2134},
pmid = {34606321},
issn = {1539-3704},
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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3404},
pmid = {34605885},
issn = {2168-6157},
}
@article {pmid34605039,
year = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1002/mus.27426},
pmid = {34605039},
issn = {1097-4598},
abstract = {INTRODUCTION: Sporadic inclusion body myositis (IBM) is a degenerative and inflammatory acquired myopathy characterised by muscle deposition of various proteins typically associated with Alzheimer's disease and other neurodegenerative diseases. While cognitive impairment is not noted as a clinical feature of IBM, evidence is lacking. We aimed to investigate whether cognitive performance of patients with IBM differs from population norms, focussing on cognitive domains affected in early Alzheimer's 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 [SD] 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 to 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 ±1SD of the normative mean. There was no evidence of associations between PACC score and either disease duration (ρ = -0.04, p = 0.87) or IBMFRS total score (ρ = 0.14, p = 0.52).<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. This article is protected by copyright. All rights reserved.},
}
@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},
doi = {10.3389/fimmu.2021.738511},
pmid = {34603320},
issn = {1664-3224},
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},
doi = {10.3389/fnins.2021.720253},
pmid = {34602969},
issn = {1662-4548},
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 {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},
}
@article {pmid34599319,
year = {2021},
author = {Lemprière, S},
title = {Genome-wide association study identifies new risk loci for Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
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},
support = {INP 025/2015.//Instituto Nacional de Pediatría, México/ ; },
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.jcyt.2021.07.018},
pmid = {34598900},
issn = {1477-2566},
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},
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 = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab098},
pmid = {34597386},
issn = {1554-6578},
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},
doi = {10.1097/MD.0000000000027319},
pmid = {34596132},
issn = {1536-5964},
support = {H2018058//Natural Science Foundation of Heilongjiang Province/ ; ZHY202087//Heilongjiang Provincial Administration of Traditional Chinese Medicine/ ; },
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 = {2021},
author = {Barenholtz Levy, H},
title = {Accelerated Approval of Aducanumab: Where Do We Stand Now?.},
journal = {The Annals of pharmacotherapy},
volume = {},
number = {},
pages = {10600280211050405},
doi = {10.1177/10600280211050405},
pmid = {34595939},
issn = {1542-6270},
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 = {},
number = {},
pages = {},
doi = {10.1111/epi.17086},
pmid = {34595752},
issn = {1528-1167},
support = {//University of Melbourne/ ; MRF1136427//Australian Government/ ; },
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 = {NS083498/NS/NINDS NIH HHS/United States ; AG049479/AG/NIA NIH HHS/United States ; P30 AG062428 01/AG/NIA NIH HHS/United States ; },
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 {pmid34376506,
year = {2021},
author = {Edmonds, EC and Smirnov, DS and Thomas, KR and Graves, LV and Bangen, KJ and Delano-Wood, L and Galasko, DR and Salmon, DP and Bondi, MW},
title = {Data-Driven vs Consensus Diagnosis of MCI: Enhanced Sensitivity for Detection of Clinical, Biomarker, and Neuropathologic Outcomes.},
journal = {Neurology},
volume = {97},
number = {13},
pages = {e1288-e1299},
pmid = {34376506},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Given prior work demonstrating that mild cognitive impairment (MCI) can be empirically differentiated into meaningful cognitive subtypes, we applied actuarial methods to comprehensive neuropsychological data from the University of California San Diego Alzheimer's Disease Research Center (ADRC) in order to identify cognitive subgroups within ADRC participants without dementia and to examine cognitive, biomarker, and neuropathologic trajectories.<br><br>METHODS: Cluster analysis was performed on baseline neuropsychological data (n = 738; mean age 71.8). Survival analysis examined progression to dementia (mean follow-up 5.9 years). CSF Alzheimer disease (AD) biomarker status and neuropathologic findings at follow-up were examined in a subset with available data.<br><br>RESULTS: Five clusters were identified: optimal cognitively normal (CN; n = 130) with above-average cognition, typical CN (n = 204) with average cognition, nonamnestic MCI (naMCI; n = 104), amnestic MCI (aMCI; n = 216), and mixed MCI (mMCI; n = 84). Progression to dementia differed across MCI subtypes (mMCI > aMCI > naMCI), with the mMCI group demonstrating the highest rate of CSF biomarker positivity and AD pathology at autopsy. Actuarial methods classified 29.5% more of the sample with MCI and outperformed consensus diagnoses in capturing those who had abnormal biomarkers, progressed to dementia, or had AD pathology at autopsy.<br><br>DISCUSSION: We identified subtypes of MCI and CN with differing cognitive profiles, clinical outcomes, CSF AD biomarkers, and neuropathologic findings over more than 10 years of follow-up. Results demonstrate that actuarial methods produce reliable cognitive phenotypes, with data from a subset suggesting unique biological and neuropathologic signatures. Findings indicate that data-driven algorithms enhance diagnostic sensitivity relative to consensus diagnosis for identifying older adults at risk for cognitive decline.},
}
@article {pmid34376505,
year = {2021},
author = {Kent, DM and Leung, LY and Zhou, Y and Luetmer, PH and Kallmes, DF and Nelson, J and Fu, S and Zheng, C and Liu, H and Chen, W},
title = {Association of Silent Cerebrovascular Disease Identified Using Natural Language Processing and Future Ischemic Stroke.},
journal = {Neurology},
volume = {97},
number = {13},
pages = {e1313-e1321},
pmid = {34376505},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVES: Silent cerebrovascular disease (SCD), comprising silent brain infarction (SBI) and white matter disease (WMD), is commonly found incidentally on neuroimaging scans obtained in routine clinical care. Their prognostic significance is not known. We aimed to estimate the incidence of and risk increase in future stroke in patients with incidentally discovered SCD.<br><br>METHODS: Patients in the Kaiser Permanente Southern California (KPSC) health system aged ≥50 years, without prior ischemic stroke, transient ischemic attack (TIA), or dementia/Alzheimer disease receiving a head CT or MRI between 2009 and 2019 were included. SBI and WMD were identified by natural language processing (NLP) from the neuroimage report.<br><br>RESULTS: Among 262,875 individuals receiving neuroimaging, NLP identified 13,154 (5.0%) with SBI and 78,330 (29.8%) with WMD. The incidence of future stroke was 32.5 (95% confidence interval [CI] 31.1, 33.9) per 1,000 patient-years for patients with SBI: 19.3 (95% CI 18.9, 19.8) for patients with WMD and 6.8 (95% CI 6.7, 7.0) for patients without SCD. The crude hazard ratio (HR) associated with SBI was 3.40 (95% CI 3.25 to 3.56) and for WMD 2.63 (95% CI 2.54 to 2.71). With MRI-discovered SBI, the adjusted HR was 2.95 (95% CI 2.53 to 3.44) for those <65 years of age and 2.15 (95% CI 1.91 to 2.41) for those ≥65. With CT scan, the adjusted HR was 2.48 (95% CI 2.19 to 2.81) for those <65 and 1.81 (95% CI 1.71 to 1.91) for those ≥65. The adjusted HR associated with a finding of WMD was 1.76 (95% CI 1.69 to 1.82) and was not modified by age or imaging modality.<br><br>DISCUSSION: Incidentally discovered SBI and WMD are common and associated with increased risk of subsequent symptomatic stroke, representing an important opportunity for stroke prevention.},
}
@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 = {},
number = {},
pages = {109371},
doi = {10.1016/j.jneumeth.2021.109371},
pmid = {34592173},
issn = {1872-678X},
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 = {},
number = {},
pages = {},
pmid = {34588623},
issn = {1476-5578},
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},
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},
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},
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},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2021.09.007},
pmid = {34582783},
issn = {1097-4199},
}
@article {pmid34581847,
year = {2021},
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 = {},
number = {},
pages = {},
pmid = {34581847},
issn = {1619-7089},
support = {RYC-2015/17430//Agencia Estatal de Investigación/ ; PI19/01315//Instituto de Salud Carlos III/ ; EAPA_791/2018//European Regional Development Fund/ ; },
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 Aging.},
journal = {The British journal of nutrition},
volume = {},
number = {},
pages = {1-47},
doi = {10.1017/S0007114521003883},
pmid = {34581265},
issn = {1475-2662},
abstract = {Alzheimer's disease (AD) is the most common major neurocognitive disorder of aging. 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 aging. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimizing 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},
}
@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 = {},
doi = {10.3390/ijerph18189597},
pmid = {34574524},
issn = {1660-4601},
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 = {},
doi = {10.3390/brainsci11091223},
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 = {},
doi = {10.3390/brainsci11091165},
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 = {},
doi = {10.3390/biomedicines9091272},
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 = {},
doi = {10.3390/cells10092394},
pmid = {34572041},
issn = {2073-4409},
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 {pmid34467976,
year = {2021},
author = {Sumien, N and Cunningham, JT and Davis, DL and Engelland, R and Fadeyibi, O and Farmer, GE and Mabry, S and Mensah-Kane, P and Trinh, OTP and Vann, PH and Wilson, EN and Cunningham, RL},
title = {Neurodegenerative Disease: Roles for Sex, Hormones, and Oxidative Stress.},
journal = {Endocrinology},
volume = {162},
number = {11},
pages = {},
doi = {10.1210/endocr/bqab185},
pmid = {34467976},
issn = {1945-7170},
support = {R01 NS0091359/NH/NIH HHS/United States ; T32 AG020494/AG/NIA NIH HHS/United States ; },
abstract = {Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50 and 70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex is also an important risk factor. The characteristic of sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions. An understudied sex hormone receptor that can induce activation of oxidative stress signaling is the membrane androgen receptor (mAR). mAR can mediate nicotinamide adenine dinucleotide-phosphate (NADPH) oxidase (NOX)-generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer disease. Further complicating this is that aging can alter sex hormone signaling. Prior to menopause, women experience more estrogens than androgens. During menopause, this sex hormone profile switches in women due to the dramatic ovarian loss of 17β-estradiol with maintained ovarian androgen (testosterone, androstenedione) production. Indeed, aging men have higher estrogens than aging women due to aromatization of androgens to estrogens. Therefore, higher activation of mAR-NOX signaling could occur in menopausal women compared with aged men, mediating the observed sex differences. Understanding of these signaling cascades could provide therapeutic targets for neurodegenerative diseases.},
}
@article {pmid34401683,
year = {2021},
author = {Benjamin, LA and Paterson, RW and Moll, R and Pericleous, C and Brown, R and Mehta, PR and Athauda, D and Ziff, OJ and Heaney, J and Checkley, AM and Houlihan, CF and Chou, M and Heslegrave, AJ and Chandratheva, A and Michael, BD and Blennow, K and Vivekanandam, V and Foulkes, A and Mummery, CJ and Lunn, MP and Keddie, S and Spyer, MJ and Mckinnon, T and Hart, M and Carletti, F and Jäger, HR and Manji, H and Zandi, MS and Werring, DJ and Nastouli, E and Simister, R and Solomon, T and Zetterberg, H and Schott, JM and Cohen, H and Efthymiou, M and , },
title = {Antiphospholipid antibodies and neurological manifestations in acute COVID-19: A single-centre cross-sectional study.},
journal = {EClinicalMedicine},
volume = {39},
number = {},
pages = {101070},
doi = {10.1016/j.eclinm.2021.101070},
pmid = {34401683},
issn = {2589-5370},
support = {/WT_/Wellcome Trust/United Kingdom ; },
abstract = {Background: A high prevalence of antiphospholipid antibodies has been reported in case series of patients with neurological manifestations and COVID-19; however, the pathogenicity of antiphospholipid antibodies in COVID-19 neurology remains unclear.<br><br>Methods: This single-centre cross-sectional study included 106 adult patients: 30 hospitalised COVID-neurological cases, 47 non-neurological COVID-hospitalised controls, and 29 COVID-non-hospitalised controls, recruited between March and July 2020. We evaluated nine antiphospholipid antibodies: anticardiolipin antibodies [aCL] IgA, IgM, IgG; anti-beta-2 glycoprotein-1 [aβ2GPI] IgA, IgM, IgG; anti-phosphatidylserine/prothrombin [aPS/PT] IgM, IgG; and anti-domain I β2GPI (aD1β2GPI) IgG.<br><br>Findings: There was a high prevalence of antiphospholipid antibodies in the COVID-neurological (73.3%) and non-neurological COVID-hospitalised controls (76.6%) in contrast to the COVID-non-hospitalised controls (48.2%). aPS/PT IgG titres were significantly higher in the COVID-neurological group compared to both control groups (p < 0.001). Moderate-high titre of aPS/PT IgG was found in 2 out of 3 (67%) patients with acute disseminated encephalomyelitis [ADEM]. aPS/PT IgG titres negatively correlated with oxygen requirement (FiO2 R=-0.15 p = 0.040) and was associated with venous thromboembolism (p = 0.043). In contrast, aCL IgA (p < 0.001) and IgG (p < 0.001) was associated with non-neurological COVID-hospitalised controls compared to the other groups and correlated positively with d-dimer and creatinine but negatively with FiO2.<br><br>Interpretation: Our findings show that aPS/PT IgG is associated with COVID-19-associated ADEM. In contrast, aCL IgA and IgG are seen much more frequently in non-neurological hospitalised patients with COVID-19. Characterisation of antiphospholipid antibody persistence and potential longitudinal clinical impact are required to guide appropriate management.<br><br>Funding: This work is supported by UCL Queen Square Biomedical Research Centre (BRC) and Moorfields BRC grants (#560441 and #557595). LB is supported by a Wellcome Trust Fellowship (222102/Z/20/Z). RWP is supported by an Alzheimer's Association Clinician Scientist Fellowship (AACSF-20-685780) and the UK Dementia Research Institute. KB is supported by the Swedish Research Council (#2017-00915) and the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), and theUK Dementia Research Institute at UCL. BDM is supported by grants from the MRC/UKRI (MR/V007181/1), MRC (MR/T028750/1) and Wellcome (ISSF201902/3). MSZ, MH and RS are supported by the UCL/UCLH NIHR Biomedical Research Centre and MSZ is supported by Queen Square National Brain Appeal.},
}
@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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3356},
pmid = {34570180},
issn = {2168-6157},
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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2942},
pmid = {34570178},
issn = {2168-6157},
}
@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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3310},
pmid = {34570177},
issn = {2168-6157},
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 = {},
number = {},
pages = {},
doi = {10.3233/JAD-215004},
pmid = {34569963},
issn = {1875-8908},
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},
doi = {10.4252/wjsc.v13.i8.1072},
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 = {2021},
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 = {},
number = {},
pages = {},
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},
support = {G0D9817N//Fonds Wetenschappelijk Onderzoek/ ; ZEN-17-441253/ALZ/Alzheimer's Association/United States ; ERC-CELLPHASE-AD -834682//H2020 European Research Council/ ; GSKE//UCB/ ; RTI2018-101850-A-100//Ministerio de Ciencia, Innovación y Universidades/ ; startup funds//Ikerbasque, Basque Foundation for Science/ ; },
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 {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},
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 {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},
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/ ; },
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 = {2021},
author = {Erekat, NS},
title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.},
journal = {Clinical anatomy (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/ca.23792},
pmid = {34558138},
issn = {1098-2353},
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},
doi = {10.1021/acsphotonics.1c00082},
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},
doi = {10.1155/2021/3064224},
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 {pmid34556954,
year = {2020},
author = {Venkatrao, M and Nagarathna, R and Majumdar, V and Patil, SS and Rathi, S and Nagendra, H},
title = {Prevalence of Obesity in India and Its Neurological Implications: A Multifactor Analysis of a Nationwide Cross-Sectional Study.},
journal = {Annals of neurosciences},
volume = {27},
number = {3-4},
pages = {153-161},
doi = {10.1177/0972753120987465},
pmid = {34556954},
issn = {0972-7531},
abstract = {Background: India is undergoing a rapid epidemiological transition, from underweight to overweight/obese population. Obesity is a major risk factor in type 2 diabetes and cardiovascular diseases, and is also implicated as a factor in neurological diseases such as Alzheimer's disease. A robust, pan-Indian estimate of obesity is not yet available.<br><br>Purpose: This study estimates the pan-Indian prevalence of obesity, stratified across nonmodifiable (age and gender) and modifiable (education and physical activity levels) factors, and across zones and urban/rural.<br><br>Methodology: Data for 1,00,531 adults from a nationwide randomized cluster sample survey (Niyantrita Madhumeha Bharata 2017, phase 1) were analyzed. Obesity was determined using body mass index, and cross-tabulations were calculated across zones, age, gender, education, physical activity, and area. To determine statistical significance, t-tests were used. The odds of obesity within each category of the various factors were calculated using binary logistic regression.<br><br>Results: Prevalence of obesity in India is 40.3%. Zonal variations were seen as follows: south highest at 46.51% and east lowest at 32.96%. Obesity was higher among women than men (41.88% vs. 38.67%), urban than rural (44.17% vs. 36.08%), and over 40 than under 40 (45.81% vs. 34.58%). More education implied a higher obesity (44.6% college vs. 38% uneducated), as did lowered physical activity (43.71% inactive vs. 32.56% vigorously active). The odds ratio for physical activity was 3.83, stronger than age (1.58), education (1.4), urban (1.3), and gender (1.2).<br><br>Conclusion: Obesity levels in India are very high, across all zones. The odds of being obese increases with age, and is higher among women and among urban dwellers. Obesity is the highest among aging urban men and women who are college educated and are sedentary. Physical activity and aging are the strongest determinants of obesity. Given the high cost of obesity in terms of type 2 diabetes, cardiovascular diseases, and Alzheimer's disease, urgent public health measures are necessary to reduce its impact.},
}
@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 = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012853},
pmid = {34556565},
issn = {1526-632X},
abstract = {OBJECTIVE: To determine whether CSF synaptic biomarkers are altered in the early preclinical stage of the Alzheimer's continuum and associated with Alzheimer's disease (AD) risk factors, primary pathology, and neurodegeneration markers.<br><br>METHODS: Cross-sectional study in the ALFA+ cohort, comprising middle-aged cognitively unimpaired participants. CSF neurogranin and GAP-43 were measured using immunoassays and SNAP-25 and synaptotagmin-1 using immunoprecipitation mass spectrometry. AD CSF biomarkers Aβ42/40, p-tau and t-tau, and the neurodegeneration biomarker 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, importantly, 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>CONCLUSION: CSF synaptic biomarkers increase in early preclinical stages of the Alzheimer's 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.},
}
@article {pmid34556345,
year = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2021.08.002},
pmid = {34556345},
issn = {0035-3787},
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},
support = {3502Z20209005//Xiamen Municipal Bureau of Science and Technology/ ; 2020J02063//Natural Science Foundation of Fujian Province/ ; 82072777//National Natural Science Foundation of China/ ; },
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 = {},
number = {},
pages = {1-17},
doi = {10.1080/13803395.2021.1982867},
pmid = {34556008},
issn = {1744-411X},
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 {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 = {},
number = {},
pages = {},
doi = {10.1038/s41380-021-01307-7},
pmid = {34548629},
issn = {1476-5578},
}
@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},
doi = {10.1371/journal.pmed.1003801},
pmid = {34555025},
issn = {1549-1676},
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 code (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 = {},
number = {},
pages = {},
doi = {10.2174/1567205018666210922110652},
pmid = {34551697},
issn = {1875-5828},
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},
doi = {10.1016/j.neurobiolaging.2021.08.012},
pmid = {34551374},
issn = {1558-1497},
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},
doi = {10.1212/WNL.0000000000012022},
pmid = {34550903},
issn = {1526-632X},
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},
}
@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},
doi = {10.2196/30990},
pmid = {34550082},
issn = {2561-326X},
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 Gonzales, 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 = {},
number = {},
pages = {},
doi = {10.1111/ejn.15472},
pmid = {34549475},
issn = {1460-9568},
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 = {},
number = {},
pages = {},
pmid = {34548654},
issn = {1759-4766},
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 {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 = {},
number = {},
pages = {},
doi = {10.1002/jssc.202100468},
pmid = {34545700},
issn = {1615-9314},
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 pre-analytical 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. This article is protected by copyright. All rights reserved.},
}
@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 = {P01 NS015655/NH/NIH HHS/United States ; R01 NS070856/NH/NIH HHS/United States ; P50 NS091856/NH/NIH HHS/United States ; I01 RX001631/RX/RRD VA/United States ; },
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 = {},
doi = {10.26508/lsa.202000703},
pmid = {34544751},
issn = {2575-1077},
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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3180},
pmid = {34542571},
issn = {2168-6157},
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},
doi = {10.2196/29210},
pmid = {34542418},
issn = {1438-8871},
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 = {},
number = {},
pages = {1-3},
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},
doi = {10.3389/fneur.2021.738465},
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},
doi = {10.3389/fneur.2021.694572},
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},
doi = {10.3389/fneur.2021.666430},
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},
doi = {10.3389/fnagi.2021.721171},
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 = {},
number = {},
pages = {HYPERTENSIONAHA12117797},
doi = {10.1161/HYPERTENSIONAHA.121.17797},
pmid = {34538105},
issn = {1524-4563},
abstract = {Research links high blood pressure variability (BPV) with stroke and cerebrovascular disease, however, its association with cognition remains unclear. Moreover, it remains uncertain which BP-derived parameter (ie, variability or mean) holds more significance in understanding vascular contributions to cognitive impairment. We searched PubMed, Embase, PsycINFO, and Scopus and performed a meta-analysis of studies that quantified the association between resting BPV with dementia or cognitive impairment in adults. Two authors independently reviewed all titles, abstracts, and full-texts and extracted data, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Study quality was assessed using the (modified) Newcastle-Ottawa Scale. A multilevel meta-analysis was used, which included effect sizes for both BPV and mean BP, with a combined end point of dementia or cognitive impairment as primary outcome. In the primary analysis, 54 effect sizes were extracted from 20 studies, with a total analytical sample of n=7 899 697. Higher systolic BPV (odds ratio [OR], 1.25 [95% CI, 1.16-1.35]), mean systolic pressure (OR, 1.12 [95% CI, 1.02-1.29]), diastolic BPV (OR, 1.20 [95% CI, 1.12-1.29]), and mean diastolic pressure (OR, 1.16 [95% CI, 1.04-1.29]) were associated with dementia and cognitive impairment. A direct comparison showed that mean BP effect sizes were less strong than BPV effect sizes (OR, 0.92 [95% CI, 0.87-0.97], P<0.01), indicating that the relative contribution of BPV exceeded that of mean BP. Methodological and statistical heterogeneity was high. Secondary analyses were less consistent as to whether BPV and mean BP were differentially associated with dementia subtypes and cognitive domains. Future studies are required to investigate BPV as a target for dementia prevention.},
}
@article {pmid34536437,
year = {2021},
author = {Naghibi, S and Shariatzadeh, 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 = {},
number = {},
pages = {113595},
doi = {10.1016/j.physbeh.2021.113595},
pmid = {34536437},
issn = {1873-507X},
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-dependent 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 = {},
number = {},
pages = {},
pmid = {34535787},
issn = {1759-4766},
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},
doi = {10.1212/NXG.0000000000000622},
pmid = {34532569},
issn = {2376-7839},
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},
doi = {10.1212/NXG.0000000000000609},
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},
doi = {10.3389/fnagi.2021.698571},
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},
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 {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 = {PI20/00465//instituto de salud carlos iii/ ; RD16/0019/0021//invictus/ ; Predoctoral Fellowship//fundació institut de recerca hospital universitari vall d'hebron/ ; 733050822//bionic project/ ; 5R01NS104147-02//foundation for the national institutes of health/ ; NR170024//selfridges group foundation/ ; },
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 = {},
number = {},
pages = {136247},
doi = {10.1016/j.neulet.2021.136247},
pmid = {34530113},
issn = {1872-7972},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2021.09.006},
pmid = {34530075},
issn = {1873-4596},
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},
support = {IH18MIRAS//ALBA Synchrotron/ ; LCF/PR/HR19/52160007//"la Caixa" Foundation/ ; SAF2017-844-R//Spanish Ministerio de Cienia, Innovación y Universidades/ ; },
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},
doi = {10.1136/bmjopen-2021-050820},
pmid = {34526343},
issn = {2044-6055},
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},
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},
doi = {10.1371/journal.pbio.3001388},
pmid = {34525093},
issn = {1545-7885},
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},
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34524654},
issn = {1720-8319},
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 = {},
number = {},
pages = {},
pmid = {34522039},
issn = {1759-4766},
abstract = {Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates that 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},
support = {81660620//National Natural Science Foundation/ ; },
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 {pmid34389521,
year = {2021},
author = {Houlihan, LM and Staudinger Knoll, AJ and Jubran, JH and Farhadi, DS and Benner, D and Zabramski, JM and Lawton, MT and Spetzler, RF and Preul, MC},
title = {Nancy Davis Reagan, First Lady with a Neurosurgical Legacy.},
journal = {World neurosurgery},
volume = {155},
number = {},
pages = {64-73},
doi = {10.1016/j.wneu.2021.08.012},
pmid = {34389521},
issn = {1878-8769},
abstract = {Various well-known people associated with the history of the presidency of the United States have experienced neurologic disease or injury, especially trauma to the head or spine. Nancy Reagan, however, as the wife of President Ronald Reagan and First Lady, would leave a significant and lasting mark on the progress of neurosurgical science and education. Recognized for endeavors against drug abuse, Alzheimer disease, and polio, her interest in neurosurgical research is less well known. Nancy's father Loyal Davis was a remarkable neurosurgeon and educator of extraordinary influence. When Barrow Neurological Institute (BNI) founder John Green experienced complications after an illness, Davis served as BNI director during 1966 - 1967. After Davis's death in 1982, Robert Spetzler, who had been a student of Davis at Northwestern University Medical School and was then BNI director, convinced Green, despite his misgivings, to support a neurosurgical laboratory recognizing Davis. In 1988, Nancy Reagan, then First Lady, dedicated the Loyal and Edith Davis Neurosurgical Research Laboratory. At the dedication, she remarked on her years growing up in the home of a pioneering neurosurgeon and remarked that "my father believed deeply in the importance of research to develop new methods for treating patients." Green and Spetzler's unified efforts honored the extraordinary career of Davis in a manner he would have appreciated, were supported by a First Lady with deep involvement in politics and philanthropy dedicated to promoting advances in medicine, and are part of neurosurgery's unique heritage.},
}
@article {pmid34380754,
year = {2021},
author = {Jeong, SH and Kim, HR and Kim, J and Kim, H and Hong, N and Jung, JH and Baik, K and Cho, H and Lyoo, CH and Ye, BS and Sohn, YH and Seong, JK and Lee, PH},
title = {Association of Dipeptidyl Peptidase-4 Inhibitor Use and Amyloid Burden in Patients With Diabetes and AD-Related Cognitive Impairment.},
journal = {Neurology},
volume = {97},
number = {11},
pages = {e1110-e1122},
doi = {10.1212/WNL.0000000000012534},
pmid = {34380754},
issn = {1526-632X},
abstract = {BACKGROUND AND OBJECTIVE: To investigate whether dipeptidyl peptidase-4 inhibitors (DPP-4i) have beneficial effects on amyloid aggregation and longitudinal cognitive outcome in diabetic Alzheimer disease-related cognitive impairment (ADCI).<br><br>METHODS: We retrospectively reviewed 282 patients with ADCI with positive 18F-florbetaben amyloid PET images. Patients were classified into 3 groups according to prior diagnosis of diabetes and DPP-4i use: diabetic patients being treated with (ADCI-DPP-4i+, n = 70) or without DPP-4i (ADCI-DPP-4i-, n = 71) and nondiabetic patients (n = 141). Multiple linear regression analyses were performed to determine intergroup differences in global and regional amyloid retention using standardized uptake value ratios calculated from cortical areas. We assessed longitudinal changes in Mini-Mental State Examination (MMSE) score using a linear mixed model.<br><br>RESULTS: The ADCI-DPP-4i+ group had lower global amyloid burden than the ADCI-DPP-4i- group (β = 0.075, SE = 0.024, p = 0.002) and the nondiabetic ADCI group (β = 0.054, SE = 0.021, p = 0.010) after adjusting for age, sex, education, cognitive status, and APOE ε4 carrier status. The ADCI-DPP-4i+ group had lower regional amyloid burden in temporo-parietal areas than either the ADCI-DPP-4i- group or the nondiabetic ADCI group. The ADCI-DPP-4i+ group showed a slower longitudinal decrease in MMSE score (β = 0.772, SE = 0.272, p = 0.005) and memory recall subscore (β = 0.291, SE = 0.116, p = 0.012) than the ADCI-DPP-4i- group.<br><br>DISCUSSION: These findings suggest that DPP-4i use is associated with low amyloid burden and favorable long-term cognitive outcome in diabetic patients with ADCI.},
}
@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},
doi = {10.1371/journal.pbio.3001358},
pmid = {34520451},
issn = {1545-7885},
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 {pmid34519052,
year = {2021},
author = {Kozlowska, U and Nichols, C and Wiatr, K and Figiel, M},
title = {From Psychiatry to Neurology: Psychedelics as Prospective Therapeutics for Neurodegenerative Disorders.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.15509},
pmid = {34519052},
issn = {1471-4159},
abstract = {The studies of psychedelics, especially psychedelic tryptamines like psilocybin, are rapidly gaining interest in neuroscience research. Much of this interest stems from recent clinical studies demonstrating that they have a unique ability to improve the debilitating symptoms of major depressive disorder (MDD) long-term after only a single treatment. Indeed, the Food and Drug Administration (FDA) has recently designated two Phase III clinical trials studying the ability of psilocybin to treat forms of MDD with "Breakthrough Therapy" status. If successful, the use of psychedelics to treat psychiatric diseases like depression would be revolutionary. As more evidence appears in the scientific literature to support their use in psychiatry to treat MDD on and substance use disorders (SUD), recent studies with rodents revealed that their therapeutic effects might extend beyond treating MDD and SUD. For example, psychedelics may have efficacy in the treatment and prevention of brain injury and neurodegenerative diseases such as Alzheimer Disease. Preclinical work has highlighted psychedelics' ability to induce neuroplasticity and synaptogenesis, and neural progenitor cell proliferation. Psychedelics may also act as immunomodulators by reducing levels of proinflammatory biomarkers, including IL-1β, IL-6, Tumor Necrosis Factor-α (TNF-α). Their exact molecular mechanisms, and induction of cellular interactions, especially between neural and glial cells, leading to therapeutic efficacy, remain to be determined. In this review, we discuss recent findings and information on how psychedelics may act therapeutically on cells within the Central Nervous System (CNS) during brain injuries and neurodegenerative diseases.},
}
@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},
doi = {10.1503/cmaj.211134},
pmid = {34518345},
issn = {1488-2329},
}
@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 = {U24 AG072122/AG/NIA NIH HHS/United States ; P01AG03991/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 ; },
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 {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 = {},
number = {},
pages = {STROKEAHA120033338},
doi = {10.1161/STROKEAHA.120.033338},
pmid = {34496627},
issn = {1524-4628},
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 {pmid34516970,
year = {2021},
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 = {P2 × 7 receptor blockade reduces Tau induced toxicity, therapeutic implications in Tauopathies.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102173},
doi = {10.1016/j.pneurobio.2021.102173},
pmid = {34516970},
issn = {1873-5118},
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 P2 × 7 receptors (P2 × 7) can sense the rise of extracellular ATP levels associated with neuroinflammation, its involvement in neurodegeneration-associated inflammation was suggested. We found a P2 × 7 upregulation in patients diagnosed with different tauopathies and in a tauopathy mouse model, P301S mice. In vivo pharmacological or genetic blockade of P2 × 7 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 (eTau) levels by reducing the expression of ectoenzyme TNAP. Accordingly, pharmacological or genetic blockade of P2 × 7 improved the cellular survival, motor and memory deficits and anxiolytic profile in P301S mice. Contrary, P2 × 7 overexpression caused a significant worsening of Tau-induced toxicity and aggravated the deteriorated motor and memory deficits in P301S mice. Our results indicate that P2 × 7 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},
}
@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},
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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3126},
pmid = {34515750},
issn = {2168-6157},
}
@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},
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},
doi = {10.3389/fneur.2021.685802},
pmid = {34512509},
issn = {1664-2295},
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},
doi = {10.3389/fneur.2021.683131},
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},
doi = {10.3389/fnagi.2021.702796},
pmid = {34512305},
issn = {1663-4365},
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},
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 {pmid34510664,
year = {2021},
author = {Maayan, G and Behar, AE and Sabater, L and Baskin, M and Hureau, C},
title = {A Water-Soluble Peptoid Chelator that Can Remove Cu2+ from Amyloid-β and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer's Disease.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {},
doi = {10.1002/anie.202109758},
pmid = {34510664},
issn = {1521-3773},
abstract = {Cu bound to Amyloid-β (Aβ) peptides can act as a catalyst for the formation of reactive oxygen species (ROS), leading to neuropathologic degradation associated with Alzheimer's disease (AD). An excellent therapeutic approach is to use a chelator that can selectively remove Cu from Cu-Aβ. This chelator should compete with Zn2+ ions (Zn) that are present in the synaptic cleft while forming a nontoxic Cu complex. Herein we describe P3, a water-soluble peptidomimetic chelator that selectively removes Cu(II) from Cu-Aβ in the presence of Zn and prevent the formation of ROS even in a reductive environment. We demonstrate, based on extensive spectroscopic analysis, that although P3 extracts Zn from Cu,Zn-Aβ faster than in removes Cu, the formed Zn complexes are kinetic products that further dissociate, while CuP3 is formed as an exclusive stable thermodynamic product. Our unique findings, combined with the bioavailability of peptoids, make P3 an excellent drug candidate in the context of AD.},
}
@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 = {},
number = {},
pages = {},
doi = {10.1016/j.annepidem.2021.09.001},
pmid = {34509621},
issn = {1873-2585},
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(SD=9) at STAR. Stroke Belt birth was associated with worse late-life executive function (β(95% CI):-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>CONCLUSION: 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 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 = {},
number = {},
pages = {174499},
doi = {10.1016/j.ejphar.2021.174499},
pmid = {34508753},
issn = {1879-0712},
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 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 icv 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 {pmid34507341,
year = {2021},
author = {Flugon, SJ and Jøranson, N and Tangen, GG},
title = {Mobility and Depressive Symptoms in Persons With Mild Cognitive Impairment and Alzheimer Dementia.},
journal = {Journal of neurologic physical therapy : JNPT},
volume = {},
number = {},
pages = {},
doi = {10.1097/NPT.0000000000000378},
pmid = {34507341},
issn = {1557-0584},
abstract = {BACKGROUND AND PURPOSE: Persons with mild cognitive impairment (MCI) and Alzheimer dementia (AD) often experience gait and balance disturbances and depressive symptoms alongside their cognitive impairment. The aim of this study was to explore the relationship between mobility and depressive symptoms in community-dwelling persons with MCI and mild to moderate AD.<br><br>METHODS: Ninety-nine participants with MCI and AD from the memory clinic at Oslo University Hospital, Ullevål, Norway, were included. The Balance Evaluation Systems Test (BESTest), 10-m walk test regular (gait speed), and dual task (naming animals, dual-task cost in percent) were used to assess mobility. The Cornell Scale for Depression in Dementia, with validated cut-off 5/6 points, was used to assess presence of depressive symptoms. Multiple regression analysis was used to explore the relationship between mobility (3 separate models) and depressive symptoms, controlled for demographic factors, comorbidity, and Mini-Mental State Examination.<br><br>RESULTS: One-third of the participants had depressive symptoms, mean (SD) gait speed was 1.09 (0.3) m/s, and median (interquartile range) BESTest percent score was 81.5 (17.6). No statistically significant associations were found between depression and BESTest, gait speed or dual-task cost, neither in the simple models (P = 0.15-0.85), nor in the 3 multivariate models (P = 0.57-0.69).<br><br>DISCUSSION AND CONCLUSIONS: In this study, we found no associations between mobility and depressive symptoms in persons with MCI and AD recruited at a memory clinic. Few participants had major symptoms of depression, which may have influenced the results. Longitudinal studies are needed to explore the long-time associations between mobility and depression.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A366).},
}
@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 = {},
number = {},
pages = {},
doi = {10.1097/CM9.0000000000001706},
pmid = {34507318},
issn = {2542-5641},
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2021.08.019},
pmid = {34506904},
issn = {1873-4596},
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 = {},
number = {},
pages = {},
doi = {10.1002/acn3.51433},
pmid = {34506082},
issn = {2328-9503},
support = {PDF-IRGP-1102//Parkinson's Disease Foundation/United States ; },
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 {pmid34505123,
year = {2021},
author = {Kshirsagar, S and Sawant, N and Morton, H and Reddy, AP and Reddy, PH},
title = {Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddab262},
pmid = {34505123},
issn = {1460-2083},
abstract = {The purpose of our study is to determine the protective effects of mitophagy enhancers against mutant APP and amyloid beta (Aβ)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (ad). Over two decades of research from our lab and others revealed that mitochondrial abnormalities are largely involved in the pathogenesis of both early-onset and late-onset ad. Emerging studies from our lab and others revealed that impaired clearance of dead or dying mitochondria is an early event in the disease process. Based on these changes, it has been proposed that mitophagy enhancers are potential therapeutic candidates to treat patients with ad. In the current study, we optimized doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. We transfected HT22 cells with mutant APP cDNA and treated with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes, cell survival; assessed mitochondrial respiration in mAPP-HT22 cells treated and untreated with mitophagy enhancers. We also assessed mitochondrial morphology in mAPP-HT22 cells treated and untreated with mitophagy enhancers. Mutant APP-HT22 cells showed increased fission, decreased fusion, synaptic &amp; mitophagy genes, reduced cell survival and defective mitochondrial respiration, and excessively fragmented and reduced length of mitochondria. However, these events were reversed in mitophagy enhancers treated mutant mAPP-HT22 cells. Cell survival was significantly increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, mitochondrial number is reduced, &amp; mitochondrial length is increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mutant APP-HT22 cells. Further, urolithin A showed strongest protective effects against mutant APP and Aβ-induced mitochondrial and synaptic toxicities in ad. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with 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},
doi = {10.1016/j.isci.2021.102993},
pmid = {34505007},
issn = {2589-0042},
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},
doi = {10.3389/fnins.2021.703783},
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 {pmid34504028,
year = {2021},
author = {Schindler, S 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, D and Bateman, RJ and Morris, JC and Xiong, C},
title = {Predicting Symptom Onset in Sporadic Alzheimer Disease With Amyloid PET.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012775},
pmid = {34504028},
issn = {1526-632X},
abstract = {OBJECTIVE: 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 using longitudinal data.<br><br>RESULTS: Amyloid accumulation was evaluated in 236 individuals who underwent more than one amyloid PET scan. The average age was 66.5 ± 9.2 years and twelve 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 twenty-two 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 (R2=0.54, p<0.0001, root mean square error (RMSE) 4.5 years); the model was more accurate after exclusion of three likely misdiagnoses (R2=0.84, p<0.0001, RMSE of 2.8 years).<br><br>CONCLUSIONS: The age of symptom onset in sporadic AD is strongly correlated with the age that 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 = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012783},
pmid = {34504027},
issn = {1526-632X},
}
@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 = {},
doi = {10.3390/ijerph18179356},
pmid = {34501947},
issn = {1660-4601},
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 = {},
doi = {10.3390/molecules26175208},
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/ ; },
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 = {},
number = {},
pages = {},
doi = {10.1001/jama.2021.15286},
pmid = {34499725},
issn = {1538-3598},
}
@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 = {},
number = {},
pages = {e13472},
doi = {10.1111/acel.13472},
pmid = {34499406},
issn = {1474-9726},
support = {AG064175/AG/NIA NIH HHS/United States ; GM088213/GM/NIGMS NIH HHS/United States ; },
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},
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 = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab087},
pmid = {34498073},
issn = {1554-6578},
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 {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//Canadian Institutes for Health Research/ ; 160728116, 215063, RGPIN-2016-05834, Postgraduate Scholarship - Doctoral//Natural Sciences and Engineering Research Council of Canada/ ; //McDonnell Foundation Scholar Award/ ; },
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1111/dmcn.15044},
pmid = {34496036},
issn = {1469-8749},
support = {AARG-NTF-20-685960/ALZ/Alzheimer's Association/United States ; 90RTHF0001-01-00//National Institute on Disability, Independent Living, and Rehabilitation Research/ ; },
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 {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 = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2941},
pmid = {34491277},
issn = {2168-6157},
}
@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},
doi = {10.3389/fpsyt.2021.709860},
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},
doi = {10.3389/fnagi.2021.701899},
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},
doi = {10.3389/fnins.2021.708547},
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},
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 = {},
number = {},
pages = {},
doi = {10.2174/1567205018666210831145825},
pmid = {34488612},
issn = {1875-5828},
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 {pmid34435242,
year = {2021},
author = {Düzel, E and Costagli, M and Donatelli, G and Speck, O and Cosottini, M},
title = {Studying Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis with 7-T magnetic resonance.},
journal = {European radiology experimental},
volume = {5},
number = {1},
pages = {36},
pmid = {34435242},
issn = {2509-9280},
support = {RF-2013-02354829//Ministero della Salute/ ; SFB 779 A07//Deutsche Forschungsgemeinschaft/ ; SFB 1315 TP B06//Deutsche Forschungsgemeinschaft/ ; SGA3, WP1, WP2//Human Brain Project/ ; },
abstract = {Ultra-high-field (UHF) magnetic resonance (MR) scanners, that is, equipment operating at static magnetic field of 7 tesla (7 T) and above, enable the acquisition of data with greatly improved signal-to-noise ratio with respect to conventional MR systems (e.g., scanners operating at 1.5 T and 3 T). The change in tissue relaxation times at UHF offers the opportunity to improve tissue contrast and depict features that were previously inaccessible. These potential advantages come, however, at a cost: in the majority of UHF-MR clinical protocols, potential drawbacks may include signal inhomogeneity, geometrical distortions, artifacts introduced by patient respiration, cardiac cycle, and motion. This article reviews the 7 T MR literature reporting the recent studies on the most widespread neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.},
}
@article {pmid34434913,
year = {2021},
author = {Wang, Y and Yang, Y and Ren, L and Shao, Y and Tao, W and Dai, XJ},
title = {Preexisting Mental Disorders Increase the Risk of COVID-19 Infection and Associated Mortality.},
journal = {Frontiers in public health},
volume = {9},
number = {},
pages = {684112},
pmid = {34434913},
issn = {2296-2565},
mesh = {Anxiety ; *COVID-19 ; Humans ; *Mental Disorders/epidemiology ; SARS-CoV-2 ; },
abstract = {Coronavirus disease 2019 (COVID-19), a respiratory disease of unknown origin, has a high rate of morbidity and mortality. Individuals with mental disorders may have a higher risk of infection and worse clinical outcomes because of a variety of factors such as poorer general resilience and lower immune function. However, there have been no studies to date specifically investigating the risk of COVID-19 and associated mortality in these patients. This was addressed in the present study by analyzing the data of 473,958 subjects included in the UK Biobank, 14,877 of whom tested positive for COVID-19 infection. Logistic regression analysis was performed to evaluate the associations between mental disorders and risks of COVID-19 infection and associated mortality. The results showed that subjects who were diagnosed with a mental disorder had a significantly higher risk of developing COVID-19 and a worse outcome as evidenced by higher rates of COVID-19-related mortality, with the strongest effects observed for dementia. Among dementia subtypes, Alzheimer disease patients had the highest risks of COVID-19 infection (7.39-fold increase) and associated mortality (2.13-fold increase). Late-life anxiety only increased the risk of developing COVID-19 while late-life depression not only was associated with a higher risk of infection but also a worse outcome. These findings highlight the need to prioritize patients with mental disorders-especially those who experience these disorders later in life-when implementing preventive strategies such as vaccinations.},
}
@article {pmid34429033,
year = {2021},
author = {Hung, C and Livesey, FJ},
title = {Endolysosome and autophagy dysfunction in Alzheimer disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-2},
doi = {10.1080/15548627.2021.1963630},
pmid = {34429033},
issn = {1554-8635},
abstract = {Abnormalities of the neuronal endolysosome and macroautophagy/autophagy system are an early and prominent feature of Alzheimer disease (AD). SORL1 is notable as a gene in which mutations are causal for a rare, autosomal dominant form of AD, and also variants that increase the risk of developing the common form of late-onset AD. In our recent study, we used patient-derived stem cells and CRISPR engineering to study the effects of SORL1 mutations on the endolysosome and autophagy system in human forebrain neurons. SORL1 mutations causal for monogenic AD are typically truncating mutations, and we found, using stem cells generated from an individual with dementia due to a heterozygous SORL1 truncation mutation, that this class of mutation results in SORL1 haploinsufficiency. Reducing SORL1 protein by half results in disrupted endosomal trafficking in patient-derived neurons, which we confirmed by studying the endolysosomal system in isogenic CRISPR-engineered SORL1 heterozygous null neurons. We also found that SORL1 homozygous null neurons develop more severe phenotypes, with endosome abnormalities, lysosome dysfunction and defects in the degradative phase of autophagy. Endolysosome and autophagy defects in SORL1 mutant neurons are dependent on APP, a key AD gene, as they are rescued by extracellular antisense oligonucleotides that reduce APP protein.},
}
@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 = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab085},
pmid = {34486652},
issn = {1554-6578},
support = {grants P30-AG028383 (UK-ADRC), 1RF1AG057754-01 (DMW), 1T32AG057461-01 (CMK), and 1F31AG069372-01 (CMK)/AG/NIA NIH HHS/United States ; },
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},
doi = {10.7717/peerj.12016},
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},
doi = {10.1212/CPJ.0000000000000940},
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},
doi = {10.1212/CPJ.0000000000001041},
pmid = {34484950},
issn = {2163-0402},
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},
doi = {10.1212/CPJ.0000000000000918},
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},
doi = {10.5770/cgj.24.493},
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},
doi = {10.3389/fpsyg.2021.703478},
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 = {},
number = {},
pages = {101159},
doi = {10.1016/j.jbc.2021.101159},
pmid = {34480901},
issn = {1083-351X},
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 wild type mouse brain. Here, we assessed the impact of Aß co-pathology, of deleting loci known to modify AD risk (Ptk2b, Grn, Tmem106b) and of pharmacological intervention with a 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 Aß, and the Aß co-injection 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 (Aβo) induced signaling, or deleting expression of the PGRN 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 into wild type mice. These studies refine our knowledge of factors capable of modulating Tau spreading.},
}
@article {pmid34480291,
year = {2021},
author = {Tyler, KL},
title = {The Link Between Alzheimer Disease and Herpes Simplex Virus Infection: Better Late Than Never, or Better Never Than Late?.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {},
pmid = {34480291},
issn = {1878-7479},
}
@article {pmid34480088,
year = {2021},
author = {Panitch, R and Hu, J and Chung, J and Zhu, C and Meng, G and Xia, W and Bennett, DA and Lunetta, KL and Ikezu, T and Au, R and Stein, TD and Farrer, LA and Jun, GR},
title = {Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE ε2 protective effect in Alzheimer disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {34480088},
issn = {1476-5578},
support = {RF1-AG057519//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01-AG048927//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U19-AG068753//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01-AG062602//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ɛ2/ɛ3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ɛ2/ɛ3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ɛ2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte-specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.},
}
@article {pmid34479720,
year = {2021},
author = {Tsigas, EZ},
title = {The Preeclampsia Foundation: the voice and views of the patient and her family.},
journal = {American journal of obstetrics and gynecology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajog.2020.10.053},
pmid = {34479720},
issn = {1097-6868},
abstract = {Preeclampsia is a disease exclusive to pregnancy and the immediate postpartum period, occurring in 4.6% of pregnancies worldwide. Preeclampsia and other gestational hypertensive disorders can affect any pregnant woman. The consequences of developing this disease can lead to severe maternal and neonatal morbidities and mortalities, including fetal growth restriction, placental abruption, preterm birth, stillbirth, and maternal death. When pregnant women recover, they are at higher risk of long-term complications such as hypertension, stroke, heart failure, renal disease, and Alzheimer disease. The consequences extend to the offspring because they are at higher risk of cardiovascular diseases, and female offspring are at greater risk of developing preeclampsia when they become pregnant. For society, preeclampsia presents an economic burden related to the additional healthcare costs associated with low birthweight, prematurity, and adverse outcomes to the mother and baby. This article shares the unique perspective of affected women and their families, the effect preeclampsia has on us, and what we hope the healthcare system can deliver for our sisters and daughters in the future. Patients and their families established the Preeclampsia Foundation 21 years ago. Devoted to education and patient advocacy to raise awareness, improve healthcare practices, and catalyze research, we share some of the Foundation's realized strategies and achievements. We tell you our stories and struggles, and we issue a call to action for all stakeholders to help fulfill our vision for a world where hypertensive disorders of pregnancy no longer threaten the lives of mothers and their babies.},
}
@article {pmid34479107,
year = {2021},
author = {Wychowaniec, JK and Moffat, J and Saiani, A},
title = {Quantitative nanomechanical properties evaluation of a family of β-sheet peptide fibres using rapid bimodal AFM.},
journal = {Journal of the mechanical behavior of biomedical materials},
volume = {124},
number = {},
pages = {104776},
doi = {10.1016/j.jmbbm.2021.104776},
pmid = {34479107},
issn = {1878-0180},
abstract = {Self-assembling peptides have become important building blocks for materials design (e.g. hydrogels) and play a crucial role in a range of diseases including Alzheimer and Parkinson. In this context, accessing the nanomechanical properties of ubiquitous β-sheet rich nanofibres (e.g.: amyloids) is key to the formulation of materials and design of therapies. Although the bulk mechanical properties of hydrogels can easily be accessed using common techniques and equipment, the mechanical properties of their constituent fibres, in particular if with radii in the nanometre scale, are more challenging to measure and estimate. In this work we show for the first time how the rapid nanomechanical mapping technique: amplitude modulation-frequency modulation (AM-FM), can be used to determine the heights, Young's moduli and viscosity coefficients of a series of β-sheet peptide nanofibres with high statistical confidence. Our results show how peptide sequence and in particular length, charge and interaction with the substrate affect the viscoelastic properties of the peptide fibres.},
}
@article {pmid34478946,
year = {2021},
author = {Ullah, R and Ali, G and Subhan, F and Khan, A and Ahsan Halim, S and Naveed, M and Kalsoom, S and Al-Harrasi, A},
title = {Attenuation of spatial memory in 5xFAD mice by targeting cholinesterases, oxidative stress and inflammatory signaling using 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone.},
journal = {International immunopharmacology},
volume = {100},
number = {},
pages = {108083},
doi = {10.1016/j.intimp.2021.108083},
pmid = {34478946},
issn = {1878-1705},
abstract = {Alzheimer's disease (AD) is classified pathologically as a progressive neurological disorder associated with memory decline. The study was designed to assess the underlying molecular signaling involved in the neuroprotective effect of the 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone (2NCP) as a novel therapeutic agent for AD. In this connection, in vitro cholinesterases inhibitory and antioxidant activities were investigated. In vivo studies were carried out on a well-known 5xFAD mice model in different behavioural models such as light/dark box,balance beam, rotarod, elevated plus maze (EPM),novel object recognition (NOR), paddling Y-maze, and Morris water maze (MWM) tests. Hippocampus (HC) and frontal cortex (FC) homogenates were examined for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, glutathione S-transferase (GST), glutathione (GSH), and catalase. Further, we examined the expression of inflammatory cytokines and Nrf2 in the HC and FC through RT-PCR. Computational studies were conducted to predict the binding mode of the 2NCP with target sites of nuclear factor-κB (NF-κB) and cholinesterases. The findings of in vitro assays revealed that the IC50 values of the 2NCP against AChE and BChE were 17 and 23 µg/ml respectively. DPPH antioxidant assay displayed an IC50 value for the 2NCP was 62 µg/ml. Whereas, theex vivo study depicted that the activities of AChE and BChEwere significantly reduced. Moreover, free radicals load, GSH level, catalase and GST activities were significantly declined. Furthermore, in vivostudies showed that the 2NCP treated animals exhibited gradual memory improvement and improved motor functions. RT-PCR study revealed that mRNA levels of the inflammatory mediators (IL-1β, IL-6, TNF-α) were significantly reduced, while the expression of antioxidant Nrf2 was significantly increased.The molecular docking studies further confirmed that the 2NCP showed excellent binding affinities for NF-κB and cholinesterases. Taken together, the 2NCP improves spatial memory and learning, short- and long-term memory,markedly inhibits cholinesterases, reduced neuroinflammation, and mitigated oxidative stress in the 5xFAD mice; hence the 2NCP may be a potential candidate for the management of AD.},
}
@article {pmid34478861,
year = {2021},
author = {Taheri, M and Oryan, SH and Eslimi Esfahani, D and Mohseni Kouchesfahani, H and Salari, A},
title = {Artemisia Absinthium improves spatial performance and neuronal injury induced by amyloid- beta in the CA1 hippocampal area of male Wistar rats.},
journal = {Neurobiology of learning and memory},
volume = {},
number = {},
pages = {107506},
doi = {10.1016/j.nlm.2021.107506},
pmid = {34478861},
issn = {1095-9564},
abstract = {Alzheimer's disease is a neurodegenerative disorder. It is characterized by the presence of two aberrant structures in the brain, those are, amyloid plaques and neurofibrillary tangles, along with neuronal death. Amyloid-beta further exacerbates the metabolic decline and results in cognitive impairments. Because of the favorable antioxidant and anti-inflammatory activities of Artemisia absinthium (wormwood), this study aimed to evaluate the effects of hydroalcoholic extract of this plant on spatial memory performance, neuronal injury, and apoptosis induced by amyloid-beta. Forty-eight male Wistar rats (220-250 g) were divided into the following groups: 1) control; 2) sham (solvent; ICV); 3) amyloid-beta 1-40 (ICV); and 4) amyloid-beta plus A. absinthium (10, 50, and 100 mg/kg/day; gavage). Congo red and TUNEL staining were performed to investigate the neuronal injury. Also, the Morris water maze (MWM) test was used to evaluate the spatial memory of the experimental groups. The results showed that spatial memory for finding the hidden platform in the MWM task decreased significantly in the amyloid-beta group, compared to the control and sham groups. In contrast, treatment with A. absinthium improved spatial memory dose-dependently and reduced tissue degeneration, amyloid plaques, and apoptosis. It seems that the hydroalcoholic extract of A. absinthium, due to its antioxidant and anti-inflammatory activities, can effectively reverse spatial memory deficits and reduce amyloid-beta plaques.},
}
@article {pmid34440421,
year = {2021},
author = {Ibanez, L and Cruchaga, C and Fernández, MV},
title = {Advances in Genetic and Molecular Understanding of Alzheimer's Disease.},
journal = {Genes},
volume = {12},
number = {8},
pages = {},
pmid = {34440421},
issn = {2073-4425},
abstract = {Alzheimer's disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are highly interconnected but can also point to the different subgroups of AD. The identification of the pathologic triggers and order of events in the disease processes are key to the design of treatments and therapies. Prevention and treatment of AD cannot be attempted using a single approach; different therapeutic strategies at specific disease stages may be appropriate. For successful prevention and treatment, biomarker assays must be designed so that patients can be more accurately monitored at specific points during the course of the disease and potential treatment. In addition, to advance the development of therapeutic drugs, models that better mimic the complexity of the human brain are needed; there have been several advances in this arena. Here, we review significant, recent developments in genetics, omics, and molecular studies that have contributed to the understanding of this disease. We also discuss the implications that these contributions have on medicine.},
}
@article {pmid34473676,
year = {2021},
author = {Basilico, S and Ciricugno, A and Gelosa, G and Magnani, FG and Mosca, L and Popescu, C and Garibotto, V and Sberna, M and Paulesu, E and Bottini, G},
title = {Clinical Characterization of Atypical Primary Progressive Aphasia in a 3-Year Longitudinal Study: A Case Report.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {34},
number = {3},
pages = {233-244},
pmid = {34473676},
issn = {1543-3641},
abstract = {The logopenic variant of primary progressive aphasia (lvPPA) is the most recent variant of primary progressive aphasia (PPA) to be identified; thus far, it has been poorly investigated. Despite being typically associated with Alzheimer disease (AD), lvPPA has recently been linked to frontotemporal lobe degeneration (FTLD), with distinctive cognitive and neural features that are worthy of further investigation. Here, we describe the neuropsychological and linguistic profile, as well as cerebral abnormalities, of an individual exhibiting PPA and carrying a pathogenetic variant in the GRN gene, from a 3-year longitudinal perspective. The individual's initial profile resembled lvPPA because it was characterized by word-finding difficulties and phonological errors in spontaneous speech in addition to sentence repetition and phonological short-term memory impairments. The individual's structural and metabolic imaging data demonstrated left temporal and bilateral frontal atrophy and hypometabolism, respectively. On follow-up, as the pathology progressed, dysprosody, stereotypical speech patterns, agrammatism, and orofacial apraxia appeared, suggesting an overlap with the nonfluent variant of PPA (nfvPPA). Severe sentence comprehension impairment also became evident. Our longitudinal and multidisciplinary diagnostic approach allowed us to better characterize the progression of a GRN-positive lvPPA profile, providing neuropsychological and imaging indicators that might be helpful to improve classification between different PPA variants and to address a nosological issue. Finally, we discuss the importance of early diagnosis of PPA given the possible overlap between different PPA variants during the progression of the pathology.},
}
@article {pmid34473671,
year = {2021},
author = {Smith, M and Van, N and Roberts, A and Hosaka, KRJ and Choi, SY and Viereck, J and Carrazana, E and Borman, P and Chen, JJ and Liow, KK},
title = {Disparities in Alzheimer Disease and Mild Cognitive Impairment Among Native Hawaiians and Pacific Islanders.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {34},
number = {3},
pages = {200-206},
pmid = {34473671},
issn = {1543-3641},
abstract = {BACKGROUND: Previous studies of racial differences in Alzheimer disease (AD) presentation have not included Native Hawaiians and Pacific Islanders (NHPI).<br><br>OBJECTIVE: To explore the presentation of AD and mild cognitive impairment (MCI) in NHPI.<br><br>METHOD: We conducted a retrospective review of patient records from Hawaii with a diagnosis of unspecified AD or MCI from September 2000 to September 2019. Variables of interest included age at diagnosis, gender, race, marital status, insurance, comorbidities, and scores on the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA).<br><br>RESULTS: We reviewed the medical records of 598 patients, including 224 Asians, 202 Whites, 87 NHPI, and 85 Other. AD was more dominant than MCI across all of the groups, with the highest percentage in NHPI. Among the mean ages of diagnosis, NHPI were the youngest. Across all groups, a higher proportion of women than men had AD, with the highest female prevalence among NHPI. Hypertension, hyperlipidemia, and type II diabetes were highest among NHPI compared with the other groups. Of individuals with MMSE/MoCA scores, there were significant variations in scores by racial group. The mean MMSE/MoCA score was highest among Whites and lowest among NHPI.<br><br>CONCLUSION: Compared with other racial groups, NHPI have a higher proportion of AD than MCI at diagnosis, are diagnosed at a younger age, have a higher female prevalence, have more comorbidities that may contribute to AD/MCI onset, and present with lower MMSE scores.},
}
@article {pmid34473668,
year = {2021},
author = {Hammers, DB and Gradwohl, BD and Kucera, A and Abildskov, TJ and Wilde, EA and Spencer, RJ},
title = {Preliminary Validation of the Learning Ratio for the HVLT-R and BVMT-R in Older Adults.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {34},
number = {3},
pages = {170-181},
pmid = {34473668},
issn = {1543-3641},
abstract = {BACKGROUND: The learning slope is typically represented as the raw difference between the final score and the score of the first learning trial. A new method for calculating the learning slope, the learning ratio (LR), was recently developed; it is typically represented as the number of items that are learned after the first trial divided by the number of items that are yet to be learned.<br><br>OBJECTIVE: To evaluate the convergent and criterion validity of the LR in order to understand its sensitivity to Alzheimer disease (AD) pathology.<br><br>METHOD: Fifty-six patients from a memory clinic underwent standard neuropsychological assessment and quantitative brain imaging. LR scores were calculated from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised and were compared with both standard memory measures and total hippocampal volumes, as well as between individuals with AD and those with mild cognitive impairment.<br><br>RESULTS: Lower LR scores were consistently associated with poorer performances on standard memory measures and smaller total hippocampal volumes, generally more so than traditional learning slope scores. The LR scores of the AD group were smaller than those of the group with mild cognitive impairment. Furthermore, the aggregation of LR scores into a single metric was partially supported.<br><br>CONCLUSION: The LR is sensitive to AD pathology along the AD continuum. This result supports previous claims that the LR score can reflect learning capacity better than traditional learning calculations can by considering the amount of information that is learned at trial 1.},
}
@article {pmid34472165,
year = {2021},
author = {Vöglein, J and Kostova, I and Arzberger, T and Noachtar, S and Dieterich, M and Herms, J and Schmitz, P and Ruf, V and Windl, O and Roeber, S and Simons, M and Höglinger, GU and Danek, A and Giese, A and Levin, J},
title = {Seizure prevalence in neurodegenerative diseases - a study of autopsy proven cases.},
journal = {European journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1111/ene.15089},
pmid = {34472165},
issn = {1468-1331},
abstract = {BACKGROUND: Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND.<br><br>METHODS: Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared among ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined.<br><br>RESULTS: 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n=144; LBD, n=103; PSP, n=93; FTLD, n=53; MSA, n=36; CBD, n=25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p=0.005), LBD (p=0.001), MSA (p=0.005) and PSP (p<0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p=0.017).<br><br>CONCLUSIONS: Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk.},
}
@article {pmid34471719,
year = {2021},
author = {Montiel-Flores, E and Mejía-García, OA and Ordoñez-Librado, JL and Gutierrez-Valdez, AL and Espinosa-Villanueva, J and Dorado-Martínez, C and Reynoso-Erazo, L and Tron-Alvarez, R and Rodríguez-Lara, V and Avila-Costa, MR},
title = {Alzheimer-like cell death after vanadium pentoxide inhalation.},
journal = {Heliyon},
volume = {7},
number = {8},
pages = {e07856},
doi = {10.1016/j.heliyon.2021.e07856},
pmid = {34471719},
issn = {2405-8440},
abstract = {Vanadium (V) toxicity depends on its oxidation state; it seems that vanadium pentoxide (V2O5) is the most toxic to the living cells. It has been reported that oral administration induces changes in motor activity and learning; in rats, I.P. administration increases lipid peroxidation levels in the cerebellum and the concentration of free radicals in the hippocampus and cerebellum. Mice that inhaled V2O5 presented a reduced number of tubulin+ in Leydig and Sertoli cells; it has also been reported that inhaled V2O5 induces loss of dendritic spines, necrosis, and hippocampus neuropil alterations; considering the direct consequence of the interaction of V with cytoskeletal components, makes us believe that V2O5 exposure could cause neuronal death in the hippocampus similar to that seen in Alzheimer disease. This work aimed to determine pyramidal hippocampal CA1 cytoskeletal alterations with Bielschowsky stain in rats exposed to V2O5. Male Wistar rats inhaled 0.02 M of V2O5 one h two times a week for two and six months. We found that rats, which inhaled V2O5 reached 56,57% of dead neurons after six months of inhalation; we recognize strong argyrophilic and collapsed somas and typical flame-shaped in all V-exposed rats hippocampus CA1 compared to controls. We also observe somatodendritic distortions. Axons and dendrites displayed thick dark bands replaced by noticeable thickening and nodosities and the cytoskeleton fibrillary proteins' linear traces. Our findings suggest that V2O5 inhalation induces Alzheimer-like cell death with evident cytoskeletal alterations.},
}
@article {pmid34469849,
year = {2021},
author = {Sanabria-Diaz, G and Demonet, JF and Rodriguez-Herreros, B and Draganski, B and Kherif, F and Melie-Garcia, L},
title = {Apolipoprotein E allele 4 effects on Single-Subject Gray Matter Networks in Mild Cognitive Impairment.},
journal = {NeuroImage. Clinical},
volume = {32},
number = {},
pages = {102799},
doi = {10.1016/j.nicl.2021.102799},
pmid = {34469849},
issn = {2213-1582},
abstract = {There is evidence that gray matter networks are disrupted in Mild Cognitive Impairment (MCI) and associated with cognitive impairment and faster disease progression. However, it remains unknown how these alterations are related to the presence of Apolipoprotein E isoform E4 (ApoE4), the most prominent genetic risk factor for late-onset Alzheimer's disease (AD). To investigate this topic at the individual level, we explore the impact of ApoE4 and the disease progression on the Single-Subject Gray Matter Networks (SSGMNets) using the graph theory approach. Our data sample comprised 200 MCI patients selected from the ADNI database, classified as non-Converters and Converters (will progress into AD). Each group included 50 ApoE4-positive ('Carriers', ApoE4 +) and 50 ApoE4-negative ('non-Carriers', ApoE4-). The SSGMNets were estimated from structural MRIs at two-time points: baseline and conversion. We investigated whether altered network topological measures at baseline and their rate of change (RoC) between baseline and conversion time points were associated with ApoE4 and disease progression. We also explored the correlation of SSGMNets attributes with general cognition score (MMSE), memory (ADNI-MEM), and CSF-derived biomarkers of AD (Aβ42, T-tau, and P-tau). Our results showed that ApoE4 and the disease progression modulated the global topological network properties independently but not in their RoC. MCI converters showed a lower clustering index in several regions associated with neurodegeneration in AD. The SSGMNets' topological organization was revealed to be able to predict cognitive and memory measures. The findings presented here suggest that SSGMNets could indeed be used to identify MCI ApoE4 Carriers with a high risk for AD progression.},
}
@article {pmid34466513,
year = {2019},
author = {Zarifkar, AH and Zarifkar, A and Nami, M and Rafati, A and Aligholi, H and Vafaee, F},
title = {Ameliorative Effects of Different Transcranial Electrical Stimulation Paradigms on the Novel Object Recognition Task in a Rat Model of Alzheimer Disease.},
journal = {Galen medical journal},
volume = {8},
number = {},
pages = {e1440},
doi = {10.31661/gmj.v8i0.1440},
pmid = {34466513},
issn = {2322-2379},
abstract = {Background: Treatment of Alzheimer as a disease that is associated with cognitive impairment has been associated with some restrictions. Recently, researchers have focused on non-pharmacological treatments, including non-invasive stimulation of the brain by transcranial electrical stimulation (tES). Four main paradigms of transcranial electrical current include transcranial direct current stimulation (tDCS), transcranial alternative current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial pulse current stimulation (tPCS). The tDCS is a possible new therapeutic option for patients with cognitive impairment, including Alzheimer disease.<br><br>Materials and Methods: The study was done on Sprague-Dawley male rats weighing 250-270 g. to develop Alzheimer's model, the cannula was implanted bilaterally into the hippocampus. Aβ 25-35 (5μg/ 2.5µl/day) was microinjected bilaterally for 4 days. Then, an electrical stimulation paradigm was applied to the animal for 6 days. Animal cognitive capacity was evaluated on day 11 and 12 by novel object recognition (NOR) test.<br><br>Results: Our results showed that application of tDCS; tACS; tRNS and tPCS reversed beta-amyloid-induced impairment (P<0.05). The tRNS Group spent total exploration time around the objects compared to other groups (P<0.05). There was no significant difference between the four different paradigms in discrimination ratio and the percentage of total exploration time.<br><br>Conclusion: The results of this study showed that the use of multiple sessions of different tES paradigms could improve Aβ-induced memory impairment in the NOR test. Therefore, based on evidence, it can be expected that in addition to using tDCS, other stimulatory paradigms may also be considered in the treatment of AD.},
}
@article {pmid34465994,
year = {2021},
author = {Jeong, HT and Youn, YC and Sung, HH and Kim, SY},
title = {Power Spectral Changes of Quantitative EEG in the Subjective Cognitive Decline: Comparison of Community Normal Control Groups.},
journal = {Neuropsychiatric disease and treatment},
volume = {17},
number = {},
pages = {2783-2790},
doi = {10.2147/NDT.S320130},
pmid = {34465994},
issn = {1176-6328},
abstract = {Purpose: The purpose of this study is to compare and analyze the power spectral changes between subjective cognitive decline (SCD) subjects and normal controls (NC) while checking the preclinical stage of AD in the SCD subjects and to use the derived data for biomarker research that can diagnose early-stage AD in the future.<br><br>Methods: We recruited 23 SCD patients and 23 normal control subjects and QEEG analysis including power spectral density (PSD) and source-level analysis were performed. An automated preprocessing procedure and statistical analysis were performed by iSync Brain® (iMediSync Inc., Republic of Korea) (https://isyncbrain.com/) using the international standard 10-20 system (19 electrodes).<br><br>Results: Absolute PSD, there was no statistically significant difference in all of the EEG power measurements of the 19 channels. In the relative PSD analysis, the average delta band power of the SCD group was significantly higher in Fp2, F4, and F8 than NC. Alpha1 band power of the O1 channel was 22.56±16.05 for the SCD group and 33.19±19.05 for the NC (p-value <0.05). Source-level analysis did not show a statistically significant difference.<br><br>Conclusion: SCD subjects showed a partial increase of delta waves in the frontal lobe region and a partial decrease in alpha1, a fast wave in the occipital region, compared to the NC. SCD is considered one of the earliest clinical symptoms of AD and it is predicted to be related to minor nerve damage. We were able to observe the power spectral changes in SCD subjects in this cross-sectional study, a large number of subjects and longitudinal studies are needed to evaluate their predictability for future deterioration such as conversion to MCI.},
}
@article {pmid34464618,
year = {2021},
author = {Saranya, V and Shankar, R and Gatasheh, MK and Zehra, S},
title = {Impact of Au144 metal clusters on the structural and inhibitory mechanism of Aβ42 peptide: A theoretical approach.},
journal = {Environmental research},
volume = {},
number = {},
pages = {111920},
doi = {10.1016/j.envres.2021.111920},
pmid = {34464618},
issn = {1096-0953},
abstract = {One of the main causes for Alzheimer disease is the abnormal self-assembly of the amyloid-beta (Aβ) peptide, which in turn forms a toxic β-rich aggregation. A recent study suggests that gold nanoparticles (AuNPs) can inhibit the Aβ aggregation. Nevertheless, the effects of AuNPs on Aβ peptide system are still ambiguous and needs exploration that is more detailed. Molecular dynamics simulations have been carried out to investigate the aggregation mechanism of Aβ42 peptide for 500 ns? During simulation, C-terminus regions of Met 35-Ala42 residues exhibits β-sheet conformations. Meanwhile, the Au144MC coordination induces substantial α-helical character, both α-helix and 310-helix structure at 0-500ns, in the region of Asp1-Arg 5 and Val36-Ile41 residues. The Au144MC strongly coordinates with Asp1, Ala2, Glu3, Phe4, Asp7, Tyr10 and Gln15 residues that plays the significant effects to loss the β-sheet geometry in the N-terminal region and it converted into random α-helix, turn and bend conformation. On comparing the RMSF of the Aβ42 peptide and Aβ42-Au144MC complex shows that the coordination of Au144MC results in greater rigidity of the Aβ42 peptide backbone regions with exemptions for the Asp1, Ala2, Glu3, Leu34, Ile41 and Ala42 residues due to the strong binding between the metal cluster and the CHC (Leu17-Ala21) region. The structural stability of the Aβ42 peptide and Aβ42-Au144MC complex is enhanced by the several intermolecular and intramolecular interactions and it was visibly revealed in the H-bond. From the above results, it is very evident that the Au144MC can be used as inhibitor agent for the oligomerization of Aβ42.},
}
@article {pmid34464365,
year = {2021},
author = {Witkowska-Plusa, U},
title = {[Status of everyday activities and cognitive activity in elderly patients with symptoms of Alzheimer's dementia during COVID-19].},
journal = {Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego},
volume = {49},
number = {292},
pages = {266-268},
pmid = {34464365},
issn = {1426-9686},
abstract = {The consequences of forced isolation due to the risk of SARS-CoV-2 infection in patients with symptoms of dementia in the elderly are only now being analyzed.<br><br>AIM: The aim of the study was to conduct a preliminary analysis of the effects of a break in implementing rehabilitation programs in patients with Alzheimer's disease with symptoms of dementia.<br><br>MATERIALS AND METHODS: The analysis included data obtained from qualification tests of 19 patients (14 women, 5 men) aged 76 to 91 years (mean 81.2 +/- 9.9 years) qualified in 2021 to return to groups at the Alzheimer Center in Warsaw. The obtained results of the performed Katz, Lawton tests and the Mini-Mental State Examination (MMSE) were compared with the results from 2020.<br><br>RESULTS: The initial assessment showed a deterioration of the general and mental condition of patients qualified for the planned activities. The Katz test for the assessment of basic activities of everyday life did not reveal any significant changes in relation to the results obtained one year ago, while the Lawton test for the assessment of complex activities of daily life showed that 13 (68%) of the subjects significantly deteriorated compared to the previous year's study. On the other hand, in the MMSE, deterioration was noted in 12 (63%) analyzed compared to their state from a year ago.<br><br>CONCLUSIONS: During the year of forced isolation due to the risk of SARS-CoV-2 infection, there was a significant deterioration in the daily activities and cognitive functions of patients with symptoms of dementia in the elderly.},
}
@article {pmid34464084,
year = {2021},
author = {Zhou, Y and Li, J and Nordberg, A and Ågren, H},
title = {Dissecting the Binding Profile of PET Tracers to Corticobasal Degeneration Tau Fibrils.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.1c00536},
pmid = {34464084},
issn = {1948-7193},
abstract = {Alzheimer's disease and primary tauopathies are characterized by the presence of tau pathology in brain. Several tau positron emission tomography (PET) tracers have been developed and studied in Alzheimer's disease (AD), but there is still a lack of 4R-tau specific tracers for non-AD tauopathies. We here present the first computational study on the binding profiles of four tau different PET tracers, PI2620, CBD2115, PM-PBB3, and MK6240, to corticobasal degeneration (CBD) tau. The in silico results showed different preferences for the various binding sites on the 4R fibril, and especially an entry site, a concave site, and a core site showed high binding affinity to these tracers. The core site and entry site both showed higher binding affinity than the surface sites, but the tracers were less likely to enter these sites. PI2620, CBD2115, and PM-PBB3 all showed higher binding affinities to CBD tau than the 3R/4R tracer MK6240. The same strategy has also been applied to AD tau fibrils, and significant differences in selectivity of binding sites were also observed. A higher binding affinity was observed for CBD2115 and PM-PBB3 to AD tau compared to PI2620. None of the studied tracers showed a selectivity for 4R compared to 3R/4R tau. This study clearly shows that identified binding sites from cryo-EM with low resolution can be further refined by metadynamics simulations in order to provide atomic resolution of the binding modes as well as of the thermodynamic properties.},
}
@article {pmid34463994,
year = {2021},
author = {Kapila, YL},
title = {Oral health's inextricable connection to systemic health: Special populations bring to bear multimodal relationships and factors connecting periodontal disease to systemic diseases and conditions.},
journal = {Periodontology 2000},
volume = {87},
number = {1},
pages = {11-16},
doi = {10.1111/prd.12398},
pmid = {34463994},
issn = {1600-0757},
abstract = {The landscape in dentistry is changing as emerging studies continue to reveal that periodontal health impacts systemic health, and vice versa. Population studies, clinical studies, and in vitro animal studies underscore the critical importance of oral health to systemic health. These inextricable relationships come to the forefront as oral diseases, such as periodontal disease, take root. Special populations bring to bear the multimodal relationships between oral and systemic health. Specifically, periodontal disease has been associated with diabetes, metabolic syndrome, obesity, eating disorders, liver disease, cardiovascular disease, Alzheimer disease, rheumatoid arthritis, adverse pregnancy outcomes, and cancer. Although bidirectional relationships are recognized, the potential for multiple comorbidities, relationships, and connections (multimodal relationships) also exists. Proposed mechanisms that mediate this connection between oral and systemic health include predisposing and precipitating factors, such as genetic factors (gene polymorphisms), environmental factors (stress, habits-such as smoking and high-fat diets/consumption of highly processed foods), medications, microbial dysbiosis and bacteremias/viremias/microbemias, and an altered host immune response. Thus, in a susceptible host, these predisposing and precipitating factors trigger the onset of periodontal disease and systemic disease/conditions. Further, high-throughput sequencing technologies are shedding light on the dark matter that comprises the oral microbiome. This has resulted in better characterization of the oral microbial dysbiosis, including putative bacterial periodontopathogens and shifts in oral virome composition during disease. Multiple laboratory and clinical studies have illustrated that both eukaryotic and prokaryotic viruses within subgingival plaque and periodontal tissues affect periodontal inflammation, putative periodontopathogens, and the host immune response. Although the association between herpesviruses and periodontitis and the degree to which these viruses directly aggravate periodontal tissue damage remain unclear, the benefits to periodontal health found from prolonged administration of antivirals in immunocompromised or immunodeficient individuals demonstrates that specific populations are possibly more susceptible to viral periodontopathogens. Thus, it may be important to further examine the implications of viral pathogen involvement in periodontitis and perhaps it is time to embrace the viral dark matter within the periodontal environment to fully comprehend the pathogenesis and systemic implications of periodontitis. Emerging data from the coronavirus disease 2019 pandemic further underscores the inextricable connection between oral and systemic health, with high levels of the severe acute respiratory syndrome coronavirus 2 angiotensin-converting enzyme 2 receptor noted on oral tissues (tongue) and an allostatic load or overload paradigm of chronic stress likely contributing to rapid breakdown of oral/dental, periodontal, and peri-implant tissues. These associations exist within a framework of viremias/bacteremias/microbemias, systemic inflammation, and/or disturbances of the immune system in a susceptible host. A thorough review of systemic and oral diseases and conditions and their mechanistic, predisposing, and precipitating factors are paramount to better addressing the oral and systemic health and needs of our patients.},
}
@article {pmid34463981,
year = {2021},
author = {Ryder, MI and Xenoudi, P},
title = {Alzheimer disease and the periodontal patient: New insights, connections, and therapies.},
journal = {Periodontology 2000},
volume = {87},
number = {1},
pages = {32-42},
doi = {10.1111/prd.12389},
pmid = {34463981},
issn = {1600-0757},
abstract = {Loss of cognitive function in the aging population, particular those with Alzheimer disease, presents unique challenges to health practitioners. For the dental practitioner these include management of periodontal diseases, caries, and other dental conditions in this special population. It is well established in the cognitively impaired patient that a lack of adherence to dental hygiene routines and professional care leads to increases in the prevalence and severity of these dental conditions, leading to increased loss of teeth. More recent evidence has indicated a possible role of the microbiota of dental plaque associated with periodontal diseases in the development and progression of Alzheimer disease, thereby supporting a two-way interaction of these two diseases. New therapies are needed to address the potential upstream events that may precede overt signs of Alzheimer disease. One of these approaches would be to target these various bacterial, viral, and other microbial pathogens associated with periodontal disease that can translocate into the bloodstream and then to distal sites, such as the brain. Such microbial translocation would lead to local inflammation and buildup of the hallmark signs of Alzheimer disease, including amyloid beta deposits, tau fragmentation and tangles, breakdown of host protective molecules, such as the apolipoproteins, and neuron toxicity. In this review, evidence for the biological basis of the role of the periodontal disease microflora on the initiation and progression of Alzheimer disease will be presented with a focus on the potential role of the keystone pathogen Porphyromonas gingivalis with its family of gingipain enzymes. The various mechanisms for which P. gingivalis gingipains may contribute to the initiation and progression of Alzheimer disease are presented. Small-molecule inhibitors of these gingipains and their effects on reducing biological markers of Alzheimer disease may have beneficial effects for the initiation and progression of loss of cognitive function in Alzheimer disease. In addition to these targeted therapies for specific periodontal pathogens, considerations for the dental practitioner in applying more general approaches to reducing the periodontal plaque microflora in the management of the cognitively impaired patient are discussed for this special population.},
}
@article {pmid34463747,
year = {2021},
author = {Fox-Fuller, JT and Artola, A and Chen, K and Pulsifer, M and Ramirez, D and Londono, N and Aguirre-Acevedo, DC and Vila-Castelar, C and Baena, A and Martinez, J and Arboleda-Velasquez, JF and Langbaum, JB and Tariot, PN and Reiman, EM and Lopera, F and Quiroz, YT},
title = {Sex Differences in Cognitive Abilities Among Children With the Autosomal Dominant Alzheimer Disease Presenilin 1 E280A Variant From a Colombian Cohort.},
journal = {JAMA network open},
volume = {4},
number = {8},
pages = {e2121697},
doi = {10.1001/jamanetworkopen.2021.21697},
pmid = {34463747},
issn = {2574-3805},
abstract = {Importance: We previously reported that children with the autosomal dominant Alzheimer disease (ADAD) presenilin 1 (PSEN1) E280A variant had early life plasma biomarker findings consistent with amyloid β overproduction. However, the cognitive functioning of children with this variant has not been characterized vs those without the variant.<br><br>Objective: To test whether cognitive functioning of children with and without the PSEN1 E280A variant in the same ADAD cohort differed by genetic status (ie, PSEN1 variant) and sex.<br><br>This cohort study was conducted among 1354 children (including 265 children with the variant) aged 6 to 16 years recruited from the Alzheimer Prevention Initiative Colombia Registry. Participants from the city of Medellín and surrounding suburban areas traveled to the University of Antioquia to undergo all procedures. Participants were administered a Spanish version of the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) to measure general cognitive functioning. Data were analyzed from July through November 2020.<br><br>Main Outcomes and Measures: Univariate general linear models were used to characterize differences on WISC-IV cognitive performance by genetic status, sex, and the interaction of genetic status with sex. Urbanity, socioeconomic status, and education were entered as covariates.<br><br>Results: Among 1354 children with ADAD (695 [51.3%] girls; mean [SD] age, 11.64 [2.64] years), there were 265 children with the variant (19.6%) and 1089 children without the variant (80.4%). Children with and without the variant did not differ by demographic variables or performance on WISC-IV indices. Irrespective of genetic status, boys had statistically significantly decreased mean scores on indices for working memory (90.27 [95% CI, 89.21-91.34] vs 92.99 [95% CI, 91.98-93.99]; mean difference = -2.72; P < .001), perceptual reasoning (91.56 [95% CI, 90.47-92.65] vs. 93.27 [95% CI, 91.23-94.30]; mean difference = -1.71; P = .03), and verbal comprehension (88.69 [95% CI, 87.54-89.84] vs. 90.81 [95% CI, 89.73-91.90]; mean difference = -2.12; P = .009) compared with girls. In the interaction between sex and genetic status, boys with the variant had worse mean working memory index performance (88.78 [95% CI, 86.86-90.70]) than girls with the variant (93.75 [95% CI, 91.95-95.55]; mean difference = -4.97; P = .001), as well as boys (91.77 [95% CI, 90.85-92.70]; mean difference = -2.99; P = .04) and girls (92.22 [95% CI, 91.32-93.13]; mean difference = -3.44; P = .009) without the variant.<br><br>Conclusions and Relevance: This study found that boys with the PSEN1 variant had decreased working memory abilities compared with girls with the variant and boys and girls without the variant, suggesting a sex-specific genetic risk in early life cognitive performance among individuals with the PSEN1 variant. This increased risk of future cognitive difficulties among boys with the variant may have important downstream implications for learning and academic achievement and could be associated with sex differences seen in adulthood on episodic memory measures.},
}
@article {pmid34460609,
year = {2020},
author = {Gambi, E and Ricciuti, M and De Santis, A},
title = {Food Intake Actions Detection: An Improved Algorithm Toward Real-Time Analysis.},
journal = {Journal of imaging},
volume = {6},
number = {3},
pages = {},
doi = {10.3390/jimaging6030012},
pmid = {34460609},
issn = {2313-433X},
abstract = {With the increase in life expectancy, one of the most important topic for scientific research, especially for the elderly, is good nutrition. In particular, with an advanced age and health issues because disorders such as Alzheimer and dementia, monitoring the subjects' dietary habits to avoid excessive or poor nutrition is a critical role. Starting from an application aiming to monitor the food intake actions of people during a meal, already shown in a previously published paper, the present work describes some improvements that are able to make the application work in real time. The considered solution exploits the Kinect v1 device that can be installed on the ceiling, in a top-down view in an effort to preserve privacy of the subjects. The food intake actions are estimated from the analysis of depth frames. The innovations introduced in this document are related to the automatic identification of the initial and final frame for the detection of food intake actions, and to the strong revision of the procedure to identify food intake actions with respect to the original work, in order to optimize the performance of the algorithm. Evaluation of the computational effort and system performance compared to the previous version of the application has demonstrated a possible real-time applicability of the solution presented in this document.},
}
@article {pmid34459862,
year = {2021},
author = {Winer, JR and Deters, KD and Kennedy, G and Jin, M and Goldstein-Piekarski, A and Poston, KL and Mormino, EC},
title = {Association of Short and Long Sleep Duration With Amyloid-β Burden and Cognition in Aging.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2876},
pmid = {34459862},
issn = {2168-6157},
abstract = {Importance: Disrupted sleep is common in aging and is associated with cognition. Age-related changes to sleep are associated with multiple causes, including early Alzheimer disease pathology (amyloid β [Aβ]), depression, and cardiovascular disease.<br><br>Objective: To investigate the associations between self-reported sleep duration and brain Aβ burden as well as the demographic, cognitive, and lifestyle variables in adults with normal cognition.<br><br>This cross-sectional study obtained data from participants in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is being conducted in 67 sites in the United States, Canada, Australia, and Japan. The sample for this analysis consisted of individuals aged 65 to 85 years who underwent an Aβ positron emission tomography (PET) scan, had complete apolipoprotein E (APOE) genotype data, and were identified as clinically normal (per a Clinical Dementia Rating score of 0) and cognitively unimpaired (per a Mini-Mental State Examination score of 25 to 30 and Logical Memory Delayed Recall test score of 6 to 18). Data were analyzed from April 3, 2020, to June 20, 2021.<br><br>Main Outcomes and Measures: The outcome was self-reported nightly sleep duration (grouped by short sleep duration: ≤6 hours, normal sleep duration: 7-8 hours, and long sleep duration: ≥9 hours) compared with demographic characteristics, Aβ burden (as measured with a fluorine 18-labeled-florbetapir PET scan), objective and subjective cognitive function measures, and lifestyle variables.<br><br>Results: The 4417 participants in the study included 2618 women (59%) and had a mean (SD) age of 71.3 (4.7) years. Self-reported shorter sleep duration was linearly associated with higher Aβ burden (β [SE] = -0.01 [0.00]; P = .005), and short sleep duration was associated with reduced cognition that was mostly in memory domains. No difference in Aβ was found between long and normal sleep duration groups (β [SE] = 0.00 [0.01]; P = .99). However, compared with normal sleep duration, both short and long sleep durations were associated with higher body mass index (short vs normal sleep duration: β [SE] = 0.48 [0.17], P = .01; long vs normal sleep duration: β [SE] = 0.97 [0.31], P = .002), depressive symptoms (short vs normal sleep duration: β [SE] = 0.31 [0.05], P < .001; long vs normal sleep duration: β [SE] = 0.39 [0.09], P < .001), and daytime napping (short vs normal sleep duration: β [SE] = 2.66 [0.77], P = .001; long vs normal sleep duration: β [SE] = 3.62 [1.38], P = .01). Long sleep duration was associated with worse performance across multiple cognitive domains.<br><br>Conclusions and Relevance: In this cross-sectional study, both short and long sleep durations were associated with worse outcomes for older adults, such as greater Aβ burden, greater depressive symptoms, higher body mass index, and cognitive decline, emphasizing the importance of maintaining adequate sleep.},
}
@article {pmid34458554,
year = {2021},
author = {Al-Hamed, FS and Kouniaris, S and Tamimi, I and Lordkipanidzé, M and Madathil, SA and Kezouh, A and Karp, I and Nicolau, B and Tamimi, F},
title = {Acetylcholinesterase inhibitors and risk of bleeding and acute ischemic events in non-hypertensive Alzheimer's patients.},
journal = {Alzheimer's &amp; dementia (New York, N. Y.)},
volume = {7},
number = {1},
pages = {e12184},
doi = {10.1002/trc2.12184},
pmid = {34458554},
issn = {2352-8737},
abstract = {Introduction: Acetylcholinesterase inhibitors (AChEIs) are commonly used to treat mild to moderate cases of Alzheimer disease (AD). To the best of our knowledge, there has been no study estimating the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Therefore, this study aimed to estimate the association between AChEIs and the risk of bleeding and cardiovascular ischemic events in patients with non-hypertensive AD.<br><br>Methods: A nested case-control study was conducted to estimate the risk of bleeding and ischemic events (angina, myocardial infarction [MI], and stroke) in patients with AD. This study was conducted using the UK Clinical Practice Research Datalink and Hospital Episode Statistics (HES) databases. The study cohort consisted of AD patients ≥65 years of age. The case groups included all AD subjects in the database who had a bleeding or ischemic event during the cohort follow-up. Four controls were selected for each case. Patients were classified as current users or past users based on a 60-day threshold of consuming the drug. Simple and multivariable conditional logistic regression analyses were used to calculate the adjusted odds ratio for bleeding events and cardiovascular events.<br><br>Results: We identified 507 cases and selected 2028 controls for the bleeding event cohort and 555 cases and 2220 controls for the ischemic event cohort. The adjusted odds ratio (OR) (95% confidence interval [CI]) for the association of AChEI use was 0.93 (0.75 to 1.16) for bleeding events, 2.58 (1.01 to 6.59) for angina, and 1.89 (1.07 to 3.33) for MI. Past users of AChEIs were also at increased risk of stroke (1.51 [1.00 to 2.27]).<br><br>Discussion: This is the first study assessing the risk of bleeding and cardiovascular events in patients with non-hypertensive AD. Our findings could be of great interest for clinicians and researchers working on AD.},
}
@article {pmid34456638,
year = {2020},
author = {Dickerson, B and Atri, A},
title = {Molecular Imaging Biomarkers in Dementia: Amyloid and tau PET imaging aids evaluation of patients suspected of having Alzheimer disease or other dementias.},
journal = {Practical neurology (Fort Washington, Pa.)},
volume = {19},
number = {9},
pages = {34-45},
pmid = {34456638},
issn = {1540-1367},
}
@article {pmid34453888,
year = {2021},
author = {Jiang, L and Lin, W and Zhang, C and Ash, PEA and Verma, M and Kwan, J and van Vliet, E and Yang, Z and Cruz, AL and Boudeau, S and Maziuk, BF and Lei, S and Song, J and Alvarez, VE and Hovde, S and Abisambra, JF and Kuo, MH and Kanaan, N and Murray, ME and Crary, JF and Zhao, J and Cheng, JX and Petrucelli, L and Li, H and Emili, A and Wolozin, B},
title = {Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2021.07.038},
pmid = {34453888},
issn = {1097-4164},
abstract = {The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.},
}
@article {pmid34451840,
year = {2021},
author = {Thakur, A and Moyo, P and van der Westhuizen, CJ and Yang, HO and Maharaj, V},
title = {A Novel Cardenolide Glycoside Isolated from Xysmalobium undulatum Reduces Levels of the Alzheimer's Disease-Associated β-Amyloid Peptides Aβ42 In Vitro.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {14},
number = {8},
pages = {},
doi = {10.3390/ph14080743},
pmid = {34451840},
issn = {1424-8247},
support = {NRF-2015M3A9A5030735//Bio &amp; Medical Technology Development Program/ ; },
abstract = {Elevated levels of the amylo β-proteins (Aβ), particularly Aβ42, are associated with a high risk of Alzheimer's disease (AD). The Aβ proteins are produced from cellular processing of the amyloid precursor proteins (APPs). To identify natural products that block the formation of Aβ-proteins from APPs, we previously screened a library of plant extracts and identified Xysmalobium undulaum (Apocynaceae) as a potential plant for further research. Here, we provide a report on the isolation and identification of the active principles from the plant species using a bioassay-guided fractionation. Fractions and resulting pure compounds from the purification process of the extract of X. undulatum were screened in vitro against APPs transfected HeLa cell lines. Three compounds, acetylated glycosydated crotoxogenin (1), xysmalogenin-3, β-d-glucopyranoside (2), and crotoxigenin 3-O-glucopyranoside (3), were subsequently isolated and their structures elucidated using NMR and mass spectrometry. Compound 1, a novel cardenolide, and 2 significantly decreased the Aβ42 levels in a dose-dependent manner while compound 3 was inactive. In silico investigations identified the AD's β-secretase enzyme, BACE1, as a potential target for these compounds with the glycoside moiety being of significance in binding to the enzyme active site. Our study provides the first report of a novel cardenolide and the potential of cardenolides as chemical scaffolds for developing AD treatment drugs.},
}
@article {pmid34449462,
year = {2021},
author = {Liang, Z and Wu, L and Gong, S and Liu, X},
title = {The cognitive dysfunction related to Alzheimer disease or cerebral small vessel disease: What's the differences.},
journal = {Medicine},
volume = {100},
number = {34},
pages = {e26967},
doi = {10.1097/MD.0000000000026967},
pmid = {34449462},
issn = {1536-5964},
support = {LY13G030020//natural science foundation of zhejiang province/ ; },
abstract = {ABSTRACT: Alzheimer disease (AD) and sporadic cerebral small vessel disease (CSVD) are common cognitive disorders. Both AD and CSVD have mental symptoms including chronic progressive cognitive impairment, dysfunction, and behavioral abnormalities. However, the differences on the cognitive dysfunction of AD and CSVD remain unclear. It is necessary to elucidate the cognitive dysfunction differences of AD and CSVD, and to identify the potential risk factors.AD or sporadic CSVD patients treated in our hospital from December 1, 2018 to May 31, 2019 were included. And we selected healthy participants as controls. The mini-mental state examination and Montreal Cognitive Assessment Scale were used for neuropsychological assessment, and related medical information were collected and compared.A total of 190 patients were included. The total mini-mental state examination scores in AD, CSVD group were significantly less than that of control group, there were significant differences in the domains of directional ability, attention and computing ability, delayed recall, and visual perception (all P < .05); the total Montreal Cognitive Assessment Scale scores in AD, CSVD group were significantly less than that of control group. There were significant differences in the domains of visual space and execution, immediate remember, attention and computing ability, language, delayed recall, and directional ability (all P < .05); diabetes was a risk factor both for AD (hazard ratio = 1.63, 95% confidence interval: 1.35-1.97) and CSVD (hazard ratio = 1.15, 95% confidence interval: 1.08-1.27).The cognitive dysfunctions of AD are difference to that of CSVD patients, and diabetes is the risk factor both for AD and CSVD, future studies are needed to further identify the prevention and treatment of AD and CSVD.},
}
@article {pmid34448373,
year = {2021},
author = {Kim, JW and Kim, DK and Lee, HS and Park, JY and Ahn, HK and Ha, JS and Lee, D and Cho, KS},
title = {Androgen Deprivation Therapy in Patients with Prostate Cancer is Associated with the Risk of Subsequent Alzheimer's Disease but not with Vascular Dementia.},
journal = {The world journal of men's health},
volume = {},
number = {},
pages = {},
doi = {10.5534/wjmh.210019},
pmid = {34448373},
issn = {2287-4208},
support = {KUOS18-02//Korean Urological Oncology Society/Korea ; },
abstract = {PURPOSE: We aimed to investigate the association between androgen deprivation therapy (ADT) and the risk of dementia according to subtypes of dementia in men with prostate cancer.<br><br>MATERIALS AND METHODS: We performed a nationwide population-based cohort study using the nationwide claims database in Korea. A total of 195,308 men with newly diagnosed prostate cancer were identified between January 2008 and December 2017, and 132,700 men were selected for analysis after applying inclusion and exclusion criteria. The patients were divided into ADT and non-ADT groups. To adjust for imbalances in relevant comorbidities between the groups, exact matching was performed. Study events included newly developed Alzheimer's disease, vascular dementia, and overall dementia. Cox proportional hazard regression models were used.<br><br>RESULTS: After exact matching, 44,854 men with prostate cancer were selected for the main analysis. In age-adjusted Cox regression analysis, the ADT group was significantly associated with increased risks for overall dementia (hazard ratio [HR], 1.070; 95% confidence interval [CI], 1.009-1.134; p=0.0232) and Alzheimer's disease (HR, 1.086; 95% CI, 1.018-1.160; p=0.0127), compared to the non-ADT group. No difference in vascular dementia risk was observed between the two groups (HR, 0.990; 95% CI, 0.870-1.126; p=0.8792).<br><br>CONCLUSIONS: The risk of overall dementia increased in men who received ADT. According to dementia subtypes, ADT was associated with an increased risk of Alzheimer's disease, but not with vascular dementia.},
}
@article {pmid34447508,
year = {2021},
author = {Soureshjani, FH and Kheirollahi, M and Yaghmaei, P and Fattahjadnematalahi, S},
title = {Possible Preventive Effect of Donepezil and Hyoscyamoside by Reduction of Plaque Formation and Neuroinflammation in Alzheimer's Disease.},
journal = {International journal of preventive medicine},
volume = {12},
number = {},
pages = {66},
doi = {10.4103/ijpvm.IJPVM_143_19},
pmid = {34447508},
issn = {2008-7802},
abstract = {Background: Alzheimer disease (AD) is the most common age-dependent dementia. The complex natural accumulation of amyloid beta (Aβ) precursor protein in hippocampus neurons is regarded as the earliest pathological feature of AD, although there are cholinergic assumptions and effective inflammation in AD. In this animal experimental study, we evaluated the preventive effect of hyoscyamoside (Hyo) and donepezil (Dz) on plaque formation and improvement of neurogenic inflammation in AD rats.<br><br>Methods: Dz was prepared and Hyo (steroidal saponin) was isolated from Hyoscymus niger. Then, Wistar rats divided into five groups including negative and positive controls, AD, Dz, and Hyo treatment groups based on the drug exposure and their behavioral alternation was examined using Morris water maze (MWM) test. Bielschowsky staining was used to detect the nerve fibers. Serum levels of interleukin (IL)-4 and IL-6 were evaluated by ELISA. The RNA expression of cyclin-dependent kinase CDK11-P58 in peripheral blood lymphocytes was performed using quantitative PCR.<br><br>Results: The MWM test showed significant changes in time the models spent to find the hidden platform. The Hyo treatment group showed a notable speed change (P < 0.01). The histopathological analysis of the hippocampal tissue revealed the inhibition of Aβ formation in the treatment groups. The treatment groups had a significant decline in the serum level of IL-6, and the IL-4 serum level was increased in the Hyo and Dz treated groups. The expression levels of CDK11-P58 was significantly decreased in the treatment groups.<br><br>Conclusions: In sum, the therapeutic effects of Hyo is comparable with that of Dz in AD rats by suppressing neuroinflammation. Thus, these compounds could be considered as a preventive agent in the AD therapy.},
}
@article {pmid34447243,
year = {2021},
author = {Wang, S and Ma, J and Zeng, Y and Zhou, G and Wang, Y and Zhou, W and Sun, X and Wu, M},
title = {Icariin, an Up-and-Coming Bioactive Compound Against Neurological Diseases: Network Pharmacology-Based Study and Literature Review.},
journal = {Drug design, development and therapy},
volume = {15},
number = {},
pages = {3619-3641},
doi = {10.2147/DDDT.S310686},
pmid = {34447243},
issn = {1177-8881},
abstract = {Icariin is a biologically active substance in Epimedii herba that is used for the treatment of neurologic disorders. However, a comprehensive analysis of the molecular mechanisms of icariin is lacking. In this review, we present a brief history of the use of icariin for medicinal purposes; describe the active chemical components of Epimedii herba; and examine the evidence from experimental studies that have uncovered molecular targets of icariin in different diseases. We also constructed a protein-protein interaction network and carried out Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analyses to predict the therapeutic actions of icariin in nervous system diseases including Alzheimer disease, Parkinson disease, ischemic stroke, depressive disorder, multiple sclerosis, glioblastoma, and hereditary spastic paraplegias. The results of our analyses can guide future studies on the application of icariin to the treatment of neurologic disorders.},
}
@article {pmid34446781,
year = {2021},
author = {Wohlschlegel, J and Argentini, M and Michiels, C and Letellier, C and Forster, V and Condroyer, C and He, Z and Thuret, G and Zeitz, C and Léger, T and Audo, I},
title = {First identification of ITM2B interactome in the human retina.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {17210},
pmid = {34446781},
issn = {2045-2322},
support = {ANR-18-IAHU-0001//IHU FOReSIGHT/ ; ANR-10-LABX-65//LABEX LIFESENSES/ ; ANR-11-IDEX-0004-0//Agence Nationale de la Recherche/ ; [BR-GE-0619-0761-INSERM]//Foundation Fighting Blindness grant/ ; },
abstract = {Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.},
}
@article {pmid34445613,
year = {2021},
author = {Oleksak, P and Novotny, M and Patocka, J and Nepovimova, E and Hort, J and Pavlik, J and Klimova, B and Valis, M and Kuca, K},
title = {Neuropharmacology of Cevimeline and Muscarinic Drugs-Focus on Cognition and Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {22},
number = {16},
pages = {},
doi = {10.3390/ijms22168908},
pmid = {34445613},
issn = {1422-0067},
support = {VT2019-2021//UHK/ ; },
abstract = {At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-β (Aβ) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.},
}
@article {pmid34445429,
year = {2021},
author = {Sini, P and Dang, TBC and Fais, M and Galioto, M and Padedda, BM and Lugliè, A and Iaccarino, C and Crosio, C},
title = {Cyanobacteria, Cyanotoxins, and Neurodegenerative Diseases: Dangerous Liaisons.},
journal = {International journal of molecular sciences},
volume = {22},
number = {16},
pages = {},
doi = {10.3390/ijms22168726},
pmid = {34445429},
issn = {1422-0067},
support = {2018-1-IT02-KA107-047494//Erasmus+/ ; CCI2014IT16M2OP005//PON/ ; Fondo di Ateneo per la Ricerca 2019-Crosio//UNISS/ ; Fondo di Ateneo per la Ricerca 2019-Iaccarino//UNISS/ ; Bando 2017- Iaccarino//Fondazione di Sardegna/ ; },
abstract = {The prevalence of neurodegenerative disease (ND) is increasing, partly owing to extensions in lifespan, with a larger percentage of members living to an older age, but the ND aetiology and pathogenesis are not fully understood, and effective treatments are still lacking. Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are generally thought to progress as a consequence of genetic susceptibility and environmental influences. Up to now, several environmental triggers have been associated with NDs, and recent studies suggest that some cyanotoxins, produced by cyanobacteria and acting through a variety of molecular mechanisms, are highly neurotoxic, although their roles in neuropathy and particularly in NDs are still controversial. In this review, we summarize the most relevant and recent evidence that points at cyanotoxins as environmental triggers in NDs development.},
}
@article {pmid34443478,
year = {2021},
author = {Manoliu, LCE and Martin, EC and Milac, AL and Spiridon, L},
title = {Effective Use of Empirical Data for Virtual Screening against APJR GPCR Receptor.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {16},
pages = {},
doi = {10.3390/molecules26164894},
pmid = {34443478},
issn = {1420-3049},
support = {PN-III-P3-3.5-EUK-2017-02-0030//Ministerul Cercetării şi Inovării/ ; },
abstract = {Alzheimer's disease is a neurodegenerative disorder incompatible with normal daily activity, affecting one in nine people. One of its potential targets is the apelin receptor (APJR), a G-protein coupled receptor, which presents considerably high expression levels in the central nervous system. In silico studies of APJR drug-like molecule binding are in small numbers while high throughput screenings (HTS) are already sufficiently many to devise efficient drug design strategies. This presents itself as an opportunity to optimize different steps in future large scale virtual screening endeavours. Here, we ran a first stage docking simulation against a library of 95 known binders and 3829 generated decoys in an effort to improve the rescoring stage. We then analyzed receptor binding site structure and ligands binding poses to describe their interactions. As a result, we devised a simple and straightforward virtual screening Stage II filtering score based on search space extension followed by a geometric estimation of the ligand-binding site fitness. Having this score, we used an ensemble of receptors generated by Hamiltonian Monte Carlo simulation and reported the results. The improvements shown herein prove that our ensemble docking protocol is suited for APJR and can be easily extrapolated to other GPCRs.},
}
@article {pmid34443456,
year = {2021},
author = {Wongrattanakamon, P and Jiaranaikulwanitch, J and Vajragupta, O and Jiranusornkul, S and Saenjum, C and Yooin, W},
title = {Potential Anti-Alzheimer Agents from Guanidinyl Tryptophan Derivatives with Activities of Membrane Adhesion and Conformational Transition Inhibitions.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {16},
pages = {},
doi = {10.3390/molecules26164863},
pmid = {34443456},
issn = {1420-3049},
support = {Not available//Chiang Mai University/ ; },
abstract = {Guanidinyl tryptophan derivatives TGN1, TGN2, TGN3, and TGN4 were synthesized, and these compounds were shown to possess in vitro inhibitory activity for amyloid aggregation in a previous study. Nevertheless, the influence of the TGN series of compounds on the binding and permeation behaviors of an Aβ monomer to the cell membranes was not elucidated. In this study, we investigated the effect of compounds in the TGN series on the behavior of an Aβ monomer regarding its toxicity toward the bilayer lipid membrane using molecular dynamics (MD) simulation. MD simulations suggest that TGN4 is a potential agent that can interfere with the movement of the Aβ monomer into the membrane. The MM-GBSA result demonstrated that TGN4 exhibits the highest affinity to the Aβ1-42 monomer but has the lowest affinity to the bilayer. Moreover, TGN4 also contributes to a decrease in the binding affinity between the Aβ1-42 monomer and the POPC membrane. Regarding the results of the binding mode and conformational analyses, a high number of amino-acid residues were shown to provide the binding interactions between TGN4 and the Aβ1-42 monomer. TGN4 also reduces the conformational transition of the Aβ1-42 monomer by means of interacting with the monomer. The present study presents molecular-level insights into how the TGN series of compounds affect the membrane adsorption and the conformational transition of the Aβ1-42 monomer, which could be valuable for the further development of new anti-Alzheimer agents.},
}
@article {pmid34442173,
year = {2021},
author = {Morales-de-Jesús, V and Gómez-Adorno, H and Somodevilla-García, M and Vilariño, D},
title = {Conversational System as Assistant Tool in Reminiscence Therapy for People with Early-Stage of Alzheimer's.},
journal = {Healthcare (Basel, Switzerland)},
volume = {9},
number = {8},
pages = {},
doi = {10.3390/healthcare9081036},
pmid = {34442173},
issn = {2227-9032},
support = {TA100520//DGAPA-UNAM PAPIIT/ ; PNPC No. CVU 626812//Consejo Nacional de Ciencia y Tecnología/ ; },
abstract = {Reminiscence therapy is a non-pharmacological intervention that helps mitigate unstable psychological and emotional states in patients with Alzheimer's disease, where past experiences are evoked through conversations between the patients and their caregivers, stimulating autobiographical episodic memory. It is highly recommended that people with Alzheimer regularly receive this type of therapy. In this paper, we describe the development of a conversational system that can be used as a tool to provide reminiscence therapy to people with Alzheimer's disease. The system has the ability to personalize the therapy according to the patients information related to their preferences, life history and lifestyle. An evaluation conducted with eleven people related to patient care (caregiver = 9, geriatric doctor = 1, care center assistant = 1) shows that the system is capable of carrying out a reminiscence therapy according to the patient information in a successful manner.},
}
@article {pmid34437876,
year = {2021},
author = {Chileski, GS and García, EN and Lértora, JW and Mussart, N and Hernández, DR and Cholich, LA},
title = {Hepatic encephalotathy in swine experimentally poisoned with Senna occidentalis seeds: effects on astrocytes.},
journal = {Toxicon : official journal of the International Society on Toxinology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.toxicon.2021.08.018},
pmid = {34437876},
issn = {1879-3150},
abstract = {Senna occidentalis may be accidentally ingested by humans and animals. In this study, the percentages of S. occidentalis seeds necessary for experimental reproduction of hepatic encephalopathy were determined in a pig model and the biochemical and microscopic pathology is described in detail, with emphasis on the astrocytes. The experimental groups (G1, G2 and G3) were fed rations containing 5%, 7.5% and 10% of S. occidentalis seeds for 7 to 11 days. Pigs from the three experimental groups showed incoordination, ataxia, disorientation, head pressing, anorexia, recumbency and depression. In addition, the enzymes aspartate aminotransferase, alkaline phosphatase and creatine phosphokinase increased in all treated animals, which also showed higher serum total bilirubin and ammonia levels than in the control group (C). Microscopically, all experimental animals revealed acute hepatocellular swelling, multifocal coagulative necrosis in the pancreas, necrosis in the cardiac muscle, severe spongiosis in brain white and grey matter, and Alzheimer type II astrocytes in grey matter of the cerebral cortex. These cells were glial fibrillary acidic protein (GFAP) negative in G3. In white matter, a decrease in the positive area occupied by GFAP-immunolabelling and in the number of astrocytes per immunoreactive area was observed in G3 animals (5.35±1.14% and 410 ± 45 cells/mm2, respectively) compared to the C animals (13.93±1.59% and 581 ± 36 cells/mm2, respectively). This loss of GFAP was accompanied by alterations in astrocyte morphology, such as shrinkage of the cell body and retraction of the extending processes. This pig model of ammonia-mediated astrocyte damage could be used to study not only poisoning by S. occidentalis, but also other medical conditions resulting in hepatoencephalopathy.},
}
@article {pmid34436517,
year = {2021},
author = {Lu, R and Aziz, NA and Reuter, M and Stöcker, T and Breteler, MMB},
title = {Evaluation of the Neuroanatomical Basis of Olfactory Dysfunction in the General Population.},
journal = {JAMA otolaryngology-- head &amp; neck surgery},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoto.2021.2026},
pmid = {34436517},
issn = {2168-619X},
abstract = {Importance: Olfactory dysfunction is a prodromal manifestation of many neurodegenerative disorders, including Alzheimer and Parkinson disease. However, its neuroanatomical basis is largely unknown.<br><br>Objective: To assess the association between olfactory brain structures and olfactory function in adults 30 years or older and to examine the extent to which olfactory bulb volume (OBV) mediates the association between central olfactory structures and olfactory function.<br><br>This cross-sectional study analyzed baseline data from the first 639 participants with brain magnetic resonance imaging (MRI) in the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Participants were enrolled between March 7, 2016, and October 31, 2017, and underwent brain MRI and olfactory assessment. Data were analyzed from March 1, 2018, to June 30, 2021.<br><br>Exposure: Volumetric measures were derived from 3-T MRI T1-weighted brain scans, and OBV was manually segmented on T2-weighted images. The mean volumetric brain measures from the right and left sides were calculated, adjusted by head size, and normalized to all participants.<br><br>Main Outcomes and Measures: Performance on the 12-item smell identification test (SIT-12) was used as a proxy for olfactory function.<br><br>Results: A total of 541 participants with complete data on MRI-derived measures and SIT-12 scores were included. This population had a mean (SD) age of 53.6 (13.1) years and comprised 306 women (56.6%). Increasing age (difference in SIT-12 score, -0.04; 95% CI, -0.05 to -0.03), male sex (-0.26; 95% CI, -0.54 to 0.02), and nasal congestion (-0.28; 95% CI, -0.66 to 0.09) were associated with worse olfactory function (SIT-12 scores). Conversely, larger OBV was associated with better olfactory function (difference in SIT-12 score, 0.46; 95% CI, 0.29-0.64). Larger volumes of amygdala (difference in OBV, 0.12; 95% CI, 0.01-0.24), hippocampus (0.16; 95% CI, 0.04-0.28), insular cortex (0.12; 95% CI, 0.01-0.24), and medial orbitofrontal cortex (0.10; 95% CI, 0.00-0.20) were associated with larger OBV. Larger volumes of amygdala (volume × age interaction effect, 0.17; 95% CI, 0.03-0.30), parahippocampal cortex (0.17; 95% CI, 0.03-0.31), and hippocampus (0.21; 95% CI, 0.08-0.35) were associated with better olfactory function only in older age groups. The age-modified association between volumes of central olfactory structures and olfactory function was largely mediated through OBV.<br><br>Conclusions and Relevance: This cross-sectional study found that olfactory bulb volume was independently associated with odor identification function and was a robust mediator of the age-dependent association between volumes of central olfactory structures and olfactory function. Thus, neurodegeneration-associated olfactory dysfunction may primarily originate from the pathology of peripheral olfactory structures, suggesting that OBV may serve as a preclinical marker for the identification of individuals who are at an increased risk of neurodegenerative diseases.},
}
@article {pmid34432674,
year = {2021},
author = {Wang, T and Guo, Z and Du, Y and Xiong, M and Yang, Z and Ren, L and He, L and Jiang, Y and McClure, MA and Mu, Q},
title = {Effects of Noninvasive Brain Stimulation (NIBS) on Cognitive Impairment in Mild Cognitive Impairment and Alzheimer Disease: A Meta-analysis.},
journal = {Alzheimer disease and associated disorders},
volume = {35},
number = {3},
pages = {278-288},
doi = {10.1097/WAD.0000000000000464},
pmid = {34432674},
issn = {1546-4156},
abstract = {OBJECTIVE: The purpose of this meta-analysis was to evaluate the beneficial effects and optimal stimulation protocol of noninvasive brain stimulation (NIBS) including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on patients with mild cognitive impairment and Alzheimer disease.<br><br>MATERIALS AND METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched until March 2020. The cognitive outcomes were extracted and the standardized mean difference with 95% confidence interval was calculated.<br><br>RESULTS: Twenty-eight studies were included. The result of NIBS showed significant effect on global cognition (P<0.05). Low-frequency rTMS over right dorsolateral prefrontal cortex (DLPFC), high-frequency rTMS (HF-rTMS) over left DLPFC, and the tDCS over left DLPFC and temporal lobe can significantly improve the memory function (P<0.05). HF-rTMS over left, right, or bilateral DLPFC can significantly improve the language function (P<0.05). Both HF-rTMS and tDCS over left DLPFC can obviously improve the executive function (P<0.05). Multiple sessions of rTMS with 80% to 100% intensity and anode tDCS with 2 mA current density are more suitable for all these functions.<br><br>CONCLUSIONS: NIBS has a beneficial effect on cognitive performance in both mild cognitive impairment and Alzheimer disease patients. Distinct optimal stimulation parameters were observed for different cognitive functions.},
}
@article {pmid34432046,
year = {2021},
author = {Pradeepkiran, JA and Munikumar, M and Reddy, AP and Reddy, PH},
title = {Protective effects of a small molecule inhibitor ligand against hyperphosphorylated tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.},
journal = {Human molecular genetics},
volume = {},
number = {},
pages = {},
doi = {10.1093/hmg/ddab244},
pmid = {34432046},
issn = {1460-2083},
abstract = {The purpose of our study is to understand the protective effects of small molecule ligands for phosphorylated tau (p-tau) in Alzheimer's disease (ad) progression. Many reports show evidence that p-tau is reported to be an important contributor to the formation of paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) in ad neurons. In ad, glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent kinase- 5 (CDK5) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), are the three important kinases responsible for tau hyperphosphorylation. Currently, there are no drugs and/or small molecules that reduce the toxicity of p-tau in ad. In the present study, we rationally selected and validated small molecule ligands that binds to the phosphorylated tau at SER23 (Ser 285). We also assessed the molecular dynamics and validated molecular docking sites for the three best ligands. Based on the best docking scores -8.09, -7.9 and - 7.8 kcal/mol, we found that ligand 1 binds to key hyperphosphorylation residues of p-tau that inhibit abnormal PHF-tau, DYRK1A, and GKS3β that reduce p-tau levels in ad. Using biochemical, molecular, immunoblotting, immunofluorescence, and transmission electron microscopy analyses, we studied the ligand 1 inhibition as well as mitochondrial and synaptic protective effects in immortalized primary hippocampal neuronal (HT22) cells. We found interactions between NAT10-262501 (ligand 1) and p-tau at key phosphorylation sites and these ligand-based inhibitions decreased PHF-tau, DYRK1A and GSK3β levels. We also found increased mitochondrial biogenesis, mitochondrial fusion and synaptic activities and reduced mitochondrial fission in ligand 1-treated mutant tau HT22 cells. Based on these results, we cautiously conclude that p-tau NAT10-262501 (ligand 1) reduces hyperphosphorylation of tau based GKS3β and CDK5 kinase regulation in ad, and aids in the maintenance of neuronal structure, mitochondrial dynamics, and biogenesis with a possible therapeutic drug target for ad.},
}
@article {pmid34431373,
year = {2021},
author = {Walker, KA and Silverstein, N and Zhou, Y and Hughes, TM and Jack, CR and Knopman, DS and Sharrett, AR and Wong, DF and Mosley, TH and Gottesman, RF},
title = {Brain White Matter Structure and Amyloid Deposition in Black and White Older Adults: The ARIC-PET Study.},
journal = {Journal of the American Heart Association},
volume = {},
number = {},
pages = {e022087},
doi = {10.1161/JAHA.121.022087},
pmid = {34431373},
issn = {2047-9980},
abstract = {Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross-sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03-1.83) after adjusting for demographic and cardiovascular risk factors. In race-stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15-3.50), compared with White participants (OR, 1.29; 95% CI, 0.89-1.89). However, the race interaction was not statistically significant (P interaction=0.09). We found no association between white matter microstructure and elevated amyloid. Conclusions The results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.},
}
@article {pmid34430087,
year = {2021},
author = {Amiri, M and Peinkhofer, C and Othman, MH and De Vecchi, T and Nersesjan, V and Kondziella, D},
title = {Global warming and neurological practice: systematic review.},
journal = {PeerJ},
volume = {9},
number = {},
pages = {e11941},
doi = {10.7717/peerj.11941},
pmid = {34430087},
issn = {2167-8359},
abstract = {Background: Climate change, including global warming, will cause poorer global health and rising numbers of environmental refugees. As neurological disorders account for a major share of morbidity and mortality worldwide, global warming is also destined to alter neurological practice; however, to what extent and by which mechanisms is unknown. We aimed to collect information about the effects of ambient temperatures and human migration on the epidemiology and clinical manifestations of neurological disorders.<br><br>Methods: We searched PubMed and Scopus from 01/2000 to 12/2020 for human studies addressing the influence of ambient temperatures and human migration on Alzheimer's and non-Alzheimer's dementia, epilepsy, headache/migraine, multiple sclerosis, Parkinson's disease, stroke, and tick-borne encephalitis (a model disease for neuroinfections). The protocol was pre-registered with PROSPERO (2020 CRD42020147543).<br><br>Results: Ninety-three studies met inclusion criteria, 84 of which reported on ambient temperatures and nine on migration. Overall, most temperature studies suggested a relationship between increasing temperatures and higher mortality and/or morbidity, whereas results were more ambiguous for migration studies. However, we were unable to identify a single adequately designed study addressing how global warming and human migration will change neurological practice. Still, extracted data indicated multiple ways by which these aspects might alter neurological morbidity and mortality soon.<br><br>Conclusion: Significant heterogeneity exists across studies with respect to methodology, outcome measures, confounders and study design, including lack of data from low-income countries, but the evidence so far suggests that climate change will affect the practice of all major neurological disorders in the near future. Adequately designed studies to address this issue are urgently needed, requiring concerted efforts from the entire neurological community.},
}
@article {pmid34429389,
year = {2021},
author = {Zeydan, B},
title = {Reproductive aging and Alzheimer disease biomarkers: an evolving field.},
journal = {Menopause (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1097/GME.0000000000001857},
pmid = {34429389},
issn = {1530-0374},
}
@article {pmid34428352,
year = {2021},
author = {Dai, Y and Peng, L and Liu, Y and Xu, Y and Qiao, J},
title = {Melatonin binds with high affinity and specificity to beta-amyloid: LC-MS provides insight into Alzheimer disease treatment.},
journal = {FEBS open bio},
volume = {},
number = {},
pages = {},
doi = {10.1002/2211-5463.13279},
pmid = {34428352},
issn = {2211-5463},
abstract = {To study the potential relationship between melatonin and beta-amyloid (Abeta), we established a liquid chromatography-mass spectrometry (LC-MS) method to quantitatively analyze melatonin, deuterated isotopes (melatonin-D4) and internal standard 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo(1,2) pyridine (IMPY) under positive (+) mode. The gradient elution was set to 6 min, and the corresponding peak time of melatonin and its isotope melatonin-D4 was 3.14 min, while the peak time for the internal standard IMPY was 3.24 min. Next, we established and optimized the molecule receptor saturation binding assay based on LC-MS to determine the melatonin affinity for beta-amyloid (Abeta). Melatonin showed a high and specific binding for Abeta. The corresponding equilibrium dissociation constant (Kd) of melatonin with Abeta 1-40 and Abeta 1-42 were 814.37±36.62 and 628.33±13.57 nmol/L; besides, the Kd of melatonin with mixed plaques (1-40 and 1-42) was 461.13±45.37 nmol/L. The results may suggest the potential mechanism of action of MT on Abeta, provide a theoretical basis for the improvement of MT treatment for Alzheimer's disease.},
}
@article {pmid34427617,
year = {2021},
author = {Rubin, R},
title = {CMS Considers Controversial Alzheimer Drug Coverage.},
journal = {JAMA},
volume = {326},
number = {8},
pages = {690},
doi = {10.1001/jama.2021.13728},
pmid = {34427617},
issn = {1538-3598},
}
@article {pmid34425883,
year = {2021},
author = {Vijverberg, EGB and Axelsen, TM and Bihlet, AR and Henriksen, K and Weber, F and Fuchs, K and Harrison, JE and Kühn-Wache, K and Alexandersen, P and Prins, ND and Scheltens, P},
title = {Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD.},
journal = {Alzheimer's research &amp; therapy},
volume = {13},
number = {1},
pages = {142},
pmid = {34425883},
issn = {1758-9193},
abstract = {BACKGROUND: Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD.<br><br>METHODS: This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics.<br><br>RESULTS: To be expected early 2023 CONCLUSION: This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498650.},
}
@article {pmid34425652,
year = {2020},
author = {Sedighi, M and Baluchnejadmojarad, T and Roghani, M},
title = {Linagliptin Protects Human SH-SY5Y Neuroblastoma Cells against Amyloid-β Cytotoxicity via the Activation of Wnt1 and Suppression of IL-6 Release.},
journal = {Iranian biomedical journal},
volume = {25},
number = {5},
pages = {343-348},
doi = {10.52547/ibj.25.5.343},
pmid = {34425652},
issn = {2008-823X},
abstract = {Background: Alzheimer's disease is one of the neurodegenerative disorders typified by the aggregate of Aβ and phosphorylated tau protein. Oxidative stress and neuroinflammation, because of Aβ peptides, are strongly involved in the pathophysiology of AD. Linagliptin shows neuroprotective properties against AD pathological processes through alleviation of neural inflammation and AMPK activation.<br><br>Methods: We assessed the benefits of linagliptin pretreatment (at 10, 20, and 50 nM concentrations), against Aβ1-42 toxicity (20 μM) in SH-SY5Y cells. The concentrations of secreted cytokines, such as TNF-α, IL-6, and IL-1β, and signaling proteins, including pCREB, Wnt1, and PKCε, were quantified by ELISA.<br><br>Results: We observed that Aβ led to cellular inflammation, which was assessed by measuring inflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, Aβ1-42 treatment impaired pCREB, PKCε, and Wnt1 signaling in human SH-SY5Y neuroblastoma cells. Addition of Linagliptin significantly reduced IL-6 levels in the lysates of cells, treated with Aβ1-42. Furthermore, linagliptin prevented the downregulation of Wnt1 in Aβ1-42-treated cells exposed.<br><br>Conclusion: The current findings reveal that linagliptin alleviates Aβ1-42-induced inflammation in SH-SY5Y cells, probably through the suppression of IL-6 release, and some of its benefits are mediated through the activation of the Wnt1 signaling pathway.},
}
@article {pmid34381201,
year = {2021},
author = {Yu, M and Sporns, O and Saykin, AJ},
title = {Author Correction: The human connectome in Alzheimer disease - relationship to biomarkers and genetics.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41582-021-00554-0},
pmid = {34381201},
issn = {1759-4766},
}
@article {pmid34424272,
year = {2021},
author = {Davis, EJ and Solsberg, CW and White, CC and Miñones-Moyano, E and Sirota, M and Chibnik, L and Bennett, DA and De Jager, PL and Yokoyama, JS and Dubal, DB},
title = {Sex-Specific Association of the X Chromosome With Cognitive Change and Tau Pathology in Aging and Alzheimer Disease.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2806},
pmid = {34424272},
issn = {2168-6157},
abstract = {Importance: The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown.<br><br>Objective: To determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD.<br><br>Design, Setting, Participants: This study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021.<br><br>Main Outcomes and Measures: The main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored.<br><br>Results: Samples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women.<br><br>Conclusions and Relevance: In this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.},
}
@article {pmid34413181,
year = {2021},
author = {Eikelboom, WS and van den Berg, E and Singleton, EH and Baart, SJ and Coesmans, M and Leeuwis, AE and Teunissen, CE and van Berckel, BNM and Pijnenburg, YAL and Scheltens, P and van der Flier, WM and Ossenkoppele, R and Papma, JM},
title = {Neuropsychiatric and Cognitive Symptoms Across the Alzheimer Disease Clinical Spectrum: Cross-sectional and Longitudinal Associations.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012598},
pmid = {34413181},
issn = {1526-632X},
abstract = {OBJECTIVE: To investigate the prevalence and trajectories of neuropsychiatric symptoms (NPS) in relation to cognitive functioning in a cohort of amyloid-β positive individuals across the Alzheimer's disease (AD) clinical spectrum.<br><br>METHODS: In this single-center observational study, we included all individuals who visited the Alzheimer Center Amsterdam and had 1) a clinical diagnosis of subjective cognitive decline (SCD), mild cognitive impairment (MCI), or probable AD dementia, and 2) were amyloid-β positive (A+). We measured NPS with the Neuropsychiatric Inventory (NPI), examining total scores and the presence of specific NPI domains. Cognition was assessed across five cognitive domains and with the MMSE. We examined trajectories including model based trends for NPS and cognitive functioning over time. We used linear mixed models to relate baseline NPI scores to cognitive functioning at baseline (whole-sample) and longitudinal time-points (subsample n=520, Mean=1.8 [SD=0.7] years follow-up).<br><br>RESULTS: We included 1,524 amyloid-β positive individuals from the Amsterdam Dementia Cohort with A+ SCD (n=113), A+ MCI (n=321), or A+ AD dementia (n=1,090). NPS were prevalent across all clinical AD stages (≥1 NPS 81.4% in SCD, 81.2% in MCI, 88.7% in dementia; ≥1 clinically relevant NPS 54.0% in SCD, 50.5% in MCI, 66.0% in dementia). Cognitive functioning showed an uniform gradual decline; while in contrast, large intra-individual heterogeneity of NPS was observed over time across all AD groups. At baseline, we found associations between NPS and cognition in dementia that were most pronounced for NPI total scores and MMSE (range β=0.18 to 0.11, FDR-adjusted p<0.05), while there were no cross-sectional relationships in SCD and MCI (range β=-0.32 to 0.36, all FDR-adjusted p>0.05). There were no associations between baseline NPS and cognitive functioning over time in any clinical stage (range β=-0.13 to 0.44, all FDR-adjusted p>0.05).<br><br>CONCLUSION: NPS and cognitive symptoms are both prevalent across the AD continuum, but show a different evolution during the course of the disease.},
}
@article {pmid34418785,
year = {2021},
author = {Pont, C and Ginex, T and Griñán-Ferré, C and Scheiner, M and Mattellone, A and Martínez, N and Arce, EM and Soriano-Fernández, Y and Naldi, M and De Simone, A and Barenys, M and Gómez-Catalán, J and Pérez, B and Sabate, R and Andrisano, V and Loza, MI and Brea, J and Bartolini, M and Bolognesi, ML and Decker, M and Pallàs, M and Luque, FJ and Muñoz-Torrero, D},
title = {From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects.},
journal = {European journal of medicinal chemistry},
volume = {225},
number = {},
pages = {113779},
doi = {10.1016/j.ejmech.2021.113779},
pmid = {34418785},
issn = {1768-3254},
abstract = {Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead.},
}
@article {pmid34418779,
year = {2021},
author = {Youn, H and Hyung, WSW and Kim, J and Lee, ES and Eo, JS and Han, CE and Han, C and Kim, SH and Jeong, HG},
title = {Brain amyloid accumulation possibly exacerbates concurrent mild cognitive impairment with subthreshold depression in older adults: A 1-year follow-up study.},
journal = {Journal of affective disorders},
volume = {295},
number = {},
pages = {93-100},
doi = {10.1016/j.jad.2021.08.017},
pmid = {34418779},
issn = {1573-2517},
abstract = {BACKGROUND: This study aimed to investigate the 1-year changes in neuropsychological test results in older adults with concomitant late-life depression (LLD) and mild cognitive impairment (MCI) according to the presence or absence of brain amyloidopathy.<br><br>METHODS: All subjects underwent 18F-florbetaben-positron emission tomography and a standardized neuropsychological battery. The subjects were divided based on brain amyloidopathy and severity of depressive symptoms into the following groups: LLD-MCI-A(+), subthreshold depression (STD)-MCI-A(+), major depressive disorder (MDD)-MCI-A(+), LLD-MCI-A(-), STD-MCI-A(-), and MDD-MCI-A(-). After one year, follow-up neurocognitive tests were conducted. Fifty-nine participants completed both the baseline and 1-year follow-up neurocognitive tests.<br><br>RESULTS: In the LLD-MCI-A(+) group, the word list recall and word list recognition scores decreased during the follow-up period. The STD-MCI-A(+) group also showed a significant decrease in word list recall score and the score/Z-score of word list recognition. On the other hand, the word list recall Z-score improved at the 1-year follow-up in the LLD-MCI-A(-) group. In particular, the MDD-MCI-A(-) group showed significant increases in word list memory score/Z-score and word list recall Z-score during the follow-up period.<br><br>LIMITATIONS: Considering that AD progresses slowly, a longer follow-up period may be required.<br><br>CONCLUSIONS: Our findings showed differences in the extent of change of neuropsychological test results depending on the severity of depressive symptoms and presence or absence of brain amyloidopathy. Our results suggest that clinicians might explore the underlying neuropathology when assessing older adults with concomitant depression and cognitive impairment, even if the symptoms of depression are not severe.},
}
@article {pmid34417350,
year = {2021},
author = {Sanders, AE},
title = {A Century-Old Problem: Cognition and Neuropsychiatric Symptoms in Alzheimer Disease.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012616},
pmid = {34417350},
issn = {1526-632X},
}
@article {pmid34416829,
year = {2021},
author = {Rummel, NG and Butterfield, DA},
title = {Altered Metabolism in Alzheimer Disease Brain: Role of Oxidative Stress.},
journal = {Antioxidants &amp; redox signaling},
volume = {},
number = {},
pages = {},
doi = {10.1089/ars.2021.0177},
pmid = {34416829},
issn = {1557-7716},
abstract = {SIGNIFICANCE: Alzheimer disease (AD) is an all-too-common condition in the aging population. However, aging does not automatically equal neurodegeneration and memory decline. Recent Advances: This review article involves metabolic changes in AD brain that are related to oxidative stress. Selected pathways are identified as potential targets for intervention in AD.<br><br>CRITICAL ISSUES: One of the main factors of AD is the oxidative imbalance within the central nervous system causing a disruption in metabolic processes. Reactive oxygen species (ROS) are a natural consequence of many cellular processes, especially those associated with mitochondria, such as the electron transport chain. Some ROS, when kept under control and maintained at reasonable levels, often play roles in cell signaling. The cellular damage of ROS arises when oxidative imbalance occurs, in which case ROS are not controlled leading to a myriad of alterations in cellular metabolic processes. These altered pathways include, among others, dysfunctional glycolysis, calcium regulation, lipid metabolism, mitochondrial processes, and mTOR pathway dysregulation.<br><br>FUTURE DIRECTIONS: Understanding how ROS can lead to these alterations can, ideally, elucidate therapeutic options for retarding AD progression in the aging population.},
}
@article {pmid34416494,
year = {2021},
author = {Tataryn, NM and Singh, V and Dyke, JP and Berk-Rauch, HE and Clausen, DM and Aronowitz, E and Norris, EH and Strickland, S and Ahn, HJ},
title = {Vascular endothelial growth factor associated dissimilar cerebrovascular phenotypes in two different mouse models of Alzheimer's Disease.},
journal = {Neurobiology of aging},
volume = {107},
number = {},
pages = {96-108},
doi = {10.1016/j.neurobiolaging.2021.07.015},
pmid = {34416494},
issn = {1558-1497},
abstract = {Vascular perturbations and cerebral hypometabolism are emerging as important components of Alzheimer's disease (AD). While various in vivo imaging modalities have been designed to detect changes of cerebral perfusion and metabolism in AD patients and animal models, study results were often heterogenous with respect to imaging techniques and animal models. We therefore evaluated cerebral perfusion and glucose metabolism of two popular transgenic AD mouse strains, TgCRND8 and 5xFAD, at 7 and 12 months-of-age under identical conditions and analyzed possible molecular mechanisms underlying heterogeneous cerebrovascular phenotypes. Results revealed disparate findings in these two strains, displaying important aspects of AD progression. TgCRND8 mice showed significantly decreased cerebral blood flow and glucose metabolism with unchanged cerebral blood volume (CBV) at 12 months-of-age whereas 5xFAD mice showed unaltered glucose metabolism with significant increase in CBV at 12 months-of-age and a biphasic pattern of early hypoperfusion followed by a rebound to normal cerebral blood flow in late disease. Finally, immunoblotting assays suggested that VEGF dependent vascular tone change may restore normoperfusion and increase CBV in 5xFAD.},
}
@article {pmid34415670,
year = {2021},
author = {Schmid, JC and Frey, K and Scheiner, M and Garzón, JFG and Stafforst, L and Fricke, JN and Schuppe, M and Schiewe, H and Zeeck, A and Weber, T and Usón, I and Kemkemer, R and Decker, M and Grond, SC},
title = {The structure of cyclodecatriene collinolactone, its biosynthesis and semisynthetic analogues: Effects of monoastral phenotype and protection from intracellular oxidative stress.},
journal = {Angewandte Chemie (International ed. in English)},
volume = {},
number = {},
pages = {},
doi = {10.1002/anie.202106802},
pmid = {34415670},
issn = {1521-3773},
abstract = {Recently described rhizolutin and collinolactone share the same novel carbon scaffold. Analyses by NMR and X-Ray crystallography prove the structure of collinolactone isolated from Streptomyces Gö 40/10 and propose a revision of rhizolutin's stereochemistry. Isotope-labelled precursor feeding indicate that collinolactone is biosynthesized via type-I polyketide synthase with Baeyer-Villiger oxidation. CRISPR based genetic strategies led to the biosynthetic gene cluster and a high-production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that analogues monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimer-protective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone analogues on glutamate-sensitive cells (HT22) and indeed, natural collinolactone points to distinct neuroprotection from intracellular oxidative stress.},
}
@article {pmid34414305,
year = {2021},
author = {Wardlaw, JM and Debette, S and Jokinen, H and De Leeuw, FE and Pantoni, L and Chabriat, H and Staals, J and Doubal, F and Rudilosso, S and Eppinger, S and Schilling, S and Ornello, R and Enzinger, C and Cordonnier, C and Taylor-Rowan, M and Lindgren, AG},
title = {ESO Guideline on covert cerebral small vessel disease.},
journal = {European stroke journal},
volume = {6},
number = {2},
pages = {IV},
doi = {10.1177/23969873211027002},
pmid = {34414305},
issn = {2396-9881},
abstract = {'Covert' cerebral small vessel disease (ccSVD) is common on neuroimaging in persons without overt neurological manifestations, and increases the risk of future stroke, cognitive impairment, dependency, and death. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist with clinical decisions about management of ccSVD, specifically white matter hyperintensities and lacunes, to prevent adverse clinical outcomes. The guidelines were developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We prioritised the clinical outcomes of stroke, cognitive decline or dementia, dependency, death, mobility and mood disorders, and interventions of blood pressure lowering, antiplatelet drugs, lipid lowering, lifestyle modifications, glucose lowering and conventional treatments for dementia. We systematically reviewed the literature, assessed the evidence, formulated evidence-based recommendations where feasible, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend patients with ccSVD and hypertension to have their blood pressure well controlled; lower blood pressure targets may reduce ccSVD progression. We do not recommend antiplatelet drugs such as aspirin in ccSVD. We found little evidence on lipid lowering in ccSVD. Smoking cessation is a health priority. We recommend regular exercise which may benefit cognition, and a healthy diet, good sleep habits, avoiding obesity and stress for general health reasons. In ccSVD, we found no evidence for glucose control in the absence of diabetes or for conventional Alzheimer dementia treatments. Randomised controlled trials with clinical endpoints are a priority for ccSVD.},
}
@article {pmid34414301,
year = {2021},
author = {Wardlaw, JM and Debette, S and Jokinen, H and De Leeuw, FE and Pantoni, L and Chabriat, H and Staals, J and Doubal, F and Rudilosso, S and Eppinger, S and Schilling, S and Ornello, R and Enzinger, C and Cordonnier, C and Taylor-Rowan, M and Lindgren, AG},
title = {ESO Guideline on covert cerebral small vessel disease.},
journal = {European stroke journal},
volume = {6},
number = {2},
pages = {CXI-CLXII},
doi = {10.1177/23969873211012132},
pmid = {34414301},
issn = {2396-9881},
abstract = {'Covert' cerebral small vessel disease (ccSVD) is common on neuroimaging in persons without overt neurological manifestations, and increases the risk of future stroke, cognitive impairment, dependency, and death. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist with clinical decisions about management of ccSVD, specifically white matter hyperintensities and lacunes, to prevent adverse clinical outcomes. The guidelines were developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We prioritised the clinical outcomes of stroke, cognitive decline or dementia, dependency, death, mobility and mood disorders, and interventions of blood pressure lowering, antiplatelet drugs, lipid lowering, lifestyle modifications, glucose lowering and conventional treatments for dementia. We systematically reviewed the literature, assessed the evidence, formulated evidence-based recommendations where feasible, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend patients with ccSVD and hypertension to have their blood pressure well controlled; lower blood pressure targets may reduce ccSVD progression. We do not recommend antiplatelet drugs such as aspirin in ccSVD. We found little evidence on lipid lowering in ccSVD. Smoking cessation is a health priority. We recommend regular exercise which may benefit cognition, and a healthy diet, good sleep habits, avoiding obesity and stress for general health reasons. In ccSVD, we found no evidence for glucose control in the absence of diabetes or for conventional Alzheimer dementia treatments. Randomised controlled trials with clinical endpoints are a priority for ccSVD.},
}
@article {pmid34410302,
year = {2021},
author = {Karlawish, J},
title = {Aducanumab and the Business of Alzheimer Disease-Some Choice.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.3123},
pmid = {34410302},
issn = {2168-6157},
}
@article {pmid34406973,
year = {2020},
author = {Wilson, R and Small, J},
title = {Care Staff Perspectives on Using Mobile Technology to Support Communication in Long-Term Care: Mixed Methods Study.},
journal = {JMIR nursing},
volume = {3},
number = {1},
pages = {e21881},
doi = {10.2196/21881},
pmid = {34406973},
issn = {2562-7600},
abstract = {BACKGROUND: Long-term care (LTC) homes provide 24-hour care for people living with complex care needs. LTC staff assist older adults living with chronic conditions such as Alzheimer disease, related dementias, and stroke, which can cause communication disorders. In addition to the complex cognitive challenges that can impact communication, further difficulties can arise from cultural-language differences between care staff and residents. Breakdowns in caregiver-resident communication can negatively impact the delivery of person-centered care. Recent advances in mobile technology, specifically mobile devices (tablets and smartphones) and their software apps, offer innovative solutions for supporting everyday communication between care staff and residents. To date, little is known about the care staff's perspectives on the different ways that mobile technology could be used to support communication with residents.<br><br>OBJECTIVE: This study aims to identify care staff's perspectives on the different ways of using devices and apps to support everyday communication with adults living in LTC homes and the priority care areas for using mobile technology to support communication with residents.<br><br>METHODS: This descriptive study employed concept mapping methods to explore care staff's perspectives about ways of using mobile technology with residents and to identify the usefulness, practicality, and probable uses of mobile technology to support communication in priority care areas. Concept mapping is an integrated mixed methods approach (qualitative and quantitative) that uses a structured process to identify priority areas for planning and evaluation. In total, 13 care staff from a single LTC home participated in this study. Concept mapping includes 2 main data collection phases: (1) statement generations through brainstorming and (2) statement structuring through sorting and rating. Brainstorming took place in person in a group session, whereas sorting and rating occurred individually after the brainstorming session. Concept mapping data were analyzed using multidimensional scaling and cluster analysis to generate numerous interpretable data maps and displays.<br><br>RESULTS: Participants generated 67 unique statements during the brainstorming session. Following the sorting and rating of the statements, a concept map analysis was performed. In total, 5 clusters were identified: (1) connect, (2) care management, (3) facilitate, (4) caregiving, and (5) overcoming barriers. Although all 5 clusters were rated as useful, with a mean score of 4.1 to 4.5 (Likert: 1-5), the care staff rated cluster 2 (care management) as highest on usefulness, practicality, and probable use of mobile technology to support communication in LTC.<br><br>CONCLUSIONS: This study provided insight into the viewpoints of care staff regarding the different ways mobile technology could be used to support caregiver-resident communication in LTC. Our findings suggest that care management, facilitating communication, and overcoming barriers are 3 priority target areas for implementing mobile health interventions to promote person-centered care and resident-centered care.},
}
@article {pmid34406560,
year = {2021},
author = {Apátiga-Pérez, R and Soto-Rojas, LO and Campa-Córdoba, BB and Luna-Viramontes, NI and Cuevas, E and Villanueva-Fierro, I and Ontiveros-Torres, MA and Bravo-Muñoz, M and Flores-Rodríguez, P and Garcés-Ramirez, L and de la Cruz, F and Montiel-Sosa, JF and Pacheco-Herrero, M and Luna-Muñoz, J},
title = {Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease.},
journal = {Metabolic brain disease},
volume = {},
number = {},
pages = {},
pmid = {34406560},
issn = {1573-7365},
support = {2015-3A2-127//Fondo Nacional de Ciencia, Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic/ ; 2018-2019-2A3-208//Fondo Nacional de Ciencia, Tecnologia, FONDOCyT, from the Ministry of Higher Education, Science and Technology, Dominican Republic/ ; },
abstract = {Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive neuropathological lesions: neuritic plaques and neurofibrillary tangles (NFTs), constituted of beta-amyloid peptide (Aβ) and phosphorylated and truncated tau proteins. Aβ deposits around cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a major contributor to vascular dysfunction in AD. Vascular amyloid deposits could be early events in AD due to dysfunction in the neurovascular unit (NVU) and the blood-brain barrier (BBB), deterioration of the gliovascular unit, and/or decrease of cerebral blood flow (CBF). These pathological events can lead to decreased Aβ clearance, facilitate a neuroinflammatory environment as well as synaptic dysfunction and, finally, lead to neurodegeneration. Here, we review the histopathological AD hallmarks and discuss the two-hit vascular hypothesis of AD, emphasizing the role of neurovascular dysfunction as an early factor that favors vascular Aβ aggregation and neurodegeneration. Addtionally, we emphasize that pericyte degeneration is a key and early element in AD that can trigger amyloid vascular accumulation and NVU/BBB dysfunction. Further research is required to better understand the early pathophysiological mechanisms associated with NVU alteration and CAA to generate early biomarkers and timely treatments for AD.},
}
@article {pmid34403885,
year = {2021},
author = {Shi, S and Li, J and Zhao, X and Liu, Q and Song, SJ},
title = {A comprehensive review: Biological activity, modification and synthetic methodologies of prenylated flavonoids.},
journal = {Phytochemistry},
volume = {191},
number = {},
pages = {112895},
doi = {10.1016/j.phytochem.2021.112895},
pmid = {34403885},
issn = {1873-3700},
abstract = {Prenylated flavonoids, a unique class of flavonoids which combine a flavonoid skeleton and a lipophilic prenyl side-chain, possess great potential biological activities including cytotoxicity, anti-inflammation, anti-Alzheimer, anti-microbial, anti-oxidant, anti-diabetes, estrogenic, vasorelaxant and enzyme inhibition. Recently, prenylated flavonoids have become an indispensable anchor for the development of new therapeutic agents, and have received increasing from medicinal chemists. The prenylated flavonoids have been outstanding developed through isolation, semi or fully synthesis in a very short period of time, which proves the great value in medicinal chemistry researches. In this review, research progress of prenylated flavonoids including natural prenylated flavonoids, structural modification, synthetic methodologies and pharmacological activities was summarized comprehensively. Furthermore, the structure-activity relationships (SARs) of prenylated flavonoids were summarized which provided a basis for the selective design and optimization of multifunctional prenylated flavonoid derivatives for the treatment of multi-factorial diseases in clinic.},
}
@article {pmid34403652,
year = {2021},
author = {Puris, E and Auriola, S and Korhonen, P and Loppi, S and Kanninen, KM and Malm, T and Koistinaho, J and Gynther, M},
title = {Systemic inflammation induced changes in protein expression of ABC transporters and ionotropic glutamate receptor subunit 1 in the cerebral cortex of familial Alzheimer`s disease mouse model.},
journal = {Journal of pharmaceutical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.xphs.2021.08.013},
pmid = {34403652},
issn = {1520-6017},
abstract = {Alzheimer's disease (AD) is an incurable disease, with complex pathophysiology and a myriad of proteins involved in its development. In this study, we applied quantitative targeted absolute proteomic analysis for investigation of changes in potential AD drug targets, biomarkers, and transporters in cerebral cortices of lipopolysaccharide (LPS)-induced neuroinflammation mouse model, familial AD mice (APdE9) with and without LPS treatment as compared to age-matched wild type (WT) mice. The ABCB1, ABCG2 and GluN1 protein expression ratios between LPS treated APdE9 and WT control mice were 0.58 (95% CI 0.44 - 0.72), 0.65 (95% CI 0.53 - 0.77) and 0.61 (95% CI 0.52 - 0.69), respectively. The protein expression levels of other proteins such as MGLL, COX-2, CytC, ABCC1, ABCC4, SLC2A1 and SLC7A5 did not differ between the study groups. Overall, the study revealed that systemic inflammation can alter ABCB1 and ABCG2 protein expression in brain in AD, which can affect intra-brain drug distribution and play a role in AD development. Moreover, the inflammatory insult caused by peripheral infection in AD may be important factor triggering changes in GluN1 protein expression. However, more studies need to be performed in order to confirm these findings. The quantitative information about the expression of selected proteins provides important knowledge, which may help in the optimal use of the mouse models in AD drug development and better translation of preclinical data to humans.},
}
@article {pmid34402289,
year = {2021},
author = {Zhang, L and Fang, DY and Liu, C and Zhao, DY and Wang, YJ and Chen, WN and Cui, Y and Guo, JF and Cong, PW and Feng, XF and Zhang, YT},
title = {[Mechanism of puerarin reversing SH-SY5Y cell injury induced by Aβ_(1-42) based on proteomics].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {46},
number = {14},
pages = {3650-3659},
doi = {10.19540/j.cnki.cjcmm.20210201.403},
pmid = {34402289},
issn = {1001-5302},
abstract = {Puerarin has the anti-Alzheimer&apos;s disease (AD) activity,which can reverse nerve injury induced by Aβand inhibit neuronal apoptosis.However,its potential pharmacodynamic mechanism still needs to be further researched.The occurrence and development of AD is due to the change of multiple metabolic links in the body,which leads to the destruction of balance.Puerarin may act on multiple targets and multiple metabolic processes to achieve therapeutic purposes.Quantitative proteomic analysis provides a new choice to understand the mechanism as completely as possible.This research adopted SH-SY5Y cells induced by Aβ_(1-42)to establish AD cell model,and Aβimmunofluorescence detection showed that Aβdecreased significantly after puerarin intervention.The mechanism of puerarin reversing SH-SY5Y cell injured by Aβ_(1-42)was further explored by using label-free non-labeled quantitative technology and Western blot detection based on bioinformatics analysis result.The results showed that most of the differential proteins were related to biological processes such as cellular component organization or biogenesis,cellular component organization and cellular component biogenesis,and they mainly participated in the top ten pathways of P value such as pathogenic Escherichia coli infection,m TOR signaling pathway,regulation of autophagy,regulation of actin cytoskeleton,spliceosome,hepatocellular carcinoma,tight junction,non-small cell lung cancer,apoptosis and gap junction.Annexin V/PI flow cytometry and TUNEL were used to detect apoptosis,and the results showed that Aβdecreased significantly and the rate of apoptosis decreased significantly after puerarin intervention.Western blot analysis found that the protein expression level of autophagy related protein LC3Ⅱwas up-regulated after Aβinduction,and the degree of this up-regulation was further enhanced in puerarin intervention group.The trend of the ratio of LC3Ⅱ/LC3Ⅰamong groups was the same as the protein expression level of LC3Ⅱ，the protein expression level of p62 in the control group,AD model group and puerarin intervention group decreased successively.Protein interaction network analysis showed that CAP1 was correlated with TUBA1B,HSP90AB2P,DNM1L,TUBA1A and ERK1/2,and the correlation between CAP1 and ERK1/2 was the highest among them.Western blot showed that the expressions of p-ERK1/2,Bax and CAP1 were significantly down-regulated and the protein expression level of Bcl-2 was significantly up-regulated after puerarin intervention.Therefore,puerarin might improve the SH-SY5Y cells injured by Aβ_(1-42)through the interaction of multiple biological processes and pathways in cells multiple locations,and CAP1 might play an important role among them.},
}
@article {pmid34402286,
year = {2021},
author = {Wang, XM and Tang, XH and Li, YY and Pu, XX and Zhou, Y},
title = {[An integrative metabolomics and network pharmacology method for exploring bioactive components and preliminary pharmacodynamics in medicinal parts of Harrisonia perforata].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {46},
number = {14},
pages = {3625-3632},
doi = {10.19540/j.cnki.cjcmm.20210312.201},
pmid = {34402286},
issn = {1001-5302},
abstract = {In this paper,metabolomics and network pharmacology were used to investigate the bioactive components of Harrisonia perforata and their possible mechanisms of action. Metabolites in the flowers,fruits,branches,leaves and stalks of H. perforata were analyzed by ultra-high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. Meanwhile,multiple statistical analysis methods including principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA)were applied to screen and identify differential compounds. With metabolomics method,9 differential compounds were preliminarily identified from leaves and other non-traditional medicinal parts. Subsequently,these compounds were explored by using network pharmacology. With gastrointestinal absorption and drug-likeness as limiting conditions,they were imported into the Swiss ADME,from which 7 compounds with potential medicinal activity were obtained. Then,their targets were predicted by PharmMapper,with Human Protein Targets Only and Normalized Fit Score>0. 9 set as limiting conditions,and 60 standardized potential targets were identified with Uniprot. KEGG(Kyoto encyclopedia of genes and genomes) pathway data was obtained using metascape and the &quot; potential active ingredients-target-pathway&quot; network was constructed with Cytoscape 3. 7. 2. The enrichment analysis of KEGG demonstrated that the 60 targets were enriched in 78 signaling pathways(min overlap: 3,P value cutoff: 0. 01,min enrichment: 1. 5),many of which are related to anti-bacteria,anti-inflammation and anti-virus,such as IL-17 signaling pathway,RIG-I-like receptor signaling pathway and NOD-like receptor signaling pathway. Finally,depending on the clinical activity of H. perforata,the relevant signaling pathways were analyzed through experimental data and literature. Dehydroconiferyl alcohol was reported to have the anti-inflammatory effect and perforamone D to possess the antimycobacterial activity. The KEGG pathway enrichment analysis showed that dehydroconiferyl alcohol could act on the Alzheimer&apos;s disease(AD) signaling pathway by targeting CDK5 R1 and BACE1. ACh E inhibitor is the most promising drug to treat AD,while dehydroconiferyl alcohol has been proved to inhibit ACh E according to literature. The experimental results revealed that the extract of leaves of H. perforata can effectively inhibit the growth of Staphylococcus aureus. These are consistent with the enrichment analysis results of KEGG. This study explored the bioactive components and pharmacodynamics of the leaves of the H. perforata,laying a theoretical foundation for its in-depth development and rational application.},
}
@article {pmid34402024,
year = {2021},
author = {Gu, J and Li, Z and Chen, H and Xu, X and Li, Y and Gui, Y},
title = {Neuroprotective Effect of Trans-Resveratrol in Mild to Moderate Alzheimer Disease: A Randomized, Double-Blind Trial.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {34402024},
issn = {2193-8253},
abstract = {INTRODUCTION: Amyloid-beta (Aβ) protein is a major component of the extracellular plaque found in the brains of individuals with Alzheimer's disease (AD). In this study, we investigated the effect of trans-resveratrol as an antagonist treatment for moderate to mild AD, as well as its safety and tolerability.<br><br>METHODS: This was a case-control study that enrolled 30 selected patients who had been clinically diagnosed with moderate to mild AD. These patients were randomly divided into two groups, namely, a placebo group (n = 15) and a trans-resveratrol group (n = 15) who received 500 mg trans-resveratrol orally once daily for 52 weeks. Brain magnetic resonance imaging (MRI) examinations were performed on and cerebrospinal fluid (CSF) samples were obtained from all participants before (baseline) and after the study (52 weeks). Enzyme-linked immunosorbent assays were used to determine the levels of plasma Aβ40 and Aβ42 and CSF Aβ40 and Aβ42.<br><br>RESULTS: The results showed that the changes over the study period in the levels of Aβ40 in the blood and CSF of the patients treated with trans-resveratrol were not statistically significant (P > 0.05). In contrast, patients who received placebo showed a significant decrease in Aβ40 levels compared with that at the beginning of the study (CSF Aβ40: P = 0.024, plasma Aβ40: P = 0.036). Analysis of the images on the brain MRI scans revealed that the brain volume of the patients treated with trans-resveratrol was significantly reduced at 52 weeks (P = 0.011) compared with that of patients in the placebo treatment group, Further analysis indicated that the level of matrix metallopeptidase 9 in the CSF of the patients treated with trans-resveratrol at 52 weeks decreased by 46% compared with that of patients in the placebo group (P = 0.033).<br><br>CONCLUSION: These results indicate that trans-resveratrol has potential neuroprotective roles in the treatment of moderate to mild AD and that its mechanism may involve a reduction in the accumulation and toxicity of Aβ in the brain of patients, thereby reducing neuroinflammation.<br><br>TRIAL REGISTRATION: Chinese clinical trial registry: CTR20151780X.},
}
@article {pmid34400543,
year = {2021},
author = {Richard, E},
title = {Selecting the target population for new Alzheimer drugs: challenges and expectations.},
journal = {Journal of medical ethics},
volume = {},
number = {},
pages = {},
doi = {10.1136/medethics-2021-107767},
pmid = {34400543},
issn = {1473-4257},
}
@article {pmid34399231,
year = {2021},
author = {Almeida, MP and Kock, FVC and de Jesus, HCR and Carlos, RM and Venâncio, T},
title = {Probing the acetylcholinesterase inhibitory activity of a novel Ru(II) polypyridyl complex and the supramolecular interaction by (STD)-NMR.},
journal = {Journal of inorganic biochemistry},
volume = {224},
number = {},
pages = {111560},
doi = {10.1016/j.jinorgbio.2021.111560},
pmid = {34399231},
issn = {1873-3344},
abstract = {Currently, acetylcholinesterase (AChE) inhibitors are the only anti-Alzheimer drugs commercially available. Despite their wide use those drugs are all dose dependent and their effect last for no longer than two years, with several side effects. The search of novel acetylcholinesterase (AChE) inhibitors remains as the main scientific route. Here we describe the synthesis, characterization, biological activity and an NMR binding-target study of a novel cis-[Ru(Bpy)2(EtPy)2]2+, (RuEtPy), Bpy = 2,2'-bipyridine and EtPy = 4,2-Ethylamino-pyridine) as a potential AChE inhibitor. The classic Ellman's colorimetric assay suggests that the RuEtPy exhibits a high inhibitory activity, following a competitive mechanism, with a remarkable low inhibition constant (Ki ≈ 16.8 μM), together with a IC50 = 39 μM. Hence, we have studied the spatial interactions for this novel candidate towards the human acetylcholinesterase (hAChE) using saturation transfer difference (STD)-NMR, in order to describe the mechanism of the interaction. NMR binding-target results shows that the 4,2-Ethylamino-Pyridine group is spatially closer to hAChE surface chemical arrangement than 2,2' bipyridine counterpart, exerting an efficient intermolecular interaction, with a low dissociation constant (KD ≈ 55 μM), probing that 4,2-Ethylamino-pyridine motif plays a key role in the inhibitory action.},
}
@article {pmid34398201,
year = {2021},
author = {Salinas, J and O'Donnell, A and Kojis, DJ and Pase, MP and DeCarli, C and Rentz, DM and Berkman, LF and Beiser, A and Seshadri, S},
title = {Association of Social Support With Brain Volume and Cognition.},
journal = {JAMA network open},
volume = {4},
number = {8},
pages = {e2121122},
doi = {10.1001/jamanetworkopen.2021.21122},
pmid = {34398201},
issn = {2574-3805},
abstract = {Importance: Cognitive resilience refers to the general capacity of cognitive processes to be less susceptible to differences in brain structure from age- and disease-related changes. Studies suggest that supportive social networks reduce Alzheimer disease and related disorder (ADRD) risk by enhancing cognitive resilience, but data on specific social support mechanisms are sparse.<br><br>Objective: To examine the association of individual forms of social support with a global neuroanatomical measure of early ADRD vulnerability and cognition.<br><br>This retrospective cross-sectional analysis used prospectively collected data from Framingham Study participants without dementia, stroke, or other neurological conditions who underwent brain magnetic resonance imaging and neuropsychological testing at the same visit. Data from this large, population-based, longitudinal cohort were collected from June 6, 1997, to December 13, 1999 (original cohort), and from September 11, 1998, to October 26, 2001 (offspring cohort). Data were analyzed from May 22, 2017, to June 1, 2021.<br><br>Exposures: Total cerebral volume and, as a modifying exposure variable, self-reported availability of 5 types of social support measured by the Berkman-Syme Social Network Index.<br><br>Main Outcomes and Measures: The primary outcome was a global measure of cognitive function. Cognitive resilience was defined as the modification of total cerebral volume's association with cognition, such that smaller β estimates (presented in SD units) indicate greater cognitive resilience (ie, better cognitive performance than estimated by lower total cerebral volume).<br><br>Results: The study included 2171 adults (164 in the original cohort and 2007 in the offspring cohort; mean [SD] age, 63 [10] years; 1183 [54%] female). High listener availability was associated with greater cognitive resilience (β = 0.08, P < .001) compared with low listener availability (β = 0.20, P = .002). Overall findings persisted after adjustment for potential confounders. Other forms of social support were not significant modifiers (advice: β = -0.04; P = .40 for interaction; love-affection: β = -0.07, P = .28 for interaction; emotional support: β = -0.02, P = .73 for interaction; and sufficient contact: β = -0.08; P = .11 for interaction).<br><br>Conclusions and Relevance: The results of this cross-sectional cohort study suggest that social support in the form of supportive listening is associated with greater cognitive resilience, independently modifying the association between lower total cerebral volume and poorer cognitive function that would otherwise indicate increased ADRD vulnerability at the preclinical stage. A refined understanding of social support mechanisms has the potential to inform strategies to reduce ADRD risk and enhance cognitive resilience.},
}
@article {pmid34398024,
year = {2021},
author = {Wu, H and Mei, F and Liu, L and Zhang, L and Hao, H and Zhang, S},
title = {Case Report/Case Series: Rare case of anti-LGI1 limbic encephalitis with rapidly progressive dementia, psychiatric symptoms, and frequently seizures: A case report.},
journal = {Medicine},
volume = {100},
number = {29},
pages = {e26654},
doi = {10.1097/MD.0000000000026654},
pmid = {34398024},
issn = {1536-5964},
support = {ZYLX201834//Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support/ ; },
abstract = {RATIONALE: Anti leucine-rich glioma inactivated 1 (LGI1) limbic encephalitis (LE) is rare autoimmune encephalitis, characterized by acute or subacute cognitive impairment, faciobrachial dystonic seizures, mental disorders, and refractory hyponatremia. As a type of treatable rapidly progressive dementia with a good prognosis, early, and accurate diagnosis is essential. We present a case of anti-LGI1 LE who was initially misdiagnosed with Alzheimer disease because his clinical manifestations were similar to Alzheimer disease.<br><br>PATIENT CONCERNS: A male patient presenting with rapidly progressive dementia, faciobrachial dystonic seizures, psychiatric disturbance, and refractory hyponatremia was admitted. The scores of Mini-Mental State Examination, Montreal Cognitive Assessment, and Neuropsychiatric Inventory were 19/30, 16/30, and 91/144, respectively. Brain magnetic resonance images indicated moderate atrophy of the hippocampus and abnormally hyperintensities in the left medial temporal and hippocampus.<br><br>DIAGNOSIS: The patient was diagnosed with anti-LGI1 LE based on the presence of LGI-1 antibodies in the cerebrospinal fluid and serum and clinical manifestations.<br><br>INTERVENTIONS: Patient was treated with glucocorticoid against LGI1, antiepileptic drug, cholinesterase inhibitors, and other adjuvant therapy.<br><br>OUTCOMES: The patient showed marked improvement on immunotherapy. Clinical symptoms were disappeared and the LGI-1 antibodies in cerebrospinal fluid and serum were both negative at the time of discharge.<br><br>CONCLUSIONS: Recognition of the specific symptoms and LGI-1 antibody test will be helpful for the early diagnosis, prompt immunotherapy, and good prognosis. This case raises the awareness that rapidly progressive dementia with frequent seizures could be caused by immunoreactions.},
}
@article {pmid34397597,
year = {2021},
author = {Wei, HC and Li, B and Ng, KP and Fu, QX and Dong, SJ and Ba, MW and Kong, M},
title = {Amyloid and tau positive mild cognitive impairment: clinical and biomarker characteristics of dementia progression.},
journal = {Chinese medical journal},
volume = {134},
number = {14},
pages = {1709-1719},
pmid = {34397597},
issn = {2542-5641},
abstract = {BACKGROUND: According to the amyloid, tau, neurodegeneration research framework classification, amyloid and tau positive (A+T+) mild cognitive impairment (MCI) individuals are defined as prodromal Alzheimer disease. This study was designed to compare the clinical and biomarker features between A+T+MCI individuals who progressed to progressive MCI (pMCI) and those who remained stable MCI (sMCI), and to identify relevant baseline clinical biomarker and features that could be used to predict progression to dementia within 2 years.<br><br>METHODS: We stratified 197 A+T+MCI individuals into pMCI (n = 64) and sMCI (n = 133) over 2 years. Demographics and cognitive assessment scores, cerebrospinal fluid (CSF), and neuroimaging biomarkers (18F-florbetapir positron emission tomography mean standardized uptake value ratios [SUVR] and structural magnetic resonance imaging [MRI]) were compared between pMCI and sMCI at baseline, 12- and 24-month follow-up. Logistic regression models then were used to evaluate clinical baseline and biomarker features that predicted dementia progression in A+T+MCI.<br><br>RESULTS: pMCI individuals had higher mean 18F-florbetapir SUVR, CSF total-tau (t-tau), and p-tau181P than those in sMCI individuals. pMCI individuals performed poorer in cognitive assessments, both global and domain specific (memory, executive, language, attention, and visuospatial skills) than sMCI. At baseline, there were significant differences in regions of interest of structural MRI between the two groups, including bilateral amygdala, hippocampus and entorhinal, bilateral inferior lateral ventricle, left superior and middle temporal, left posterior and caudal anterior cingulate (P < 0.05). Baseline CSF t-tau levels and cognitive scores of Montreal cognitive assessment, functional assessment questionnaire, and everyday cognition by the patient's study partner language domain could predict progression to dementia in A+T+MCI within 2 years.<br><br>CONCLUSIONS: In future clinical trials, specific CSF and cognitive measures that predict dementia progression in A+T+MCI might be useful risk factors for assessing the risk of dementia progression.},
}
@article {pmid34397409,
year = {2021},
author = {Schild, AK and Volk, J and Scharfenberg, D and Schuermann, K and Meiberth, D and Onur, OA and Jessen, F and Maier, F},
title = {Social Cognition in Patients with Amnestic Mild Cognitive Impairment and Mild Dementia of the Alzheimer Type.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-201126},
pmid = {34397409},
issn = {1875-8908},
abstract = {BACKGROUND: Social cognition (SC) is a core criterion for neurocognitive disorders. However, findings in patients with amnestic mild cognitive impairment (aMCI) and dementia of the Alzheimer type (DAT) are inconsistent.<br><br>OBJECTIVE: We report assessments of emotion recognition (ER), affective and cognitive theory of mind (ToM) in young (YC) and older controls (OC) compared to aMCI and DAT.<br><br>METHODS: 28 aMCI, 30 DAT, 30 YC, and 29 OC received tests of SC and a comprehensive neuropsychological assessment. Analysis of covariance was used to determine group differences. Multiple regression models were applied to identify predictors for each SC task.<br><br>RESULTS: In controls, OC performed worse in ER and both ToM tasks compared to YC except for one subtest. No significant differences were found between OC and patients concerning ER and affective ToM. In cognitive ToM, differences between OC and patients depended on content and cognitive load with significant impairment in DAT compared to OC. A cognitive composite score predicted SC in OC, but not in patients. Associations of SC with single cognitive domains were found in all groups with language and complex attention as best predictors. Not all variance of SC performance was explained by variance in cognitive domains.<br><br>CONCLUSION: Lower performance on SC tasks in OC versus YC was confirmed, although not all tasks were equally affected. With progressive cognitive impairment, cognitive ToM is more impaired than ER or affective ToM. SC seems to be at least partly independent of other cognitive domains, justifying its inclusion in batteries for dementia diagnostic.},
}
@article {pmid34396361,
year = {2021},
author = {Liu, KY and Acosta-Cabronero, J and Hong, YT and Yi, YJ and Hämmerer, D and Howard, R and , },
title = {FDG-PET assessment of the locus coeruleus in Alzheimer's disease.},
journal = {Neuroimage. Reports},
volume = {1},
number = {1},
pages = {100002},
doi = {10.1016/j.ynirp.2020.100002},
pmid = {34396361},
issn = {2666-9560},
abstract = {Sensitive and reliable in vivo imaging of the locus coeruleus (LC) is important to develop and evaluate its potential as a biomarker in neurodegenerative diseases such as Alzheimer's disease (AD). It is not known whether AD-related alterations in LC integrity can be detected using 18F-labelled fluoro-2-deoxyglucose (FDG) positron emission tomography (PET). Mean FDG-PET images from AD patients (N ​= ​193) and controls (N ​= ​256) from the ADNI database were co-registered to a study-wise anatomical template. Regional LC median standardized uptake value ratio (SUVR) values were obtained using four previously published LC masks and normalized to values from pons and cerebellar vermis reference regions. To support the validity of our methods, other regions previously reported to be most and least affected metabolically in AD were also compared to controls. The LC did not show between-group differences in FDG-PET signal, whereas the mammillary bodies did, despite these regions having comparable volumes and SUVR ranges. Brain regions previously reported to be most and least affected metabolically in AD compared to controls showed medium-to-large and small effect sizes for SUVR differences respectively. The results do not support the current application of LC FDG-PET signal as an in vivo biomarker for AD. Methodological and demographic factors potentially contributing to these findings are discussed. Future research may investigate age-related differences in LC FDG-PET signal and higher resolution images to fully explore its biomarker potential.},
}
@article {pmid34396116,
year = {2021},
author = {Williams, ME and Elman, JA and McEvoy, LK and Andreassen, OA and Dale, AM and Eglit, GML and Eyler, LT and Fennema-Notestine, C and Franz, CE and Gillespie, NA and Hagler, DJ and Hatton, SN and Hauger, RL and Jak, AJ and Logue, MW and Lyons, MJ and McKenzie, RE and Neale, MC and Panizzon, MS and Puckett, OK and Reynolds, CA and Sanderson-Cimino, M and Toomey, R and Tu, XM and Whitsel, N and Xian, H and Kremen, WS},
title = {12-year prediction of mild cognitive impairment aided by Alzheimer's brain signatures at mean age 56.},
journal = {Brain communications},
volume = {3},
number = {3},
pages = {fcab167},
doi = {10.1093/braincomms/fcab167},
pmid = {34396116},
issn = {2632-1297},
abstract = {Neuroimaging signatures based on composite scores of cortical thickness and hippocampal volume predict progression from mild cognitive impairment to Alzheimer's disease. However, little is known about the ability of these signatures among cognitively normal adults to predict progression to mild cognitive impairment. Towards that end, a signature sensitive to microstructural changes that may predate macrostructural atrophy should be useful. We hypothesized that: (i) a validated MRI-derived Alzheimer's disease signature based on cortical thickness and hippocampal volume in cognitively normal middle-aged adults would predict progression to mild cognitive impairment; and (ii) a novel grey matter mean diffusivity signature would be a better predictor than the thickness/volume signature. This cohort study was part of the Vietnam Era Twin Study of Aging. Concurrent analyses compared cognitively normal and mild cognitive impairment groups at each of three study waves (ns = 246-367). Predictive analyses included 169 cognitively normal men at baseline (age = 56.1, range = 51-60). Our previously published thickness/volume signature derived from independent data, a novel mean diffusivity signature using the same regions and weights as the thickness/volume signature, age, and an Alzheimer's disease polygenic risk score were used to predict incident mild cognitive impairment an average of 12 years after baseline (follow-up age = 67.2, range = 61-71). Additional analyses adjusted for predicted brain age difference scores (chronological age minus predicted brain age) to determine if signatures were Alzheimer-related and not simply ageing-related. In concurrent analyses, individuals with mild cognitive impairment had higher (worse) mean diffusivity signature scores than cognitively normal participants, but thickness/volume signature scores did not differ between groups. In predictive analyses, age and polygenic risk score yielded an area under the curve of 0.74 (sensitivity = 80.00%; specificity = 65.10%). Prediction was significantly improved with addition of the mean diffusivity signature (area under the curve = 0.83; sensitivity = 85.00%; specificity = 77.85%; P = 0.007), but not with addition of the thickness/volume signature. A model including both signatures did not improve prediction over a model with only the mean diffusivity signature. Results held up after adjusting for predicted brain age difference scores. The novel mean diffusivity signature was limited by being yoked to the thickness/volume signature weightings. An independently derived mean diffusivity signature may thus provide even stronger prediction. The young age of the sample at baseline is particularly notable. Given that the brain signatures were examined when participants were only in their 50 s, our results suggest a promising step towards improving very early identification of Alzheimer's disease risk and the potential value of mean diffusivity and/or multimodal brain signatures.},
}
@article {pmid34395228,
year = {2021},
author = {Kumamoto, A and Chiba, Y and Suda, A and Hishimoto, A and Kase, A},
title = {A Severe Dementia Case in End of Life Care with Psychiatric Symptoms Treated by Perampanel.},
journal = {Journal of epilepsy research},
volume = {11},
number = {1},
pages = {93-95},
doi = {10.14581/jer.21012},
pmid = {34395228},
issn = {2233-6249},
abstract = {Epilepsy is known to comorbid with Alzheimer's disease. It can promote cognitive decline, and eventually worsen their prognosis and mortality. It is sometimes difficult to find a suitable drug because of the adverse effects. Perampanel has a unique mechanism of action that antagonizes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type glutamate receptor. Here, we report a case of severe dementia due to Alzheimer's disease with intractable epilepsy, which perampanel effected for controlling seizures with less adverse effects. The subject is an 89-year-old Japanese woman with severe dementia due to Alzheimer's disease and intractable myoclonic epilepsy. She also had psychiatric symptoms, such as circadian rhythm disorder and irritability. Valproic acid, lacosamide, or carbamazepine were prescribed, but none of them was effective. Shortly after perampanel started, however, myoclonus and these psychiatric symptoms improved. Moreover, it did not cause any obvious adverse effects, which made it possible to continue perampanel until the end of her life. Perampanel may be useful for controlling intractable epilepsy accompanied by Alzheimer's disease. It may also improve psychiatric symptoms with less adverse effect. Accumulation of studies is necessary to evaluate the effectiveness of perampanel on the epilepsy of Alzheimer's disease patients and further understand that mechanism.},
}
@article {pmid34393775,
year = {2021},
author = {Ning, F and Chen, L and Chen, L and Liu, X and Zhu, Y and Hu, J and Xie, G and Xia, J and Shi, K and Lan, Z and Wang, P},
title = {Combination of Polygoni Multiflori Radix Praeparata and Acori Tatarinowii Rhizoma Alleviates Learning and Memory Impairment in Scopolamine-Treated Mice by Regulating Synaptic-Related Proteins.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {679573},
doi = {10.3389/fphar.2021.679573},
pmid = {34393775},
issn = {1663-9812},
abstract = {Polygoni Multiflori Radix Praeparata (ZhiHeShouWu, PMRP) and Acori Tatarinowii Rhizoma (ShiChangPu, ATR) and their traditional combination (PA) are frequently used in traditional Chinese medicine to prevent and treat Alzheimer disease (AD) based on the theory that PMRP tonifies the kidney and ATR dissipates phlegm. However, the components of PA and their mechanisms of action are not known. The present study analyzed the active components of PA, and investigated the protective effect of PA against cognitive impairment induced by scopolamine in mice along with the underlying mechanism.The aqueous extract of PA was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography (GC)-MS in order to identify the major components. To evaluate the protective effect of PA against cognitive dysfunction, mice were orally administered PA, PMRP, or ATR for 30 days before treatment with scopolamine. Learning and memory were assessed in mice with the Morris water maze test; neurotransmitter levels in the hippocampus were analyzed by HPLC-MS; and the expression of synapse-related proteins in the hippocampus was detected by western blotting and immunohistochemistry. Eight active compounds in PA and rat plasma were identified by HPLC-MS and GC-MS. Plasma concentrations of 2,3,5,4'-tetrahydroxystilbene-2-O-β-d-glucoside, emodin, α-asarone, and asarylaldehyde were increased following PA administration; meanwhile, gallic acid, emodin-8-O-β-d-glucopyranoside, β-asarone, and cis-methyl isoeugenol concentrations were similar in rats treated with PA, PMRP, and ATR. In scopolamine-treated mice, PA increased the concentrations of neurotransmitters in the hippocampus, activated the brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) signaling pathway, and increased the expression of p90 ribosomal S6 kinase (p90RSK) and postsynaptic density (PSD)95 proteins. Thus, PA alleviates cognitive deficits by enhancing synaptic-related proteins, suggesting that it has therapeutic potential for the treatment of aging-related diseases such as AD.},
}
@article {pmid34393191,
year = {2021},
author = {Ezzati, A and Zammit, AR and Lipton, RB},
title = {Comparing Performance of Different Predictive Models in Estimating Disease Progression in Alzheimer Disease.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000474},
pmid = {34393191},
issn = {1546-4156},
abstract = {BACKGROUND: Automatic classification techniques provide tools to analyze complex data and predict disease progression.<br><br>METHODS: A total of 305 cognitively normal; 475 patients with amnestic mild cognitive impairment (aMCI); and 162 patients with dementia were included in this study. We compared the performance of 3 different methods in predicting progression from aMCI to dementia: (1) index-based model; (2) logistic regression (LR); and (3) ensemble linear discriminant (ELD) machine learning models. LR and ELD models were trained using data from cognitively normal and dementia subgroups, and subsequently were applied to aMCI subgroup to predict their disease progression.<br><br>RESULTS: Performance of ELD models were better than LR models in prediction of conversion from aMCI to Alzheimer dementia at all time frames. ELD models performed better when a larger number of features were used for prediction.<br><br>CONCLUSION: Machine learning models have substantial potential to improve the predictive ability for cognitive outcomes.},
}
@article {pmid34392236,
year = {2021},
author = {Halmos, T and Suba, I},
title = {Role of endocrinological factors and metabolic processes in regulating life-span.},
journal = {Orvosi hetilap},
volume = {162},
number = {33},
pages = {1318-1327},
doi = {10.1556/650.2021.32200},
pmid = {34392236},
issn = {1788-6120},
abstract = {Összefoglaló. Az emberek a lehető leghosszabb ideig akarnak élni, jó egészségben. Ha kiküszöbölnénk a kedvezőtlen külső körülményeket, a várható élettartam meghaladhatná a 100 évet. A 20. és 21. században a jóléti társadalmakban a várható élettartam jelentősen megnőtt, így Magyarországon is. Az áttekintett irodalom alapján megvizsgáltuk, hogy a genetika és az öröklődés mellett milyen endokrinológiai és metabolikus tényezők játszanak szerepet az élet meghosszabbításában. Megvizsgáltunk minden endogén tényezőt, amely pozitívan vagy negatívan befolyásolhatja az életkorral összefüggő betegségeket (Alzheimer-kór, szív- és érrendszeri betegségek, rák) és az élettartamot. Kiemeltük a hyperinsulinaemia, az inzulinrezisztencia, a metabolikus szindróma öregedést gyorsító hatását, az inzulinszerű növekedési hormon-1 ellentmondásos szerepét, valamint az élet meghosszabbításában részt vevő, újabban felfedezett peptideket, mint a klotho és a humanin. Ismertettük a mitochondriumok szerepét az élettartam meghatározásában, bemutattuk a mitohormesis folyamatát és annak stresszvédő funkcióját. Bemutattuk a rapamicin célszervét, az mTOR-t, amelynek gátlása meghosszabbítja az élettartamot, valamint a szirtuinokat. Kitértünk az autophagia folyamatára, és ismertettük a szenolitikumok szerepét az öregedésben. Az időskori autoimmunitás csökkenése hozzájárul az élettartam rövidüléséhez, utaltunk a thymus koordináló szerepére. Kiemeltük a bélmikrobiom fontos szerepét az élettartam szabályozásában. Hivatkoztunk a "centenáriusok" megfigyeléséből nyert humánadatokra. Megvizsgáltuk, milyen beavatkozási lehetőségek állnak rendelkezésre az egészségben tölthető élettartam meghosszabbításához. Az életmódbeli lehetőségek közül kiemeltük a kalóriabevitel-csökkentés és a testmozgás jótékony szerepét. Megvizsgáltuk egyes gyógyszerek feltételezett hatásait. Ezek közé tartozik a metformin, az akarbóz, a rezveratrol. E gyógyszerek mindegyikének hatása hasonló a kalóriamegszorításéhoz. Nincs olyan "csodaszer", amely igazoltan meghosszabbítja az élettartamot emberben. Egyes géneknek és génmutációknak jótékony hatásuk van, de ezt környezeti tényezők, betegségek, balesetek és más külső ártalmak módosíthatják. Kiemeljük az elhízás, az alacsony fokozatú gyulladás és az inzulinrezisztencia öregedésre gyakorolt gyorsító hatását. A metabolikus szindróma elterjedtsége miatt ez jelentős népegészségügyi kockázatot jelent. Az inzulin, a növekedési hormon és az inzulinszerű növekedési faktorok hatásainak értékelése továbbra is ellentmondásos. Az egészséges, szellemileg és fizikailag aktív életmód, a kalóriacsökkentés mindenképpen előnyös. Az életet meghosszabbító szerek értékelése még vitatott. Orv Hetil. 2021; 162(33): 1318-1327. Summary. People want to live as long as possible in good health. If we eliminate the unfavorable external conditions, the life expectancy could exceed 100 years. In the 20th and 21th centuries, life expectancy in welfare societies increased significantly, including in Hungary. Based on the reviewed literature, we examined what endocrinological and metabolic factors play a role in prolonging life in addition to genetics and inheritance. We examined all endogenous factors that can positively or negatively affect age-related diseases (Alzheimer's disease, cardiovascular disease, cancer) and longevity. We highlighted the aging effects of hyperinsulinemia, insulin resistance, metabolic syndrome, the controversial role of insulin-like growth factor-1, and more recently discovered peptides involved in prolonging lifespan, such as klotho and humanin. We described the role of mitochondria in determining longevity, we demonstrated the process of mitohormesis and its stress-protective function. We presented the target organ of rapamycin, mTOR, the inhibition of which prolongs lifespan, as well as sirtuins. We covered the process of autophagy and described the role of senolytics in aging. The decrease in autoimmunity in old age contributes to the shortening of life expectancy, we referred to the coordinating role of the thymus. We highlighted the important role of intestinal microbiome in the regulation of longevity. We referred to human data obtained from observations on "centenarians". We examined what intervention options are available to prolong healthy life expectancy. Among the lifestyle options, we highlighted the beneficial role of calorie reduction and exercise. We examined the putative beneficial effects of some drugs. These include metformin, acarbose, resveratrol. The effect of each of these drugs is similar to calorie restriction. There is no "miracle cure" that has been shown to prolong life-span in humans. Some genes and gene mutations have beneficial effects, but this can be modified by environmental factors, diseases, accidents, and other external harms. We highlight the accelerating effects of obesity, low-grade inflammation, and insulin resistance on aging. Due to the prevalence of metabolic syndrome, this poses a significant risk to public health. The assessment of the effects of insulin, growth hormone, and insulin-like growth factors remains controversial. A healthy, mentally and physically active lifestyle, calorie reduction is definitely beneficial. The evaluation of life-prolonging agents is still controversial. Orv Hetil. 2021; 162(33): 1318-1327.},
}
@article {pmid34391822,
year = {2021},
author = {Mosaferi, B and Jand, Y and Salari, AA},
title = {Antibiotic-induced gut microbiota depletion from early adolescence exacerbates spatial but not recognition memory impairment in adult male C57BL/6 mice with Alzheimer-like disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.brainresbull.2021.08.004},
pmid = {34391822},
issn = {1873-2747},
abstract = {Gut microbiota dysbiosis is associated with cognitive dysfunctions and Alzheimer's disease (AD). This study set out to better understand the relationship between gut microbiota depletion and cognitive abilities in mice with or without Alzheimer-like disease. Male C57BL/6 mice from early adolescence received an antibiotic cocktail, and then in adulthood, animals were subjected to a stereotaxic surgery to induce Alzheimer-like disease using amyloid-beta (Aβ)1-42 microinjection. To assess cognitive functions in mice, three behavioural tests including the Y maze, object recognition, and Morris water maze were used. We also measured brain-derived-neurotrophic factor (BDNF), tumour-necrosis factor (TNF)-α, interleukin (IL)-6, and Aβ42 in the brain. Our findings showed that antibiotics treatment impaired object recognition memory, whereas did not alter spatial memory in healthy mice. Antibiotics treatment in mice significantly exacerbated spatial memory impairment following the induction of AD in both the Y maze and Morris water maze test. There were significant correlations between these behavioural tests. In addition, healthy animals treated with antibiotics displayed a significant reduction in brain IL-6. We observed that antibiotics treatment significantly decreased both cytokines TNF-α and IL-6 in the brain of AD-induced mice. However, no alterations were found in brain BDNF levels following both antibiotics treatment and AD induction. These findings show that antibiotic-induced gut microbiota depletion from early adolescence to adulthood can impair cognitive abilities in mice with or without Alzheimer-like disease. Overall, this study suggests that gut microbiota manipulation from early adolescence to adulthood may adversely affect the normal development of cognitive functions later in life.},
}
@article {pmid34388235,
year = {2021},
author = {Priemer, DS and Folkerth, RD},
title = {Dementia in the Forensic Setting: Diagnoses Obtained Using a Condensed Protocol at the Office of Chief Medical Examiner, New York City.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab059},
pmid = {34388235},
issn = {1554-6578},
abstract = {Individuals with dementia may come to forensic autopsy, partly because of non-natural deaths (e.g. fall-related), and/or concerns of abuse/neglect. At the New York City Office of Chief Medical Examiner (NYC OCME), brains from such cases are submitted for neurodegenerative disease (ND) work-up. Seventy-eight sequential cases were evaluated using a recently published condensed protocol for the NIA-AA guidelines for the neuropathologic assessment of Alzheimer disease (AD), a cost-cutting innovation in diagnostic neuropathology. ND was identified in 74 (94.9%) brains; the most common were AD (n = 41 [52.5%]), primary age-related tauopathy (n = 26 [33.3%]), and Lewy body disease ([LBD], n = 25 [32.1%]). Others included age-related tau astrogliopathy, hippocampal sclerosis of aging, progressive supranuclear palsy, multiple system atrophy, amyotrophic lateral sclerosis, argyrophilic grain disease, and Creutzfeldt-Jakob disease. 26.8% of AD cases involved a non-natural, dementia-related death, versus 40.0% for LBD. Finally, 70 (89.7%) cases had chronic cerebrovascular disease, 53 (67.9%) being moderate-to-severe. We present a diverse distribution of NDs notable for a high rate of diagnoses associated with falls (e.g. LBD), a potential difference from the hospital neuropathology experience. We also report a high burden of cerebrovascular disease in demented individuals seen at the NYC OCME. Finally, we demonstrate that the aforementioned condensed protocol is applicable for a variety of ND diagnoses.},
}
@article {pmid34383681,
year = {2021},
author = {Moussavi, Z and Koski, L and Fitzgerald, PB and Millikin, C and Lithgow, B and Jafari-Jozani, M and Wang, X},
title = {Repeated Transcranial Magnetic Stimulation for Improving Cognition in Alzheimer Disease: Protocol for an Interim Analysis of a Randomized Controlled Trial.},
journal = {JMIR research protocols},
volume = {10},
number = {8},
pages = {e31183},
doi = {10.2196/31183},
pmid = {34383681},
issn = {1929-0748},
abstract = {BACKGROUND: Many clinical trials investigating treatment efficacy require an interim analysis. Recently we have been running a large, multisite, randomized, placebo-controlled, double-blind clinical trial investigating the effect of repetitive transcranial magnetic stimulation (rTMS) treatment for improving or stabilizing the cognition of patients diagnosed with Alzheimer disease.<br><br>OBJECTIVE: The objectives of this paper are to report on recruitment, adherence, and adverse events (AEs) to date, and to describe in detail the protocol for interim analysis of the clinical trial data. The protocol will investigate whether the trial is likely to reach its objectives if continued to the planned maximum sample size.<br><br>METHODS: The specific requirements of the analytic protocol are to (1) ensure the double-blind nature of the data while doing the analysis, (2) estimate the predictive probabilities of success (PPoSs), (3) estimate the numbers needed to treat, (4) re-estimate the initial required sample size. The initial estimate of sample size was 208. The interim analysis will be based on 150 patients who will be enrolled in the study and finish at least 8 weeks of the study. Our protocol for interim analysis, at the very first stage, is to determine the response rate for each participant to the treatment (either sham or active), while ensuring the double-blind nature of the data. The blinded data will be analyzed by a statistician to investigate the treatment efficacy. We will use Bayesian PPoS to predict the success rate and determine whether the study should continue.<br><br>RESULTS: The enrollment has been slowed significantly due to the COVID-19 pandemic and lockdown. Nevertheless, so far 133 participants have been enrolled, while 22 of these have been withdrawn or dropped out for various reasons. In general, rTMS has been found tolerable with no serious AE. Only 2 patients dropped out of the study due to their intolerability to rTMS pulses.<br><br>CONCLUSIONS: Overall, the study with the same protocol is going as expected with no serious AE or any major protocol deviation.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815.<br><br>DERR1-10.2196/31183.},
}
@article {pmid34382514,
year = {2021},
author = {Ahmad, SS and Younis, K and Philippe, J and Aschner, M and Khan, H},
title = {Strategic approaches to target the enzymes using natural compounds for the management of Alzheimer's disease: A review.},
journal = {CNS &amp; neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/1871527320666210811160007},
pmid = {34382514},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disease. It is clinically characterized by memory loss and intellectual decrease, among other neurological deficits. The etiology of AD is not completely understood but includes amyloid plaques and intracellular helical filaments as well as neurofibrillary tangles with hyperphosphorylated tau protein. AD is also associated with alterations in amyloid processing genes, such as PSEN1 or PSEN2 and APP. The modulation immune system, cholesterol metabolism, and synaptic vesicle endocytosis have all been shown to remediate AD. In this review, enzymes such as AChE, BuChE, β-secretase, γ-secretase, MAO, and RAGE are discussed as potential targets for AD treatment. The aim of this review was to addresses the molecular mechanisms as well as various genetic factors in AD etiology. The use of natural compounds against these targets might be beneficial for the management of AD.},
}
@article {pmid34379124,
year = {2021},
author = {Desai, P and Evans, D and Dhana, K and Aggarwal, NT and Wilson, RS and McAninch, E and Rajan, KB},
title = {Longitudinal Association of Total Tau Concentrations and Physical Activity With Cognitive Decline in a Population Sample.},
journal = {JAMA network open},
volume = {4},
number = {8},
pages = {e2120398},
doi = {10.1001/jamanetworkopen.2021.20398},
pmid = {34379124},
issn = {2574-3805},
abstract = {Importance: Tau is a brain protein located in neurons and develops abnormally in individuals with Alzheimer disease. New technology is convenient for measuring blood total tau concentrations and provides a unique and increased opportunity for early intervention to slow cognitive decline.<br><br>Objective: To evaluate the association of physical activity and total tau concentrations with cognitive decline at baseline and over time.<br><br>The Chicago Health and Aging Project is a population-based cohort study conducted in 4 Chicago communities. Data collection occurred in 3-year cycles between 1993 and 2012. Participants completed in-home interviews. Clinical evaluations, which included blood samples, were performed with a stratified random sample of 1159 participants. Statistical analyses were conducted from October 30, 2020, to May 25, 2021.<br><br>Exposures: Physical activity and total serum tau concentrations. Data on physical activity were obtained through self-report items, and a sum of minutes per week was calculated. Little physical activity was defined as no participation in a minimum of 4 of the items on the physical activity measure. Medium activity was defined as participating in less than 150 minutes of physical activity per week, and high activity was defined as participating in 150 minutes or more of physical activity per week.<br><br>Main Outcomes and Measures: The main outcome for this study is global cognitive function, measured through a battery of cognitive tests. The study hypothesis was developed after data were collected.<br><br>Results: Of the 1159 participants in the study, 728 were women (63%), and 696 were African American (60%); the mean (SD) age was 77.4 (6.0) years, and the mean (SD) educational level was 12.6 (3.5) years. Participants with high total tau concentrations with medium physical activity had a 58% slower rate of cognitive decline (estimate, -0.028 standard deviation unit [SDU] per year [95% CI, -0.057 to 0.002 SDU per year]; difference, 0.038 SDU per year [95% CI, 0.011-0.065 SDU per year]), and those with high physical activity had a 41% slower rate of cognitive decline (estimate, -0.038 SDU per year [95% CI, -0.068 to -0.009 SDU per year]; difference, 0.027 SDU per year [95% CI, -0.002 to 0.056 SDU per year]), compared with those with little physical activity. Among participants with low total tau concentrations, medium physical activity was associated with a 2% slower rate of cognitive decline (estimate, -0.050 SDU per year [95% CI, -0.069 to -0.031 SDU per year]; difference, 0.001 SDU per year [95% CI, -0.019 to 0.021 SDU per year]), and high physical activity was associated with a 27% slower rate of cognitive decline (estimate, -0.037 SDU per year [95% CI, -0.055 to -0.019 SDU per year]; difference, 0.014 SDU per year [95% CI, -0.007 to 0.034 SDU per year]), compared with little physical activity. Individual tests of cognitive function showed similar results.<br><br>Conclusions and Relevance: This study suggests that, among participants with both high and low total tau concentrations, physical activity was associated with slower cognitive decline. Results support the potential utility of blood biomarkers in measuring the benefits associated with health behaviors and may contribute to specifying target populations or informing interventions for trials that focus on improving physical activity behavior. Future work should examine the association of total tau concentrations with other health behaviors and physical activity types.},
}
@article {pmid34378891,
year = {2021},
author = {Pierzynowska, K and Cyske, Z and Gaffke, L and Rintz, E and Mantej, J and Podlacha, M and Wiśniewska, K and Ĺťabińska, M and Sochocka, M and Lorenc, P and Bielańska, P and Giecewicz, I and Węgrzyn, G},
title = {Potential of genistein-induced autophagy in the treatment of neurodegenerative diseases.},
journal = {Postepy biochemii},
volume = {67},
number = {2},
pages = {117-129},
doi = {10.18388/pb.2021_380},
pmid = {34378891},
issn = {0032-5422},
abstract = {Development of therapies for neurodegenerative diseases, disorders characterized by progressing loss of neurons, is a great challenge for current medicine. Searching for drugs for these diseases is being proceeded in many laboratories in the world. To date, several therapeutical strategies have been proposed which, however, are either of insufficient efficacy or at the early preclinical stages. One of the newest concepts is elevated efficiency of degradation of protein aggregates which are causes of 70% of these diseases. Autophagy, i.e. lysosomal degradation of macromolecules, is a process which could be employed in such a strategy Searching for a compound which would not only stimulate autophagy but also reveal safety in a long-term usage and be able to cross the blood-brain-barrier led to studies on one of flavonoids, genistein which occurs at high concentrations in soy. Experiments with this compound indicated its enormous efficiency in removing protein aggregated formed by beta-amyloid, hyperphosphorylated tau protein, and mutant huntingtin. Moreover, using animal models of these diseases, correction of cognitive and motoric symptoms was demonstrated. Considering safety of genistein as well as its ability to crossing the blood-brain-barrier, one may assume that this molecule is a candidate for an effective drug in therapies of not only Alzheimer disease and Huntington disease, but also other disorders caused be protein aggregates. In this article, recent results of studies on the use of genistein in different models of neurodegenerative diseases are summarized, with special emphasis on its autophagy-dependent action.},
}
@article {pmid34378488,
year = {2021},
author = {Saris, IMJ and Aghajani, M and Reus, LM and Visser, PJ and Pijnenburg, Y and van der Wee, NJA and Bilderbeck, AC and Raslescu, A and Malik, A and Mennes, M and Koops, S and Arrango, C and Ayuso-Mateos, JL and Dawson, GR and Marston, H and Kas, MJ and Penninx, BWJH and , },
title = {Social Dysfunction is Transdiagnostically Associated with Default Mode Network Dysconnectivity in Schizophrenia and Alzheimer's Disease.},
journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry},
volume = {},
number = {},
pages = {1-32},
doi = {10.1080/15622975.2021.1966714},
pmid = {34378488},
issn = {1814-1412},
abstract = {Objectives Social dysfunction is one of the most common signs of major neuropsychiatric disorders. The Default Mode Network (DMN) is crucially implicated in both psychopathology and social dysfunction, although the transdiagnostic properties of social dysfunction remains unknown. As part of the pan-European PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project, we explored cross-disorder impact of social dysfunction on DMN connectivity.Methods We studied DMN intrinsic functional connectivity in relation to social dysfunction by applying Independent Component Analysis and Dual Regression on resting-state fMRI data, among Schizophrenia (SZ; N = 48), Alzheimer Disease (AD; N = 47) patients and healthy controls (HC; N = 55). Social dysfunction was operationalized via the Social Functioning Scale (SFS) and De Jong-Gierveld Loneliness Scale (LON).Results Both SFS &amp; LON were independently associated with diminished DMN connectional integrity within rostromedial prefrontal DMN subterritories (pcorrected range =0.02-0.04). The combined effect of these indicators (Mean.SFS + LON) on diminished DMN connectivity was even more pronounced (both spatially and statistically), independent of diagnostic status, and not confounded by key clinical or sociodemographic effects, comprising large sections of rostromedial and dorsomedial prefrontal cortex (pcorrected =0.01).Conclusions These findings pinpoint DMN connectional alterations as putative transdiagnostic endophenotypes for social dysfunction, and could aid personalized care initiatives grounded in social behavior.},
}
@article {pmid34378237,
year = {2021},
author = {Gove, D and Rune Nielsen, T and Smits, C and Charlotta Plejert, and Rauf, MA and Parveen, S and Jaakson, S and Golan-Shemesh, D and Lahav, D and Kaur, R and Karen Herz, M and Monsees, J and René Thyrian, J and Georges, J},
title = {The challenges of achieving timely diagnosis and culturally appropriate care of people with dementia from minority ethnic groups in Europe.},
journal = {International journal of geriatric psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1002/gps.5614},
pmid = {34378237},
issn = {1099-1166},
support = {//European Commission/ ; //Robert Bosch Stiftung/ ; },
abstract = {In a just society, everyone should have equal access to healthcare in terms of prevention, assessment, diagnosis, treatment and care. Europe is a multicultural society made up of people who identify with a wide range of ethnic groups. Many older people from minority ethnic groups also have a direct migration background. Several studies have shown that there is a lack of equity in relation to dementia diagnoses and care because equal opportunities do not necessarily translate into equal outcomes. An expert ethics working group led by Alzheimer Europe has produced an extensive report on this issue, a policy brief and a guide for health and social care workers. In this brief summary, the authors/members of the expert working group present some of the key challenges and recommendations for healthcare clinicians striving to provide timely diagnosis and good quality care and treatment to people with dementia from all ethnic groups. This article is protected by copyright. All rights reserved.},
}
@article {pmid34376823,
year = {2021},
author = {Chen, Z and Schwulst, SJ and Mentis, AA},
title = {APOE4-mediated Alzheimer disease and "Vascular"-"Meningeal Lymphatic" components: towards a novel therapeutic era?.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {34376823},
issn = {1476-5578},
}
@article {pmid34349617,
year = {2021},
author = {Wei, Z and Koya, J and Reznik, SE},
title = {Insulin Resistance Exacerbates Alzheimer Disease via Multiple Mechanisms.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {687157},
pmid = {34349617},
issn = {1662-4548},
abstract = {Alzheimer disease (AD) is a chronic neurodegenerative disease that accounts for 60-70% of dementia and is the sixth leading cause of death in the United States. The pathogenesis of this debilitating disorder is still not completely understood. New insights into the pathogenesis of AD are needed in order to develop novel pharmacologic approaches. In recent years, numerous studies have shown that insulin resistance plays a significant role in the development of AD. Over 80% of patients with AD have type II diabetes (T2DM) or abnormal serum glucose, suggesting that the pathogenic mechanisms of insulin resistance and AD likely overlap. Insulin resistance increases neuroinflammation, which promotes both amyloid β-protein deposition and aberrant tau phosphorylation. By increasing production of reactive oxygen species, insulin resistance triggers amyloid β-protein accumulation. Oxidative stress associated with insulin resistance also dysregulates glycogen synthase kinase 3-β (GSK-3β), which leads to increased tau phosphorylation. Both insulin and amyloid β-protein are metabolized by insulin degrading enzyme (IDE). Defects in this enzyme are the basis for a strong association between T2DM and AD. This review highlights multiple pathogenic mechanisms induced by insulin resistance that are implicated in AD. Several pharmacologic approaches to AD associated with insulin resistance are presented.},
}
@article {pmid34375908,
year = {2021},
author = {Ekblad, LL and Visser, PJ and Tijms, BM and , },
title = {Proteomic correlates of cortical thickness in cognitively normal individuals with normal and abnormal cerebrospinal fluid beta-amyloid1-42.},
journal = {Neurobiology of aging},
volume = {107},
number = {},
pages = {42-52},
doi = {10.1016/j.neurobiolaging.2021.07.003},
pmid = {34375908},
issn = {1558-1497},
abstract = {Cortical atrophy is an early feature of Alzheimer´s disease (AD). The biological processes associated with variability in cortical thickness remain largely unknown. We studied 220 cerebrospinal fluid (CSF) proteins to evaluate biological pathways associated with cortical thickness in 34 brain regions in 79 cognitively normal older individuals with normal (>192 ng/L, n = 47), and abnormal (≤192 ng/L, n = 32) CSF beta-amyloid1-42 (Aβ42). Interactions for Aβ42 status were tested. Panther GeneOntology and Cytoscape ClueGO analyses were used to evaluate biological processes associated with regional cortical thickness. 170 (77.3 %) proteins related with cortical thickness in at least 1 brain region across the total group, and 171 (77.7 %) proteins showed Aβ42 specific associations. Higher levels of proteins related to axonal and synaptic integrity, amyloid accumulation, and inflammation were associated with thinner cortex in lateral temporal regions, the rostral anterior cingulum, the lateral occipital cortex and the pars opercularis only in the abnormal Aβ42 group. Alterations in CSF proteomics are associated with a regional cortical atrophy in the earliest stages of AD.},
}
@article {pmid34374777,
year = {2021},
author = {Mendsaikhan, A and Tooyama, I and Serrano, GE and Beach, TG and Walker, DG},
title = {Loss of Lysosomal Proteins Progranulin and Prosaposin Associated with Increased Neurofibrillary Tangle Development in Alzheimer Disease.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab056},
pmid = {34374777},
issn = {1554-6578},
abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disease causing cognitive decline in the aging population. To develop disease-modifying treatments, understanding the mechanisms behind the pathology is important, which should include observations using human brain samples. We reported previously on the association of lysosomal proteins progranulin (PGRN) and prosaposin (PSAP) with amyloid plaques in non-demented aged control and AD brains. In this study, we investigated the possible involvement of PGRN and PSAP in tangle formation using human brain tissue sections of non-demented aged control subjects and AD cases and compared with cases of frontotemporal dementia with granulin (GRN) mutations. The study revealed that decreased amounts of PGRN and PSAP proteins were detected even in immature neurofibrillary tangles, while colocalization was still evident in adjacent neurons in all cases. Results suggest that neuronal loss of PGRN preceded loss of PSAP as tangles developed and matured. The GRN mutation cases exhibited almost complete absence of PGRN in most neurons, while PSAP signal was preserved. Although based on correlative data, we suggest that reduced levels of PGRN and PSAP and their interaction in neurons might predispose to accumulation of p-Tau protein.},
}
@article {pmid34374234,
year = {2021},
author = {Yang, D and Qiao, J and Wang, JX and Wei, WY and Zhao, ZX and Cai, HY},
title = {[Effects of B-GOS on cognitive behavior and depression of transgenic mice with Alzheimer's disease].},
journal = {Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology},
volume = {37},
number = {3},
pages = {240-246},
doi = {10.12047/j.cjap.6105.2021.028},
pmid = {34374234},
issn = {1000-6834},
abstract = {Objective: To investigate the effects of novel BimunoGalactooligosaccharides (B-GOS) on cognitive behavior and depression of APP/PS1/tau Alzheimer's disease transgenic mice. Methods: Five-month-old male APP/PS1/tau AD transgenic mice and C57BL/6J control mice were divide into C57+Vehicle group, C57+B-GOS group, APP/PS1/tau+Vehicle group and APP/PS1/tau+B-GOS group, with 10 mice in each group. After continuous administration of B-GOS for 5 months, the cognitive behavior and depressive mood changes of mice in each group were detected by open field experiment, new object recognition experiment, Y maze experiment, Morris water maze experiment, tail suspension test, forced swimming test and conditioned fear experiment, respectively. Results: ①Open field experiment: the percentage of activity time in the central area of open field in APP/PS1/tau+Vehicle group mice was significantly lower than that in C57+Vehicle group mice (P＜0.01), and was remarkably increased after B-GOS intervention (P＜0.05). ② New object recognition experiment: the new object recognition index (NOI) of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P＜0.01), and was observably increased after B-GOS intervention (P＜0.05). ③ Y maze experiment: the spontaneous alternation correct rate of APP/PS1/tau+Vehicle group mice was notably lower than that in C57+Vehicle group (P＜0.01), and was distinctly increased after B-GOS intervention (P＜0.01). ④ Classical water maze experiment: the escape latency of APP/PS1/tau+Vehicle group mice on the 4th and 5th days was significantly longer than that of C57+Vehicle group mice (P＜0.01), which was markedly shortened after B-GOS intervention (P＜0.05). During the space exploration phase, the percentage of swimming time in the target quadrant and the times of crossing the platform in APP/PS1/tau+Vehicle group mice were significantly lower than those in C57+Vehicle group mice (P＜0.01), which were notably increased after B-GOS intervention (P＜0.01). ⑤ Tail suspension test and forced swimming test: the percentage of immobility time in APP/PS1/tau+Vehicle group mice was dramatically higher than that in C57+Vehicle group mice (P＜0.01), and was obviously reduced after B-GOS intervention (P＜ 0.01). ⑥ Conditioned fear experiment: before conditioned stimulus (CS), the freezing ratio of mice in each group had no statistical difference (P＞0.05). After CS, the freezing ratio of APP/PS1/tau+Vehicle group mice was significantly lower than that of C57+Vehicle group mice (P＜0.01), and was notably increased after B-GOS intervention (P＜0.01). Conclusion: B-GOS could reverse the cognitive behavioral impairment of APP/PS1/tau mice and alleviate their depression to a large extent.},
}
@article {pmid34353220,
year = {2021},
author = {Tueth, LE and Earhart, GM and Rawson, KS},
title = {Association between falls in Alzheimer disease and scores on the Balance Evaluation Systems Test (BESTest) and MiniBESTest.},
journal = {Somatosensory &amp; motor research},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/08990220.2021.1959309},
pmid = {34353220},
issn = {1369-1651},
abstract = {BACKGROUND AND PURPOSE: Alzheimer disease (AD) is the most common form of dementia and the sixth leading cause of death in the United States. Falls are associated with AD and can lead to injury. The Balance Evaluation Systems Test (BESTest) is a balance measure used in other neurological conditions to predict fall risk. The purpose of this study is to examine the relationship between MiniBestest, BESTest, and BESTest subsection scores and fall incidence among individuals with a diagnosis of mild AD.<br><br>METHODS: The study was a single centre, prospective, observational cohort study. Participants completed baseline questionnaires including a demographic form, a fall history questionnaire and the Barthel Index of Activities of Daily Living (ADLs). Balance and gait were assessed using the MiniBESTest and BESTest. After completing baseline assessment, participants were given monthly fall calendars to track falls for the next 12 months.<br><br>RESULTS: MiniBESTest total raw score for fallers was 13.4 out of 28 (SD = 3.6) and for non-fallers was 18.4 of out 28 (SD = 3.7). MiniBESTest total percentage score for fallers was 47.8% (SD = 12.8%) and for non-fallers was 65.5% (SD = 13.1%). BESTest total percentage scores for fallers was 58.2% (SD = 3.9%) and for non-fallers was 73.9% (SD = 7.9%). Subsections II-IV of the BESTest correlated with faller status.<br><br>DISCUSSION AND CONCLUSIONS: Among individuals with mild AD, fall status was associated with certain balance deficits on the BESTest including moving body outside base of support (subsection II), changing centre of mass (subsection III), and reacting to external perturbations (subsection IV). Future studies could explore differences between AD and other neurological conditions and how physical therapy could improve these areas to reduce fall risk.},
}
@article {pmid34370289,
year = {2021},
author = {Debieu, S and Solier, S and Colombeau, L and Versini, A and Sindikubwabo, F and Forrester, A and Müller, S and Cañeque, T and Rodriguez, R},
title = {Small Molecule Regulators of Ferroptosis.},
journal = {Advances in experimental medicine and biology},
volume = {1301},
number = {},
pages = {81-121},
pmid = {34370289},
issn = {0065-2598},
abstract = {Ferroptosis is a dedicated mode of cell death involving iron, reactive oxygen species and lipid peroxidation. Involved in processes such as glutathione metabolism, lysosomal iron retention or interference with lipid metabolism, leading either to activation or inhibition of ferroptosis. Given the implications of ferroptosis in diseases such as cancer, aging, Alzheimer and infectious diseases, new molecular mechanisms underlying ferroptosis and small molecules regulators that target those mechanisms have prompted a great deal of interest. Here, we discuss the current scenario of small molecules modulating ferroptosis and critically assess what is known about their mechanisms of action.},
}
@article {pmid34367470,
year = {2021},
author = {Zhang, T and Liu, N and Wei, W and Zhang, Z and Li, H},
title = {Integrated Analysis of Weighted Gene Coexpression Network Analysis Identifying Six Genes as Novel Biomarkers for Alzheimer's Disease.},
journal = {Oxidative medicine and cellular longevity},
volume = {2021},
number = {},
pages = {9918498},
doi = {10.1155/2021/9918498},
pmid = {34367470},
issn = {1942-0994},
abstract = {Background: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease; however, there are no comprehensive therapeutic interventions. Therefore, this study is aimed at identifying novel molecular targets that may improve the diagnosis and treatment of patients with AD.<br><br>Methods: In our study, GSE5281 microarray dataset from the GEO database was collected and screened for differential expression analysis. Genes with a P value of <0.05 and ∣log2FoldChange | >0.5 were considered differentially expressed genes (DEGs). We further profiled and identified AD-related coexpression genes using weighted gene coexpression network analysis (WGCNA). Functional enrichment analysis was performed to determine the characteristics and pathways of the key modules. We constructed an AD-related model based on hub genes by logistic regression and least absolute shrinkage and selection operator (LASSO) analyses, which was also verified by the receiver operating characteristic (ROC) curve.<br><br>Results: In total, 4674 DEGs were identified. Nine distinct coexpression modules were identified via WGCNA; among these modules, the blue module showed the highest positive correlation with AD (r = 0.64, P = 3e - 20), and it was visualized by establishing a protein-protein interaction network. Moreover, this module was particularly enriched in "pathways of neurodegeneration-multiple diseases," "Alzheimer disease," "oxidative phosphorylation," and "proteasome." Sixteen genes were identified as hub genes and further submitted to a LASSO regression model, and six genes (EIF3H, RAD51C, FAM162A, BLVRA, ATP6V1H, and BRAF) were identified based on the model index. Additionally, we assessed the accuracy of the LASSO model by plotting an ROC curve (AUC = 0.940).<br><br>Conclusions: Using the WGCNA and LASSO models, our findings provide a better understanding of the role of biomarkers EIF3H, RAD51C, FAM162A, BLVRA, ATP6V1H, and BRAF and provide a basis for further studies on AD progression.},
}
@article {pmid34367051,
year = {2021},
author = {Dos Santos, NV and Yariwake, VY and Marques, KDV and Veras, MM and Fajersztajn, L},
title = {Air Pollution: A Neglected Risk Factor for Dementia in Latin America and the Caribbean.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {684524},
doi = {10.3389/fneur.2021.684524},
pmid = {34367051},
issn = {1664-2295},
abstract = {The risk of dementia and Alzheimer's disease in Latin America and the Caribbean (LAC) rises with increasing age and polluted air. Currently, at least 172 million people breathe unhealthy levels of air pollution in LAC countries. Several cohort studies have indicated that air pollution increases the risk of developing dementia and neurodegenerative diseases, but the mechanisms underlying the association are still not clear. Air pollution causes and aggravates five established risk factors for dementia (obesity, hypertension, stroke, diabetes mellitus, and heart diseases) and is linked to three other risk factors (physical inactivity, cognitive inactivity, and depression). Some of these risk factors could be mediating the association between air pollution and dementia. Reducing the risks for dementia is crucial and urgently needed in LAC countries. There is room for improving air quality in many urban areas in the LAC region and other low- and middle-income countries (LMICs), a routealready explored by many urban areas in developing regions. Moreover, reducing air pollution has proved to improve health outcomes before. In this article, we propose that despite the ongoing and valid scientific discussion, if air pollution can or cannot directly affect the brain and cause or aggravate dementia, we are ready to consider air pollution as a potentially modifiable risk factor for dementia in LAC and possibly in other LMICs. We suggest that controlling and reducing current air pollution levels in LAC and other LMIC regions now could strongly contribute.},
}
@article {pmid34366938,
year = {2021},
author = {Kalafatis, C and Modarres, MH and Apostolou, P and Marefat, H and Khanbagi, M and Karimi, H and Vahabi, Z and Aarsland, D and Khaligh-Razavi, SM},
title = {Validity and Cultural Generalisability of a 5-Minute AI-Based, Computerised Cognitive Assessment in Mild Cognitive Impairment and Alzheimer's Dementia.},
journal = {Frontiers in psychiatry},
volume = {12},
number = {},
pages = {706695},
doi = {10.3389/fpsyt.2021.706695},
pmid = {34366938},
issn = {1664-0640},
abstract = {Introduction: Early detection and monitoring of mild cognitive impairment (MCI) and Alzheimer's Disease (AD) patients are key to tackling dementia and providing benefits to patients, caregivers, healthcare providers and society. We developed the Integrated Cognitive Assessment (ICA); a 5-min, language independent computerised cognitive test that employs an Artificial Intelligence (AI) model to improve its accuracy in detecting cognitive impairment. In this study, we aimed to evaluate the generalisability of the ICA in detecting cognitive impairment in MCI and mild AD patients. Methods: We studied the ICA in 230 participants. 95 healthy volunteers, 80 MCI, and 55 mild AD participants completed the ICA, Montreal Cognitive Assessment (MoCA) and Addenbrooke's Cognitive Examination (ACE) cognitive tests. Results: The ICA demonstrated convergent validity with MoCA (Pearson r=0.58, p<0.0001) and ACE (r=0.62, p<0.0001). The ICA AI model was able to detect cognitive impairment with an AUC of 81% for MCI patients, and 88% for mild AD patients. The AI model demonstrated improved performance with increased training data and showed generalisability in performance from one population to another. The ICA correlation of 0.17 (p = 0.01) with education years is considerably smaller than that of MoCA (r = 0.34, p < 0.0001) and ACE (r = 0.41, p < 0.0001) which displayed significant correlations. In a separate study the ICA demonstrated no significant practise effect over the duration of the study. Discussion: The ICA can support clinicians by aiding accurate diagnosis of MCI and AD and is appropriate for large-scale screening of cognitive impairment. The ICA is unbiased by differences in language, culture, and education.},
}
@article {pmid34366342,
year = {2021},
author = {Thorlacius-Ussing, G and Bruun, M and Gjerum, L and Frederiksen, KS and Rhodius-Meester, HFM and van der Flier, WM and Waldemar, G and Hasselbalch, SG},
title = {Comparing a Single Clinician Versus a Multidisciplinary Consensus Conference Approach for Dementia Diagnostics.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-210278},
pmid = {34366342},
issn = {1875-8908},
abstract = {BACKGROUND: Evidence-based recommendations on the optimal evaluation approach for dementia diagnostics are limited. This impedes a harmonized workup across clinics and nations.<br><br>OBJECTIVE: To evaluate the diagnostic performance of a multidisciplinary consensus conference compared to a single clinician approach.<br><br>METHODS: In this prospective study, we enrolled 457 patients with suspected cognitive decline, from two European memory clinics. A diagnostic evaluation was performed at baseline independently in two ways: 1) by a single clinician and 2) at a multidisciplinary consensus conference. A syndrome diagnosis and an etiological diagnosis was made. The confidence in the diagnosis was recorded using a visual analogue scale. An expert panel re-evaluation diagnosis served as reference for the baseline syndrome diagnosis and a 12-24-month follow-up diagnosis for the etiological diagnosis.<br><br>RESULTS: 439 patients completed the study. We observed 12.5%discrepancy (k = 0.81) comparing the baseline syndrome diagnoses of the single clinician to the consensus conference, and 22.3%discrepancy (k = 0.68) for the baseline etiological diagnosis. The accuracy of the baseline etiological diagnosis was significantly higher at the consensus conference and was driven mainly by increased accuracy in the MCI group. Confidence in the etiological diagnosis at baseline was significantly higher at the consensus conference (p < 0.005), especially for the frontotemporal dementia diagnosis.<br><br>CONCLUSION: The multidisciplinary consensus conference performed better on diagnostic accuracy of disease etiology and increased clinicians' confidence. This highlights the importance of a multidisciplinary diagnostic evaluation approach for dementia diagnostics, especially when evaluating patients in the MCI stage.},
}
@article {pmid34365076,
year = {2021},
author = {Duarte-Abritta, B and Sánchez, SM and Abulafia, C and Gustafson, DR and Vázquez, S and Sevlever, G and Castro, MN and Fiorentini, L and Villarreal, MF and Guinjoan, SM},
title = {Amyloid and anatomical correlates of executive functioning in middle-aged offspring of patients with late-onset Alzheimer's disease.},
journal = {Psychiatry research. Neuroimaging},
volume = {316},
number = {},
pages = {111342},
doi = {10.1016/j.pscychresns.2021.111342},
pmid = {34365076},
issn = {1872-7506},
abstract = {A traditional hallmark of cognitive impairment associated with late-onset Alzheimer´s disease (LOAD) is episodic memory impairment. However, early alterations have been identified in brain regions associated with executive function in asymptomatic, middle-age offspring of patients with LOAD (O-LOAD) compared to those with no family history. We hypothesized that executive function among O-LOAD would correlate with structural and amyloid brain imaging differently from those without a family history of LOAD (control subjects, CS). Executive function, cortical thickness, and in-vivo Aβ deposits were quantified in 30 O-LOAD and 25 CS. Associations were observed among O-LOAD only. Cortical thickness in the left lateral orbitofrontal cortex was positively associated with Design Fluency. The Stroop Color and Word Test, correlated positively with right rostral mid-frontal cortex thickness. Trails Making Test-B was inversely related to left medial orbitofrontal thickness. Tower of London total time was positively associated with β-amyloid deposition in the right precuneus. These results support previous evidence that early executive dysfunction might reflect subtle, early changes in persons at risk of LOAD and suggests that executive function alterations deserve further exploration in the LOAD literature.},
}
@article {pmid34360133,
year = {2021},
author = {Godefroy, V and Levy, R and Bouzigues, A and Rametti-Lacroux, A and Migliaccio, R and Batrancourt, B},
title = {ECOCAPTURE@HOME: Protocol for the Remote Assessment of Apathy and Its Everyday-Life Consequences.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {15},
pages = {},
pmid = {34360133},
issn = {1660-4601},
support = {Appel à Projets FRC 2020 - le cerveau protégé de/par son environnement//Fédération pour la Recherche sur le Cerveau/ ; },
abstract = {Apathy, a common neuropsychiatric symptom associated with dementia, has a strong impact on patients' and caregivers' quality of life. However, it is still poorly understood and hard to define. The main objective of the ECOCAPTURE programme is to define a behavioural signature of apathy using an ecological approach. Within this program, ECOCAPTURE@HOME is an observational study which aims to validate a method based on new technologies for the remote monitoring of apathy in real life. For this study, we plan to recruit 60 couples: 20 patient-caregiver dyads in which patients suffer from behavioral variant Fronto-Temporal Dementia, 20 patient-caregiver dyads in which patients suffer from Alzheimer Disease and 20 healthy control couples. These dyads will be followed for 28 consecutive days via multi-sensor bracelets collecting passive data (acceleration, electrodermal activity, blood volume pulse). Active data will also be collected by questionnaires on a smartphone application. Using a pool of metrics extracted from these passive and active data, we will validate a measurement model for three behavioural markers of apathy (i.e., daytime activity, quality of sleep, and emotional arousal). The final purpose is to facilitate the follow-up and precise diagnosis of apathy, towards a personalised treatment of this condition within everyday life.},
}
@article {pmid34364289,
year = {2021},
author = {Akbor, MM and Kim, J and Nomura, M and Sugioka, J and Kurosawa, N and Isobe, M},
title = {A candidate gene of Alzheimer diseases was mutated in senescence-accelerated mouse prone (SAMP) 8 mice.},
journal = {Biochemical and biophysical research communications},
volume = {572},
number = {},
pages = {112-117},
doi = {10.1016/j.bbrc.2021.07.095},
pmid = {34364289},
issn = {1090-2104},
abstract = {The senescence-accelerated mouse prone (SAMP) 8 strain exhibits age-related learning and memory deficits (LMD) at 2 months of age. We have found strong association of chromosome 12 locus with learning memory deficit (LMD) phenotype in SAMP8 strain. In the course of searching candidate gene, here we identified solute carrier family 24 sodium/potassium/calcium exchanger member 4 (Slc24a4) in SAMP8 chromosome 12 LMD possessing one single nucleotide polymorphism causing amino acid replacement of Threonine at 413 position with Methionine. Since SLC24A4 has been postulated as a candidate of late onset Alzheimer's diseases (LOAD), we further analyze the functional importance of this polymorphism. By expressing Slc24a4 protein in HEK293 cells, here we showed polymorphic SAMP8 type Slc24a4-T413 M causing significant loss of calcium ion (Ca2+) transporter activity in cells compared with that of wild type mouse (Slc24a4-WT). However, no study yet shows any functional association of human SLC24A4 polymorphism with the onset of LOAD pathogenesis. Thus, our present finding may further help to clarify the importance of this ion exchanger with age related cognitive dysfunction.},
}
@article {pmid34363663,
year = {2021},
author = {Kim, SH and Farrell, K and Cosentino, S and Vonsattel, JG and Faust, PL and Cortes, EP and Bennet, DA and Louis, ED and Crary, JF},
title = {Tau Isoform Profile in Essential Tremor Diverges From Other Tauopathies.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab073},
pmid = {34363663},
issn = {1554-6578},
abstract = {Patients with essential tremor (ET) frequently develop concurrent dementia, which is often assumed to represent co-morbid Alzheimer disease (AD). Autopsy studies have identified a spectrum of tau pathologies in ET and tau isoforms have not been examined in ET. We performed immunoblotting using autopsy cerebral cortical tissue from patients with ET (n = 13), progressive supranuclear palsy ([PSP], n = 10), Pick disease ([PiD], n = 2), and AD (n = 7). Total tau in ET samples was similar to that in PSP and PiD but was significantly lower than that in AD. Abnormal tau levels measured using the AT8 phospho-tau specific (S202/T205/S208) monoclonal antibody in ET were similar to those in PSP but were lower than in PiD and AD. In aggregates, tau with 3 microtubule-binding domain repeats (3R) was significantly higher in AD than ET, while tau with 4 repeats (4R) was significantly higher in PSP. Strikingly, the total tau without N-terminal inserts in ET was significantly lower than in PSP, PiD, and AD, but total tau with other N-terminal inserts was not. Monomeric tau with one insert in ET was similar to that in PSP and PiD was lower than in AD. Thus, ET brains exhibit an expression profile of tau protein isoforms that diverges from that of other tauopathies.},
}
@article {pmid34363401,
year = {2021},
author = {Darusman, HS and Li Wern, T and Sajuthi, D and Schapiro, SJ and Hau, J},
title = {Age-related cognitive impairment is associated with low serum concentrations of testosterone and CSF levels of amyloid beta 42 in male cynomolgus monkeys (Macaca fascicularis).},
journal = {Journal of medical primatology},
volume = {},
number = {},
pages = {},
doi = {10.1111/jmp.12536},
pmid = {34363401},
issn = {1600-0684},
support = {//Ministry of Finance of The Republic of Indonesia on The Research and Productive Innovation (RISPRO) LPDP program (Contract Id. PRJ/29/LPDP/2019)./ ; },
abstract = {Aged memory-impaired cynomolgus monkeys had significantly lower levels of cerebrospinal amyloid (Aβ42) and serum testosterone compared with young animals and non-memory-impaired controls. Our findings confirm similar findings in the human and substantiate the usefulness of the cynomolgus monkey as a spontaneous model for aging-associated senile dementia of the Alzheimer type.},
}
@article {pmid34362766,
year = {2021},
author = {},
title = {ARPA-H Elicits Enthusiasm, Raises Questions.},
journal = {Cancer discovery},
volume = {},
number = {},
pages = {},
doi = {10.1158/2159-8290.CD-ND2021-0112},
pmid = {34362766},
issn = {2159-8290},
abstract = {The Biden administration recently proposed creating the Advanced Research Projects Agency for Health, a biomedical research agency under the NIH to accelerate research for widespread diseases such as diabetes, Alzheimer disease, and cancer. Although many researchers express enthusiasm for the idea, questions remain about how the entity would function and mesh with existing institutes and agencies.},
}
@article {pmid34362303,
year = {2021},
author = {Kile, S and Au, W and Parise, C and Rose, K and Donnel, T and Hankins, A and Au, Y and Chan, M and Ghassemi, A},
title = {Five-year outcomes after IVIG for mild cognitive impairment due to alzheimer disease.},
journal = {BMC neuroscience},
volume = {22},
number = {1},
pages = {49},
pmid = {34362303},
issn = {1471-2202},
support = {9471100-1107542//Sutter Health/ ; },
abstract = {BACKGROUND: The purpose of this study was to assess the five-year treatment effects of a short course of intravenous immunoglobulin (IVIG) in subjects with mild cognitive impairment (MCI) due to Alzheimer disease (AD).<br><br>METHODS: Fifty subjects 50 to 84 years of age with MCI due to AD were administered 0.4 g/kg 10% IVIG or 0.9% saline every two weeks x five doses in a randomized double-blinded design as part of a two-year study. Twenty-seven subjects completed an additional three-year extension study. MRI brain imaging, cognitive testing, and conversion to dementia were assessed annually. Participants were stratified into early MCI (E-MCI) and late MCI (L-MCI). The primary endpoint was brain atrophy measured as annualized percent change in ventricular volume (APCV) annually for five years. ANOVA was used to compare annualized percent change in ventricular volume from baseline between the groups adjusting for MCI status (E-MCI, L-MCI).<br><br>RESULTS: Differences in brain atrophy between the groups, which were statistically significant after one year, were no longer significant after five years. IVIG-treated L-MCI subjects did demonstrate a delay in conversion to dementia of 21.4 weeks.<br><br>CONCLUSION: An eight-week course of IVIG totaling 2 g/kg in MCI is safe but is not sufficient to sustain an initial reduction in brain atrophy or a temporary delay in conversion to dementia at five years. Other dosing strategies of IVIG in the early stages of AD should be investigated to assess more sustainable disease-modifying effects. Trial registration ClinicalTrials.gov NCT01300728. Registered 23 February 2011.},
}
@article {pmid34362026,
year = {2021},
author = {Del Pinto, R and Grassi, D and Bocale, R and Carubbi, F and Ferri, C and Desideri, G},
title = {Blood Pressure Profiles and Cognitive Function from Adulthood to Old Age: Chasing a Golden Middle Way?.},
journal = {Journal of clinical medicine},
volume = {10},
number = {15},
pages = {},
doi = {10.3390/jcm10153243},
pmid = {34362026},
issn = {2077-0383},
abstract = {With the demographic shift toward advanced ages, it is imperative to understand the biological mechanisms behind common, disabling age-related diseases such as cognitive impairment in its mild form to overt dementia. Hypertension, a major cardiovascular risk factor, is epidemiologically linked to vascular and Alzheimer-type dementia, with possible mechanisms being atherosclerotic macro- and microvascular damage leading to neuronal cell death, as well as proinflammatory events responsible for neurodegeneration. Nevertheless, there is currently a knowledge gap as to which population to target, what the diagnostics test, and how to manage early pathogenic events in order to prevent such a dramatic and disabling condition. While clinical trials data support the benefit of active BP control with antihypertensive medications on the risk of future cognitive impairment, hypotension appears to be related to accelerated cognitive decline in both the fit and the cognitively frail elderly. Dedicated, technologically advanced studies assessing the relation of BP with dementia are needed to clarify the pathophysiological mechanisms in the association before a tailored preventive, diagnostic, and therapeutic approach to one of the most widespread modern medical challenges becomes a reality.},
}
@article {pmid34361099,
year = {2021},
author = {Esselun, C and Theyssen, E and Eckert, GP},
title = {Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease.},
journal = {International journal of molecular sciences},
volume = {22},
number = {15},
pages = {},
doi = {10.3390/ijms22158333},
pmid = {34361099},
issn = {1422-0067},
abstract = {(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA's effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA's effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis.},
}
@article {pmid34360264,
year = {2021},
author = {Besser, LM and Chang, LC and Hirsch, JA and Rodriguez, DA and Renne, J and Rapp, SR and Fitzpatrick, AL and Heckbert, SR and Kaufman, JD and Hughes, TM},
title = {Longitudinal Associations between the Neighborhood Built Environment and Cognition in US Older Adults: The Multi-Ethnic Study of Atherosclerosis.},
journal = {International journal of environmental research and public health},
volume = {18},
number = {15},
pages = {},
doi = {10.3390/ijerph18157973},
pmid = {34360264},
issn = {1660-4601},
support = {K01AG063895/AG/NIA NIH HHS/United States ; },
abstract = {Few studies have examined associations between neighborhood built environments (BE) and longitudinally measured cognition. We examined whether four BE characteristics were associated with six-year change in global cognition and processing speed. We obtained data on 1816 participants without dementia from the Multi-Ethnic Study of Atherosclerosis. BE measures included social destination density, walking destination density, proportion of land dedicated to retail, and network ratio (street connectivity). Global cognition was measured with the Cognitive Abilities Screening Instrument (CASI) and processing speed with the Digit Symbol Coding test (DSC). Multivariable random intercept logistic models tested associations between neighborhood BE at 2010-2012 and maintained/improved cognition (versus decline) from 2010-2018, and mediation by minutes of physical activity (PA)/week. The sample was an average of 67 years old (standard deviation = 8.2) (first cognitive measurement) and racially/ethnically diverse (29% African American, 11% Chinese, 17% Hispanic, 44% White). Compared to individuals with no walking destinations in the 1-mile surrounding their residence, those with 716 walking destinations (maximum observed) were 1.24 times more likely to have maintain/improved DSC score (Odds ratio: 1.24; 95% confidence interval: 1.03-1.45). No other associations were observed between BE and cognition, and PA minutes/week did not mediate the association between walking destination density and DSC change. This study provides limited evidence for an association between greater neighborhood walking destinations and maintained/improved processing speed in older age and no evidence for associations between the other BE characteristics and cognition. Future studies with finer grained BE and cognitive measures and longer-term follow up may be required.},
}
@article {pmid34357949,
year = {2021},
author = {Arce-López, B and Alvarez-Erviti, L and De Santis, B and Izco, M and López-Calvo, S and Marzo-Sola, ME and Debegnach, F and Lizarraga, E and López de Cerain, A and González-Peñas, E and Vettorazzi, A},
title = {Biomonitoring of Mycotoxins in Plasma of Patients with Alzheimer's and Parkinson's Disease.},
journal = {Toxins},
volume = {13},
number = {7},
pages = {},
doi = {10.3390/toxins13070477},
pmid = {34357949},
issn = {2072-6651},
support = {Project-43, 2019 modality A//Departamento de Salud, Gobierno de Navarra/ ; AGL2017-85732-R//Ministerio de Economía, Industria y Competitividad, Gobierno de España/ ; },
abstract = {Exposure to environmental contaminants might play an important role in neurodegenerative disease pathogenesis, such as Parkinson´s disease (PD) and Alzheimer´s disease (AD). For the first time in Spain, the plasmatic levels of 19 mycotoxins from patients diagnosed with a neurodegenerative disease (44 PD and 24 AD) and from their healthy companions (25) from La Rioja region were analyzed. The studied mycotoxins were aflatoxins B1, B2, G1, G2 and M1, T-2 and HT-2, ochratoxins A (OTA) and B (OTB), zearalenone, sterigmatocystin (STER), nivalenol, deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, deepoxy-deoxynivalenol, neosolaniol, diacetoxyscirpenol and fusarenon-X. Samples were analyzed by LC-MS/MS before and after treatment with β-glucuronidase/arylsulfatase in order to detect potential metabolites. Only OTA, OTB and STER were detected in the samples. OTA was present before (77% of the samples) and after (89%) the enzymatic treatment, while OTB was only detectable before (13%). Statistically significant differences in OTA between healthy companions and patients were observed but the observed differences might seem more related to gender (OTA levels higher in men, p-value = 0.0014) than the disease itself. STER appeared only after enzymatic treatment (88%). Statistical analysis on STER, showed distributions always different between healthy controls and patients (patients' group > controls, p-value < 0.0001). Surprisingly, STER levels weakly correlated positively with age in women (rho = 0.3384), while OTA correlation showed a decrease of levels with age especially in the men with PD (rho = -0.4643).},
}
@article {pmid34356897,
year = {2021},
author = {Brunetti, D and Catania, A and Viscomi, C and Deleidi, M and Bindoff, LA and Ghezzi, D and Zeviani, M},
title = {Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration.},
journal = {Biomedicines},
volume = {9},
number = {7},
pages = {},
doi = {10.3390/biomedicines9070833},
pmid = {34356897},
issn = {2227-9059},
support = {SoE-SEED2020_MI.to.AD//Università degli Studi di Milano/ ; GSP20003_PAsAtaxia002//Fondazione Telethon/ ; GGP19007//Fondazione Telethon/ ; GGP20013//Fondazione Telethon/ ; Young Investigator Award VH-NG-1123//Helmholtz Association/ ; },
abstract = {Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of PITRM1 deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches.},
}
@article {pmid34354924,
year = {2021},
author = {Ni, R and Villois, A and Dean-Ben, XL and Chen, Z and Vaas, M and Stavrakis, S and Shi, G and deMello, A and Ran, C and Razansky, D and Arosio, P and Klohs, J},
title = {In-vitro and in-vivo characterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice.},
journal = {Photoacoustics},
volume = {23},
number = {},
pages = {100285},
doi = {10.1016/j.pacs.2021.100285},
pmid = {34354924},
issn = {2213-5979},
abstract = {The abnormal deposition of fibrillar beta-amyloid (Aβ) deposits in the brain is one of the major histopathological hallmarks of Alzheimer's disease (AD). Here, we characterized curcumin-derivative CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of brain Aβ deposits in the arcAβ mouse model of AD cerebral amyloidosis. CRANAD-2 showed a specific and quantitative detection of Aβ fibrils in vitro, even in complex mixtures, and it is capable of distinguishing between monomeric and fibrillar forms of Aβ. In vivo epi-fluorescence microscopy and optoacoustic tomography after intravenous CRANAD-2 administration demonstrated higher cortical retention in arcAβ compared to non-transgenic littermate mice. Immunohistochemistry showed co-localization of CRANAD-2 and Aβ deposits in arcAβ mouse brain sections, thus verifying the specificity of the probe. In conclusion, we demonstrate suitability of CRANAD-2 for optical detection of Aβ deposits in animal models of AD pathology, which facilitates mechanistic studies and the monitoring of putative treatments targeting Aβ deposits.},
}
@article {pmid34353357,
year = {2021},
author = {Iida, MA and Farrell, K and Walker, JM and Richardson, TE and Marx, GA and Bryce, CH and Purohit, D and Ayalon, G and Beach, TG and Bigio, EH and Cortes, EP and Gearing, M and Haroutunian, V and McMillan, CT and Lee, EB and Dickson, DW and McKee, AC and Stein, TD and Trojanowski, JQ and Woltjer, RL and Kovacs, GG and Kofler, JK and Kaye, J and White, CL and Crary, JF},
title = {Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study.},
journal = {Acta neuropathologica communications},
volume = {9},
number = {1},
pages = {134},
pmid = {34353357},
issn = {2051-5960},
support = {R01 AG054008/NH/NIH HHS/United States ; R01 AG060961/NH/NIH HHS/United States ; R01 NS095252/NH/NIH HHS/United States ; R01 NS086736/NH/NIH HHS/United States ; F32 AG056098/NH/NIH HHS/United States ; P30 AG066514/NH/NIH HHS/United States ; R01 AG062348/NH/NIH HHS/United States ; P30 AG010124/NH/NIH HHS/United States ; P01 AG017586/NH/NIH HHS/United States ; R01 AG066152/NH/NIH HHS/United States ; P50 AG005133/NH/NIH HHS/United States ; P50 AG005138/NH/NIH HHS/United States ; P30 AG066514/NH/NIH HHS/United States ; U24 NS072026/NH/NIH HHS/United States ; P30 AG019610/NH/NIH HHS/United States ; P30 AG013854/NH/NIH HHS/United States ; P30 NS055077/NH/NIH HHS/United States ; P50 AG025688/NH/NIH HHS/United States ; P30 AG08017/NH/NIH HHS/United States ; U54 NS115266/NH/NIH HHS/United States ; R01 AG062348/NH/NIH HHS/United States ; R01 AG062348/NH/NIH HHS/United States ; U19 AG062418/NH/NIH HHS/United States ; 75N95019C00049/NH/NIH HHS/United States ; NIRG-15-363188/ALZ/Alzheimer's Association/United States ; },
abstract = {Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.},
}
@article {pmid34352166,
year = {2021},
author = {Conejero, I and Dubois, J and Gutierrez, LA and Delrieu, J and Arbus, C and Garcia, M and Lopez-Castroman, J and Courtet, P and Gabelle, A},
title = {Amyloid Burden and Depressive Symptom Trajectories in Older Adults at Risk of Developing Cognitive Decline.},
journal = {The Journal of clinical psychiatry},
volume = {82},
number = {5},
pages = {},
doi = {10.4088/JCP.20m13410},
pmid = {34352166},
issn = {1555-2101},
abstract = {Objective: Little is known about the amyloid load impact on depressive symptoms or disorders, although it can modulate the cognitive trajectory in older adults. Here, we analyzed, in individuals at risk of Alzheimer's dementia, the relationship between amyloid load and depressive symptoms changes over time.<br><br>Methods: This study included ≥ 70-year-old participants from the French Multidomain Alzheimer Preventive Trial (MAPT) (May 2008 to February 2011) who underwent brain amyloid load measurement by β-amyloid-[18F] florbetapir-PET at baseline and had spontaneous memory complaints and/or limitation in 1 instrumental activity of daily living or slow walking gait (N = 264). Symptoms of depression were measured with the Geriatric Depression Scale-15 items (GDS) at baseline and 6, 12, 24, and 36 months of follow-up. Four GDS factors were determined by principal component analysis (PCA): life satisfaction, level of apathy, self-esteem, and anxiety. Amyloid positive status was defined based on the amyloid load in 6 Alzheimer's dementia-related regions. Regional amyloid load was based on 3 dimensions defined by PCA. The longitudinal links between depressive symptomatology and amyloid load (ie, cortical AV45 and amyloid load dimensions) were analyzed using linear mixed-multivariate models.<br><br>Results: At baseline, 11% of participants had depressive symptoms (GDS > 5) and 34% were amyloid-positive. The global amyloid load was not associated with worsening of the total GDS score but only with the impairment of self-esteem factor during the follow-up after adjustment for age, sex, education level, and drug intake, dementia, and Mini-Mental State Examination score (β = -0.029, 95% CI [-0.052 to -0.007], P = .003). Regional amyloid load in hippocampus and bilateral caudate nucleus protected significantly from self-esteem decrease during the 3-year follow-up.<br><br>Conclusions: Although amyloid load shows no impact on GDS score in subjects at risk of Alzheimer's dementia, amyloid load may influence the progression of depressive dimension (self-esteem) with different effects according to the regional burden.<br><br>Trial Registration: ClinicalTrials.gov identifier: NCT00672685.},
}
@article {pmid34350401,
year = {2021},
author = {Bajic, V and Misic, N and Stankovic, I and Zaric, B and Perry, G},
title = {Alzheimer's and Consciousness: How Much Subjectivity Is Objective?.},
journal = {Neuroscience insights},
volume = {16},
number = {},
pages = {26331055211033869},
doi = {10.1177/26331055211033869},
pmid = {34350401},
issn = {2633-1055},
abstract = {Does Alzheimer Disease show a decline in cognitive functions that relate to the awareness of external reality? In this paper, we will propose a perspective that patients with increasing symptoms of AD show a change in the awareness of subjective versus objective representative axis of reality thus consequently move to a more internal like perception of reality. This paradigm shift suggests that new insights into the dynamicity of the conscious representation of reality in the AD brain may give us new clues to the very early signs of memory and self-awareness impairment that originates from, in our view the microtubules. Dialog between Adso and William, in Umberto Eco's The Name of the Rose, Third Day: Vespers. "But how does it happen," I said with admiration, "that you were able to solve the mystery of the library looking at it from the outside, and you were unable to solve it when you were inside?" "Thus, God knows the world, because He conceived it in His mind, as if it was from the outside, before it was created, and we do not know its rule, because we live inside it, having found it already made."},
}
@article {pmid34350395,
year = {2021},
author = {Sharma, P and Montgomery, RN and Graves, RS and Meyer, K and Hunt, SL and Vidoni, ED and Mahnken, JD and Swerdlow, RH and Burns, JM and Mudaranthakam, DP},
title = {CONSENSUS: a Shiny application of dementia evaluation and reporting for the KU ADC longitudinal Clinical Cohort database.},
journal = {JAMIA open},
volume = {4},
number = {3},
pages = {ooab060},
doi = {10.1093/jamiaopen/ooab060},
pmid = {34350395},
issn = {2574-2531},
abstract = {Background: The University of Kansas Alzheimer's Disease Center (KU ADC) maintains several large databases to track participant recruitment, enrollment, and capture various research-related activities. It is challenging to manage and coordinate all the research-related activities. One of the crucial activities involves generating a consensus diagnosis and communicating with participants and their primary care providers.<br><br>Process: To effectively manage the cohort, the KU ADC utilizes a combination of open-source electronic data capture (EDC) (i.e. REDCap), along with other homegrown data management and analytic systems developed using R-studio and Shiny.<br><br>Process evaluation: In this article, we describe the method and utility of the user-friendly dashboard that was developed for the rapid reporting of dementia evaluations which allows clinical researchers to summarize recruitment metrics, automatically generate letters to both participants and healthcare providers, which ultimately help optimize workflows.<br><br>Conclusions: We believe this general framework would be beneficial to any institution that build reports and summarizing key metrics of their research from longitudinal databases.},
}
@article {pmid34350389,
year = {2021},
author = {Kumar, S and Oh, I and Schindler, S and Lai, AM and Payne, PRO and Gupta, A},
title = {Machine learning for modeling the progression of Alzheimer disease dementia using clinical data: a systematic literature review.},
journal = {JAMIA open},
volume = {4},
number = {3},
pages = {ooab052},
doi = {10.1093/jamiaopen/ooab052},
pmid = {34350389},
issn = {2574-2531},
abstract = {Objective: Alzheimer disease (AD) is the most common cause of dementia, a syndrome characterized by cognitive impairment severe enough to interfere with activities of daily life. We aimed to conduct a systematic literature review (SLR) of studies that applied machine learning (ML) methods to clinical data derived from electronic health records in order to model risk for progression of AD dementia.<br><br>Materials and Methods: We searched for articles published between January 1, 2010, and May 31, 2020, in PubMed, Scopus, ScienceDirect, IEEE Explore Digital Library, Association for Computing Machinery Digital Library, and arXiv. We used predefined criteria to select relevant articles and summarized them according to key components of ML analysis such as data characteristics, computational algorithms, and research focus.<br><br>Results: There has been a considerable rise over the past 5 years in the number of research papers using ML-based analysis for AD dementia modeling. We reviewed 64 relevant articles in our SLR. The results suggest that majority of existing research has focused on predicting progression of AD dementia using publicly available datasets containing both neuroimaging and clinical data (neurobehavioral status exam scores, patient demographics, neuroimaging data, and laboratory test values).<br><br>Discussion: Identifying individuals at risk for progression of AD dementia could potentially help to personalize disease management to plan future care. Clinical data consisting of both structured data tables and clinical notes can be effectively used in ML-based approaches to model risk for AD dementia progression. Data sharing and reproducibility of results can enhance the impact, adaptation, and generalizability of this research.},
}
@article {pmid34347883,
year = {2021},
author = {Dolton, MJ and Chesterman, A and Moein, A and Sink, KM and Waitz, A and Blondeau, K and Kerchner, GA and Hu, N and Brooks, L and Wetzel-Smith, MK and Roden, A and Deshmukh, A and Peng, K and Carrasco-Triguero, M and Smith, J and Ostrowitzki, S and Quartino, A},
title = {Safety, Tolerability and Pharmacokinetics of High-Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers.},
journal = {Clinical pharmacology and therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1002/cpt.2385},
pmid = {34347883},
issn = {1532-6535},
abstract = {Compared with intravenous formulations, subcutaneous (SC) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume SC administration (>10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523; GP40201) that evaluated SC crenezumab, an anti-Aβ monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics in 68 participants (aged 50-80 years) who received single ascending doses (600-7200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and pharmacokinetics in 72 participants (aged 18-80 years) who received different combinations of dose (1700-6800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/min), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting AEs in either study. There were no meaningful differences in pain scores between reference placebo (4 mL), test placebo (4-40 mL) or crenezumab (600-7200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but in some cases was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately dose-proportional pharmacokinetics, and SC bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume SC crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile.},
}
@article {pmid34347576,
year = {2021},
author = {Chhetri, G},
title = {Emerging Roles of IL-34 in Neurodegenerative &amp; Neurological Infectious Disease.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/00207454.2021.1963962},
pmid = {34347576},
issn = {1563-5279},
abstract = {Neurological infections are often devastating in their clinical presentation. Although significant advances have made in neuroimaging techniques and molecular tools for diagnosis, as well as in anti-infective therapy, these diseases always difficult to diagnose and treat. Neuroparasitic infections and virus infections lead to neurological infections. In the nervous system, various cytokines and chemokines act as neuroinflammatory agents, neuromodulators, regulate neurodevelopment, and synaptic transmission. Among the most important cytokines, Interleukins (ILs) are a large group of immunomodulatory proteins that elicit a wide variety of responses in cells and tissues. These ILs are involved in pro and anti-inflammatory effects, systemic inflammation, immune system modulation and play crucial roles in fighting cancer, infectious disease, and neurological disorders. Interleukin-34 (IL-34) identified by screening a comprehensive human protein library containing ∼3400 secreted and extracellular domain proteins in a human monocyte viability assay. Recent evidence has disclosed the crucial roles of IL-34 in the proliferation and differentiation of mononuclear phagocyte lineage cells, osteoclastogenesis, and inflammation. Additionally, IL-34 plays an important role in development, homeostasis, and disease. Dysregulation in IL-34 function can lead to various inflammatory &amp; infectious diseases (e.g. Inflammatory bowel disease, liver fibrosis, Systemic Lupus erythematosus, rheumatoid arthritis), neurological disorders (e.g. Alzheimer disease) and neurological infectious disease (e.g. West Nile virus disease). In this review, we explore the biological role of IL-34 in addition to various impairments caused by dysregulation in IL-34 and discuss their potential links that may lead to important therapeutic and/or preventive strategies for these disorders.},
}
@article {pmid34347557,
year = {2021},
author = {Mehrdad, J and Leila, E and Emsehgol, N},
title = {The Effect of Vitamin B12 on Synaptic Plasticity of Hippocampus in Alzheimer's disease model rats.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-8},
doi = {10.1080/00207454.2021.1962863},
pmid = {34347557},
issn = {1563-5279},
abstract = {Background: Hippocampus cells, responsible for learning and memory, are disturbed in Alzheimer's disease (AD), resulting in production of several inflammatory markers, such as neurexin 1 -neuroligin, cyclooxygenase-2 (COX-2), and caspase-3 proteins, used in measurement of AD's severity and development. Vitamin B12, which plays a role in brain functioning, has anti-inflammatory properties and its impairment is associated with apoptosis in Alzheimer's disease. This study aimed to investigate the effect of vitamin B12 on restoration of Synaptic Plasticity on scopolamine-induced AD in rats.Methods: To simulate AD, Rats, except the control group were i.p. injected with 3 mg/kg scopolamine. Before scopolamine the pretreatment group vitamin B12 (0.5, 2, and 4 mg/kg) was injected every day for the next 14 days. After 24 h, sectioning the rats' brains, the concentration of postsynaptic density protein 95 (PSD-95), neurexin 1-neurolgin, COX-2, and caspase-3 proteins in hippocampus were measured using immunoblotting.Results: B12 significantly enhanced molecular balance. PSD-95 and neurexin 1 and neuroligin concentrations were significantly reduced, whereas COX-2 and activated caspase-3 were enhanced in the hippocampus of scopolamine-injected subjects. Their alterations were decreased after B12 administration.Conclusions: Vitamin B12 protected scopolamine-injected rats and inhibited hippocampal inflammation and apoptosis and preserved pre- and post-synaptic proteins and possibly synaptic integrity in hippocampus route.},
}
@article {pmid34345361,
year = {2021},
author = {do Vale-Britto, PHF and Rabin, L and Spindola, L and Nitrini, R and Brucki, SMD},
title = {Assessment of judgment ability in a Brazilian sample of patients with mild cognitive impairment and dementia.},
journal = {Dementia &amp; neuropsychologia},
volume = {15},
number = {2},
pages = {200-209},
doi = {10.1590/1980-57642021dn15-020007},
pmid = {34345361},
issn = {1980-5764},
abstract = {Judgment is the ability to make sound decisions after consideration of relevant information, possible solutions, likely outcomes, and contextual factors. Loss of judgment is common in patients with mild cognitive impairment (MCI) and dementia. The Test of Practical Judgment (TOP-J) evaluates practical judgment in adults and the elderly, with 15- and 9-item versions that require individuals to listen to scenarios about everyday problems and report their solutions.<br><br>Objective: Adaptation of TOP-J for a Brazilian sample, preparation of a reduced version and verification of the accuracy of both.<br><br>Methods: Eighty-five older adults, including 26 with MCI, 20 with Alzheimer's disease (AD), 15 with frontotemporal dementia behavioral variant (FTDbv) and 24 controls, underwent neuropsychological assessment including the Brazilian adaptation of the TOP-J (TOP-J-Br).<br><br>Results: On both TOP-J-Br versions, controls outperformed MCI, AD and FTDbv patients (p<0.001) and MCI outperformed AD and FTDbv (p<0.001). For the TOP-J/15-Br, the best cutoff for distinguishing controls and patients had a sensitivity of 91.7%, specificity of 59.0% and area under the curve of 0.8. For the TOP-J/9-Br, the best cutoff for distinguishing controls and patients had a sensitivity of 79.9%, specificity of 72.1% and area under the curve of 0.82.<br><br>Conclusion: The TOP-J/15-Br, and particularly the TOP-J/9-Br, showed robust psychometric properties and the potential for clinical utility in Brazilian older adults at various stages of neurodegenerative cognitive decline.},
}
@article {pmid34345359,
year = {2021},
author = {Maryam, RS and Sahar, J and Hastono, SP and Harimurti, K},
title = {Common symptoms of Alzheimer's dementia that are easily recognizable by families.},
journal = {Dementia &amp; neuropsychologia},
volume = {15},
number = {2},
pages = {186-191},
doi = {10.1590/1980-57642021dn15-020005},
pmid = {34345359},
issn = {1980-5764},
abstract = {The increase in dementia incidence among the elderly is directly related to aging, which is associated with changes in bodily functions and other health-related risk factors. Alzheimer's dementia is the most prevalent form of dementia, and individuals in the late stages are predominantly dependent on other family members. Therefore, it is important for families, as the closest support group, to recognize common symptoms early.<br><br>Objective: To provide a family-friendly guide to the ten common symptoms of Alzheimer's dementia.<br><br>Methods: This is a descriptive survey-based research that included 354 families comprising elderly people (≥60 years) residing in Jakarta. The instrument aimed at identifying ten common Alzheimer's dementia symptoms in Indonesia. Descriptive statistical analysis based on frequency tables was used.<br><br>Results: The participant's major characteristics were age ≥66 years (52.3%), female sex (70.3%) and primary school education (87.3%). The predominant symptoms experienced by 42.4% of the elderly included forgetting recent events and asking questions and narrating a particular detail repeatedly. The remaining 35.6% demonstrated signs of forgetting where an item was placed and frequently suspecting others of theft and concealment of personal items.<br><br>Conclusion: The symptoms of frequently forgetting new events and the location of personal belongings are of particular concern for families, as they have a propensity to progress and interfere with daily activities. Therefore, the families of affected individuals are expected to identify this symptom early on and present the affected individual for screening or examination at a health care facility.},
}
@article {pmid34343840,
year = {2021},
author = {Ambellan, F and Zachow, S and Tycowicz, CV},
title = {Rigid motion invariant statistical shape modeling based on discrete fundamental forms data from the osteoarthritis initiative and the Alzheimer' disease neuroimaging initiative.},
journal = {Medical image analysis},
volume = {73},
number = {},
pages = {102178},
doi = {10.1016/j.media.2021.102178},
pmid = {34343840},
issn = {1361-8423},
abstract = {We present a novel approach for nonlinear statistical shape modeling that is invariant under Euclidean motion and thus alignment-free. By analyzing metric distortion and curvature of shapes as elements of Lie groups in a consistent Riemannian setting, we construct a framework that reliably handles large deformations. Due to the explicit character of Lie group operations, our non-Euclidean method is very efficient allowing for fast and numerically robust processing. This facilitates Riemannian analysis of large shape populations accessible through longitudinal and multi-site imaging studies providing increased statistical power. Additionally, as planar configurations form a submanifold in shape space, our representation allows for effective estimation of quasi-isometric surfaces flattenings. We evaluate the performance of our model w.r.t. shape-based classification of hippocampus and femur malformations due to Alzheimer's disease and osteoarthritis, respectively. In particular, we outperform state-of-the-art classifiers based on geometric deep learning as well as statistical shape modeling especially in presence of sparse training data. To provide insight into the model's ability of capturing biological shape variability, we carry out an analysis of specificity and generalization ability.},
}
@article {pmid34342862,
year = {2021},
author = {Cardinali, CAEF and Martins, YA and Torrão, AS},
title = {Use of Hormone Therapy in Postmenopausal Women with Alzheimer's Disease: A Systematic Review.},
journal = {Drugs &amp; aging},
volume = {},
number = {},
pages = {},
pmid = {34342862},
issn = {1179-1969},
abstract = {BACKGROUND: Around two-thirds of patients with Alzheimer's disease (AD) are women, which could be related to the depletion of female sexual hormones at menopause. The replacement of these hormones with hormone therapy (HT) to possibly decrease AD risk or treat AD patients has generated conflicting results in the literature.<br><br>OBJECTIVE: Our aim was to systematically review the relationship between HT use in postmenopausal women with AD and the risk of developing or treating AD symptoms.<br><br>DATA SOURCES: The PubMed, LILACS, Scopus, Scielo, and Web of Science databases were searched from January 1994 to December 2020 using the descriptors 'Alzheimer Disease OR Alzheimer's Disease' and 'Hormone Replacement Therapy OR Estrogen Replacement Therapy'.<br><br>STUDY SELECTION: Observational and controlled clinical trials including postmenopausal women diagnosed with AD and evaluating HT efficacy were eligible for inclusion.<br><br>DATA EXTRACTION: Extracted data comprise study design, covariates, inclusion criteria for sample selection, AD diagnosis criteria, biases, HT regimen, and cognitive measurement tools used.<br><br>RESULTS: Overall, 25 studies were selected. Among the 14 observational studies, 8 reported an improvement in cognitive function and a decrease in AD risk, especially in younger postmenopausal women. Five observational studies did not demonstrate any association between HT and AD, and one study reported an increase in AD risk, regardless of time of HT initiation. Of the 11 controlled clinical trials included, 7 showed an amelioration in cognitive function after HT. The remaining 4 trials saw no difference between HT and control.<br><br>CONCLUSION: Both observational and controlled clinical trials had methodological issues and discrepancies in inclusion criteria and HT protocols. These inconsistencies made it difficult to establish an association between HT and AD.},
}
@article {pmid34342112,
year = {2021},
author = {Kennedy, KJ and Forsythe, D and Wagner, J and Eckert, M},
title = {Clinical pathways for the evidence-based management of behavioural and psychological symptoms of dementia in a residential aged care facility: A rapid review.},
journal = {Australasian journal on ageing},
volume = {},
number = {},
pages = {},
doi = {10.1111/ajag.12990},
pmid = {34342112},
issn = {1741-6612},
support = {//Nurses Memorial Foundation of South Australia/ ; },
abstract = {OBJECTIVES: We aimed to identify a clinical pathway, or practice guidelines to inform a clinical pathway, for the management of behavioural and psychological symptoms of dementia (BPSD) in residential aged care facilities (RACFs).<br><br>METHODS: Fifteen evidence sources were searched, and publications were appraised for methodological quality.<br><br>RESULTS: Seven publications met the inclusion criteria, but no clinical pathways were found. These publications emphasised prevention via respectful, person-centred care; non-pharmacological interventions prioritised; and potential dangers of antipsychotic use. Pharmacological management was only recommended: when there is a high risk of harm; as a short-term option, to be regularly monitored and discontinued as soon as possible; and used in conjunction with investigation into the causes of BPSD and the introduction of non-pharmacological therapies.<br><br>CONCLUSION: This rapid review provided high-quality, current guidelines and recommendations on the prevention and management of BPSD that can inform the development of an evidence-based clinical pathway for use in Australian RACFs.},
}
@article {pmid34341704,
year = {2021},
author = {Lazarev, VF and Tsolaki, M and Mikhaylova, ER and Benken, KA and Shevtsov, MA and Nikotina, AD and Lechpammer, M and Mitkevich, VA and Makarov, AA and Moskalev, AA and Kozin, SA and Margulis, BA and Guzhova, IV and Nudler, E},
title = {Extracellular GAPDH Promotes Alzheimer Disease Progression by Enhancing Amyloid-β Aggregation and Cytotoxicity.},
journal = {Aging and disease},
volume = {12},
number = {5},
pages = {1223-1237},
doi = {10.14336/AD.2020.1230},
pmid = {34341704},
issn = {2152-5250},
abstract = {Neuronal cell death at late stages of Alzheimer's disease (AD) causes the release of cytosolic proteins. One of the most abundant such proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), forms stable aggregates with extracellular amyloid-β (Aβ). We detect these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal cells, neural degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aβ-stimulated neurodegeneration. CSF from animals with enhanced GAPDH expression demonstrates increased cytotoxicity in vitro. Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aβ aggregates and reversed memory deficit in AD transgenic mice. These findings argue that extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, and, thus, is a promising pharmacological target for AD.},
}
@article {pmid34257422,
year = {2021},
author = {Kallionpää, RA and Valtanen, M and Auranen, K and Uusitalo, E and Rinne, JO and Peltonen, S and Peltonen, J},
title = {Increased risk for dementia in neurofibromatosis type 1.},
journal = {Genetics in medicine : official journal of the American College of Medical Genetics},
volume = {},
number = {},
pages = {},
pmid = {34257422},
issn = {1530-0366},
abstract = {PURPOSE: To determine the risk for dementia in neurofibromatosis type 1 (NF1) using a Finnish nationwide cohort of individuals with NF1, and data from national registries.<br><br>METHODS: A Finnish cohort of 1,349 individuals with confirmed NF1 according to the US National Institutes of Health (NIH) diagnostic criteria was compared with a control cohort of 13,870 individuals matched for age, sex, and area of residence. Dementia-related hospital visits were retrieved from the Finnish Care Register for Health Care using International Classification of Diseases, 10th revision (ICD-10) diagnosis codes G30 and F00-F03. Purchases of antidementia drugs were queried with Anatomical Therapeutic Chemical (ATC) classification code N06D from the drug reimbursement register maintained by the Social Insurance Institution of Finland. The follow-up spanned 1998-2014.<br><br>RESULTS: Totals of 16 and 165 individuals with at least two dementia-related diagnoses or drug purchases were identified in the NF1 and control cohorts, respectively. The hazard ratio for dementia in NF1 was 1.67 (95% confidence interval [CI] 1.00-2.80, P = 0.050). In an analysis stratified by the type of dementia, the risk for Alzheimer disease was increased in NF1 compared to controls with a hazard ratio of 2.88 (95% CI 1.47-5.66, P = 0.002).<br><br>CONCLUSION: Dementia and especially Alzheimer disease are previously unrecognized neurological complications of NF1.},
}
@article {pmid34339416,
year = {2021},
author = {Zhang, GQ and Chen, JL and Luo, Y and Mathur, MB and Anagnostis, P and Nurmatov, U and Talibov, M and Zhang, J and Hawrylowicz, CM and Lumsden, MA and Critchley, H and Sheikh, A and Lundbäck, B and Lässer, C and Kankaanranta, H and Lee, SH and Nwaru, BI},
title = {Menopausal hormone therapy and women's health: An umbrella review.},
journal = {PLoS medicine},
volume = {18},
number = {8},
pages = {e1003731},
doi = {10.1371/journal.pmed.1003731},
pmid = {34339416},
issn = {1549-1676},
abstract = {BACKGROUND: There remains uncertainty about the impact of menopausal hormone therapy (MHT) on women's health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes.<br><br>METHODS AND FINDINGS: We searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412).<br><br>CONCLUSIONS: MHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.},
}
@article {pmid34338566,
year = {2021},
author = {Boada, M and Martínez-Lage, P and Serrano-Castro, P and Costa, M and Páez, A},
title = {Therapeutic plasma exchange with albumin: a new approach to treat Alzheimer's Disease.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737175.2021.1960823},
pmid = {34338566},
issn = {1744-8360},
abstract = {Introduction: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia. It has a complex pathophysiology that is not yet completely understood, where multiple central, systemic and environmental factors play a key role in disease progression. Understanding the multifactorial nature of AD is paramount to formulate new therapies.Areas covered: The authors reviewed the role of the amyloid-β-binding, antioxidant and immunomodulatory properties of albumin in AD and the use of therapeutic plasma exchange (PE) in neurology. The results from the Alzheimer Management By Albumin Replacement (AMBAR) trial that combined the use of PE with albumin replacement in patients with mild-to-moderate AD, are also analyzed.Expert opinion: Findings from the AMBAR study provide encouraging results in the treatment of AD with PE and albumin replacement, especially in patients at the moderate stage of the disease, who showed less cognitive decline from baseline compared with placebo in most of the variables analyzed. Further research is warranted to ascertain the possible mechanisms of action underlying these results. Different cohorts of patients that may also benefit from this treatment, such as those with mild cognitive impairment or other types of dementia, could also be the target of additional studies.},
}
@article {pmid34338287,
year = {2021},
author = {Perry, BL and McConnell, WR and Peng, S and Roth, A and Coleman, M and Manchella, M and Roessler, M and Francis, H and Sheean, H and Apostolova, L},
title = {Social Networks and Cognitive Function: An Evaluation of Social Bridging and Bonding Mechanisms.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnab112},
pmid = {34338287},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Social connectedness has been linked prospectively to cognitive aging, but there is little agreement about the social mechanisms driving this relationship. This study evaluated nine measures of social connectedness, focusing on two forms of social enrichment - access to an expansive and diverse set of loosely connected individuals (i.e., social bridging) and integration in a supportive network of close ties (i.e., social bonding).<br><br>RESEARCH DESIGN AND METHODS: This study used egocentric network and cognitive data from 311 older adults in the Social Networks in Alzheimer Disease (SNAD) study. Linear regressions were used to estimate the association between social connectedness and global cognitive function, episodic memory, and executive function.<br><br>RESULTS: Measures indicative of social bridging (larger network size, lower density, presence of weak ties, and proportion non-kin) were consistently associated with better cognitive outcomes, while measures of social bonding (close ties, multiplex support, higher frequency of contact, better relationship quality, and being married) largely produced null effects.<br><br>DISCUSSION AND IMPLICATIONS: These findings suggest that the protective benefits of social connectedness for cognitive function and memory may operate primarily through a cognitive reserve mechanism that is driven by irregular contact with a larger and more diverse group of peripheral others.},
}
@article {pmid34338277,
year = {2021},
author = {Tsuji, K and Ishii, T and Kobayakawa, T and Ohashi, N and Nomura, W and Tamamura, H},
title = {Fluorescence resonance energy transfer-based screening for protein kinase C ligands using 6-methoxynaphthalene-labeled 1,2-diacylglycerol-lactones.},
journal = {Organic &amp; biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d1ob00814e},
pmid = {34338277},
issn = {1477-0539},
abstract = {Protein kinase C (PKC) is associated with a central cellular signal transduction pathway and disorders such as cancer and Alzheimer-type dementia and is therefore a target for the treatment of these diseases. The development of simple methods suitable for high-throughput screening to find potent PKC ligands is desirable. We have developed an assay based on fluorescence-quenching screening with a solvatochromic fluorophore attached to a competitive probe and its alternative method based on Förster/fluorescence resonance energy transfer (FRET) phenomena. Here, an improved FRET-based PKC binding assay using a diacylglycerol (DAG) lactone labeled with a donor fluorescent dye, 6-methoxynaphthalene (6MN), was developed. The 6MN-labeled DAG-lactone has a higher binding affinity for the PKCδ C1b domain and the fluorescent PKCδ C1b domain labeled by fluorescein as an acceptor fluorescent dye (Fl-δC1b) than the diethylaminocoumarin (DEAC)-labeled DAG-lactone. The combination of the 6MN-labeled DAG-lactone and Fl-δC1b showed a change in fluorescence response larger than that of the DEAC-labeled DAG-lactone and Fl-δC1b. The IC50 values of known PKC ligands calculated by the present FRET-based method using 6MN-labeled DAG-lactone agree well with the Ki values obtained by the conventional radioisotope-based assays. Some false positive compounds, identified by the previous solvatochromic fluorophore-based method, were found to be negative by this method. The present FRET-based PKC binding assay is more sensitive and could be more useful.},
}
@article {pmid34335619,
year = {2021},
author = {Fessler, J and Angiari, S},
title = {The Role of T Cell Senescence in Neurological Diseases and Its Regulation by Cellular Metabolism.},
journal = {Frontiers in immunology},
volume = {12},
number = {},
pages = {706434},
doi = {10.3389/fimmu.2021.706434},
pmid = {34335619},
issn = {1664-3224},
abstract = {Immunosenescence is a state of dysregulated leukocyte function characterised by arrested cell cycle, telomere shortening, expression of markers of cellular stress, and secretion of pro-inflammatory mediators. Immunosenescence principally develops during aging, but it may also be induced in other pathological settings, such as chronic viral infections and autoimmune diseases. Appearance of senescent immune cells has been shown to potentially cause chronic inflammation and tissue damage, suggesting an important role for this process in organismal homeostasis. In particular, the presence of senescent T lymphocytes has been reported in neurological diseases, with some works pointing towards a direct connection between T cell senescence, inflammation and neuronal damage. In this minireview, we provide an overview on the role of T cell senescence in neurological disorders, in particular in multiple sclerosis and Alzheimer disease. We also discuss recent literature investigating how metabolic remodelling controls the development of a senescence phenotype in T cells. Targeting metabolic pathways involved in the induction of senescent T cells may indeed represent a novel approach to limit their inflammatory activity and prevent neuroinflammation and neurodegeneration.},
}
@article {pmid34335238,
year = {2021},
author = {El Idrissi, F and Gressier, B and Devos, D and Belarbi, K},
title = {A Computational Exploration of the Molecular Network Associated to Neuroinflammation in Alzheimer's Disease.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {630003},
doi = {10.3389/fphar.2021.630003},
pmid = {34335238},
issn = {1663-9812},
abstract = {Neuroinflammation, as defined by the presence of classically activated microglia, is thought to play a key role in numerous neurodegenerative disorders such as Alzheimer's disease. While modulating neuroinflammation could prove beneficial against neurodegeneration, identifying its most relevant biological processes and pharmacological targets remains highly challenging. In the present study, we combined text-mining, functional enrichment and protein-level functional interaction analyses to 1) identify the proteins significantly associated to neuroinflammation in Alzheimer's disease over the scientific literature, 2) distinguish the key proteins most likely to control the neuroinflammatory processes significantly associated to Alzheimer's disease, 3) identify their regulatory microRNAs among those dysregulated in Alzheimer's disease and 4) assess their pharmacological targetability. 94 proteins were found to be significantly associated to neuroinflammation in Alzheimer's disease over the scientific literature and IL4, IL10 and IL13 signaling as well as TLR-mediated MyD88- and TRAF6-dependent responses were their most significantly enriched biological processes. IL10, TLR4, IL6, AKT1, CRP, IL4, CXCL8, TNF-alpha, ITGAM, CCL2 and NOS3 were identified as the most potent regulators of the functional interaction network formed by these immune processes. These key proteins were indexed to be regulated by 63 microRNAs dysregulated in Alzheimer's disease, 13 long non-coding RNAs and targetable by 55 small molecules and 8 protein-based therapeutics. In conclusion, our study identifies eleven key proteins with the highest ability to control neuroinflammatory processes significantly associated to Alzheimer's disease, as well as pharmacological compounds with single or pleiotropic actions acting on them. As such, it may facilitate the prioritization of diagnostic and target-engagement biomarkers as well as the development of effective therapeutic strategies against neuroinflammation in Alzheimer's disease.},
}
@article {pmid34333330,
year = {2021},
author = {Zhang, YM and Zheng, T and Huang, TT and Gu, PP and Gou, LS and Ma, TF and Liu, YW},
title = {Sarsasapogenin attenuates Alzheimer-like encephalopathy in diabetes.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {91},
number = {},
pages = {153686},
doi = {10.1016/j.phymed.2021.153686},
pmid = {34333330},
issn = {1618-095X},
abstract = {BACKGROUND: A crosstalk exists between diabetes and Alzheimer's disease (AD), and diabetic encephalopathy displays AD-like disorders. Sarsasapogenin (Sar) has strong anti-inflammatory efficacy, showing neuroprotection and memory-enhancement effects.<br><br>PURPOSE: This study aims to verify the ameliorative effects of Sar on diabetic encephalopathy in vivo and in vitro, and to clarify the mechanisms from attenuation of AD-like pathology.<br><br>METHODS: Streptozotocin-induced type 1 diabetic rats and high glucose-cultured SH-SY5Y cells were used in this study. After Sar treatment (20 and 60 mg/kg) for consecutive 9 weeks, Morris water maze and novel object recognition tasks were performed. Hematoxylin-eosin staining was used for examining loss of neurons in CA1 area and ki67 expression for reflecting neurogenesis in DG area of hippocampus. Aβ production pathway and tau phosphorylation kinase cascade were examined in these two models.<br><br>RESULTS: Sar improved learning and memory ability, loss of neurons and reduction of neurogenesis in the hippocampus of diabetic rats. Moreover, Sar suppressed Aβ overproduction due to up-regulation of BACE1 in protein and mRNA and tau hyperphosphorylation from inactivation of AKT/GSK-3β cascade in the hippocampus and cerebral cortex of diabetic rats and high glucose-cultured SH-SY5Y cells, and PPARγ antagonism abolished the effects of Sar on key molecules in the two pathways. Additionally, it was found that high glucose-stimulated Aβ overproduction was prior to tau hyperphosphorylation in neurons.<br><br>CONCLUSION: Sar alleviated diabetic encephalopathy, which was obtained through inhibitions of Aβ overproduction and tau hyperphosphorylation mediated by the activation of PPARγ signaling. Hence, Sar is a good candidate compound for AD-like disorders.},
}
@article {pmid34315986,
year = {2021},
author = {Jeong, SM and Shin, DW and Yoo, TG and Cho, MH and Jang, W and Lee, J and Kim, S},
title = {Association between statin use and Alzheimer's disease with dose response relationship.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {15280},
pmid = {34315986},
issn = {2045-2322},
abstract = {This study aimed to determine the dose-response relationship between the levels of statin exposure and the incidence of Alzheimer's disease (AD). We included 119,013 Korean adults (≥ 60 years old) using a database from the Korean National Health Insurance Service (2002-2013). Statin exposure was treated as a time-varying variable. Incidence of AD was defined by the first claim code for AD with anti-Alzheimer drugs. AD occurred in 9467 cases during a median 7.2 years of follow-up. Overall, statin use was not associated with an increased risk of AD incidence [adjusted hazard ratio (aHR) = 1.04; 95% confidence interval (CI) = 0.99-1.10]. When examined by level of statin exposure, statin prescription < 540 days during a 2-year window time was associated with a higher risk for incidence of AD compared to statin non-use. However, days of prescription ≥ 540 and cumulative defined daily dose ≥ 540 of statin were associated with decreased risk of AD [aHR (95% CI) = 0.87 (0.80-0.95) and 0.79 (0.68-0.92), respectively]. Our findings indicate that less persistent statin use is associated with increased risk of AD, whereas persistent and adherent statin use is associated with decreased risk of AD.},
}
@article {pmid34331941,
year = {2021},
author = {Kalaria, RN and Sepulveda-Falla, D},
title = {Cerebral Small Vessel Disease in Sporadic and Familial Alzheimer Disease.},
journal = {The American journal of pathology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajpath.2021.07.004},
pmid = {34331941},
issn = {1525-2191},
abstract = {Alzheimer's disease is the most common cause of dementia. Biological definitions of AD are limited to the cerebral burden of amyloid β plaques, neurofibrillary pathology and neurodegeneration. However, current evidence suggests various features of small vessel disease (SVD) are part and parcel of and covertly modify both sporadic and familial AD. Neuroimaging studies suggest white matter hyperintensities (WMH) explained by vascular mechanisms occur frequently in the AD spectrum. Recent advances have further emphasised that frontal periventricular and posterior WMH are associated with cerebral amyloid angiopathy (CAA) in familial AD. While there is debate whether SVD markers precede the classically recognised biomarkers of disease, post-mortem studies show that SVD pathology incorporating small cortical and subcortical infarcts, microinfarcts, microbleeds, perivascular spacing and white matter attenuation is commonly found in sporadic as well as in mutation carriers with confirmed familial AD. Ageing-related cerebral vessel pathologies such as arteriolosclerosis and CAA modify progression or worsen risk by shifting the threshold for cognitive impairment and AD dementia. The incorporation of SVD as a biomarker is legitimately warranted in the biological definition of AD. Therapeutic interventions at directly reducing the burden of brain amyloid β have had no major impact on the disease or delaying cognitive deterioration but lowering the risk of vascular disease seems the only rational approach to tackle both early and late onset AD dementia.},
}
@article {pmid34331352,
year = {2021},
author = {Kurucu, H and Colom-Cadena, M and Davies, C and Wilkins, L and King, D and Rose, J and Tzioras, M and Tulloch, JH and Smith, C and Spires-Jones, TL},
title = {Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer's disease.},
journal = {European journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1111/ene.15043},
pmid = {34331352},
issn = {1468-1331},
abstract = {BACKGROUND: Synapse degeneration in Alzheimer's disease (AD) correlates strongly with cognitive decline. There is well-established excitatory synapse loss in Alzheimer's disease with known contributions of pathological amyloid beta (Aβ) to excitatory synapse dysfunction and loss. Despite clear changes in circuit excitability in AD and model systems, relatively little is known about pathology in inhibitory synapses.<br><br>METHODS: Here we examined human post-mortem brain samples (n=5 control, 10 AD cases) from temporal and occipital cortices to examine whether inhibitory synapses and neurons are lost in AD and whether Aβ may contribute to inhibitory synapse degeneration. Inhibitory neurons were counted in all 6 cortical layers using stereology software, and array tomography was used to examine synapse density and accumulation of Aβ in synaptic terminals.<br><br>RESULTS: We observe differing inhibitory neuron densities in the different cortical layers. The highest inhibitory neuron density was observed in layer 4 in both brain regions and visual cortex had higher inhibitory neuron density than temporal cortex. There was significantly lower inhibitory neuron density in AD than in control cases in all 6 cortical layers. High-resolution array tomography imaging reveals plaque-associated loss of inhibitory synapses and accumulation of Aβ in a small subset of inhibitory presynaptic terminals with the most accumulation near amyloid plaques.<br><br>CONCLUSIONS: Inhibitory neuron and synapse loss in AD may contribute to disrupted excitatory/inhibitory balance and cognitive decline. Future work is warranted to determine whether targeting inhibitory synapse loss could be a useful therapeutic strategy.},
}
@article {pmid34329683,
year = {2021},
author = {Sato, K and Watamura, N and Fujioka, R and Mihira, N and Sekiguchi, M and Nagata, K and Ohshima, T and Saito, T and Saido, TC and Sasaguri, H},
title = {A 3rd generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {101004},
doi = {10.1016/j.jbc.2021.101004},
pmid = {34329683},
issn = {1083-351X},
abstract = {We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice, respectively). These models showed Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aβ metabolism and clearance because the Arctic mutation renders Aβ resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aβ antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aβ by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new 3rd generation mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice, and will help accelerate the development of disease-modifying therapies to treat preclinical AD.},
}
@article {pmid34328428,
year = {2021},
author = {O'Loughlin, P and Pavithra, P and Regan, J and Bennett, M and Knight, R and Lenaert, B and Marquez, M and Taddeo, M and Griffith, J and Shapiro, R and Farina, F},
title = {A Randomized Controlled Trial Investigating the Feasibility of a Low-Intensity Psychological Intervention for Fear of Memory Loss and Quality of Life in Older Adults: Protocol for the Reducing Fear and Avoidance of Memory Loss (REFRAME) Study.},
journal = {JMIR research protocols},
volume = {10},
number = {7},
pages = {e30514},
doi = {10.2196/30514},
pmid = {34328428},
issn = {1929-0748},
abstract = {BACKGROUND: Dementia is the most feared disease associated with aging. Prolonged fears about memory loss and dementia can have harmful consequences even in the absence of cognitive decline. Fear of dementia is associated with poorer health outcomes and psychological well-being and increased memory failures in older adults.<br><br>OBJECTIVE: We will conduct a randomized controlled trial to determine the feasibility of a tailored, web-based mindfulness program to reduce fear of memory loss and increase quality of life in older adults experiencing heightened fear.<br><br>METHODS: Eighty participants will be recruited and divided into 2 groups (40 in each group). One group will receive psychoeducation plus mindfulness training. A second group will receive psychoeducation, mindfulness training, and additional modules targeting maladaptive behavioral avoidance (ie, social and cognitive withdrawal).<br><br>RESULTS: Our recent etiological model posits that maladaptive behavioral avoidance strategies critically underlie psychosocial dysfunction associated with fear of memory loss. Thus, we predict better outcomes in the second group, including reduced fear of memory loss (primary outcome), Alzheimer disease, anxiety, and subjective memory failures, and increased quality of life (secondary outcomes). Outcome measures will be applied at 5 time points (before, baseline, interim, and after the intervention, and at 3-month follow-up). Data will be analyzed using mixed models and correlations.<br><br>CONCLUSIONS: Results from this study will contribute to the current literature on dementia-related fear and improve our understanding of how to effectively address and reduce these fears.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT04821960; https://clinicaltrials.gov/ct2/show/NCT04821960.<br><br>PRR1-10.2196/30514.},
}
@article {pmid34324551,
year = {2021},
author = {Pérez-Arancibia, R and Ordoñez, JL and Rivas, A and Pihán, P and Sagredo, A and Ahumada, U and Barriga, A and Seguel, I and Cárdenas, C and Vidal, RL and Hetz, C and Delporte, C},
title = {A phenolic-rich extract from Ugni molinae berries reduces abnormal protein aggregation in a cellular model of Huntington's disease.},
journal = {PloS one},
volume = {16},
number = {7},
pages = {e0254834},
doi = {10.1371/journal.pone.0254834},
pmid = {34324551},
issn = {1932-6203},
abstract = {Accumulation of misfolded proteins in the brain is a common hallmark of most age-related neurodegenerative diseases. Previous studies from our group identified the presence of anti-inflammatory and antioxidant compounds in leaves derived from the Chilean berry Ugni molinae (murtilla), in addition to show a potent anti-aggregation activity in models of Alzheimer´s disease. However, possible beneficial effects of berry extracts of murtilla was not investigated. Here we evaluated the efficacy of fruit extracts from different genotypes of Chilean-native U. molinae on reducing protein aggregation using cellular models of Huntington´s disease and assess the correlation with their chemical composition. Berry extraction was performed by exhaustive maceration with increasing-polarity solvents. An unbiased automatic microscopy platform was used for cytotoxicity and protein aggregation studies in HEK293 cells using polyglutamine-EGFP fusion proteins, followed by secondary validation using biochemical assays. Phenolic-rich extracts from murtilla berries of the 19-1 genotype (ETE 19-1) significantly reduced polyglutamine peptide aggregation levels, correlating with the modulation in the expression levels of autophagy-related proteins. Using LC-MS and molecular network analysis we correlated the presence of flavonoids, phenolic acids, and ellagitannins with the protective effects of ETE 19-1 effects on protein aggregation. Overall, our results indicate the presence of bioactive components in ethanolic extracts from U. molinae berries that reduce the load of protein aggregates in living cells.},
}
@article {pmid34322508,
year = {2021},
author = {Sukkar, SG and Muscaritoli, M},
title = {A Clinical Perspective of Low Carbohydrate Ketogenic Diets: A Narrative Review.},
journal = {Frontiers in nutrition},
volume = {8},
number = {},
pages = {642628},
doi = {10.3389/fnut.2021.642628},
pmid = {34322508},
issn = {2296-861X},
abstract = {Low carbohydrates diets (LCDs), which provide 20-120 g of carbohydrates per day, have long been used as therapeutic options in the treatment of severe obesity, type 2 diabetes mellitus and other morbid conditions, with good results in terms of weight loss and control of the main metabolic parameters, at least in the short and medium term. According to the caloric content and the macronutrient composition, we can classify LCDs in hypocaloric, normoproteic diets [such as the Very Low-Calorie Ketogenic Diet (VLCKD) or the protein-sparing modified fasting (PSMF)], hypocaloric, hyperproteic and hyperlipidic diets (e.g., Atkins, Paleo diets…) and normocaloric, normo-/hyperproteic diets (eucaloric KD), the latter mainly used in patients with brain tumors (gliomas) and refractory epilepsy. In addition to LCD diets, another interesting dietary approach which gained attention in the last few decades is fasting and its beneficial effects in terms of modulation of metabolic pathways, cellular processes and hormonal secretions. Due to the impossibility of using fasting regimens for long periods of time, several alternative strategies have been proposed that can mimic the effects, including calorie restriction, intermittent or alternating fasting, and the so-called fasting mimicking diets (FMDs). Recent preclinical studies have shown positive effects of FMDs in various experimental models of tumors, diabetes, Alzheimer Disease, and other morbid conditions, but to date, the scientific evidence in humans is limited to some opens studies and case reports. The purpose of our narrative review is to offer an overview of the characteristics of the main dietary regimens applied in the treatment of different clinical conditions as well as of the scientific evidence that justifies their use, focusing on low and zero-carb diets and on the different types of fasting.},
}
@article {pmid34321636,
year = {2021},
author = {Wood, H},
title = {Astrocytic IL-3 could help microglia protect against Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34321636},
issn = {1759-4766},
}
@article {pmid34320558,
year = {2021},
author = {Chauhan, AV and Guralnik, J and dosReis, S and Sorkin, JD and Badjatia, N and Albrecht, JS},
title = {Repetitive Traumatic Brain Injury Among Older Adults.},
journal = {The Journal of head trauma rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1097/HTR.0000000000000719},
pmid = {34320558},
issn = {1550-509X},
abstract = {OBJECTIVE: To determine the incidence of and assess risk factors for repetitive traumatic brain injury (TBI) among older adults in the United States.<br><br>DESIGN: Retrospective cohort study.<br><br>SETTING: Administrative claims data obtained from the Centers for Medicare &amp; Medicaid Services' Chronic Conditions Data Warehouse.<br><br>PARTICIPANTS: Individuals 65 years or older and diagnosed with TBI between July 2008 and September 2012 drawn from a 5% random sample of US Medicare beneficiaries.<br><br>MAIN MEASURES: Repetitive TBI was identified as a second TBI occurring at least 90 days after the first occurrence of TBI following an 18-month TBI-free period. We identified factors associated with repetitive TBI using a log-binomial model.<br><br>RESULTS: A total of 38 064 older Medicare beneficiaries experienced a TBI. Of these, 4562 (12%) beneficiaries sustained at least one subsequent TBI over up to 5 years of follow-up. The unadjusted incidence rate of repetitive TBI was 3022 (95% CI, 2935-3111) per 100 000 person-years. Epilepsy was the strongest predictor of repetitive TBI (relative risk [RR] = 1.44; 95% CI, 1.25-1.56), followed by Alzheimer disease and related dementias (RR = 1.32; 95% CI 1.20-1.45), and depression (RR = 1.30; 95% CI, 1.21-1.38).<br><br>CONCLUSIONS: Injury prevention and fall-reduction interventions could be targeted to identify groups of older adults at an increased risk of repetitive head injury. Future work should focus on injury-reduction initiatives to reduce the risk of repetitive TBI as well as assessment of outcomes related to repetitive TBI.},
}
@article {pmid34319442,
year = {2021},
author = {Chen, CD and Joseph-Mathurin, N and Sinha, N and Zhou, A and Li, Y and Friedrichsen, K and McCullough, A and Franklin, EE and Hornbeck, R and Gordon, B and Sharma, V and Cruchaga, C and Goate, A and Karch, C and McDade, E and Xiong, C and Bateman, RJ and Ghetti, B and Ringman, JM and Chhatwal, J and Masters, CL and McLean, C and Lashley, T and Su, Y and Koeppe, R and Jack, C and Klunk, WE and Morris, JC and Perrin, RJ and Cairns, NJ and Benzinger, TLS},
title = {Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease.},
journal = {Acta neuropathologica},
volume = {},
number = {},
pages = {},
pmid = {34319442},
issn = {1432-0533},
support = {P30AG066444, P01AG026276, P01AG03991, UF1AG032438, U19 AG032438, U19 AG024904/NH/NIH HHS/United States ; U19AG032438/NH/NIH HHS/United States ; P30NS098577/NH/NIH HHS/United States ; K01AG053474/NH/NIH HHS/United States ; DGE-1745038//National Science Foundation/ ; AARFD-20-681815/ALZ/Alzheimer's Association/United States ; },
abstract = {Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem-commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.},
}
@article {pmid34315132,
year = {2021},
author = {Zeng, P and Fang, M and Zhao, H and Guo, J},
title = {A network pharmacology approach to uncover the key ingredients in Ginkgo Folium and their anti-Alzheimer's disease mechanisms.},
journal = {Aging},
volume = {13},
number = {undefined},
pages = {},
doi = {10.18632/aging.203348},
pmid = {34315132},
issn = {1945-4589},
abstract = {This study aimed to identify potential anti-Alzheimer's disease (AD) targets and action mechanisms of Ginkgo Folium (GF) through a network pharmacology approach. Eighty-four potential targets of 10 active anti-AD ingredients of GF were identified, among which genkwanin (GK) had the greatest number of AD-related targets. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathway of GF against AD was Alzheimer disease (hsa05010). More importantly, 29 of the 84 targets were significantly correlated with tau, Aβ or both Aβ and tau pathology. In addition, GO analysis suggested that the main biological processes of GF in AD treatment were the regulation of chemical synaptic transmission (GO:0007268), neuron death (GO:0070997), amyloid-beta metabolic process (GO:0050435), etc. We further investigated the anti-AD effects of GK using N2A-APP cells (a classical cellular model of AD). Treatment N2A-APP cells with 100 μM GK for 48 h affected core targets related to tau pathology (such as CDK5 and GSK3β). In conclusion, these findings indicate that GF exerts its therapeutic effects on AD by acting directly on multiple pathological processes of AD.},
}
@article {pmid34314956,
year = {2021},
author = {Voronkov, M and Ataiants, J and Cocchiaro, B and Stock, JB and Lankenau, SE},
title = {A vicious cycle of neuropathological, cognitive and behavioural sequelae of repeated opioid overdose.},
journal = {The International journal on drug policy},
volume = {97},
number = {},
pages = {103362},
doi = {10.1016/j.drugpo.2021.103362},
pmid = {34314956},
issn = {1873-4758},
abstract = {In the midst of an escalating U.S. opioid crisis, the immediate focus of public health interventions is on fatal overdose prevention. Few studies, however, have sought to examine the long-term health consequences of exposure to repeated nonfatal opioid overdose. We reviewed recent literature to examine three corresponding downstream health outcomes of repeated overdose: a) neurodegenerative processes; b) cognition and memory; and c) overdose risk behaviours. We found a remarkable congruency among available biochemical and cognitive data on how nonfatal overdose precipitates various pathological feedforward and feedback loops that affect people who use opioids for years to come. We found however that downstream behavioural implications of neurodegenerative and cognitive sequelae are less studied despite being most proximal to an overdose. Findings point to a vicious cycle of nonfatal overdose leading to neurodegeneration - closely resembling Alzheimer Disease - that results in cognitive decline that in turn leads to potentially reduced adherence to safe drug use behaviours. The collected evidence not only brings into the focus the long-term health consequences of nonfatal overdose from the perspectives of biology, neuroscience, and public health, but also creates new cross-disciplinary context and awareness in the research and public health community that should benefit people at risk.},
}
@article {pmid34314593,
year = {2021},
author = {Heinken, A and Basile, A and Hertel, J and Thinnes, C and Thiele, I},
title = {Genome-Scale Metabolic Modeling of the Human Microbiome in the Era of Personalized Medicine.},
journal = {Annual review of microbiology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-micro-060221-012134},
pmid = {34314593},
issn = {1545-3251},
abstract = {The human microbiome plays an important role in human health and disease. Meta-omics analyses provide indispensable data for linking changes in microbiome composition and function to disease etiology. Yet, the lack of a mechanistic understanding of, e.g., microbiome-metabolome links hampers the translation of these findings into effective, novel therapeutics. Here, we propose metabolic modeling of microbial communities through constraint-based reconstruction and analysis (COBRA) as a complementary approach to meta-omics analyses. First, we highlight the importance of microbial metabolism in cardiometabolic diseases, inflammatory bowel disease, colorectal cancer, Alzheimer disease, and Parkinson disease. Next, we demonstrate that microbial community modeling can stratify patients and controls, mechanistically link microbes with fecal metabolites altered in disease, and identify host pathways affected by the microbiome. Finally, we outline our vision for COBRA modeling combined with meta-omics analyses and multivariate statistical analyses to inform and guide clinical trials, yield testable hypotheses, and ultimately propose novel dietary and therapeutic interventions. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.},
}
@article {pmid34313551,
year = {2021},
author = {Tong, BC and Wu, AJ and Huang, AS and Dong, R and Malampati, S and Iyaswamy, A and Krishnamoorthi, S and Sreenivasmurthy, SG and Zhu, Z and Su, C and Liu, J and Song, J and Lu, JH and Tan, J and Pan, W and Li, M and Cheung, KH},
title = {Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/15548627.2021.1945220},
pmid = {34313551},
issn = {1554-8635},
abstract = {ABBREVIATIONS: Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta precursor protein; ATP6V1B1/V-ATPase V1b1: ATPase H+ transporting V1 subunit B1; AVs: autophagy vacuoles; BAF: bafilomycin A1; CFC: contextual/cued fear conditioning assay; CHX: Ca2+/H+ exchanger; CTF-β: carboxy-terminal fragment derived from β-secretase; CTSD: cathepsin D; fAD: familial Alzheimer disease; GFAP: glial fibrillary acidic protein; LAMP1: lysosomal associated membrane protein 1; LTP: long-term potentiation; MCOLN1/TRPML1: mucolipin 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPT: microtubule associated protein tau; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TBS: theta burst stimulation; TEM: transmission electronic microscopy; TPCN2/TPC2: two pore segment channel 2; WT: wild-type; V-ATPase: vacuolar type H+-ATPase.},
}
@article {pmid34313331,
year = {2021},
author = {Arevalo-Rodriguez, I and Smailagic, N and Roqué-Figuls, M and Ciapponi, A and Sanchez-Perez, E and Giannakou, A and Pedraza, OL and Bonfill Cosp, X and Cullum, S},
title = {Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI).},
journal = {The Cochrane database of systematic reviews},
volume = {7},
number = {},
pages = {CD010783},
pmid = {34313331},
issn = {1469-493X},
abstract = {BACKGROUND: Dementia is a progressive global cognitive impairment syndrome. In 2010, more than 35 million people worldwide were estimated to be living with dementia. Some people with mild cognitive impairment (MCI) will progress to dementia but others remain stable or recover full function. There is great interest in finding good predictors of dementia in people with MCI. The Mini-Mental State Examination (MMSE) is the best-known and the most often used short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings.<br><br>OBJECTIVES: To determine the accuracy of the Mini Mental State Examination for the early detection of dementia in people with mild cognitive impairment SEARCH METHODS: We searched ALOIS (Cochrane Dementia and Cognitive Improvement Specialized Register of diagnostic and intervention studies (inception to May 2014); MEDLINE (OvidSP) (1946 to May 2014); EMBASE (OvidSP) (1980 to May 2014); BIOSIS (Web of Science) (inception to May 2014); Web of Science Core Collection, including the Conference Proceedings Citation Index (ISI Web of Science) (inception to May 2014); PsycINFO (OvidSP) (inception to May 2014), and LILACS (BIREME) (1982 to May 2014). We also searched specialized sources of diagnostic test accuracy studies and reviews, most recently in May 2014: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). No language or date restrictions were applied to the electronic searches and methodological filters were not used as a method to restrict the search overall so as to maximize sensitivity. We also checked reference lists of relevant studies and reviews, tracked citations in Scopus and Science Citation Index, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on MMSE for dementia diagnosis to try to locate possibly relevant but unpublished data.<br><br>SELECTION CRITERIA: We considered longitudinal studies in which results of the MMSE administered to MCI participants at baseline were obtained and the reference standard was obtained by follow-up over time. We included participants recruited and clinically classified as individuals with MCI under Petersen and revised Petersen criteria, Matthews criteria, or a Clinical Dementia Rating = 0.5. We used acceptable and commonly used reference standards for dementia in general, Alzheimer's dementia, Lewy body dementia, vascular dementia and frontotemporal dementia.<br><br>DATA COLLECTION AND ANALYSIS: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create two by two tables for dementia in general and other dementias. Two authors independently performed quality assessment using the QUADAS-2 tool. Due to high heterogeneity and scarcity of data, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic curve.<br><br>MAIN RESULTS: In this review, we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of the MMSE in conversion from MCI to all-cause dementia and eight studies assessed this test in conversion from MCI to Alzheimer´s disease dementia. Only one study provided information about the MMSE and conversion from MCI to vascular dementia. For conversion from MCI to dementia in general, the accuracy of baseline MMSE scores ranged from sensitivities of 23% to 76% and specificities from 40% to 94%. In relationship to conversion from MCI to Alzheimer's disease dementia, the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%. Only one study provided information about conversion from MCI to vascular dementia, presenting a sensitivity of 36% and a specificity of 80% with an incidence of vascular dementia of 6.2%. Although we had planned to explore possible sources of heterogeneity, this was not undertaken due to the scarcity of studies included in our analysis.<br><br>AUTHORS' CONCLUSIONS: Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia.},
}
@article {pmid34312362,
year = {2021},
author = {Lv, S and Zhou, X and Li, Y and Zhang, S and Wang, Y and Jia, S and Niu, X and Wang, L and Peng, D},
title = {The Association Between Plasma α-Synuclein (α-syn) Protein, Urinary Alzheimer-Associated Neuronal Thread Protein (AD7c-NTP), and Apolipoprotein Epsilon 4 (ApoE ε4) Alleles and Cognitive Decline in 60 Patients with Alzheimer's Disease Compared with 28 Age-Matched Normal Individuals.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {27},
number = {},
pages = {e932998},
doi = {10.12659/MSM.932998},
pmid = {34312362},
issn = {1643-3750},
abstract = {BACKGROUND Accumulating evidence has shown that alpha-synuclein (alpha-syn) pathology is involved in the pathophysiology of Alzheimer's disease (AD). This study aimed to investigate the association between the levels of plasma alpha-syn protein, urinary Alzheimer-associated neuronal thread protein (AD7c-NTP), apolipoprotein epsilon 4 (ApoE ε4) alleles and cognitive decline in 60 AD patients compared with 28 age-matched normal controls (NCs) at a single center. MATERIAL AND METHODS All participants underwent alpha-syn, apolipoprotein E (ApoE), AD7c-NTP, cholesterol (CHO), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TGs) analyses, neuropsychological scale assessments and neuroimaging analysis. Moreover, urine and peripheral blood samples were collected from all participants. The levels of plasma alpha-syn and AD7c-NTP were assayed using an enzyme-linked immunosorbent assay (ELISA) kit. Other test results were obtained from China-Japan Friendship Hospital. RESULTS We found that plasma alpha-syn levels were significantly different between AD patients and NCs (p=0.045). alpha-Syn levels were also associated with AD7c-NTP (r=0.231, p=0.03) but not ApoE e4 (Z=-0.147, p=0.883) levels. Neither a-syn [CHO (p=0.432), HDL (p=0.484), LDL (p=0.733) or TGs (p=0.253)] nor AD7c-NTP [CHO (p=0.867), HDL (p=0.13), LDL (p=0.57) or TGs (p=0.678)] had a relationship with lipids. CONCLUSIONS This study showed that the levels of plasma alpha-syn protein and urinary AD7c-NTP were significantly increased in AD patients compared with NCs, but not with ApoE alleles or serum lipid levels.},
}
@article {pmid34311759,
year = {2021},
author = {Sarahian, N and Sarvazad, H and Sajadi, E and Rahnejat, N and Eskandari Roozbahani, N},
title = {Investigation of common risk factors between polycystic ovary syndrome and Alzheimer's disease: a narrative review.},
journal = {Reproductive health},
volume = {18},
number = {1},
pages = {156},
pmid = {34311759},
issn = {1742-4755},
mesh = {*Alzheimer Disease/epidemiology/etiology ; *Anovulation ; Female ; Humans ; *Hyperandrogenism ; *Insulin Resistance ; *Polycystic Ovary Syndrome/complications ; Risk Factors ; },
abstract = {BACKGROUND: The most common endocrine and metabolic disorders in premenopausal women is polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, chronic anovulation, and/or ultrasound evidence of small ovarian cysts. Obesity and insulin resistance are also the main factors influencing the clinical manifestations of this syndrome. Alzheimer's disease (AD) is the most typical progressive neurodegenerative disorder of the brain, and recent studies suggest a relationship between endocrinal dysregulation and neuronal loss during AD pathology.<br><br>AIM: This study aimed to evaluate the common risk factors for Alzheimer's and PCOS based on previous studies. Knowing the common risk factors and eliminating them may prevent neurodegenerative Alzheimer's disease in the future.<br><br>METHOD: In this narrative review, international databases, including Google Scholar, Scopus, PubMed, and the Web of Science, were searched to retrieve the relevant studies. The relevant studies' summaries were categorized to discuss the possible pathways that may explain the association between Alzheimer's and PCOS signs/symptoms and complications.<br><br>RESULTS: According to our research, the factors involved in Alzheimer's and PCOS disorders may share some common risk factors. In patients with PCOS, increased LH to FSH ratio, decreased vitamin D, insulin resistance, and obesity are some of the most important factors that may increase the risk of Alzheimer's disease.},
}
@article {pmid34294142,
year = {2021},
author = {Ettcheto, M and Sánchez-Lopez, E and Cano, A and Carrasco, M and Herrera, K and Manzine, PR and Espinosa-Jimenez, T and Busquets, O and Verdaguer, E and Olloquequi, J and Auladell, C and Folch, J and Camins, A},
title = {Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer's disease in metabolically stressed APPswe/PS1dE9 mice.},
journal = {Cell &amp; bioscience},
volume = {11},
number = {1},
pages = {141},
pmid = {34294142},
issn = {2045-3701},
support = {SAF2017-84283-R//I+D+I RETOS/ ; CB06/05/0024//CIBERNED/ ; 2015/26084-1//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; 2017/13224-5//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
abstract = {BACKGROUND: Several studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20 mg kg-1 d-1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD.<br><br>RESULTS: Our studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other alterations associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response.<br><br>CONCLUSIONS: Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.},
}
@article {pmid34310820,
year = {2021},
author = {Foxe, D and Irish, M and D'Mello, M and Barhon, L and Burrell, JR and Kessels, RPC and Piguet, O},
title = {The Box Task: A novel tool to differentiate the primary progressive aphasias.},
journal = {European journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1111/ene.15035},
pmid = {34310820},
issn = {1468-1331},
abstract = {OBJECTIVE: Differentiating the primary progressive aphasia (PPA) variants in clinical settings remains complex and challenging, especially for the logopenic (lv-PPA) and non-fluent variants (nfv-PPA). Recent studies suggest that visuospatial memory is more compromised in lv-PPA than in nfv-PPA and is relatively spared in the semantic variant (sv-PPA). Accordingly, assessment of visuospatial memory performance may assist in the differential diagnosis of PPA variants. Here, we investigated the utility of a novel computerised visuospatial working memory test-the Box Task-to differentiate the three PPA variants and typical Alzheimer's disease (AD).<br><br>METHODS: Eighteen lv-PPA, 14 nfv-PPA, 23 sv-PPA, 33 AD patients, and 32 healthy controls matched for age and education were recruited. All participants completed the computerised Box Task and WMS-III Spatial Span as measures of visuospatial working memory.<br><br>RESULTS: The lv-PPA group made significantly more Box Task between-search errors than nfv-PPA, sv-PPA and control groups. The AD group, however, displayed the greatest impairments on this measure relative to the PPA variants. Logistic regression analyses in lv-PPA and nfv-PPA demonstrated that the combination of Box Task between-search error variables (i.e., 4- and 6-box levels) could correctly classify 72% of lv-PPA patients and nearly 79% of nfv-PPA patients. Area under the receiver operator characteristics curve (AUC) analyses revealed the Box Task was more sensitive than Spatial Span at differentiating lv-PPA from nfv-PPA.<br><br>CONCLUSIONS: Our findings suggest that a simple, computerised measure of visuospatial working memory-the Box Task-shows potential diagnostic utility in differentiating lv-PPA from the other PPA variants.},
}
@article {pmid34310441,
year = {2021},
author = {Bastin, C and Bahri, MA and Giacomelli, F and Miévis, F and Lemaire, C and Degueldre, C and Balteau, E and Guillaume, B and Salmon, E},
title = {Familiarity in Mild Cognitive Impairment as a Function of Patients' Clinical Outcome 4 Years Later.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000466},
pmid = {34310441},
issn = {1546-4156},
abstract = {OBJECTIVES: The current study addresses the nature of memory difficulties in amnestic mild cognitive impairment (aMCI). Whereas recollection is consistently found to be impaired in aMCI, the results on familiarity are divergent. One potential factor that could explain this divergence in findings relates to the heterogeneity of aMCI patients, so that only those aMCI patients who develop Alzheimer disease (AD) may present with impaired familiarity. The present study aimed at testing this hypothesis.<br><br>METHODS: A group of 45 aMCI patients and a group of 26 healthy older adults performed a verbal recognition memory test with the Remember/Know paradigm to assess recollection and familiarity processes. All participants were followed for 4 years with clinical and neuropsychological testing. At the end of follow-up, 22 aMCI patients progressed to AD and 23 aMCI patients remained stable. Ini