@article {pmid35773306, year = {2022}, author = {Malta, SM and Batista, LL and Silva, HCG and Franco, RR and Silva, MH and Rodrigues, TS and Correia, LIV and Martins, MM and Venturini, G and Espindola, FS and da Silva, MV and Ueira-Vieira, C}, title = {Identification of bioactive peptides from a Brazilian kefir sample, and their anti-Alzheimer potential in Drosophila melanogaster.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {11065}, pmid = {35773306}, issn = {2045-2322}, support = {APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia in the elderly, affecting cognitive, intellectual, and motor functions. Different hypotheses explain AD's mechanism, such as the amyloidogenic hypothesis. Moreover, this disease is multifactorial, and several studies have shown that gut dysbiosis and oxidative stress influence its pathogenesis. Knowing that kefir is a probiotic used in therapies to restore dysbiosis and that the bioactive peptides present in it have antioxidant properties, we explored its biotechnological potential as a source of molecules capable of modulating the amyloidogenic pathway and reducing oxidative stress, contributing to the treatment of AD. For that, we used Drosophila melanogaster model for AD (AD-like flies). Identification of bioactive peptides in the kefir sample was made by proteomic and peptidomic analyses, followed by in vitro evaluation of antioxidant and acetylcholinesterase inhibition potential. Flies were treated and their motor performance, brain morphology, and oxidative stress evaluated. Finally, we performed molecular docking between the peptides found and the main pathology-related proteins in the flies. The results showed that the fraction with the higher peptide concentration was positive for the parameters evaluated. In conclusion, these results revealed these kefir peptide-rich fractions have therapeutic potential for AD.}, }
@article {pmid35611968, year = {2022}, author = {Albrecht, JS and Gardner, RC and Wiebe, D and Bahorik, A and Xia, F and Yaffe, K}, title = {Comparison Groups Matter in Traumatic Brain Injury Research: An Example with Dementia.}, journal = {Journal of neurotrauma}, volume = {}, number = {}, pages = {}, doi = {10.1089/neu.2022.0107}, pmid = {35611968}, issn = {1557-9042}, abstract = {The association between traumatic brain injury (TBI) and risk for Alzheimer disease and related dementias (ADRD) has been investigated in multiple studies, yet reported effect sizes have varied widely. Large differences in comorbid and demographic characteristics between individuals with and without TBI could result in spurious associations between TBI and poor outcomes, even when control for confounding is attempted. Yet, inadvertent control for post-TBI exposures (e.g., psychological and physical trauma) could result in an underestimate of the effect of TBI. Choice of the unexposed or comparison group is critical to estimating total associated risk. The objective of this study was to highlight how selection of the comparison group impacts estimates of the effect of TBI on risk for ADRD. Using data on Veterans aged ≥55 years obtained from the Veterans Health Administration (VA) for years 1999-2019, we compared risk of ADRD between Veterans with incident TBI (n = 9440) and (1) the general population of Veterans who receive care at the VA (All VA) (n = 119,003); (2) Veterans who received care at a VA emergency department (VA ED) (n = 111,342); and (3) Veterans who received care at a VA ED for non-TBI trauma (VA ED NTT) (n = 65,710). In inverse probability of treatment weighted models, TBI was associated with increased risk of ADRD compared with All VA (hazard ratio [HR] 1.94; 95% confidence interval [CI] 1.84, 2.04), VA ED (HR 1.42; 95% CI 1.35, 1.50), and VA ED NTT (HR 1.12; 95% CI 1.06, 1.18). The estimated effect of TBI on incident ADRD was strongly impacted by choice of the comparison group.}, }
@article {pmid35767725, year = {2022}, author = {Tariq, S and Mutahir, S and Khan, MA and Mutahir, Z and Hussain, S and Ashraf, M and Bao, X and Zhou, B and Stark, CB and Khan, IU}, title = {Synthesis, in vitro cholinesterase inhibition, molecular docking, DFT and ADME studies of novel 1,3,4-oxadiazole 2-thiol derivatives.}, journal = {Chemistry & biodiversity}, volume = {}, number = {}, pages = {}, doi = {10.1002/cbdv.202200157}, pmid = {35767725}, issn = {1612-1880}, abstract = {A sequence of 1,3,4-oxadiazole 2-thiol derivatives bearing various alkyl or aryl moieties was designed, synthesized, and characterized by modern spectroscopic methods to yield 17 compounds (6a - 6q) which were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in search of 'lead' compounds for the treatment of Alzheimer disease (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC 50 values ranging from 11.730.49 to 27.360.29 µM for AChE and 21.830.39 to 39.430.44 µM for BChE, inhibiting both enzymes within a limited range. The SAR ascertained that the substitution of the aromatic moiety had a profound effect on the AChE and BChE inhibitory potential as compared to the aliphatic substitutions which were supported by the molecular docking studies. In silico ADME studies reinforced the drug-likeness of most of the synthesized molecules. These results were additionally supplemented by the molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps got from DFT calculations. ESP maps expose that on all structures, there are two potential binding sites conquered by the most positive and most negative districts.}, }
@article {pmid35754975, year = {2022}, author = {Galvin-McLaughlin, D and Klee, D and Memmott, T and Peters, B and Wiedrick, J and Fried-Oken, M and Oken, B and , }, title = {Methodology and preliminary data on feasibility of a neurofeedback protocol to improve visual attention to letters in mild Alzheimer's disease.}, journal = {Contemporary clinical trials communications}, volume = {28}, number = {}, pages = {100950}, doi = {10.1016/j.conctc.2022.100950}, pmid = {35754975}, issn = {2451-8654}, abstract = {Background: Brain-computer interface (BCI) systems are controlled by users through neurophysiological input for a variety of applications, including communication, environmental control, and motor rehabilitation. Although individuals with severe speech and physical impairment are the primary users of this technology, BCIs have emerged as a potential tool for broader populations, including delivering cognitive training/interventions with neurofeedback (NFB).<br><br>Methods: This paper describes the development and preliminary testing of a protocol for use of a BCI system with NFB as an intervention for people with mild Alzheimer's disease (AD). The intervention focused on training visual attention and language skills, as AD is often associated with functional impairments in both. This funded pilot study called for enrolling five participants with mild AD in a six-week BCI EEG-based NFB intervention that followed a four-to-seven-week baseline phase. While two participants completed the study, the remaining three participants could not complete the intervention phase because of COVID-19 restrictions.<br><br>Results: Preliminary pilot results suggested: (1) participants with mild AD were able to participate in a study with multiple assessments per week and complete all outcome measures, (2) most outcome measures were reliable during the baseline phase, and (3) all participants with mild AD learned to operate a BCI spelling system with training.<br><br>Conclusions: Although preliminary results demonstrate practical feasibility to deliver NFB intervention using a BCI to adults with AD, completion of the protocol in its entirety with more participants is needed to further assess whether implementing NFB-based cognitive intervention is justified by functional treatment outcomes.<br><br>Trial registration: This study was registered with ClinicalTrials.gov (NCT03790774).}, }
@article {pmid35751894, year = {2022}, author = {Kim, HH and Jung, NH}, title = {Effects of Assistive Technology Application in Dementia Intervention for People with Mild Cognitive Impairment &amp; Mild Alzheimer Type Dementia and Caregiver.}, journal = {Alternative therapies in health and medicine}, volume = {}, number = {}, pages = {}, pmid = {35751894}, issn = {1078-6791}, abstract = {Background: Dementia, a degenerative disease, requires alternative treatment to maintain function, but previous studies suggest only the therapeutic effect of a temporary program.<br><br>Primary Study Objective: The current study aimed to examine the effects of assistive technologies on cognitive function, daily living ability, and psychosocial symptoms in elderlies with mild cognitive impairment, elderlies with mild dementia and their caregivers.<br><br>Design: The research team designed an experimental study that used application as the intervention.<br><br>Setting: To recruit participants living in the local community, research participation was supported through local public health centers, welfare centers, and social welfare organizations. Evaluation and intervention were conducted by visiting the participant's home.<br><br>Participant: The study participants were 29 Mild Cognitive Impairment (MCI) and 16 mild Alzheimer type dementia (AD) patients over the age of 75 with a total of 45 patients, 10 MCI caregivers and 11 AD caregivers with a total of 21 caregivers.<br><br>Intervention: The assistive technologies used for intervention are 3 area (8 daily living assistive devices, 7 safety assistive technologies, and 7 cognitive assistive technologies). Up to 5 assistive technologies were provided to one subject, and they were instructed to use them every day for 8 weeks.<br><br>Outcome measure: Participants were evaluated at baseline and postintervention using specific scales appropriate to an area: cognitive function, activities of daily living, depression, anxiety, quality of life, satisfaction.<br><br>Results: Cognitive function showed statistically significant changes in the MCI group. Basic activities of daily living, depression, anxiety, quality of life, satisfaction showed statistically significant positive effects in both MCI and AD groups. Instrumental activities of daily living did not show any statistically significant differences.<br><br>Conclusion: As an alternative to dementia care in the future, the application and management of assistive technologies for each area should be provided at the government level.}, }
@article {pmid35751775, year = {2022}, author = {Kullenberg, H and Rossen, J and Johansson, UB and Hagströmer, M and Nyström, T and Kumlin, M and Svedberg, MM}, title = {Increased levels of insulin-degrading enzyme in patients with type 2 diabetes mellitus.}, journal = {Endocrine}, volume = {}, number = {}, pages = {}, pmid = {35751775}, issn = {1559-0100}, abstract = {PURPOSE: Decreasing levels of serum insulin-degrading enzyme (IDE) have been associated with an increased risk for Alzheimer´s disease (AD) in patients with type 2 diabetes mellitus (T2DM). Research on serum IDE levels in patients with T2DM is sparse and the aim of this study was to explore serum levels of IDE in patients with T2DM.<br><br>METHOD: Blood serum samples were obtained from a biobank. Samples from subjects with T2DM and without metabolic disease were divided into subgroups; lifestyle treatment (n = 10), oral antidiabetic treatment (n = 17), insulin treatment (n = 20) and metabolically healthy controls (n = 18). Serum levels of IDE were analysed using specific ELISA assays.<br><br>RESULTS: Serum levels of IDE were elevated in subjects with T2DM compared to metabolically healthy individuals (p = 0.033). No significant differences were detected between treatment subgroups.<br><br>CONCLUSION: The present study indicates that patients with T2DM have increased serum IDE levels, compared to metabolically healthy individuals. However, for IDE to be clinically useful as a biomarker, its full function and possible use needs to be further elucidated in larger studies showing reproducible outcomes.}, }
@article {pmid35745206, year = {2022}, author = {Budryn, G and Majak, I and Grzelczyk, J and Szwajgier, D and Rodríguez-Martínez, A and Pérez-Sánchez, H}, title = {Hydroxybenzoic Acids as Acetylcholinesterase Inhibitors: Calorimetric and Docking Simulation Studies.}, journal = {Nutrients}, volume = {14}, number = {12}, pages = {}, doi = {10.3390/nu14122476}, pmid = {35745206}, issn = {2072-6643}, abstract = {One of the symptoms of Alzheimer's disease (AD) is low acetylcholine level due to high acetylcholinesterase (AChE) activity. For this reason, AChE inhibitors are used in the treatment of AD, the prolonged use of which may cause a cholinergic crisis. There is a need to search for safe natural AChE inhibitors. The study analyzed 16 hydroxybenzoic acids using calorimetry and docking simulation as AChE inhibitors. All tested compounds were shown to inhibit the hydrolysis of ACh. The best properties were shown by methyl syringinate, which acted as competitive inhibitor at a catalytic site. The tested compounds also interacted with the anionic or peripheral binding site known to block β-amyloid plaques formation. The activity of the tested hydroxybenzoic acids IC50 ranged from 5.50 to 34.19 µmol/µmol of AChE, and the binding constant Ka from 20.53 to 253.16 L/mol, which proves their reversible, non-toxic effect, and activity at physiological concentrations.}, }
@article {pmid35743271, year = {2022}, author = {Azman, KF and Zakaria, R}, title = {Recent Advances on the Role of Brain-Derived Neurotrophic Factor (BDNF) in Neurodegenerative Diseases.}, journal = {International journal of molecular sciences}, volume = {23}, number = {12}, pages = {}, doi = {10.3390/ijms23126827}, pmid = {35743271}, issn = {1422-0067}, support = {None//Universiti Sains Malaysia/ ; }, abstract = {Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are essential for neuronal survival and growth. The signaling cascades initiated by BDNF and its receptor are the key regulators of synaptic plasticity, which plays important role in learning and memory formation. Changes in BDNF levels and signaling pathways have been identified in several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, and have been linked with the symptoms and course of these diseases. This review summarizes the current understanding of the role of BDNF in several neurodegenerative diseases, as well as the underlying molecular mechanism. The therapeutic potential of BDNF treatment is also discussed, in the hope of discovering new avenues for the treatment of neurodegenerative diseases.}, }
@article {pmid35733944, year = {2022}, author = {Coerver, K and Yu, MM and D'Abreu, A and Wasserman, M and Nair, KV}, title = {Practical Considerations in the Administration of Aducanumab for the Neurologist.}, journal = {Neurology. Clinical practice}, volume = {12}, number = {2}, pages = {169-175}, doi = {10.1212/CPJ.0000000000001144}, pmid = {35733944}, issn = {2163-0402}, abstract = {Aducanumab (Aduhelm), developed by the biotechnology firm Biogen in Cambridge, MA, was approved using the less common accelerated approval pathway by the Federal Drug Administration (FDA) reserved for treatments that fill a significant unmet need.1 Its approval on June 7, 2021, has been met with an outpouring of opinions from prescribers, insurers, advocacy groups, and hospital systems regarding its risk-benefit profile.2-4 Originally approved for all forms of Alzheimer disease (AD), the FDA updated aducanumab's labeling on July 8, 2021, for "treatment in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials."5 With 6 million people nationally in the United States who suffer from AD and an anticipated one-third of those who may now fulfill the criteria under the revised labeling, the implications of aducanumab's approval continue to generate national interest.6.}, }
@article {pmid35731901, year = {2022}, author = {Lirong, W and Mingliang, Z and Mengci, L and Qihao, G and Zhenxing, R and Xiaojiao, Z and Tianlu, C}, title = {The clinical and mechanistic roles of bile acids in depression, Alzheimer's disease, and stroke.}, journal = {Proteomics}, volume = {}, number = {}, pages = {e2100324}, doi = {10.1002/pmic.202100324}, pmid = {35731901}, issn = {1615-9861}, abstract = {The burden of neurological and neuropsychiatric disorders continues to grow with significant impacts on human health and social economy worldwide. Increasing clinical and preclinical evidences have implicated that bile acids (BAs) are involved in the onset and progression of neurological and neuropsychiatric diseases. Here, we summarized recent studies of BAs in three types of highly prevalent brain disorders, depression, Alzheimer's disease, and stroke. The shared and specific BA profiles were explored and potential markers associated with disease development and progression were summarized. The mechanistic roles of BAs were reviewed with focuses on inflammation, gut-brain-microbiota axis, cellular apoptosis. We also discussed future perspectives for the prevention and treatment of neurological and neuropsychiatric disorders by targeting BAs and related molecules and gut microbiota. Our understanding of BAs and their roles in brain disorders is still evolving. A large number of questions still need to be addressed on the emerging crosstalk among central, peripheral, intestine and their contribution to brain and mental health. This article is protected by copyright. All rights reserved.}, }
@article {pmid35731567, year = {2022}, author = {Schinle, M and Erler, C and Kaliciak, M and Milde, C and Stock, S and Gerdes, M and Stork, W}, title = {Digital Health Apps in the Context of Dementia: Questionnaire Study to Assess the Likelihood of Use Among Physicians.}, journal = {JMIR formative research}, volume = {6}, number = {6}, pages = {e35961}, doi = {10.2196/35961}, pmid = {35731567}, issn = {2561-326X}, abstract = {BACKGROUND: Age-related diseases such as dementia are playing an increasingly important role in global population development. Thus, prevention, diagnostics, and interventions require more accessibility, which can be realized through digital health apps. With the app on prescription, Germany made history by being the first country worldwide to offer physicians the possibility to prescribe and reimburse digital health apps as of the end of the year 2020.<br><br>OBJECTIVE: Considering the lack of knowledge about correlations with the likelihood of use among physicians, this study aimed to address the question of what makes the use of a digital health app by physicians more likely.<br><br>METHODS: We developed and validated a novel measurement tool-the Digital Health Compliance Questionnaire (DHCQ)-in an interdisciplinary collaboration of experts to assess the role of proposed factors in the likelihood of using a health app. Therefore, a web-based survey was conducted to evaluate the likelihood of using a digital app called DemPredict to screen for Alzheimer dementia. Within this survey, 5 latent dimensions (acceptance, attitude toward technology, technology experience, payment for time of use, and effort of collection), the dependent variable likelihood of use, and answers to exploratory questions were recorded and tested within directed correlations. Following a non-probability-sampling strategy, the study was completed by 331 physicians from Germany in the German language, of whom 301 (90.9%) fulfilled the study criteria (eg, being in regular contact with patients with dementia). These data were analyzed using a range of statistical methods to validate the dimensions of the DHCQ.<br><br>RESULTS: The DHCQ revealed good test theoretical measures-it showed excellent fit indexes (Tucker-Lewis index=0.98; comparative fit index=0.982; standardized root mean square residual=0.073; root mean square error of approximation=0.037), good internal consistency (Cronbach α=.83), and signs of moderate to large correlations between the DHCQ dimensions and the dependent variable. The correlations between the variables acceptance, attitude toward technology, technology experience, and payment for the time of use and the dependent variable likelihood of use ranged from 0.29 to 0.79, and the correlation between effort of the collection and likelihood of use was -0.80. In addition, we found high levels of skepticism regarding data protection, and the age of the participants was found to be negatively related to their technical experience and attitude toward technology.<br><br>CONCLUSIONS: In the context of the results, increased communication between the medical and technology sectors and significantly more awareness raising are recommended to make the use of digital health apps more attractive to physicians as they can be adjusted to their everyday needs. Further research could explore the connection between areas such as adherence on the patient side and its impact on the likelihood of use by physicians.}, }
@article {pmid35726411, year = {2022}, author = {Maria de Souza, M and Ribeiro Cenci, A and Faoro Teixeira, K and Machado, V and Garcia Mendes Schuler, MC and Elisa Gonçalves, A and Paula Dalmagro, A and André Cazarin, C and Luiz Gomes Ferreira, L and Sena de Oliveira, A and Defini Andricopulo, A}, title = {DYRK1A inhibitors and perspectives for the treatment of Alzheimer's disease.}, journal = {Current medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/0929867329666220620162018}, pmid = {35726411}, issn = {1875-533X}, abstract = {BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disease and the most common form of dementia, especially in the elderly. Due to the increase in life expectancy, in recent years there has been an exorbitant growth in the number of people affected by this disease, causing serious problems for health systems. In recent years, research has been intensified to find new therapeutic approaches that prevent the progression of the disease. In this sense, recent studies indicate that the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) gene, which is located on chromosome 21q22.2 and overexpressed in Down syndrome (DS), may play a significant role in developmental brain disorders and early onset neurodegeneration, neuronal loss and dementia in DS and AD. Inhibiting DYRK1A may serve to stop the phenotypic effects of its overexpression and, therefore, is a potential treatment strategy for the prevention of age-associated neurodegeneration, including Alzheimer-type pathology.<br><br>OBJECTIVE: in this review, we investigate the contribution of DYRK1A inhibitors as potential anti-AD agents.<br><br>METHODS: A search in the literature to compile an in vitro dataset including IC50 values involving DYRK1A was performed from 2014 to the present day. In addition, we carried out structure-activity relationship studies based on in vitro and in silico data.<br><br>RESULTS: molecular modeling and enzyme kinetics studies indicate that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity.<br><br>CONCLUSION: further evaluation of DYRK1A inhibitors may contribute to new therapeutic approaches for AD.}, }
@article {pmid35726096, year = {2022}, author = {Jellinger, KA}, title = {Morphological basis of Parkinson disease-associated cognitive impairment: an update.}, journal = {Journal of neural transmission (Vienna, Austria : 1996)}, volume = {}, number = {}, pages = {}, pmid = {35726096}, issn = {1435-1463}, abstract = {Cognitive impairment is one of the most salient non-motor symptoms of Parkinson disease (PD) that poses a significant burden on the patients and carers as well as being a risk factor for early mortality. People with PD show a wide spectrum of cognitive dysfunctions ranging from subjective cognitive decline and mild cognitive impairment (MCI) to frank dementia. The mean frequency of PD with MCI (PD-MCI) is 25.8% and the pooled dementia frequency is 26.3% increasing up to 83% 20 years after diagnosis. A better understanding of the underlying pathological processes will aid in directing disease-specific treatment. Modern neuroimaging studies revealed considerable changes in gray and white matter in PD patients with cognitive impairment, cortical atrophy, hypometabolism, dopamine/cholinergic or other neurotransmitter dysfunction and increased amyloid burden, but multiple mechanism are likely involved. Combined analysis of imaging and fluid markers is the most promising method for identifying PD-MCI and Parkinson disease dementia (PDD). Morphological substrates are a combination of Lewy- and Alzheimer-associated and other concomitant pathologies with aggregation of α-synuclein, amyloid, tau and other pathological proteins in cortical and subcortical regions causing destruction of essential neuronal networks. Significant pathological heterogeneity within PD-MCI reflects deficits in various cognitive domains. This review highlights the essential neuroimaging data and neuropathological changes in PD with cognitive impairment, the amount and topographical distribution of pathological protein aggregates and their pathophysiological relevance. Large-scale clinicopathological correlative studies are warranted to further elucidate the exact neuropathological correlates of cognitive impairment in PD and related synucleinopathies as a basis for early diagnosis and future disease-modifying therapies.}, }
@article {pmid35715872, year = {2022}, author = {Valenzuela, M and Duncan, T and Abey, A and Johnson, A and Boulamatsis, C and Dalton, MA and Jacobson, E and Brunel, L and Child, G and Simpson, D and Buckland, M and Lowe, A and Siette, J and Westbrook, F and McGreevy, P}, title = {Autologous skin-derived neural precursor cell therapy reverses canine Alzheimer dementia-like syndrome in a proof of concept veterinary trial.}, journal = {Stem cell research &amp; therapy}, volume = {13}, number = {1}, pages = {261}, pmid = {35715872}, issn = {1757-6512}, mesh = {*Alzheimer Disease/therapy ; Animals ; Cell- and Tissue-Based Therapy ; Dogs ; Hippocampus/pathology ; Humans ; *Neural Stem Cells/metabolism ; Rats ; Synapses/metabolism ; }, abstract = {BACKGROUND: Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis.<br><br>METHODS: A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses; these were compared to a brain bank (N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N = 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation.<br><br>RESULTS: Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits.<br><br>CONCLUSIONS: With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.}, }
@article {pmid35720658, year = {2022}, author = {Mecê, AM and Abreu, VC and Lamas, GM and Tacla, RDR and Minekawa, TB and Ramos, CD and Balthazar, MLF}, title = {Lithium Intoxication as a cause of reversible dementia mimicking FDG PET features of Alzheimer's disease.}, journal = {Dementia &amp; neuropsychologia}, volume = {16}, number = {2}, pages = {249-252}, doi = {10.1590/1980-5764-DN-2021-0105}, pmid = {35720658}, issn = {1980-5764}, abstract = {Rapidly progressive dementia (RPD) is a rare neurological disorder. Drug toxicity is among the differential diagnoses, including the use of lithium, in which an overdosage might cause cognitive dysfunction. Clinical suspicion, laboratory confirmation, and drug interruption are key points in the management of lithium intoxication. We described a 66-year-old female patient under treatment with lithium who developed an RPD associated with parkinsonian symptoms. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) showed an "Alzheimer-like" pattern, while cerebrospinal fluid biomarkers for the disease were negative. There was a significant clinical and radiological improvement after lithium interruption. Lithium intoxication is a potentially reversible cause of RPD, as demonstrated in this case report. Drug discontinuation should be considered even in patients with normal levels of this metal, if cognitive impairment is detected. 18F-FDG PET/CT images may show an "Alzheimer-like" image pattern in acute intoxication and are useful for monitoring these patients.}, }
@article {pmid35719254, year = {2022}, author = {Abiyev, A and Yakaryılmaz, FD and Öztürk, ZA}, title = {A new diagnostic approach in Alzheimer's disease: The critical flicker fusion threshold.}, journal = {Dementia &amp; neuropsychologia}, volume = {16}, number = {1}, pages = {89-96}, doi = {10.1590/1980-5764-DN-2021-0054}, pmid = {35719254}, issn = {1980-5764}, abstract = {Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Although AD treatment is still insufficient despite all the recent developments, detection and treatment in the early stage of disease have provided more clinical benefits.<br><br>Objective: In this study, we aimed to use the critical flicker fusion (CFF) threshold test to diagnose AD in the early stage.<br><br>Methods: In this study, 120 patients (above 65 years of age) and 50 control groups who were admitted to geriatrics outpatient clinic and diagnosed in early- and middle-stage AD were included. The remaining 58 patients and 25 healthy volunteers underwent comprehensive geriatric assessment and CFF testing.<br><br>Results: The mean CFF value of AD group was significantly lower than the control group (36.44±7.00 vs. 44.24±3.82, p<0.001, respectively). There was a significant difference in standardized mini-mental state examination (MMSE) score in both groups (18.05±5.25 vs. 25.96±2.85, p<0.001, respectively). There was also a positive correlation between CFF value and MMSE score (p<0.001, r=0.459). Thirty-four patients were in the early-stage AD group and 24 patients were in the middle-stage AD group. There was a significant difference in CFF values between the three groups when we compared the patients in early- and middle-stage AD and control groups (p<0.001). The mean CFF values in patients with early- and middle-stage AD were 37.93±7.33 and 34.97±7.43, respectively. The mean age, gender, education level, and the number of drugs used did not show a statistically significant difference in both groups (p>0.05). The cutoff value for the CFF variable was determined as 39 Hz [p<0.001; area under the curve (AUC)=0.852; sensitivity=70.69% (95% confidence interval [95%CI] 57.3-81.9); specificity=92.00% (95%CI 74.00-99.00)].<br><br>Conclusions: There is a significant difference in mean CFF values between AD and healthy groups. CFF testing may play an important role in diagnosing AD in the early stage.}, }
@article {pmid35718871, year = {2022}, author = {Maltais, M and de Souto Barreto, P and Bowman, GL and Smith, AD and Cantet, C and Andrieu, S and Rolland, Y}, title = {Omega-3 Supplementation for the Prevention of Cognitive Decline in Older Adults: Does It Depend on Homocysteine Levels?.}, journal = {The journal of nutrition, health &amp; aging}, volume = {26}, number = {6}, pages = {615-620}, doi = {10.1007/s12603-022-1809-5}, pmid = {35718871}, issn = {1760-4788}, mesh = {Aged ; Cognition ; *Cognitive Dysfunction/drug therapy/prevention &amp; control ; Dietary Supplements ; *Fatty Acids, Omega-3/pharmacology/therapeutic use ; Homocysteine ; Humans ; }, abstract = {BACKGROUND: Recent evidence point towards an interaction between omega-3 (n-3) polyunsaturated fatty acids (PUFA) and plasma homocysteine (Hcy).<br><br>OBJECTIVES: This study tested the hypothesis that effects of red blood cell n-3 PUFA are modified according to baseline plasma Hcy in the large Mulit-domain Alzheimer Prevention Trial (MAPT) throughout the 3-years of treatment with an additional 2 years of observational follow-up.<br><br>DESIGN: Experimental study.<br><br>PARTICIPANTS: From the 1680 participants that were randomized in the four groups of the MAPT study (two of which received n-3 PUFA, the other two without n-3 PUFA), 782 were selected because they had baseline data on both Hcy and n-3 PUFA.<br><br>MEASUREMENTS: Cognitive performance was measured with a broad set of cognitive tests including free and total recall of the cued selective reminding test, digit symbol substitution test, category naming test and Trail-making tests (TMT-A and B) and Clinical dementia rating scale.<br><br>RESULTS: We found a significant association between TMT-A and red blood cell n-3 PUFA levels in participants with Hcy values ≤16.8 µMol/L after adjustments at baseline (Estimate: -1.3, 95% CI: -2.3; -0.3, p=0.01). Additionally, participants with high Hcy values had a significant worsening after adjustments in TMT-B after a 5-year n-3 PUFA supplementation, compared to low levels of Hcy (Mean difference: 34.8, 95% CI: 7.8;61.7).<br><br>CONCLUSION: This study shows that Hcy levels could modify the association between red blood cell n-3 PUFA and executive function. People with high Hcy may benefit less from a n-3 PUFA supplementation to prevent cognitive decline.}, }
@article {pmid35717103, year = {2022}, author = {Newberg, AB and Coble, R and Khosravi, M and Alavi, A}, title = {Positron Emission Tomography-Based Assessment of Cognitive Impairment and Dementias, Critical Role of Fluorodeoxyglucose in such Settings.}, journal = {PET clinics}, volume = {17}, number = {3}, pages = {479-494}, doi = {10.1016/j.cpet.2022.03.009}, pmid = {35717103}, issn = {1879-9809}, mesh = {*Cognitive Dysfunction/diagnostic imaging ; *Dementia/diagnostic imaging/metabolism ; Fluorodeoxyglucose F18 ; Humans ; *Neurodegenerative Diseases/diagnostic imaging ; Positron-Emission Tomography/methods ; Radiopharmaceuticals ; }, abstract = {Positron emission tomography (PET) has been a key component in the diagnostic armamentarium for assessing neurodegenerative diseases such as Alzheimer or Parkinson disease. PET imaging has been useful for diagnosing these disorders, identifying their pathophysiology, and following their treatment. Further, PET imaging has been extensively used for both clinical and research purposes, particularly for helping with potential therapeutic approaches for managing neurodegenerative diseases. This article will review the current literature regarding PET imaging in patients with neurodegenerative disorders. This includes an evaluation of the most commonly used tracer fluorodeoxyglucose that measures cerebral glucose metabolism, tracers that assess neurotransmitter systems, and tracers designed to reveal disease-specific pathophysiological processes. With the continuing development of an expanding variety of radiopharmaceuticals, PET imaging will likely play a prominent role in future research and clinical applications for neurodegenerative diseases.}, }
@article {pmid35714514, year = {2022}, author = {Majerova, P and Olesova, D and Golisova, G and Buralova, M and Michalicova, A and Vegh, J and Piestansky, J and Bhide, M and Hanes, J and Kovac, A}, title = {Analog of kynurenic acid decreases tau pathology by modulating astrogliosis in rat model for tauopathy.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {152}, number = {}, pages = {113257}, doi = {10.1016/j.biopha.2022.113257}, pmid = {35714514}, issn = {1950-6007}, abstract = {Kynurenines have immunomodulatory and neuroactive properties and can influence the central nervous system. Previous studies showed the involvement of the kynurenines in the pathogenesis and progression of neurodegenerative disease. In neurodegenerative disorders, including tauopathies, the tryptophan metabolism is shifted toward neurotoxic agents and the reduction of neuroprotectant products. Astrocyte-derived kynurenic acid serves as a neuroprotectant. However, systemic administration of kynurenic acid is not effective because of low permeability across the blood-brain barrier (BBB). We used a kynurenic acid analog with similar biological activity but higher brain permeability to overcome BBB limitations. In the present study, we used amide derivate of kynurenic acid N-(2-N, N-dimethylaminoethyl)- 4-oxo-1 H-quinoline-2-carboxamid (KYNA-1). We administered KYNA-1 for three months to tau transgenic rats SHR-24 and analyzed the effect on tau pathology and activation of glial cells. Primary glial cell cultures were applied to identify the mechanism of the KYNA-1 effect. KYNA-1 was not toxic to rats after chronic three-month administration. When chronically administered, KYNA-1 reduced hyperphosphorylation of insoluble tau in the brain of transgenic rats. Noteworthily, the plasma total tau was also reduced. We determined that the effect of KYNA-1 on tau pathology was induced through the modulation of glial activation. KYNA-1 inhibited LPS induced activation of astrocytes and induced transformation of microglia to M2 phenotype. We identified that the administration of KYNA-1 reduced tau hyperphosphorylation and neuroinflammation. KYNA-1 may serve as a promising treatment for tauopathies.}, }
@article {pmid35714473, year = {2022}, author = {George, N and Jawaid Akhtar, M and Al Balushi, KA and Alam Khan, S}, title = {Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents.}, journal = {Bioorganic chemistry}, volume = {127}, number = {}, pages = {105941}, doi = {10.1016/j.bioorg.2022.105941}, pmid = {35714473}, issn = {1090-2120}, abstract = {Alzheimer's disease (AD) is a neurological disorder that leads to dementia i.e., progressive memory loss accompanied with worsening of thinking ability of an individual. The cause of AD is not fully understood but it progresses with age where brain cells gradually die over time. According to the World Health Organization (WHO), currently 50 million people worldwide are affected by dementia and 60-70% of the cases belong to AD. Cumulative research over the past few decades have shown that molecules that act at a single target possess limited efficacy since these investigational drugs are not able to act against complex pathologies and thus do not provide permanent cure. Designing of multi-target directed ligands (MTDLs) appears to be more beneficial and a rational approach to treat chronic complex diseases including neurodegenerative diseases. Recently, MTDLs are being extensively researched by the medicinal chemists for the development of drugs for the treatment of various multifactorial diseases. Indole is one of the privileged scaffolds which is considered as an essential mediator between the gut-brain axis because of its neuroprotective, anti-inflammatory, β-amyloid anti-aggregation and antioxidant activities. Herein, we have reviewed the potential of some indole-hybrids acting at multiple targets in the pathogenesis of AD. We have reviewed research articles from the year 2014-2021 from various scientific databases and highlighted the synthetic strategies, mechanisms of neuroprotection, toxicity, structure activity relationships and molecular docking studies of various indole-hybrid derivatives. This literature review of published data on indole derivatives indicated that developing indole hybrids have improved the pharmacokinetic profile with lower toxicity, provided synergistic effect, helped to develop more potent compounds and prevented drug-drug interactions. It is evident that this class of compounds have potential to inhibit multiple enzymes targets involved in the pathogenesis of AD and therefore indole hybrids as MTDLs may play an important role in the development of anti-AD molecules.}, }
@article {pmid35709892, year = {2022}, author = {Fu, X and Liu, J and Xie, J and Chen, G and Zhang, H and Meng, F and Wu, M and Li, Q and Liu, Y and Wang, W and Dai, J and Wang, D and Zhao, D and Li, C and Wang, X}, title = {Identification of potential therapeutic and diagnostic characteristics of Alzheimer disease by targeting the miR-132-3p/FOXO3a-PPM1F axis in APP/PS1 mice.}, journal = {Brain research}, volume = {1790}, number = {}, pages = {147983}, doi = {10.1016/j.brainres.2022.147983}, pmid = {35709892}, issn = {1872-6240}, abstract = {Alzheimer disease (AD) is a neurodegenerative disorder, which is characterized by progressive impairment of memory and cognition. Early diagnosis and treatment of AD has become a leading topic of research. In this study, we explored the effects of the miR-132-3p/FOXO3a-PPM1F axis on the onset of AD for possible early diagnosis and therapy. We found that miR-132-3p levels in the hippocampus and blood were drastically decreased in APP/PS1 mice from 9 months of age, and bi-directional manipulation of miR-132-3p levels induced magnified effects on learning memory behaviors, and manifestation of AD-related pathological characteristics and inflammatory cytokines in APP/PS1 mice of relevant ages. The hippocampal PPM1F expression levels were significantly elevated in APP/PS1 mice from 3 months of age, which was correlated with miR-132-3p levels at different ages. Overexpression of PPM1F remarkably accelerated the progression of learning memory deficits and associated pathological factors in APP/PS1 mice. Further, we showed that miR-132-3p modulated the expression of PPM1F via FOXO3a in HT22 cells. Finally, using peripheral blood samples of human study participants, we found that the miR-132-3p and PPM1F expression levels in patients with AD were also altered with prominent correlations. In conclusion, miR-132-3p indirectly regulates PPM1F expression by targeting FOXO3a, which could play an extensive role in contributing to the establishment of early diagnosis, treatment, and pathogenesis of AD.}, }
@article {pmid35707521, year = {2022}, author = {Paes-Colli, Y and Aguiar, AFL and Isaac, AR and Ferreira, BK and Campos, RMP and Trindade, PMP and de Melo Reis, RA and Sampaio, LS}, title = {Phytocannabinoids and Cannabis-Based Products as Alternative Pharmacotherapy in Neurodegenerative Diseases: From Hypothesis to Clinical Practice.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {917164}, doi = {10.3389/fncel.2022.917164}, pmid = {35707521}, issn = {1662-5102}, abstract = {Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide. Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders. In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer's disease, Parkinson's disease and Multiple Sclerosis's patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system. In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines.}, }
@article {pmid35691883, year = {2022}, author = {Kajikawa, T and Mastellos, DC and Hasturk, H and Kotsakis, GA and Yancopoulou, D and Lambris, JD and Hajishengallis, G}, title = {C3-targeted host-modulation approaches to oral inflammatory conditions.}, journal = {Seminars in immunology}, volume = {}, number = {}, pages = {101608}, doi = {10.1016/j.smim.2022.101608}, pmid = {35691883}, issn = {1096-3618}, abstract = {Periodontitis is an inflammatory disease caused by biofilm accumulation and dysbiosis in subgingival areas surrounding the teeth. If not properly treated, this oral disease may result in tooth loss and consequently poor esthetics, deteriorated masticatory function and compromised quality of life. Epidemiological and clinical intervention studies indicate that periodontitis can potentially aggravate systemic diseases, such as, cardiovascular disease, type 2 diabetes mellitus, rheumatoid arthritis, and Alzheimer disease. Therefore, improvements in the treatment of periodontal disease may benefit not only oral health but also systemic health. The complement system is an ancient host defense system that plays pivotal roles in immunosurveillance and tissue homeostasis. However, complement has unwanted consequences if not controlled appropriately or excessively activated. Complement overactivation has been observed in patients with periodontitis and in animal models of periodontitis and drives periodontal inflammation and tissue destruction. This review places emphasis on a promising periodontal host-modulation therapy targeting the complement system, namely the complement C3-targeting drug, AMY-101. AMY-101 has shown safety and efficacy in reducing gingival inflammation in a recent Phase 2a clinical study. We also discuss the potential of AMY-101 to treat peri-implant inflammatory conditions, where complement also seems to be involved and there is an urgent unmet need for effective treatment.}, }
@article {pmid35700915, year = {2022}, author = {Yao, Q and Tang, F and Wang, Y and Yan, Y and Dong, L and Wang, T and Zhu, D and Tian, M and Lin, X and Shi, J}, title = {Effect of cerebellum stimulation on cognitive recovery in patients with Alzheimer disease: A randomized clinical trial.}, journal = {Brain stimulation}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.brs.2022.06.004}, pmid = {35700915}, issn = {1876-4754}, abstract = {INTRODUCTION: Evidence indicates that the cerebellum is involved in cognitive processing. However, the specific mechanisms through which the cerebellum repetitive transcranial magnetic stimulation (rTMS) contributes to the cognitive state are unclear.<br><br>METHODS: In the current randomized, double-blind, sham-controlled trial, 27 patients with Alzheimer's disease (AD) were randomly allotted to one of the two groups: rTMS-real or rTMS-sham. We investigated the efficacy of a four-week treatment of bilateral cerebellum rTMS to promote cognitive recovery and alter specific cerebello-cerebral functional connectivity.<br><br>RESULTS: The cerebellum rTMS significantly improves multi-domain cognitive functions, directly associated with the observed intrinsic functional connectivity between the cerebellum nodes and the dorsolateral prefrontal cortex (DLPFC), medial frontal cortex, and the cingulate cortex in the real rTMS group. In contrast, the sham stimulation showed no significant impact on the clinical improvements and the cerebello-cerebral connectivity.<br><br>CONCLUSION: Our results depict that 5 Hz rTMS of the bilateral cerebellum is a promising, non-invasive treatment of cognitive dysfunction in AD patients. This cognitive improvement is accompanied by brain connectivity modulation and is consistent with the pathophysiological brain disconnection model in AD patients.}, }
@article {pmid35697158, year = {2022}, author = {Lin, J and Niu, Z and Xue, Y and Gao, J and Zhang, M and Li, M and Peng, Y and Zhang, S and Li, W and Zhang, Q and Li, X}, title = {Chronic Vitamin D3 Supplementation Alleviates Cognition Impairment via Inhibition of Oxidative Stress Regulated by PI3K/AKT/Nrf2 in APP/PS1 Transgenic Mice.}, journal = {Neuroscience letters}, volume = {}, number = {}, pages = {136725}, doi = {10.1016/j.neulet.2022.136725}, pmid = {35697158}, issn = {1872-7972}, abstract = {Oxidative stress plays essential role in the pathogenesis of Alzheimer's disease, and vitamin D3 (VD3) is a nutrient with neuroprotective and antioxidant activities. The present study aimed to confirm the neuroprotective effect and the ameliorative effect of cortical oxidative stress of VD3 in APP/PS1 transgenic mice. APP/PS1 mice were treated with VD3 for 20 weeks. After treatment, Morris Water Maze test was used to evaluate cognitive level. Western blotting was used to determine APP, p-tau, tau and PI3K/AKT/Nrf2 pathway-related protein expression levels. Immunohistochemical staining was performed to determine the levels of β amyloid peptide (Aβ) deposition. Enzyme linked immunosorbent assay was used to determine the 25(OH)D3 levels and oxidative stress status. Our results showed that treatment with VD3 ameliorated behavioral deficits of APP/PS1 mice. In addition, the administration of VD3 significantly increased the cortical 25(OH)D3 levels, while reducing the levels of cortical Aβ deposition and decreasing the expression levels of cortical APP, tau and p-tau in APP/PS1 mice. Moreover, VD3 protected the cortex against oxidative stress by enhancing the levels of superoxide dismutase, glutathione and total antioxidant capacity, and downregulating the malondialdehyde levels. Furthermore, VD3 clearly activated the PI3K/AKT/Nrf2 pathway, thereby elevating the expression levels of HO1 and NQO1. We concluded that VD3 improved cognitive function and cortical Alzheimer-like pathology of APP/PS1 mice, which may be related to the inhibition of oxidative stress via activation the PI3K/AKT/Nrf2 pathway.}, }
@article {pmid35694933, year = {2022}, author = {Wang, J and Battioui, C and McCarthy, A and Dang, X and Zhang, H and Man, A and Zou, J and Kyle, J and Munsie, L and Pugh, M and Biglan, K}, title = {Evaluating the Use of Digital Biomarkers to Test Treatment Effects on Cognition and Movement in Patients with Lewy Body Dementia.}, journal = {Journal of Parkinson's disease}, volume = {}, number = {}, pages = {}, doi = {10.3233/JPD-213126}, pmid = {35694933}, issn = {1877-718X}, abstract = {BACKGROUND: PRESENCE was a Phase 2 trial assessing mevidalen for symptomatic treatment of Lewy body dementia (LBD). Participants received daily doses (10, 30, or 75 mg) of mevidalen (LY3154207) or placebo for 12 weeks.<br><br>OBJECTIVE: To evaluate if frequent cognitive and motor tests using an iPad app and wrist-worn actigraphy to track activity and sleep could detect mevidalen treatment effects in LBD.<br><br>METHODS: Of 340 participants enrolled in PRESENCE, 238 wore actigraphy for three 2-week periods: pre-, during, and post-intervention. A subset of participants (n = 160) enrolled in a sub-study using an iPad trial app with 3 tests: digital symbol substitution (DSST), spatial working memory (SWM), and finger-tapping. Compliance was defined as daily test completion or watch-wearing ≥23 h/day. Change from baseline to week 12 (app) or week 8 (actigraphy) was used to assess treatment effects using Mixed Model Repeated Measures analysis. Pearson correlations between sensor-derived features and clinical endpoints were assessed.<br><br>RESULTS: Actigraphy and trial app compliance was > 90% and > 60%, respectively. At baseline, daytime sleep positively correlated with Epworth Sleepiness Scale score (p < 0.01). Physical activity correlated with improvement on Movement Disorder Society -Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II (p < 0.001). Better scores of DSST and SWM correlated with lower Alzheimer Disease Assessment Scale -Cognitive 13-Item Scale (ADAS-Cog13) (p < 0.001). Mevidalen treatment (30 mg) improved SWM (p < 0.01), while dose-dependent decreases in daytime sleep (10 mg: p < 0.01, 30 mg: p < 0.05, 75 mg: p < 0.001), and an increase in walking minutes (75 mg dose: p < 0.001) were observed, returning to baseline post-intervention.<br><br>CONCLUSION: Devices used in the LBD population achieved adequate compliance and digital metrics detected statistically significant treatment effects.}, }
@article {pmid35682567, year = {2022}, author = {Han, BH and Cofell, B and Everhart, E and Humpal, C and Kang, SS and Lee, SK and Kim-Han, JS}, title = {Amentoflavone Promotes Cellular Uptake and Degradation of Amyloid-Beta in Neuronal Cells.}, journal = {International journal of molecular sciences}, volume = {23}, number = {11}, pages = {}, doi = {10.3390/ijms23115885}, pmid = {35682567}, issn = {1422-0067}, abstract = {Deposition of fibrillar forms of amyloid β-protein (Aβ) is commonly found in patients with Alzheimer's disease (AD) associated with cognitive decline. Impaired clearance of Aβ species is thought to be a major cause of late-onset sporadic AD. Aβ secreted into the extracellular milieu can be cleared from the brain through multiple pathways, including cellular uptake in neuronal and non-neuronal cells. Recent studies have showed that the naturally-occurring polyphenol amentoflavone (AMF) exerts anti-amyloidogenic effects. However, its effects on metabolism and cellular clearance of Aβ remain to be tested. In the present study, we demonstrated that AMF significantly increased the cellular uptake of both Aβ1-40 and Aβ1-42, but not inverted Aβ42-1 in mouse neuronal N2a cells. Though AMF promoted internalization of cytotoxic Aβ1-42, it significantly reduced cell death in our assay condition. Our data further revealed that the internalized Aβ is translocated to lysosomes and undergoes enzymatic degradation. The saturable kinetic of Aβ uptake and our pharmacologic experiments showed the involvement of receptor-mediated endocytosis, in part, through the class A scavenger receptors as a possible mechanism of action of AMF. Taken together, our findings indicate that AMF can lower the levels of extracellular Aβ by increasing their cellular uptake and clearance, suggesting the therapeutic potential of AMF for the treatment of AD.}, }
@article {pmid35682542, year = {2022}, author = {Licastro, F}, title = {Special Issue Editorial: "Infections, Inflammation and Neurodegeneration in Alzheimer Disease" Infections, Neuronal Senescence, and Dementia.}, journal = {International journal of molecular sciences}, volume = {23}, number = {11}, pages = {}, doi = {10.3390/ijms23115865}, pmid = {35682542}, issn = {1422-0067}, abstract = {Alzheimer's disease (AD) is a complex chronic disease of the brain characterized by several neurodegenerative mechanisms and is responsible for most dementia cases in the elderly. Declining immunity during ageing is often associated with peripheral chronic inflammation, and chronic neuroinflammation is a constant component of AD brain pathology. In the Special Issue published in 2021 eight papers were collected regarding different aspects of neurodegeneration associated with AD. Five papers presented and discussed infectious agents involved in brain AD pathology and three discussed data regarding receptors regulation and possible treatment of the disease. Below I will discuss and further elaborate on topics related to infections, inflammation, and neurodegenerative pathways in AD and brain senescence. The topic presented here may contribute to early intervention protocols for preventing or slowing the progression of cognitive deterioration in the elderly.}, }
@article {pmid35678410, year = {2022}, author = {Rose, RV and Kass, JS}, title = {The Medicolegal and Ethical Dimensions of Physician Prescription Reluctance.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {28}, number = {3}, pages = {937-941}, doi = {10.1212/CON.0000000000001164}, pmid = {35678410}, issn = {1538-6899}, abstract = {ABSTRACT: This article addresses the potential legal ramifications for neurologists caring for patients with Alzheimer disease (AD) who elect neither to prescribe aducanumab nor to refer patients with AD for treatment with aducanumab. To prevail against a neurologist for failing to prescribe aducanumab or refer for aducanumab treatment, the plaintiff would have to establish that the neurologist's failure to prescribe the medication or refer for treatment was a breach of the standard of care. The standard of care is conceptualized as the generally accepted approach to diagnosing or treating a condition. However, the controversy surrounding the US Food and Drug Administration's (FDA's) approval process for aducanumab (which was based on the drug's efficacy at reducing brain amyloidosis rather than on clinically meaningful efficacy) as well as the American Academy of Neurology (AAN) position statement on aducanumab and the recent decision by the Centers for Medicare &amp; Medicaid Services (CMS) to limit Medicare coverage of the drug and its associated costs to patients enrolled in qualifying clinical trials indicate that aducanumab cannot yet be considered the standard of care for the treatment of AD. Although deciding not to prescribe aducanumab does not violate the standard of care, neurologists treating patients with AD and not recommending this treatment should explain to their patients and their patients' surrogate decision makers why they are not recommending the treatment.}, }
@article {pmid35678408, year = {2022}, author = {Carlsson, CM}, title = {Management of Dementia.}, journal = {Continuum (Minneapolis, Minn.)}, volume = {28}, number = {3}, pages = {885-900}, pmid = {35678408}, issn = {1538-6899}, abstract = {PURPOSE OF REVIEW: This article describes an approach to managing patients following a diagnosis of dementia, including medical management, nonpharmacologic strategies, safety interventions, caregiver support, mobilization of community resources, and advanced care planning.<br><br>RECENT FINDINGS: Dementia clinical syndromes are frequently caused by mixed pathologies, leading to varied clinical presentations that include memory loss, behavioral changes, communication challenges, safety concerns, and loss of independent function. Medications for treating dementia currently target cognitive and behavioral symptoms, although disease-modifying therapies for Alzheimer disease may be making their way into widespread clinical practice soon. Identification and treatment of co-occurring medical problems, such as obstructive sleep apnea, adverse medication effects, mood disorders, hearing loss, pain, alcohol misuse, and vascular risk factors, may mitigate the impact of these conditions on cognitive decline. Mobilization of clinical and community-based interprofessional teams will ensure that people with dementia and their care partners have the expertise, support, and access to resources they need. Addressing goals of care early in the disease course will allow people with dementia to contribute to their care plan by expressing their wishes.<br><br>SUMMARY: Developing a structured approach to treating common causes of dementia and related comorbid medical conditions, identifying a local network of interprofessional clinical and community-based referrals, and providing readily available educational resources will help clinicians provide quality dementia care management that extends beyond the clinic visit. Encouraging patients and families to engage in clinical research will advance the identification of effective therapies, preventive strategies, and quality care models for the future.}, }
@article {pmid35676734, year = {2022}, author = {Rejc, L and Gómez-Vallejo, V and Joya, A and Arsequell, G and Egimendia, A and Castellnou, P and Ríos-Anglada, X and Cossío, U and Baz, Z and Iglesias, L and Capetillo-Zarate, E and Ramos-Cabrer, P and Martin, A and Llop, J}, title = {Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography.}, journal = {Alzheimer's research &amp; therapy}, volume = {14}, number = {1}, pages = {80}, pmid = {35676734}, issn = {1758-9193}, support = {MDM-2017-0720//Agencia Estatal de Investigación/ ; PID2020-117656RB-100//Agencia Estatal de Investigación/ ; PID2020-117656RB-100//Agencia Estatal de Investigación/ ; MDM-2017-0720//Agencia Estatal de Investigación/ ; MDM-2017-0720//Agencia Estatal de Investigación/ ; MDM-2017-0720//Agencia Estatal de Investigación/ ; PID2020-117656RB-100//Agencia Estatal de Investigación/ ; PID2020-118546RB-I00//Agencia Estatal de Investigación/ ; RYC-2017-22412//Agencia Estatal de Investigación/ ; PID2020-117656RB-100//Agencia Estatal de Investigación/ ; 17/C/2017//Fundació la Marató de TV3/ ; 17/C/2017//Fundació la Marató de TV3/ ; CB06/0005/0076//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; IT1203-19//Eusko Jaurlaritza,Spain/ ; BIO18/IC/006//Eusko Jaurlaritza/ ; EAPA_791/2018//European Commission/ ; }, abstract = {BACKGROUND: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (xc-), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [18F]DPA-714 and [18F]FSPG for their ability to detect TSPO and xc- biomarkers, respectively, in the 5xFAD mouse model for AD.<br><br>METHODS: Expression of TSPO and xc- system was assessed longitudinally (2-12 months of age) on 5xFAD mice and their respective controls by positron emission tomography (PET) imaging using radioligands [18F]DPA-714 and [18F]FSPG. In parallel, in the same mice, amyloid-β plaque deposition was assessed with the amyloid PET radiotracer [18F]florbetaben. In vivo findings were correlated to ex vivo immunofluorescence staining of TSPO and xc- in microglia/macrophages and astrocytes on brain slices. Physiological changes of the brain tissue were assessed by magnetic resonance imaging (MRI) in 12-month-old mice.<br><br>RESULTS: PET studies showed a significant increase in the uptake of [18F]DPA-714 and [18F]FSPG in the cortex, hippocampus, and thalamus in 5xFAD but not in WT mice over time. The results correlate with Aβ plaque deposition. Ex vivo staining confirmed higher TSPO overexpression in both, microglia/macrophages and astrocytes, and overexpression of xc- in non-glial cells of 5xFAD mice. Additionally, the results show that Aβ plaques were surrounded by microglia/macrophages overexpressing TSPO. MRI studies showed significant tissue shrinkage and microstructural alterations in 5xFAD mice compared to controls.<br><br>CONCLUSIONS: TSPO and xc- overexpression can be assessed by [18F]DPA-714 and [18F]FSPG, respectively, and correlate with the level of Aβ plaque deposition obtained with a PET amyloid tracer. These results position the two tracers as promising imaging tools for the evaluation of disease progression. Longitudinal in vivo study in the 5xFAD mouse model shows that TSPO and oxidative stress assessment through [18F]DPA-714 and [18F]FSPG-PET imaging, respectively, could serve as a potential tool for the evaluation of Alzheimer disease progression.}, }
@article {pmid35669870, year = {2022}, author = {Somaa, FA and de Graaf, TA and Sack, AT}, title = {Transcranial Magnetic Stimulation in the Treatment of Neurological Diseases.}, journal = {Frontiers in neurology}, volume = {13}, number = {}, pages = {793253}, doi = {10.3389/fneur.2022.793253}, pmid = {35669870}, issn = {1664-2295}, abstract = {Transcranial Magnetic Stimulation (TMS) has widespread use in research and clinical application. For psychiatric applications, such as depression or OCD, repetitive TMS protocols (rTMS) are an established and globally applied treatment option. While promising, rTMS is not yet as common in treating neurological diseases, except for neurorehabilitation after (motor) stroke and neuropathic pain treatment. This may soon change. New clinical studies testing the potential of rTMS in various other neurological conditions appear at a rapid pace. This can prove challenging for both practitioners and clinical researchers. Although most of these neurological applications have not yet received the same level of scientific/empirical scrutiny as motor stroke and neuropathic pain, the results are encouraging, opening new doors for TMS in neurology. We here review the latest clinical evidence for rTMS in pioneering neurological applications including movement disorders, Alzheimer's disease/mild cognitive impairment, epilepsy, multiple sclerosis, and disorders of consciousness.}, }
@article {pmid35663962, year = {2022}, author = {Qin, Q and Wang, M and Yin, Y and Tang, Y}, title = {The Specific Mechanism of TREM2 Regulation of Synaptic Clearance in Alzheimer's Disease.}, journal = {Frontiers in immunology}, volume = {13}, number = {}, pages = {845897}, doi = {10.3389/fimmu.2022.845897}, pmid = {35663962}, issn = {1664-3224}, abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease. Synaptic dysfunction is an integral feature of AD pathophysiology and a significant factor in early cognitive impairment in AD. Microglia, which are intrinsic immune cells in the central nervous system, play important regulatory roles in the process of synapse formation. Microglia can refine synaptic connections through synaptic clearance to ensure accurate synaptic transmission. Synaptic clearance is not only existed during central nervous system development but also aberrantly activated during AD pathology. However, the mechanisms of synaptic clearance in AD remain to be investigated. TREM2 is involved in the synaptic clearance of microglia, acting alone or with other molecules, such as apolipoprotein E (APOE). In addition, C1q is essential for microglia-mediated synaptic clearance. In this review, we systematically summarized the potential mechanisms of microglia involved in synaptic clearance, comprehensively reviewed the role of TREM2 in microglia regulating synaptic clearance and proposed our hypothesis that TREM2 interacts with APOE and C1q to promote synaptic clearance. This review provides new insights into the role of TREM2 regulation in microglia synaptic clearance and provides potential prospects for the treatment of AD.}, }
@article {pmid35663575, year = {2022}, author = {Liu, XL and Ouyang, FB and Hu, LT and Sun, P and Yang, J and Sun, YJ and Liao, MS and Lan, LF and Pei, Z and Fan, YH}, title = {Mesenchymal Stem Cells Improve Cognitive Impairment and Reduce Aβ Deposition via Promoting AQP4 Polarity and Relieving Neuroinflammation in Rats With Chronic Hypertension-Induced Cerebral Small-Vessel Disease.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {883503}, doi = {10.3389/fnagi.2022.883503}, pmid = {35663575}, issn = {1663-4365}, abstract = {Cerebral small-vessel disease (CSVD) is the main cause of vascular cognitive impairment (VCI), and the accumulation of amyloid β-protein (Aβ) may be significantly involved in CSVD-induced VCI. The imbalance between Aβ production and clearance is believed to be an important pathological mechanism of Aβ deposition in Alzheimer disease. In this study, we aimed to disclose the roles of aquaporin 4 (AQP4) and neuroinflammation in CSVD, which were the key factors for Aβ clearance and production, respectively, and the effect of mesenchymal stem cells (MSCs) on Aβ deposition and these two factors. The stroke-prone renovascular hypertensive (RHRSP) rats were grouped and received MSC and MSC + AS1517499 (an inhibitor of pSTAT6). The latter was used to explore the underlying mechanism. The cognitive function, white matter lesions, Aβ expression, expression, and polarity of AQP4, neuroinflammation and the STAT6 pathway were investigated. Compared with sham-operated rats, RHRSP rats showed spatial cognitive impairment, white matter lesions and Aβ deposition. Moreover, AQP4 polarity disorder and neuroinflammatory activation were found, which were linked to Aβ deposition. Treatment with MSCs markedly improved cognitive tasks and reduced Aβ deposition but failed to reduce white-matter lesions. Furthermore, MSCs not only promoted AQP4 polarity but also alleviated neuroinflammation probably through the STAT6 pathway. The present study demonstrated that Aβ deposition, AQP4 polarity disorder and neuroinflammation might be involved in CSVD and the regulatory effects of MSCs on them suggested potential therapeutic value for CSVD.}, }
@article {pmid35657793, year = {2022}, author = {García Marín, ID and Camarillo López, RH and Martínez, OA and Padilla-Martínez, II and Correa-Basurto, J and Rosales-Hernández, MC}, title = {New compounds from heterocyclic amines scaffold with multitarget inhibitory activity on Aβ aggregation, AChE, and BACE1 in the Alzheimer disease.}, journal = {PloS one}, volume = {17}, number = {6}, pages = {e0269129}, doi = {10.1371/journal.pone.0269129}, pmid = {35657793}, issn = {1932-6203}, abstract = {The preset neurodegenerations in Alzheimer disease (AD) are due to several mechanisms such as amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, neurofibrillary tangles, cholinergic dysfunction, among others. The aim of this work was to develop multitarget molecules for the treatment of AD. Therefore, a family of 64 molecules was designed based on ligand structure pharmacophores able to inhibit the activity of beta secretase (BACE1) and acetylcholinesterase (AChE) as well as to avoid amyloid beta (Aβ1-42) oligomerization. The backbone of designed molecules consisted of a trisubstituted aromatic ring, one of the substituents was a heterocyclic amine (piperidine, morpholine, pyrrolidine or N-methyl pyrrolidine) separated from the aromatic system by three carbon atoms. The set of compounds was screened in silico employing molecular docking calculations and chemoinformatic analyses. Based on Gibbs free energy of binding, binding mode and in silico predicted toxicity results, three of the best candidates were selected, synthesized, and evaluated in vitro; F3S4-m, F2S4-m, and F2S4-p. All three compounds prevented Aβ1-42 aggregation (F3S4-m in 30.5%, F2S4-p in 42.1%, and F2S4-m in 60.9%). Additionally, inhibitory activity against AChE (ki 0.40 μM and 0.19 μM) and BACE1 (IC50 15.97 μM and 8.38 μM) was also observed for compounds F2S4-m and F3S4-m, respectively. Despite the BACE IC50 results demonstrated that all compounds are very less potent respect to peptidomimetic inhibitor (PI-IV IC50 3.20 nM), we can still say that F3S4-m is capable to inhibit AChE and BACE1.}, }
@article {pmid35657283, year = {2022}, author = {Malaiya, A and Singhai, M and Singh, M and Prajapati, SK and Choudhury, H and Fatima, M and Alexander, A and Dubey, SK and Greish, K and Kesharwani, P}, title = {Recent Update on the Alzheimer's Disease Progression, Diagnosis and Treatment Approaches.}, journal = {Current drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1389450123666220526155144}, pmid = {35657283}, issn = {1873-5592}, abstract = {Alzheimer's disease (AD) is a multifactorial, progressive, neurodegenerative disorder, manifested by the loss of memory and cognitive abilities, behavioral disturbance and progressive impairment of activities of daily life. The sharp rise in the number of AD patients has brought it with-in the top eight health issues in the world. It is associated with the distribution of misfolded aggre-gates of protein within the brain. However, Alois Alzheimer initially mentioned that the reduction in brain volume in AD might be associated with the "deposition of a special substance in the cortex". The resulting plaque found in extracellular space in the AD brain and hippocampus region, known as senile plaques, is the characteristic feature underlying Alzheimer's pathology, where the role of amy-loid-β (Aβ) peptide formation from proteolytic cleavage of amyloid precursor protein (APP) by secre-tase enzyme is eminent. Therefore, this review has highlighted the molecular pathophysiology of AD with a variety of available diagnostic and treatment strategies for the management of the disease, with a focus on the advancement toward clinical research to provide new effective and safe tool in the diagnosis, treatment or management of AD.}, }
@article {pmid35649652, year = {2022}, author = {Chapleau, M and Iaccarino, L and Soleimani-Meigooni, D and Rabinovici, GD}, title = {The Role of Amyloid PET in Imaging Neurodegenerative Disorders: A Review.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {63}, number = {Suppl 1}, pages = {13S-19S}, doi = {10.2967/jnumed.121.263195}, pmid = {35649652}, issn = {1535-5667}, abstract = {Imaging of amyloid deposition using PET has been available in research studies for 2 decades and has been approved for clinical use by the U.S. Food and Drug Administration, the European Medicines Agency, and other regulatory agencies around the world. Amyloid PET is a crucial tool for the diagnosis of Alzheimer disease, as it allows the noninvasive detection of amyloid plaques, a core neuropathologic feature that defines the disease. The clinical use of amyloid PET is expected to increase with recent accelerated approval in the United States of aducanumab, an antiamyloid monoclonal antibody, for the treatment of mild cognitive impairment and mild dementia due to Alzheimer disease. However, amyloid pathology can also be found in cognitively unimpaired older adults and in patients with other neurodegenerative disorders. The aim of this review is to provide an up-to-date overview of the application of amyloid PET in neurodegenerative diseases. We provide an in-depth analysis of the clinical, pathologic, and imaging correlates; a comparison with other available biomarkers; and a review of the application of amyloid PET in clinical trials and clinical utility studies.}, }
@article {pmid35649647, year = {2022}, author = {Groot, C and Villeneuve, S and Smith, R and Hansson, O and Ossenkoppele, R}, title = {Tau PET Imaging in Neurodegenerative Disorders.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {63}, number = {Suppl 1}, pages = {20S-26S}, doi = {10.2967/jnumed.121.263196}, pmid = {35649647}, issn = {1535-5667}, abstract = {The advent of PET ligands that bind tau pathology has enabled the quantification and visualization of tau pathology in aging and in Alzheimer disease (AD). There is strong evidence from neuropathologic studies that the most widely used tau PET tracers (i.e., 18F-flortaucipir, 18F-MK6240, 18F-RO948, and 18F-PI2620) bind tau aggregates formed in AD in the more advanced (i.e., ≥IV) Braak stages. However, tracer binding in most non-AD tauopathies is weaker and overlaps to a large extent with known off-target binding regions, limiting the quantification and visualization of non-AD tau pathology in vivo. Off-target binding is generally present in the substantia nigra, basal ganglia, pituitary, choroid plexus, longitudinal sinuses, meninges, or skull in a tracer-specific manner. Most cross-sectional studies use the inferior aspect of the cerebellar gray matter as a reference region, whereas for longitudinal analyses, an eroded white matter reference region is sometimes selected. No consensus has yet been reached on whether to use partial-volume correction of tau PET data. Although an increased neocortical tau PET signal is rare in cognitively unimpaired individuals, even in amyloid-β-positive cases, such a signal holds important prognostic information because preliminary data suggest that an elevated tau PET signal predicts cognitive decline over time. Also, in symptomatic stages of AD (i.e., mild cognitive impairment or AD dementia), tau PET shows great potential as a prognostic marker because an elevated baseline tau PET retention forecasts future cognitive decline and brain atrophy. For differential diagnostic use, the primary utility of tau PET is to differentiate AD dementia from other neurodegenerative diseases, as is in line with the conditions for the approval of 18F-flortaucipir by the U.S. Food and Drug Administration for clinical use. The differential diagnostic performance drops substantially at the mild-cognitive-impairment stage of AD, and there is no sufficient evidence for detection of sporadic non-AD primary tauopathies at the individual level for any of the currently available tau PET tracers. In conclusion, while the field is currently addressing outstanding methodologic issues, tau PET is gradually moving toward clinical application as a diagnostic and possibly prognostic marker in dementia expert centers and as a tool for selecting participants, assessing target engagement, and monitoring treatment effects in clinical trials.}, }
@article {pmid35648810, year = {2022}, author = {Spurrier, J and Nicholson, L and Fang, XT and Stoner, AJ and Toyonaga, T and Holden, D and Siegert, TR and Laird, W and Allnutt, MA and Chiasseu, M and Brody, AH and Takahashi, H and Nies, SH and Cañamás, AP and Sadasivam, P and Lee, S and Li, S and Zhang, L and Huang, YH and Carson, RE and Cai, Z and Strittmatter, SM}, title = {Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q.}, journal = {Science translational medicine}, volume = {14}, number = {647}, pages = {eabi8593}, doi = {10.1126/scitranslmed.abi8593}, pmid = {35648810}, issn = {1946-6242}, abstract = {Microglia-mediated synaptic loss contributes to the development of cognitive impairments in Alzheimer's disease (AD). However, the basis for this immune-mediated attack on synapses remains to be elucidated. Treatment with the metabotropic glutamate receptor 5 (mGluR5) silent allosteric modulator (SAM), BMS-984923, prevents β-amyloid oligomer-induced aberrant synaptic signaling while preserving physiological glutamate response. Here, we show that oral BMS-984923 effectively occupies brain mGluR5 sites visualized by [18F]FPEB positron emission tomography (PET) at doses shown to be safe in rodents and nonhuman primates. In aged mouse models of AD (APPswe/PS1ΔE9 overexpressing transgenic and AppNL-G-F/hMapt double knock-in), SAM treatment fully restored synaptic density as measured by [18F]SynVesT-1 PET for SV2A and by histology, and the therapeutic benefit persisted after drug washout. Phospho-TAU accumulation in double knock-in mice was also reduced by SAM treatment. Single-nuclei transcriptomics demonstrated that SAM treatment in both models normalized expression patterns to a far greater extent in neurons than glia. Last, treatment prevented synaptic localization of the complement component C1Q and synaptic engulfment in AD mice. Thus, selective modulation of mGluR5 reversed neuronal gene expression changes to protect synapses from damage by microglial mediators in rodents.}, }
@article {pmid35644025, year = {2022}, author = {Pereira, GRC and Gonçalves, LM and Abrahim-Vieira, BA and De Mesquita, JF}, title = {In silico analyses of acetylcholinesterase (AChE) and its genetic variants in interaction with the anti-Alzheimer drug Rivastigmine.}, journal = {Journal of cellular biochemistry}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcb.30277}, pmid = {35644025}, issn = {1097-4644}, support = {//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)/ ; //Financiadora de Estudos e Projetos (FINEP)/ ; //Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)/ ; //Universidade Federal do Estado do Rio de Janeiro/ ; //NVIDIA Corporation/ ; }, abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide. Despite causing great social and economic impact, there is currently no cure for AD. The most effective therapy to manage AD symptoms is based on acetylcholinesterase inhibitors (AChEi), from which rivastigmine presented numerous benefits. However, mutations in AChE, which affect approximately 5% of the population, can modify protein structure and function, changing the individual response to Alzheimer's treatment. In this study, we performed computer simulations of AChE wild type and variants R34Q, P135A, V333E, and H353N, identified by one or more genome-wide association studies, to evaluate their effects on protein structure and interaction with rivastigmine. The functional effects of AChE variants were predicted using eight machine learning algorithms, while the evolutionary conservation of AChE residues was analyzed using the ConSurf server. Autodock4.2.6 was used to predict the binding modes for the hAChE-rivastigmine complex, which is still unknown. Molecular dynamics (MD) simulations were performed in triplicates for the AChE wild type and mutants using the GROMACS packages. Among the analyzed variants, P135A was classified as deleterious by all the functional prediction algorithms, in addition to occurring at highly conserved positions, which may have harmful consequences on protein function. The molecular docking results suggested that rivastigmine interacts with hAChE at the upper active-site gorge, which was further confirmed by MD simulations. Our MD findings also suggested that the complex hAChE-rivastigmine remains stable over time. The essential dynamics revealed flexibility alterations at the active-site gorge upon mutations P135A, V333E, and H353N, which may lead to strong and nonintuitive consequences to hAChE binding. Nonetheless, similar binding affinities were registered in the MMPBSA analysis for the hAChE wild type and variants when complexed to rivastigmine. Finally, our findings indicated that the rivastigmine binding to hAChE is an energetically favorable process mainly driven by negatively charged amino acids.}, }
@article {pmid35643882, year = {2022}, author = {Djemil, S and Sames, AM and Pak, DTS}, title = {ACh Transfers: Homeostatic Plasticity of Cholinergic Synapses.}, journal = {Cellular and molecular neurobiology}, volume = {}, number = {}, pages = {}, pmid = {35643882}, issn = {1573-6830}, support = {R21AG066016/NH/NIH HHS/United States ; TL1TR001431/TR/NCATS NIH HHS/United States ; }, abstract = {The field of homeostatic plasticity continues to advance rapidly, highlighting the importance of stabilizing neuronal activity within functional limits in the context of numerous fundamental processes such as development, learning, and memory. Most homeostatic plasticity studies have been focused on glutamatergic synapses, while the rules that govern homeostatic regulation of other synapse types are less understood. While cholinergic synapses have emerged as a critical component in the etiology of mammalian neurodegenerative disease mechanisms, relatively few studies have been conducted on the homeostatic plasticity of such synapses, particularly in the mammalian nervous system. An exploration of homeostatic mechanisms at the cholinergic synapse may illuminate potential therapeutic targets for disease management and treatment. We will review cholinergic homeostatic plasticity in the mammalian neuromuscular junction, the autonomic nervous system, central synapses, and in relation to pathological conditions including Alzheimer disease and DYT1 dystonia. This work provides a historical context for the field of cholinergic homeostatic regulation by examining common themes, unique features, and outstanding questions associated with these distinct cholinergic synapse types and aims to inform future research in the field.}, }
@article {pmid35581440, year = {2022}, author = {Plowey, ED and Bussiere, T and Rajagovindan, R and Sebalusky, J and Hamann, S and von Hehn, C and Castrillo-Viguera, C and Sandrock, A and Budd Haeberlein, S and van Dyck, CH and Huttner, A}, title = {Alzheimer disease neuropathology in a patient previously treated with aducanumab.}, journal = {Acta neuropathologica}, volume = {}, number = {}, pages = {}, pmid = {35581440}, issn = {1432-0533}, support = {P30-AG066508/AG/NIA NIH HHS/United States ; P50-AG047270-01/AG/NIA NIH HHS/United States ; }, abstract = {Amyloid beta (Aβ) plaque is a defining pathologic feature of Alzheimer disease (AD). Aducanumab, a monoclonal IgG1 that selectively binds aggregated species of Aβ, has been shown by amyloid positron emission tomography (Amyloid PET) to reduce Aβ plaques in patients with prodromal and mild AD. This is the first autopsy report of the AD neuropathology in a patient previously treated with aducanumab. The patient was an 84-year-old woman who was randomized to the placebo arm of the PRIME Phase 1b study (221AD103). The patient progressed to moderate dementia (MMSE = 14/30), beyond the targeted early AD treatment stage, before receiving aducanumab in the long-term extension (LTE). The patient then received 32 monthly doses of aducanumab, titrated up to 6 mg/kg, for a cumulative dose of 186 mg/kg. In the LTE, Amyloid PET scans demonstrated robust Aβ plaque reduction, from a composite standard uptake value ratio (SUVR) of 1.5 at screening to < 1.1 at 56 weeks post-aducanumab dosing. MRI examinations were negative for amyloid-related imaging abnormalities (ARIA). She passed away in hospice care 4 months after her last dose of aducanumab. The postmortem neuropathologic examination confirmed AD neuropathologic changes. Aβ and IBA1 immunohistochemistry assays demonstrated sparse residual Aβ plaque engaged by amoeboid reactive microglia. Phospho-Tau (pTau) immunohistochemistry demonstrated neocortical neurofibrillary degeneration (Braak stage V, NIA/AA Stage B3). However, the density of pTau neuropathology, including neuritic plaque pTau (NP-Tau), appeared lower in the PRIME LTE Patient compared to a reference cohort of untreated Braak stage V-VI, NIA/AA Stage B3 AD cases. Taken together, this case report is the first to provide Amyloid PET and neuropathologic evidence substantiating the impact of aducanumab to reduce Aβ plaque neuropathology in a patient with AD. Furthermore, this report underscores the critical importance of autopsy neuropathology studies to augment our understanding of aducanumab's mechanism of action and impact on AD biomarkers.}, }
@article {pmid35638276, year = {2022}, author = {Ansari, B and Behl, T and Pirzada, AS and Khan, H}, title = {Caralluma edulis (Apocynaceae): A comprehensive review on its Traditional uses, Phytochemical profile and pharmacological effects.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/1568026622666220527092825}, pmid = {35638276}, issn = {1873-4294}, abstract = {Caralluma edulis is a well-known species of the genus Caralluma from Apocynaceae, commonly known as chunga. Caralluma species are mostly succulent perennial herbs, several of which are edible species. The plant has an outstanding therapeutic background in the traditional system of treatment. It has been recommended for the treatment of a number medical disorder such as hypertension, Alzheimer disease, rheumatism, gastric problems and leprosy. Traditionally the stem was boiled in water and this extract was then used to cure diabetes. The pharmacological effects of C.edulis have also been explored in various in vitro and in vivo experiments. In this regard, the extract of the plant exhibited strong antioxidant activity, analgesic, against inflammation as well as xylene mediated ear edema for topical effects. The significant anti-hyperlipidemic effect of the plant extract is also reported. However, the extract was found insignificant in the reversal of alloxan-induced diabetes in rabbit model at test doses. These pharmacological effects are strongly supported by the presence of different bioactive phytochemicals in the plant. These groups of compounds include sterols, terpenoids, flavonoids, and pregnane glycosides. C.edulis is a very potential member of the genus Caralluma with strong traditional history, phytochemistry and phytopharmacology, needed further exploration for clinically used lead compounds. In this review, we have focused to combined different reported data on the traditional uses of the plant, phytochemical profile and pharmacological effects in different experimental assay and subsequent future prospects.}, }
@article {pmid35636355, year = {2022}, author = {Turhan, G and Küçük, H and Isik, EO}, title = {Spatio-temporal convolution for classification of alzheimer disease and mild cognitive impairment.}, journal = {Computer methods and programs in biomedicine}, volume = {221}, number = {}, pages = {106825}, doi = {10.1016/j.cmpb.2022.106825}, pmid = {35636355}, issn = {1872-7565}, abstract = {BACKGROUND AND OBJECTIVE: Dementia refers to the loss of memory and other cognitive abilities. Alzheimer's disease (AD), which patients eventually die from, is the most common cause of dementia. In USA, %60 to %80 of dementia cases, are caused by AD. An estimate of 5.2 million people from all age groups have been diagnosed with AD in 2014. Mild cognitive impairment (MCI) is a preliminary stage of dementia with noticeable changes in patient's cognitive abilities. Individuals, who bear MCI symptoms, are prone to developing AD. Therefore, identification of MCI patients is very critical for a plausible treatment before it reaches to AD, the irreversible stage of this neurodegenerative disease.<br><br>METHODS: Development of machine learning algorithms have recently gained a significant pace in early diagnosis of Alzheimer's disease (AD). In this study, a (2+1)D convolutional neural network (CNN) architecture has been proposed to distinguish mild cognitive impairment (MCI) from AD, based on structural magnetic resonance imaging (MRI). MRI scans of AD and MCI subjects were procured from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. 507 scans of 223 AD patients and 507 scans of 204 MCI patients were obtained for the computational experiments.<br><br>RESULTS: The outcome and robustness of 2D convolutions, 3D convolutions and (2+1)D convolutions were compared. The CNN algorithms incorporated 2 to 6 convolutional layers, depending on the architecture, followed by 4 pooling layers and 3 fully connected layers. (2+1)D convolutional neural network model resulted in the best classification performance with 85% auc score, in addition to an almost two times faster convergence compared to classical 3D CNN methods.<br><br>CONCLUSIONS: Application of (2+1)D CNN algorithm to large datasets and deeper neural network models can provide a significant advantage in speed, due to its architecture handling images in spatial and temporal dimensions separately.}, }
@article {pmid35634646, year = {2022}, author = {Batawi, AH}, title = {Ginkgo biloba extract mitigates the neurotoxicity of AlCl3 in Alzheimer rat's model: Role of Apolipoprotein E4 and clusterin genes in stimulating ROS generation and apoptosis.}, journal = {The International journal of neuroscience}, volume = {}, number = {}, pages = {1-16}, doi = {10.1080/00207454.2022.2082968}, pmid = {35634646}, issn = {1563-5279}, abstract = {Purpose: Alzheimer's disease (AD) appears as a result of an increase in the accumulation of amyloid beta peptide (Aβ) and a decrease in neurotransmitters (Acetylcholine) within the brain cells which may be due to increase in acetylcholinesterase (AchE) activity and change in expression of Apolipoprotein E4 (ApoE4) and Clusterin (Clu) genes. The aim of the present study was using natural products such as Ginkgo biloba (G. biloba) extract that has the potential to reduce Aβ formation and increase AchE inhibition with its ability to save neuronal DNA from damage. Methods: Sixty male aged rats were divided into six experimental groups exposed to AlCl3 to induce AD model and were treated with G. biloba extract. Collected brain tissues were used to assess the apoptosis rate, reactive oxygen species (ROS) generation, AchE inhibitory activity, expression alteration in ApoE4 and Clu genes, DNA fragmentations and gutathione peroxidase (GPx) activity. Results: The results exhibited that rats exposed to AlCl3 increased significantly rate of apoptosis, ROS formation, DNA fragmentation, up-regulation of ApoE4 and Clu genes as well as decrease of AchE inhibitory activity and GPx activity compared with those in control rats. However, treatment of AlCl3-rats with G. biloba extract improved the above neurotoxicity results induced by AlCl3 exposure. Conclusion: It is therefore likely that G. biloba extract's protective properties against AD are due to its ability to activate the response against oxidative stress.}, }
@article {pmid35629325, year = {2022}, author = {Buchke, S and Sharma, M and Bora, A and Relekar, M and Bhanu, P and Kumar, J}, title = {Mitochondria-Targeted, Nanoparticle-Based Drug-Delivery Systems: Therapeutics for Mitochondrial Disorders.}, journal = {Life (Basel, Switzerland)}, volume = {12}, number = {5}, pages = {}, doi = {10.3390/life12050657}, pmid = {35629325}, issn = {2075-1729}, abstract = {Apart from ATP generation, mitochondria are involved in a wide range of functions, making them one of the most prominent organelles of the human cell. Mitochondrial dysfunction is involved in the pathophysiology of several diseases, such as cancer, neurodegenerative diseases, cardiovascular diseases, and metabolic disorders. This makes it a target for a variety of therapeutics for the diagnosis and treatment of these diseases. The use of nanoparticles to target mitochondria has significant importance in modern times because they provide promising ways to deliver drug payloads to the mitochondria by overcoming challenges, such as low solubility and poor bioavailability, and also resolve the issues of the poor biodistribution of drugs and pharmacokinetics with increased specificity. This review assesses nanoparticle-based drug-delivery systems, such as liposomes, DQAsome, MITO-Porters, micelles, polymeric and metal nanocarriers, as well as quantum dots, as mitochondria-targeted strategies and discusses them as a treatment for mitochondrial disorders.}, }
@article {pmid35628602, year = {2022}, author = {Russ, H and Mazzanti, M and Parsons, C and Riemann, K and Gebauer, A and Rammes, G}, title = {The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid β Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {10}, pages = {}, doi = {10.3390/ijms23105794}, pmid = {35628602}, issn = {1422-0067}, support = {The binding experiments, the pharmacokinetic studies, and the in vivo LTP studies have been financially supported by Merz Pharmaceuticals, Frankfurt.//Galimedix/ ; }, abstract = {Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer's disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients' brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.}, }
@article {pmid35621378, year = {2022}, author = {Tung, BT and Hang, TTT and Kim, NB and Nhung, NH and Linh, VK and Thu, DK}, title = {Molecular docking and molecular dynamics approach to identify potential compounds in Huperzia squarrosa for treating Alzheimer's disease.}, journal = {Journal of complementary &amp; integrative medicine}, volume = {}, number = {}, pages = {}, doi = {10.1515/jcim-2021-0462}, pmid = {35621378}, issn = {1553-3840}, abstract = {OBJECTIVES: Alzheimer's disease (AD) is a lingering progressive neurodegenerative disorder that causes patients to lose cognitive function. The enzyme Acetylcholinesterase (AChE), Butyrylcholinesterase (BuChE), Monoamine oxidase A (MAO A), Beta-secretase cleavage enzyme (BACE 1) and N-methyl-D-aspartate (NMDA) receptors play an important role in the pathogenesis of Alzheimer's disease. Therefore, inhibiting enzymes is an effective method to treat Alzheimer disease. In this study, we evaluated in silico inhibitory effects of AChE, BuChE, MAO A, BACE 1 and NMDA enzyme of Huperzia squarrosa's compounds.<br><br>METHODS: The three-dimensional (3D) of N-methyl-D-aspartate receptor (PDB ID: 1PBQ), enzyme β-secretase 1 (PDB ID: 4X7I), enzyme monoamine oxidase A (PDB ID: 2Z5X), enzyme butyrylcholinesterase (PDB ID: 4BDS) and enzyme acetylcholinesterase (PDB ID: 1EVE) were retrieved from the Protein Data Bank RCSB. Molecular docking was done by Autodock vina software and molecular dynamics (MD) simulation of the ligand-protein complex with the least binding energy pose was perfomed by MOE. Lipinski Rule of Five is used to compare compounds with drug-like and non-drug-like properties. Pharmacokinetic parameters of potential compounds were evaluated using the pkCSM tool.<br><br>RESULTS: Based on previous publication of Huperzia squarrosa, we have collected 15 compounds. In these compounds, huperzine B, huperzinine, lycoposerramine U N-oxide, 12-epilycodine N-oxide showed strongly inhibit the five AChE, BuChE, MAO A, BACE 1 and NMDA targets for Alzheimer's treatment. Lipinski rule of five and ADMET predict have shown that four above compounds have drug-likeness properties, good absorption ability and cross the blood-brain barrier, which have the most potential to become drugs for the treatment of Alzheimer's in the future. Furthermore, MD study showed that huperzine B and huperzinine have stability of the docking pose with NMDA target.<br><br>CONCLUSIONS: In this study, we found two natural compounds in Huperzia squarrosa including Huperzine B and Huperzinine have drug-likeness properties, good absorption ability and cross the blood-brain barrier, which have potential to become drugs for the treatment of Alzheimer's in the future.}, }
@article {pmid35609415, year = {2022}, author = {Zhang, JY and Ma, S and Liu, X and Du, Y and Zhu, X and Liu, Y and Wu, X}, title = {Activating transcription factor 6 regulates cystathionine to increase autophagy and restore memory in Alzheimer' s disease model mice.}, journal = {Biochemical and biophysical research communications}, volume = {615}, number = {}, pages = {109-115}, doi = {10.1016/j.bbrc.2022.05.053}, pmid = {35609415}, issn = {1090-2104}, abstract = {Endoplasmic reticulum stress (ER stress) plays a crucial role in the process of Alzheimer's disease (AD). Activating transcription factor 6 (ATF6) is a crucial sensor of ER stress. In AD patients, the homeostasis of the endogenous signal H2S produced by cystathionine γ-lyase (CTH) is in disbalance. However, the role of ATF6 and CTH in AD is rarely reported. Herein, we found that ATF6 and CTH were reduced in AD patients and APP/PS1 mice by immunohistochemistry and western blots. In LN229 and U87 MG cells, knockdown of ATF6 attenuated CTH expression, whereas overexpression of ATF6 resulted in upregulation of CTH. Brain-specific ATF6 knockout mice expressed significantly down-regulated CTH in the hippocampus and cortex compared to wild-type mice. Mechanistically, ATF6 and CTH increased H2S generation and autophagy-related proteins. Further we observed that CTH promoted the sulfhydration of αSNAP. This is probably to be the specific mechanism by which AFT6 promotes autophagy. Through in vivo studies, we found that αSNAP sulfhydration expression was significantly lower in ATF6 knockout mice than in wild-type mice. Decreased ATF6 impaired spatial memory retention, while addition of CTH rescued memory loss. Together, we demonstrate that ATF6 positively regulates the expression of CTH, which is closely related to the rescue of AD. Targeting the ATF6/CTH signal pathway may provide a new strategy for the treatment of AD.}, }
@article {pmid35596580, year = {2022}, author = {Neri, S and Mastroianni, G and Gardella, E and Aguglia, U and Rubboli, G}, title = {Epilepsy in neurodegenerative diseases.}, journal = {Epileptic disorders : international epilepsy journal with videotape}, volume = {24}, number = {2}, pages = {249-273}, doi = {10.1684/epd.2021.1406}, pmid = {35596580}, issn = {1950-6945}, abstract = {Although epilepsy as a comorbidity in neurodegenerative disorders is increasingly recognized, its incidence is still underestimated and the features of epilepsy in the different neurodegenerative conditions are still poorly defined. Improved health care, resulting in increased longevity, will unavoidably lead to an increment of epilepsy cases in the elderly. Thus, it is conceivable to expect that neurologists will have to deal with these comorbid conditions to a growing extent in the future. In this seminar, we provide an updated overview of the clinical features, pathophysiological mechanisms and diagnostic and treatment approaches of epilepsy in the most common neurodegenerative disorders (such as Alzheimer disease and other types of dementia, Parkinson disease, Down syndrome, prion diseases, and progressive myoclonus epilepsies), aiming to provide a tool that can help epileptologists and neurologists in the diagnosis and management of this increasingly reported comorbidity.}, }
@article {pmid35596040, year = {2022}, author = {El-Ganainy, SO and Soliman, OA and Ghazy, AA and Allam, M and Elbahnasi, AI and Mansour, AM and Gowayed, MA}, title = {Intranasal Oxytocin Attenuates Cognitive Impairment, β-Amyloid Burden and Tau Deposition in Female Rats with Alzheimer's Disease: Interplay of ERK1/2/GSK3β/Caspase-3.}, journal = {Neurochemical research}, volume = {}, number = {}, pages = {}, pmid = {35596040}, issn = {1573-6903}, abstract = {Oxytocin is a neuropeptide hormone that plays an important role in social bonding and behavior. Recent studies indicate that oxytocin could be involved in the regulation of neurological disorders. However, its role in modulating cognition in Alzheimer's disease (AD) has never been explored. Hence, the present study aims to investigate the potential of chronic intranasal oxytocin in halting memory impairment &amp; AD pathology in aluminum chloride-induced AD in female rats. Morris water maze was used to assess cognitive dysfunction in two-time points throughout the treatment period. In addition, neuroprotective effects of oxytocin were examined by assessing hippocampal acetylcholinesterase activity, β-amyloid 1-42 protein, and Tau levels. In addition, ERK1/2, GSK3β, and caspase-3 levels were assessed as chief neurobiochemical mediators in AD. Hippocampi histopathological changes were also evaluated. These findings were compared to the standard drug galantamine alone and combined with oxytocin. Results showed that oxytocin restored cognitive functions and improved animals' behavior in the Morris test. This was accompanied by a significant decline in acetylcholinesterase activity, 1-42 β-amyloid and Tau proteins levels. Hippocampal ERK1/2 and GSK3β were also reduced, exceeding galantamine effects, thus attenuating AD pathological hallmarks formation. Determination of caspase-3 revealed low cytoplasmic positivity, indicating the ceasing of neuronal death. Histopathological examination confirmed these findings, showing restored hippocampal cells structure. Combined galantamine and oxytocin treatment showed even better biochemical and histopathological profiles. It can be thus concluded that oxytocin possesses promising neuroprotective potential in AD mediated via restoring cognition and suppressing β-amyloid, Tau accumulation, and neuronal death.}, }
@article {pmid35595841, year = {2022}, author = {Beach, TG}, title = {A History of Senile Plaques: From Alzheimer to Amyloid Imaging.}, journal = {Journal of neuropathology and experimental neurology}, volume = {81}, number = {6}, pages = {387-413}, doi = {10.1093/jnen/nlac030}, pmid = {35595841}, issn = {1554-6578}, support = {//Civin Laboratory for Neuropathology/ ; P30 AG19610/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; //Arizona Department of Health Services/ ; //Arizona Biomedical Research Commission/ ; //Sun Health Foundation and the Michael J. Fox Foundation for Parkinson's Research/ ; }, abstract = {Senile plaques have been studied in postmortem brains for more than 120 years and the resultant knowledge has not only helped us understand the etiology and pathogenesis of Alzheimer disease (AD), but has also pointed to possible modes of prevention and treatment. Within the last 15 years, it has become possible to image plaques in living subjects. This is arguably the single greatest advance in AD research since the identification of the Aβ peptide as the major plaque constituent. The limitations and potentialities of amyloid imaging are still not completely clear but are perhaps best glimpsed through the perspective gained from the accumulated postmortem histological studies. The basic morphological classification of plaques into neuritic, cored and diffuse has been supplemented by sophisticated immunohistochemical and biochemical analyses and increasingly detailed mapping of plaque brain distribution. Changes in plaque classification and staging have in turn contributed to changes in the definition and diagnostic criteria for AD. All of this information continues to be tested by clinicopathological correlations and it is through the insights thereby gained that we will best be able to employ the powerful tool of amyloid imaging.}, }
@article {pmid35595404, year = {2022}, author = {Zúñiga Santamaría, T and Yescas Gómez, P and Fricke Galindo, I and González González, M and Ortega Vázquez, A and López López, M}, title = {Pharmacogenetic studies in Alzheimer disease.}, journal = {Neurologia (Barcelona, Spain)}, volume = {37}, number = {4}, pages = {287-303}, doi = {10.1016/j.nrleng.2018.03.022}, pmid = {35595404}, issn = {2173-5808}, abstract = {INTRODUCTION: Alzheimer disease (AD) is the most common cause of dementia and is considered one of the main causes of disability and dependence affecting quality of life in elderly people and their families. Current pharmacological treatment includes acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine; however, only one-third of patients respond to treatment. Genetic factors have been shown to play a role in this inter-individual variability in drug response.<br><br>DEVELOPMENT: We review pharmacogenetic reports of AD-modifying drugs, the pharmacogenetic biomarkers included, and the phenotypes evaluated. We also discuss relevant methodological considerations for the design of pharmacogenetic studies into AD. A total of 33 pharmacogenetic reports were found; the majority of these focused on the variability in response to and metabolism of donepezil. Most of the patients included were from Caucasian populations, although some studies also include Korean, Indian, and Brazilian patients. CYP2D6 and APOE are the most frequently studied biomarkers. The associations proposed are controversial.<br><br>CONCLUSIONS: Potential pharmacogenetic biomarkers for AD have been identified; however, it is still necessary to conduct further research into other populations and to identify new biomarkers. This information could assist in predicting patient response to these drugs and contribute to better treatment decision-making in a context as complex as ageing.}, }
@article {pmid35588964, year = {2022}, author = {Yener, G and Hünerli-Gündüz, D and Yıldırım, E and Aktürk, T and Başar-Eroğlu, C and Bonanni, L and Del Percio, C and Farina, F and Ferri, R and Güntekin, B and Hajós, M and Ibáñez, A and Jiang, Y and Lizio, R and Lopez, S and Noce, G and Parra, M and Randall, F and Stocchi, F and Babiloni, C}, title = {Treatment effects on event-related EEG potentials and oscillations in Alzheimer's disease.}, journal = {International journal of psychophysiology : official journal of the International Organization of Psychophysiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijpsycho.2022.05.008}, pmid = {35588964}, issn = {1872-7697}, abstract = {Alzheimer's disease dementia (ADD) is the most diffuse neurodegenerative disorder belonging to mild cognitive impairment (MCI) and dementia in old persons. This disease is provoked by an abnormal accumulation of amyloid-beta and tauopathy proteins in the brain. Very recently, the first disease-modifying drug has been licensed with reserve (i.e., Aducanumab). Therefore, there is a need to identify and use biomarkers probing the neurophysiological underpinnings of human cognitive functions to test the clinical efficacy of that drug. In this regard, event-related electroencephalographic potentials (ERPs) and oscillations (EROs) are promising candidates. Here, an Expert Panel from the Electrophysiology Professional Interest Area of the Alzheimer's Association and Global Brain Consortium reviewed the field literature on the effects of the most used symptomatic drug against ADD (i.e., Acetylcholinesterase inhibitors) on ERPs and EROs in ADD patients with MCI and dementia at the group level. The most convincing results were found in ADD patients. In those patients, Acetylcholinesterase inhibitors partially normalized ERP P300 peak latency and amplitude in oddball paradigms using visual stimuli. In these same paradigms, those drugs partially normalize ERO phase-locking at the theta band (4-7 Hz) and spectral coherence between electrode pairs at the gamma (around 40 Hz) band. These results are of great interest and may motivate multicentric, double-blind, randomized, and placebo-controlled clinical trials in MCI and ADD patients for final cross-validation.}, }
@article {pmid35585909, year = {2022}, author = {Park, KH and Jang, JW and Suh, J and Yi, S and Bae, JS and Lim, JS and Lee, H and Chin, J and Park, YH and Hong, YJ and Kim, GH and , }, title = {Executive Summary of the 2021 International Conference of Korean Dementia Association: A Report From the Academic Committee of the Korean Dementia Association.}, journal = {Dementia and neurocognitive disorders}, volume = {21}, number = {2}, pages = {45-58}, doi = {10.12779/dnd.2022.21.2.45}, pmid = {35585909}, issn = {2384-0757}, abstract = {Recently, aducanumab, a beta amyloid targeted immunotherapy, has been approved by the US Food and Drug Administration for the treatment of Alzheimer's dementia (AD). Although many questions need to be answered, this approval provides a promising hope for the development of AD drugs that could be supported by new biomarkers such as blood-based ones and composite neuropsychological tests that can confirm pathologic changes in early stages of AD. It is important to elucidate the complexity of AD which is known to be associated with other factors such as vascular etiologies and neuro-inflammation. Through the second international conference of the Korean Dementia Association (KDA), researchers from all over the world have participated in the exchange of opinions with KDA members on the most up-to-date topics. The Academic Committee of the KDA summarizes lectures to provide the depth of the conference as well as discussions. This will be an important milestone to widen the latest knowledge in the research of AD's diagnosis, therapeutics, pathogenesis that can lead to the establishment of future directions.}, }
@article {pmid35585820, year = {2022}, author = {R, M and M, S and V, C}, title = {The Involvement of Melatonin and Tasimelteon against Alzheimer's Disease.}, journal = {Current drug safety}, volume = {}, number = {}, pages = {}, doi = {10.2174/1574886317666220517125644}, pmid = {35585820}, issn = {2212-3911}, abstract = {BACKGROUND: Alzheimer's disease is an age-dependent neurodegenerative disease with a progressive cognition and memory loss, insomnia and other abnormal behavioral changes. Amongst various hypothesis for the AD pathophysiology, the occupational stress-induced Alzheimer's has recently caught up an escalation in AD cases.<br><br>OBJECTIVE: Studies pertaining to the same suggests that stress leads to insomnia or sleep disruption, which further leads to neuroinflammation cum oxidative stress, both of which are major harbingers towards AD. Additionally, overall sleep deficit is associated with a progressive cognitive and memory decline, which adds more inconvenience to Alzheimer's disease. Based on this, any triumphant AD management needs a pharmacological intervention that can not only antagonize the amyloid beta induced neurotoxicity but also correct the sleep-wake cycle disruption. Chronobiotic therapeutics like melatonin offer vital neuroprotective effects by eliciting its action through more than one of the pathologies of AD. This is also bolstered by the finding that endogenous melatonin levels are lower in AD patients. This melatonin replacement therapy can be especially useful in AD treatment, but only in the early phases of the disease and in cases where the melatonin receptors are intact and functioning.<br><br>CONCLUSION: To negate such limitations, and to extend the action and therapeutic efficacy of melatonin-mediated actions towards AD treatment, melatonin analogue like Tasimelteon can pose a high therapeutic value in AD treatment superior to that provided by melatonin. This review encapsulates all details about how AD is believed to occur, how current situations influence it along with how melatonin and Tasimelteon act towards treating Alzheimer's.}, }
@article {pmid35579487, year = {2022}, author = {Nagai, Y and Yamazaki, T and Sugita, T and Shibata, N}, title = {Brexpiprazole-Associated Pisa Syndrome (Pleurothotonus) in a Patient With Dementia.}, journal = {Clinical neuropharmacology}, volume = {45}, number = {3}, pages = {72-73}, doi = {10.1097/WNF.0000000000000500}, pmid = {35579487}, issn = {1537-162X}, abstract = {OBJECTIVES: The aims of the study were to report brexpiprazole-induced Pisa syndrome (PS) in a patient with Alzheimer disease and to discuss the pathophysiology and the treatment of PS.<br><br>METHODS: We report a 71-year-old female patient with Alzheimer disease. After 2 months medication of brexpiprazole, she presented PS. By switching to quetiapine, the symptom was ameliorated; however, transient acute dystonia was occurred.<br><br>CONCLUSIONS: Drug-induced PS may be associated with dopamine-acetylcholine imbalance. This imbalance causes the dysfunction of the cortex and basal ganglia and the dysfunction of sensory and somatosensory system. Stopping the offending drugs is a choice for the treatment of PS. This is the first report of PS-induced brexpiprazole.}, }
@article {pmid35576219, year = {2022}, author = {Andrade, JM and Pachar, P and Trujillo, L and Cartuche, L}, title = {Suillin: A mixed-type acetylcholinesterase inhibitor from Suillus luteus which is used by Saraguros indigenous, southern Ecuador.}, journal = {PloS one}, volume = {17}, number = {5}, pages = {e0268292}, doi = {10.1371/journal.pone.0268292}, pmid = {35576219}, issn = {1932-6203}, abstract = {Suillus luteus (L.) Roussel is an edible mushroom commonly known as slippery jack or "Kallampa" by indigenous people from Loja province. It is used in traditional medicine to manage gastrointestinal disorders and headaches. In addition, edible mushrooms have been used for neurodegenerative diseases; however, there is no report about the anticholinesterase effect produced by this species. The aim of this work was to isolate the main secondary metabolite of Suillus luteus and characterize its inhibitory potential against acetylcholinesterase. Fruiting bodies were extracted with ethanol (EtOH) and ethyl acetate (EtOAc). From the EtOAc, suillin, is reported as the major compound. The cholinesterase inhibitory potential of extracts and the major isolated compound was assessed by Ellman´s method and progression curves were recorded at 405 nm for 60 min. Donepezil hydroclhoride was used as a positive control. The samples were dissolved in methanol at 10 mg/mL and two more 10× dilutions were included to obtain final concentrations of 1, 0.1 and 0.01 mg/mL at the mix of reaction. IC50, Km, Vmax, and Ki were calculated for suillin. Suillin (200 mg) along with linoleic acid, ergosterol peroxide and ergosterol were isolated. The EtOH and EtOAc extracts exerted a moderate inhibitory effect (IC50 > 200 μg/mL. In adittion, suillin exerted a non-competitive mixed mechanism. against AChE with an IC50 value of 31.50 μM and Ki of 17.25 μM. To the best of our knowledge, this is the first report of the anticholinesterase effect of Suillus luteus and suillin. The kinetic parameters and the moderate potency of the compound determined in this study, encourage us to propose suillin as a promising chemopreventing agent for the treatment of neurodegenerative diseases such as Alzheimer.}, }
@article {pmid35572832, year = {2022}, author = {Shang, Q and Zhang, Q and Liu, X and Zhu, L}, title = {Prediction of Early Alzheimer Disease by Hippocampal Volume Changes under Machine Learning Algorithm.}, journal = {Computational and mathematical methods in medicine}, volume = {2022}, number = {}, pages = {3144035}, doi = {10.1155/2022/3144035}, pmid = {35572832}, issn = {1748-6718}, abstract = {This research was aimed at discussing the application value of different machine learning algorithms in the prediction of early Alzheimer's disease (AD), which was based on hippocampal volume changes in magnetic resonance imaging (MRI). In the research, the 84 cases in American Alzheimer's disease neuroimaging initiative (ADNI) database were selected as the research data. Based on the scoring results of cognitive function, all cases were divided into three groups, including cognitive function normal (normal group), early mild cognitive impairment (e-MCI group), and later mild cognitive impairment (l-MCI group) groups. Each group included 28 cases. The features of hippocampal volume changes in MRI images of the patients in different groups were extracted. The samples of training set and test set were established. Besides, the established support vector machine (SVM), decision tree (DT), and random forest (RF) prediction models were used to predict e-MCI. Metalinear regression was utilized to analyze MRI feature data, and the predictive accuracy, sensitivity, and specificity of different models were calculated. The result showed that the volumes of hippocampal left CA1, left CA2-3, left CA4-DG, left presubiculum, left tail, right CA2-3, right CA4-DG, right presubiculum, and right tail in e-MCI group were all smaller than those in normal group (P < 0.01). The corresponding volume of hippocampal subregions in l-MCI group was remarkably reduced compared with that in normal group (P < 0.001). The volumes of regions left CA1, left CA2-3, left CA4-DG, right CA2-3, right CA4-DG, and right presubiculum were all positively correlated with logical memory test-delay recall (LMT-DR) score (R 2 = 0.1702, 0.3779, 0.1607, 0.1620, 0.0426, and 0.1309; P < 0.001). The predictive accuracy of training set sample by DT, SVM, and RF was 86.67%, 93.33%, and 98.33%, respectively. Based on the changes in the volumes of left CA4-DG, right CA2-3, and right CA4-DG, the predictive accuracy of e-MCI and l-MCI by RF model was both higher than those by DT model (P < 0.01). Besides, the predictive accuracy, sensitivity, and specificity of e-MCI by RF model was all notably higher than those by DT model (P < 0.01). The above results demonstrated that the effective early AD prediction models were established by the volume changes in hippocampal subregions, which was based on RF in the research. The establishment of early AD prediction models offered certain reference basis to the diagnosis and treatment of AD patients.}, }
@article {pmid35571129, year = {2022}, author = {Lacroix, C and Alleman-Brimault, I and Zalta, A and Rouby, F and Cassé-Perrot, C and Jouve, E and Attolini, L and Guilhaumou, R and Micallef, J and Blin, O}, title = {What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {883987}, doi = {10.3389/fphar.2022.883987}, pmid = {35571129}, issn = {1663-9812}, abstract = {Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes. Some show benefits on motor symptoms and others on non-motor symptoms and quality of life. Concerning patients' view, several web surveys were collected, highlighting the real use of cannabis to relieve symptoms of neurological disorders, mostly outside a medical pathway. This anarchic use keeps questioning particularly in terms of risks: consumption of street cannabis, drug-drug interactions with usual medical treatment, consideration of medical history, and adverse reactions (psychiatric, respiratory, cardiovascular disorders, etc.), underlining the importance of a medical supervision. To date, most scientific data support the therapeutic potential of cannabis in neurological disorders. As far as patients and patients' associations are calling for it, there is an urgent need to manage clinical studies to provide stronger evidence and secure medical cannabis use.}, }
@article {pmid35565661, year = {2022}, author = {Esselun, C and Dieter, F and Sus, N and Frank, J and Eckert, GP}, title = {Walnut Oil Reduces Aβ Levels and Increases Neurite Length in a Cellular Model of Early Alzheimer Disease.}, journal = {Nutrients}, volume = {14}, number = {9}, pages = {}, doi = {10.3390/nu14091694}, pmid = {35565661}, issn = {2072-6643}, support = {62500262//California Walnut Commission/ ; }, abstract = {(1) Background: Mitochondria are the cells' main source of energy. Mitochondrial dysfunction represents a key hallmark of aging and is linked to the development of Alzheimer's disease (AD). Maintaining mitochondrial function might contribute to healthy aging and the prevention of AD. The Mediterranean diet, including walnuts, seems to prevent age-related neurodegeneration. Walnuts are a rich source of α-linolenic acid (ALA), an essential n3-fatty acid and the precursor for n3-long-chain polyunsaturated fatty acids (n3-PUFA), which might potentially improve mitochondrial function. (2) Methods: We tested whether a lipophilic walnut extract (WE) affects mitochondrial function and other parameters in human SH-SY5Y cells transfected with the neuronal amyloid precursor protein (APP695). Walnut lipids were extracted using a Soxhlet Extraction System and analyzed using GC/MS and HPLC/FD. Adenosine triphosphate (ATP) concentrations were quantified under basal conditions in cell culture, as well as after rotenone-induced stress. Neurite outgrowth was investigated, as well as membrane integrity, cellular reactive oxygen species, cellular peroxidase activity, and citrate synthase activity. Beta-amyloid (Aβ) was quantified using homogenous time-resolved fluorescence. (3) Results: The main constituents of WE are linoleic acid, oleic acid, α-linolenic acid, and γ- and δ-tocopherol. Basal ATP levels following rotenone treatment, as well as citrate synthase activity, were increased after WE treatment. WE significantly increased cellular reactive oxygen species but lowered peroxidase activity. Membrane integrity was not affected. Furthermore, WE treatment reduced Aβ1-40 and stimulated neurite growth. (4) Conclusions: WE might increase ATP production after induction of mitochondrial biogenesis. Decreased Aβ1-40 formation and enhanced ATP levels might enhance neurite growth, making WE a potential agent to enhance neuronal function and to prevent the development of AD. In this sense, WE could be a promising agent for the prevention of AD.}, }
@article {pmid35563031, year = {2022}, author = {Michailidis, M and Tata, DA and Moraitou, D and Kavvadas, D and Karachrysafi, S and Papamitsou, T and Vareltzis, P and Papaliagkas, V}, title = {Antidiabetic Drugs in the Treatment of Alzheimer's Disease.}, journal = {International journal of molecular sciences}, volume = {23}, number = {9}, pages = {}, doi = {10.3390/ijms23094641}, pmid = {35563031}, issn = {1422-0067}, abstract = {The public health burden of type 2 diabetes mellitus and Alzheimer's disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in patients with type 2 diabetes mellitus. Therefore, in recent years, there has been a substantial interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in Alzheimer's disease. Human studies in patients with mild cognitive impairment and Alzheimer's disease have shown that administration of some antidiabetic medications, such as intranasal insulin, metformin, incretins, and thiazolidinediones, can improve cognition and memory. This review aims to examine the latest evidence on antidiabetic medications as a potential candidate for the treatment of Alzheimer's disease.}, }
@article {pmid35553375, year = {2022}, author = {Pradhan, LK and Sahoo, PK and Chauhan, S and Das, SK}, title = {Recent Advances Towards Diagnosis and Therapeutic Fingerprinting for Alzheimer's Disease.}, journal = {Journal of molecular neuroscience : MN}, volume = {}, number = {}, pages = {}, pmid = {35553375}, issn = {1559-1166}, support = {5/4-5/3/04/DHR/Neuro/206//2020-NCD-I dated 4th January 2022//Indian Council of Medical Research/ ; 5/4-5/3/04/DHR/Neuro/206//2020-NCD-I dated 4th January 2022//Indian Council of Medical Research/ ; }, abstract = {Since the report of "a peculiar severe disease process of the cerebral cortex" by Alois Alzheimer in 1906, it was considered to be a rare condition characterized by loss of cognition, memory impairment, and pathological markers such as senile plaques or neurofibrillary tangles (NFTs). Later on, the report was published in the textbook "Psychiatrie" and the disease was named as Alzheimer's disease (AD) and was known to be the consequences of aging; however, owing to its complex etiology, there is no cure for the progressive neurodegenerative disorder. Our current understanding of the mechanisms involved in the pathogenesis of AD is still at the mechanistic level. The treatment strategies applied currently only alleviate the symptoms and co-morbidities. For instance, the available treatments such as the usage of acetylcholinesterase inhibitors and N-methyl D-aspartate antagonists have minimal impact on the disease progression and target the later aspects of the disease. The recent advancements in the last two decades have made us more clearly understand the pathophysiology of the disease which has led to the development of novel therapeutic strategies. This review gives a brief idea about the various facets of AD pathophysiology and its management through modern investigational therapies to give a new direction for development of targeted therapeutic measures.}, }
@article {pmid35552815, year = {2022}, author = {Yang, SY and He, XY and Dobkin, C and Brown, WT}, title = {Infantile Neurodegeneration results from Mutants of 17β-Hydroxysteroid Dehydrogenase Type 10 rather than Aβ-Binding Alcohol Dehydrogenase.}, journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology}, volume = {36 Suppl 1}, number = {}, pages = {}, doi = {10.1096/fasebj.2022.36.S1.R3674}, pmid = {35552815}, issn = {1530-6860}, abstract = {Type 10 17β-hydroxysteroid dehydrogenase (17β-HSD10), a mitochondrial homo-tetrameric multifunctional protein encoded by the HSD17B10 gene is necessary for brain cognitive function. Missense mutations on this gene resulted in HSD10 mitochondrial disease, an inborn error in isoleucine metabolism. A 5-methylcytosine hotspot in this gene underlying a 388C ̵T transition leads to the HSD10(p.R130C) mutant responsible for about half cases of infantile neurodegeneration. Less females suffers with this disease and usually has milder clinical manifestation due to the X-inactivation. The binding capability of this dehydrogenase to Aβ-peptide may play a role in senile neurodegeneration, namely Alzheimer disease, but it appears unrelated to infantile neurodegeneration. Unfortunately, this research field has been interfered by reports of the Aβ-peptide binding alcohol dehydrogenase (ABAD) or endoplasmic reticulum-associated Aβ binding protein (ERAB). Both reflect some dubious features of 17β-HSD10. It is clarified here that ERAB is merely a subunit of 17β-HSD10, having a fictitious association with the endoplasmic reticulum. 17β-HSD10 exhibits L-3-hydroxyacyl-CoA dehydrogenase activity so also known as short chain 3-hydorxyacyl-CoA dehydrogenase (SCHAD), but it is not involved in the ketone body metabolism as reported for ABAD's function in the cellular response to nutritional stress. Furthermore, the reported generalized alcohol dehydrogenase data underlying the ABAD activity could not be based upon valid reproducible experiments, and the rediscovery of its mitochondrial localization was preceded by unreferenced 17β-HSD10 research. Clarification of unreliable ABAD/ERAB data may invigorate this research field, and open new approaches to the understanding and treatment of the HSD17B10gene related disorders including infantile neurodegeneration and Alzheimer's disease.}, }
@article {pmid35543643, year = {2022}, author = {Burkett, BJ and Babcock, JC and Lowe, VJ and Graff-Radford, J and Subramaniam, RM and Johnson, DR}, title = {PET Imaging of Dementia: Update 2022.}, journal = {Clinical nuclear medicine}, volume = {}, number = {}, pages = {}, doi = {10.1097/RLU.0000000000004251}, pmid = {35543643}, issn = {1536-0229}, abstract = {ABSTRACT: PET imaging plays an essential role in achieving earlier and more specific diagnoses of dementia syndromes, important for clinical prognostication and optimal medical management. This has become especially vital with the recent development of pathology-specific disease-modifying therapy for Alzheimer disease, which will continue to evolve and require methods to select appropriate treatment candidates. Techniques that began as research tools such as amyloid and tau PET have now entered clinical use, making nuclear medicine physicians and radiologists essential members of the care team. This review discusses recent changes in the understanding of dementia and examines the roles of nuclear medicine imaging in clinical practice. Within this framework, multiple cases will be shown to illustrate a systematic approach of FDG PET interpretation and integration of PET imaging of specific molecular pathology including dopamine transporters, amyloid, and tau. The approach presented here incorporates contemporary understanding of both common and uncommon dementia syndromes, intended as an updated practical guide to assist with the sophisticated interpretation of nuclear medicine examinations in the context of this rapidly and continually developing area of imaging.}, }
@article {pmid35543641, year = {2022}, author = {Wassef, HR and Colletti, PM}, title = {Commentary: Aducanumab-Related ARIA: Paean or Lament?.}, journal = {Clinical nuclear medicine}, volume = {}, number = {}, pages = {}, pmid = {35543641}, issn = {1536-0229}, abstract = {ABSTRACT: Høilund-Carlsen and colleagues raise important issues related to amyloid PET, diagnosis of Alzheimer disease, and recently approved antiamyloid treatment aducanumab. We discuss new developments that may direct us to methods of presymptomatic detection of Alzheimer disease and development of effective prevention and therapy.}, }
@article {pmid35543009, year = {2022}, author = {Ritchie, CW and Waymont, JMJ and Pennington, C and Draper, K and Borthwick, A and Fullerton, N and Chantler, M and Porteous, ME and Danso, SO and Green, A and McWhirter, L and Muniz Terrera, G and Simpson, S and Thompson, G and Trépel, D and Quinn, TJ and Kilgour, A}, title = {The Scottish Brain Health Service Model: Rationale and Scientific Basis for a National Care Pathway of Brain Health Services in Scotland.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {9}, number = {2}, pages = {348-358}, doi = {10.14283/jpad.2021.63}, pmid = {35543009}, issn = {2426-0266}, abstract = {In order to address the oft-cited societal, economic, and health and social care impacts of neurodegenerative diseases, such as Alzheimer's disease, we must move decisively from reactive to proactive clinical practice and to embed evidence-based brain health education throughout society. Most disease processes can be at least partially prevented, slowed, or reversed. We have long neglected to intervene in neurodegenerative disease processes, largely due to a misconception that their predominant symptom - cognitive decline - is a normal, age-related process, but also due to a lack of multi-disciplinary collaboration. We now understand that there are modifiable risk factors for neurodegenerative diseases, that successful management of common comorbidities (such as diabetes and hypertension) can reduce the incidence of neurodegenerative disease, and that disease processes begin (and, crucially, can be detected, reduced, and delayed, prevented, or treated) decades earlier in life than had previously been appreciated. Brain Health Scotland, established by Scottish Government and working in partnership with Alzheimer Scotland, propose far-reaching public health and clinical practice approaches to reduce neurodegenerative disease incidence. Focusing here on Brain Health Scotland's clinical offerings, we present the Scottish Model for Brain Health Services. To our knowledge, the Scottish Model for Brain Health, built on foundations of personalised risk profiling, targeted risk reduction and prevention, early disease detection, equity of access, and harnessing comprehensive data to assist in clinical decision-making, marks the first example of a nationwide approach to overhauling clinical, societal, and political approaches to the prevention, assessment, and treatment of neurodegenerative disease.}, }
@article {pmid35543002, year = {2022}, author = {Lewis, CK and Bernstein, OM and Grill, JD and Gillen, DL and Sultzer, DL}, title = {Anxiety and Depressive Symptoms and Cortical Amyloid-β Burden in Cognitively Unimpaired Older Adults.}, journal = {The journal of prevention of Alzheimer's disease}, volume = {9}, number = {2}, pages = {286-296}, doi = {10.14283/jpad.2022.13}, pmid = {35543002}, issn = {2426-0266}, abstract = {BACKGROUND: There is evidence of relationships between behavioral symptoms and increased risk for Alzheimer's Disease and/or Alzheimer's Disease biomarkers. However, the nature of this relationship is currently unknown.<br><br>OBJECTIVES: To evaluate the relationship between anxiety and depressive symptoms and amyloid-β deposition in cognitively unimpaired older adults, and to assess mediating effects of either objective or subjective cognitive skills.<br><br>DESIGN: Cross-sectional analysis of screening data from participants enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study (ClinicalTrials.gov Identifier: NCT02008357).<br><br>SETTING: Data analysis.<br><br>PARTICIPANTS: 4492 cognitively unimpaired adults, age 65-85, enrolled in the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study.<br><br>MEASUREMENTS: We used linear regression to estimate the associations between amyloid-β standard uptake value ratio (SUVR) and Geriatric Depression Scale (GDS) and State Trait Anxiety Inventory (STAI) scores while adjusting for potential confounding factors as well as for Cognitive Function Index (CFI) or Preclinical Alzheimer's Cognitive Composite (PACC) scores as possible mediational variables.<br><br>RESULTS: 4399 subjects with complete covariates were included (mean age: 71.3, 59% female), GDS ranged 0-13 (mean: 1.0), and STAI ranged 6-24 (mean: 9.9). Amyloid-β SUVR was modestly associated with STAI; mean STAI score was estimated to be 0.275 points higher (95% CI: 0.038, 0.526; p-value = 0.023) for each 0.5-point increase in cortical amyloid-β SUVR. Subjective cognitive decline (CFI) attenuated the relationship between SUVR and STAI, while objective cognitive function (PACC) did not. No statistically significant relationship between SUVR and GDS was observed (p = 0.326).<br><br>CONCLUSIONS: In cognitively unimpaired adults with low levels of depression and anxiety, cortical amyloid-β deposition is associated with anxiety but not depressive symptoms. Attenuation of this relationship by subjective cognitive difficulties suggests that anxiety may be partly due to such a perception resulting from cortical amyloid-β deposition.}, }
@article {pmid35533333, year = {2022}, author = {Yuan, A and Lee, CS}, title = {Retinal Biomarkers for Alzheimer Disease: The Facts and the Future.}, journal = {Asia-Pacific journal of ophthalmology (Philadelphia, Pa.)}, volume = {11}, number = {2}, pages = {140-148}, pmid = {35533333}, issn = {2162-0989}, abstract = {ABSTRACT: Alzheimer disease (AD) is a significant cause of morbidity and mortality worldwide, with limited treatment options and considerable diagnostic challenges. Identification and validation of retinal changes that correlate with clinicopathologic features of AD could provide a noninvasive method of screening and monitoring progression of disease, with notable implications for developing new therapies, particularly in its preclinical stages. Retinal biomarkers that have been studied to date include structural changes in neurosensory retinal layers, alterations in vascular architecture and function, and pathologic deposition of proteins within the retina, which have all demonstrated variable correlation with the presence of preclinical or clinical AD. Evolution of specialized retinal imaging modalities and advances in artificial intelligence hold great promise for future study in this burgeoning field. The current status of research in retinal biomarkers, and some of the challenges that will need to be addressed in future work, are reviewed herein.}, }
@article {pmid35532913, year = {2022}, author = {Rafii, MS and Sol, O and Mobley, WC and Delpretti, S and Skotko, BG and Burke, AD and Sabbagh, MN and Yuan, SH and Rissman, RA and Pulsifer, M and Evans, C and Evans, AC and Beth, G and Fournier, N and Gray, JA and Dos Santos, AM and Hliva, V and Vukicevic, M and Kosco-Vilbois, M and Streffer, J and Pfeifer, A and Feldman, HH}, title = {Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2022.0983}, pmid = {35532913}, issn = {2168-6157}, abstract = {Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-β (Aβ). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aβ pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined.<br><br>Objective: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aβ immunoglobulin G titers.<br><br>This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up.<br><br>Interventions: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 μg or 1000 μg, or placebo.<br><br>Main Outcomes and Measures: Primary outcomes were measures of safety and tolerability as well as antibody titers.<br><br>Results: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aβ immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 μg and 2 receiving 1000 μg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aβ1-40 and Aβ1-42 levels among individuals receiving ACI-24.<br><br>Conclusions and Relevance: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aβ antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02738450.}, }
@article {pmid35530176, year = {2022}, author = {Revuelta, M and Urrutia, J and Villarroel, A and Casis, O}, title = {Microglia-Mediated Inflammation and Neural Stem Cell Differentiation in Alzheimer's Disease: Possible Therapeutic Role of KV1.3 Channel Blockade.}, journal = {Frontiers in cellular neuroscience}, volume = {16}, number = {}, pages = {868842}, doi = {10.3389/fncel.2022.868842}, pmid = {35530176}, issn = {1662-5102}, abstract = {Increase of deposits of amyloid β peptides in the extracellular matrix is landmark during Alzheimer's Disease (AD) due to the imbalance in the production vs. clearance. This accumulation of amyloid β deposits triggers microglial activation. Microglia plays a dual role in AD, a protective role by clearing the deposits of amyloid β peptides increasing the phagocytic response (CD163, IGF-1 or BDNF) and a cytotoxic role, releasing free radicals (ROS or NO) and proinflammatory cytokines (TNF-α, IL-1β) in response to reactive gliosis activated by the amyloid β aggregates. Microglia activation correlated with an increase KV1.3 channels expression, protein levels and current density. Several studies highlight the importance of KV1.3 in the activation of inflammatory response and inhibition of neural progenitor cell proliferation and neuronal differentiation. However, little is known about the pathways of this activation in neural stem cells differentiation and proliferation and the role in amyloid β accumulation. In recent studies using in vitro cells derived from mice models, it has been demonstrated that KV1.3 blockers inhibit microglia-mediated neurotoxicity in culture reducing the expression and production of the pro-inflammatory cytokines IL-1β and TNF-α through the NF-kB and p38MAPK pathway. Overall, we conclude that KV1.3 blockers change the course of AD development, reducing microglial cytotoxic activation and increasing neural stem cell differentiation. However, further investigations are needed to establish the specific pathway and to validate the use of this blocker as therapeutic treatment in Alzheimer patients.}, }
@article {pmid35525893, year = {2022}, author = {Shabbir, A and Rehman, K and Akash, MSH and Akbar, M and Chaudhary, Z and Panichayupakaranant, P and Shah, MA}, title = {Differential neuroprotective effect of curcuminoid formulations in aluminum chloride-induced Alzheimer's disease.}, journal = {Environmental science and pollution research international}, volume = {}, number = {}, pages = {}, pmid = {35525893}, issn = {1614-7499}, abstract = {Alzheimer's disease (AD) is a slowly progressive brain degenerative disorder which gradually impairs memory, thinking, and ability to perform easy routine tasks. This degenerative disorder mainly targets the elderly people and has imposed an endemic burden on society. Hence, there is a crucial need to investigate the efficacious herbal pharmacotherapies that can effectively mitigate and prevent the pathological hallmarks of AD. The current study aims to explore the potential efficacy of curcuminoid-rich extract (CRE) and its ternary complex (TC). Experimental rodents were administered with AlCl3 (300 mg/kg) to induce AD and treated with rivastigmine, curcuminoid crude extract, CRE, and TC orally for three consecutive weeks. Neurobehavioral, biochemical, and histopathological studies were performed from the last week of the study period. The mRNA expression of different pathological biomarkers was estimated by RT-qPCR analysis. The results of the study suggested that CRE and TC significantly improved the behavioral, biochemical parameters and acetylcholinesterase inhibitory activity in treatment groups. Histological analysis was also carried out indicating that the neurodegenerative changes and neuronal loss were stabilized by CRE and TC supplementation. CRE and TC supplementation remarkably downregulated the interleukin-1α, tumor necrosis factor-α, interleukin-1β, acetylcholinesterase, and β-secretase pathological gene expression. Hence, it was concluded that CRE and TC may act as promising candidates in the prevention of AD via numerous underlying signaling pathways.}, }
@article {pmid35516456, year = {2022}, author = {Wang, Z and Cheng, S}, title = {Effects of Pramipexole Combined with Nerve Growth Factor on Cognitive Impairment and Urinary AD7c-NTP Expression in Patients with Parkinson's Disease.}, journal = {Computational and mathematical methods in medicine}, volume = {2022}, number = {}, pages = {3398732}, doi = {10.1155/2022/3398732}, pmid = {35516456}, issn = {1748-6718}, abstract = {Objective: To explore the effects of pramipexole combined with nerve growth factor (NGF) on cognitive impairment and urinary Alzheimer-associated neural thread protein (AD7c-NTP) expression in patients with Parkinson's disease (PD).<br><br>Methods: Fifty patients with PD treated in our hospital from February 2020 to April 2021 were enrolled. The patients were arbitrarily assigned into control group and study group. The former was treated with pramipexole, and the latter was treated with pramipexole combined with NGF. The efficacy, cognitive function, serum inflammatory factors, cortisol levels, serum macrophage migration inhibitory factor (MIF), brain-derived neurotrophic factor (BDNF), urine AD7c-NTP levels, and the incidence of adverse reactions were compared.<br><br>Results: First of all, the effective rate in the study group was higher compared to the control group (P < 0.05). After treatment, the cognitive function was enhanced, and the scores of Montreal cognitive assessment (MoCA) in the study group were higher compared to the control group (P < 0.05). The levels of serum IL-6, CRP, and TNF-α decreased after treatment, and the levels of serum IL-6, CRP, and TNF-α in the study group were remarkably lower compared to the control group (P < 0.05). In addition, the levels of serum DA, NE, and 5-HT increased after treatment, and the levels of serum DA, NE, and 5-HT in the study group were remarkably higher compared to the control group (P < 0.05). Then, the levels of serum MIF and urine AD7c-NTP decreased and BDNF increased after treatment, and the level of BDNF in the study group was higher compared to the control group, while the levels of serum MIF and urine AD7c-NTP in the study group were lower compared to the control group (P < 0.05). Finally, the adverse reactions were compared. The incidence of adverse reactions in the study group was lower compared to the control group, and the difference exhibited not statistically significant (16.00% vs. 24.00%, P > 0.05).<br><br>Conclusion: Pramipexole combined with NGF therapy not only can effectively strengthen the cognitive impairment of patients with PD and promote clinical efficacy and high safety but also can inhibit inflammatory state, regulate brain neurotransmitters, and reduce urinary AD7c-NTP levels.}, }
@article {pmid35513705, year = {2022}, author = {Tang, Y and Zhang, D and Zhang, Y and Liu, Y and Miller, Y and Gong, K and Zheng, J}, title = {Cross-seeding between Aβ and SEVI indicates a pathogenic link and gender difference between alzheimer diseases and AIDS.}, journal = {Communications biology}, volume = {5}, number = {1}, pages = {417}, pmid = {35513705}, issn = {2399-3642}, support = {2107619//NSF | Directorate for Engineering (ENG/OAD)/ ; }, abstract = {Amyloid-β (Aβ) and semen-derived enhancer of viral infection (SEVI) are considered as the two causative proteins for central pathogenic cause of Alzheimer's disease (AD) and HIV/AIDS, respectively. Separately, Aβ-AD and SEVI-HIV/AIDS systems have been studied extensively both in fundamental research and in clinical trials. Despite significant differences between Aβ-AD and SEVI-HIV/AIDS systems, they share some commonalities on amyloid and antimicrobial characteristics between Aβ and SEVI, there are apparent overlaps in dysfunctional neurological symptoms between AD and HIV/AIDS. Few studies have reported a potential pathological link between Aβ-AD and SEVI-HIV/AIDS at a protein level. Here, we demonstrate the cross-seeding interactions between Aβ and SEVI proteins using in vitro and in vivo approaches. Cross-seeding of SEVI with Aβ enabled to completely prevent Aβ aggregation at sub-stoichiometric concentrations, disaggregate preformed Aβ fibrils, reduce Aβ-induced cell toxicity, and attenuate Aβ-accumulated paralysis in transgenic AD C. elegans. This work describes a potential crosstalk between AD and HIV/AIDS via the cross-seeding between Aβ and SEVI, identifies SEVI as Aβ inhibitor for possible treatment or prevention of AD, and explains the role of SEVI in the gender difference in AD.}, }
@article {pmid35491796, year = {2022}, author = {Whitehouse, PJ and Saini, V}, title = {Making the Case for the Accelerated Withdrawal of Aducanumab.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {}, doi = {10.3233/JAD-220264}, pmid = {35491796}, issn = {1875-8908}, abstract = {U.S. Food and Drug Administration-s (FDA) approval of aducanumab (Aduhelm® in the US) as a treatment for mild cognitive impairment of the Alzheimer type and Alzheimer-s disease has raised such major concerns about efficacy, safety, FDA processes, and regulatory capture that Biogen-s license to market this biologic should be immediately withdrawn. Aducanumab has not demonstrated benefit to patients, failed to meet regulatory guidelines, and is likely to cause both individual and societal harm.}, }
@article {pmid35486540, year = {2022}, author = {Ahmed, K and Mitchell, DGV and Blair, M and Coleman, K and Pasternak, SH and Ruiz-Garcia, R and Finger, E}, title = {Disentangling Reversal-learning Impairments in Frontotemporal Dementia and Alzheimer Disease.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {}, number = {}, pages = {}, pmid = {35486540}, issn = {1543-3641}, abstract = {BACKGROUND: Individuals with frontotemporal dementia (FTD) often present with poor decision-making, which can affect both their financial and social situations. Delineation of the specific cognitive impairments giving rise to impaired decision-making in individuals with FTD may inform treatment strategies, as different neurotransmitter systems have been associated with distinct patterns of altered decision-making.<br><br>OBJECTIVE: To use a reversal-learning paradigm to identify the specific cognitive components of reversal learning that are most impaired in individuals with FTD and those with Alzheimer disease (AD) in order to inform future approaches to treatment for symptoms related to poor decision-making and behavioral inflexibility.<br><br>METHOD: We gave 30 individuals with either the behavioral variant of FTD or AD and 18 healthy controls a stimulus-discrimination reversal-learning task to complete. We then compared performance in each phase between the groups.<br><br>RESULTS: The FTD group demonstrated impairments in initial stimulus-association learning, though to a lesser degree than the AD group. The FTD group also performed poorly in classic reversal learning, with the greatest impairments being observed in individuals with frontal-predominant atrophy during trials requiring inhibition of a previously advantageous response.<br><br>CONCLUSION: Taken together, these results and the reversal-learning paradigm used in this study may inform the development and screening of behavioral, neurostimulatory, or pharmacologic interventions aiming to address behavioral symptoms related to stimulus-reinforcement learning and response inhibition impairments in individuals with FTD.}, }
@article {pmid35484241, year = {2022}, author = {Li, S and Stern, AM}, title = {Bioactive human Alzheimer brain soluble Aβ: pathophysiology and therapeutic opportunities.}, journal = {Molecular psychiatry}, volume = {}, number = {}, pages = {}, pmid = {35484241}, issn = {1476-5578}, abstract = {The accumulation of amyloid-β protein (Aβ) plays an early role in the pathogenesis of Alzheimer's disease (AD). The precise mechanism of how Aβ accumulation leads to synaptic dysfunction and cognitive impairment remains unclear but is likely due to small soluble oligomers of Aβ (oAβ). Most studies have used chemical synthetic or cell-secreted Aβ oligomers to study their pathogenic mechanisms, but the Aβ derived from human AD brain tissue is less well characterized. Here we review updated knowledge on the extraction and characterization of bioactive human AD brain oAβ and the mechanisms by which they cause hippocampal synaptic dysfunction. Human AD brain-derived oAβ can impair hippocampal long-term potentiation (LTP) and enhance long-term depression (LTD). Many studies suggest that oAβ may directly disrupt neuronal NMDA receptors, AMPA receptors and metabotropic glutamate receptors (mGluRs). oAβ also impairs astrocytic synaptic functions, including glutamate uptake, D-serine release, and NMDA receptor function. We also discuss oAβ-induced neuronal hyperexcitation. These results may suggest a multi-target approach for the treatment of AD, including both oAβ neutralization and reversal of glutamate-mediated excitotoxicity.}, }
@article {pmid35478169, year = {2022}, author = {Vecchio, F}, title = {Cognitive training and neuromodulation for Alzheimer treatment.}, journal = {Aging}, volume = {undefined}, number = {undefined}, pages = {}, doi = {10.18632/aging.204044}, pmid = {35478169}, issn = {1945-4589}, }
@article {pmid35420708, year = {2022}, author = {Yamaguchi, S and Narukawa, M}, title = {Combinations of Drug Candidate Properties Affecting Development Success and Discontinuation for 5 Diseases: Lymphoma, Non-Small Cell Lung Cancer, Arthritis, Depression, and Alzheimer Disease.}, journal = {Journal of clinical pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1002/jcph.2063}, pmid = {35420708}, issn = {1552-4604}, abstract = {The effects of the properties of drug candidates on their successful approval for the treatment of diseases are substantial. However, the success rate of candidates when their properties are combined has not been sufficiently evaluated. We aimed to identify combinations of properties (target, action, and modality) that increased the approval success rate of drug candidates for 5 diseases as well as to understand the characteristics of discontinued candidates. We calculated the approval success rates by combining the properties of drug candidates developed for 5 diseases (non-small cell lung cancer, lymphoma, arthritis, depression, and Alzheimer disease [AD]), using candidates for which clinical development was initiated between 2000 and 2010. We also analyzed the phases and the reasons for the discontinuation of candidates of the 5 diseases for which development was discontinued. Probable combinations of properties with relatively high success rates for the diseases except for Alzheimer disease were found. These combinations of properties were considered appropriate in light of the pathology of each disease. The percentage of candidates discontinued in phase III for Alzheimer disease was higher than that for the other diseases. The reasons for discontinuation showed different trends between combinations of properties that had high and low approval success rates. As the effects of the properties of candidates on the success rate vary depending on the intended disease, pharmaceutical companies need to consider the probability of success of candidates for individual diseases for more efficient candidate selection.}, }
@article {pmid35475789, year = {2022}, author = {Jacobson, N and Lithgow, B and Jafari Jozani, M and Moussavi, Z}, title = {The Effect of Transcranial Alternating Current Stimulation With Cognitive Training on Executive Brain Function in Individuals With Dementia: Protocol for a Crossover Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {11}, number = {4}, pages = {e37282}, doi = {10.2196/37282}, pmid = {35475789}, issn = {1929-0748}, abstract = {BACKGROUND: Although memory and cognitive declines are associated with normal brain aging, they may also be precursors to dementia.<br><br>OBJECTIVE: We aim to offer a novel approach to prevent or slow the progress of neurodegenerative dementia, or plausibly, improve the cognitive functions of individuals with dementia.<br><br>METHODS: We will recruit and enroll 75 participants (older than 50 years old with either mild cognitive impairment or probable early or moderate dementia) for this double-blind randomized controlled study to estimate the efficacy of active transcranial alternating current stimulation with cognitive treatment (in comparison with sham transcranial alternating current stimulation). This will be a crossover study; a cycle consists of sham or active treatment for a period of 4 weeks (5 days per week, in two 30-minute sessions with a half-hour break in between), and participants are randomized into 2 groups, with stratification by age, sex, and cognitive level (measured with the Montreal Cognitive Assessment). Outcomes will be assessed before and after each treatment cycle. The primary outcomes are changes in Wechsler Memory Scale Older Adult Battery and Alzheimer Disease Assessment Scale scores. Secondary outcomes are changes in performance on tests of frontal lobe functioning (verbal fluency), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), mood changes (Montgomery-Åsberg Depression Rating Scale), and short-term recall (visual 1-back task). Exploratory outcome measures will also be assessed: static and dynamic vestibular response using electrovestibulography, neuronal changes using functional near-infrared spectroscopy, and change in spatial orientation using virtual reality navigation.<br><br>RESULTS: As of February 10, 2022, the study is ongoing: 7 patients have been screened, and all were deemed eligible for and enrolled in the study; 4 participants have completed baseline assessments.<br><br>CONCLUSIONS: We anticipate that transcranial alternating current stimulation will be a well-tolerated treatment, with no serious side effects and with considerable short- and long-term cognitive improvements.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov NCT05203523; https://clinicaltrials.gov/show/NCT05203523.<br><br>DERR1-10.2196/37282.}, }
@article {pmid35456590, year = {2022}, author = {Danish, SM and Gupta, A and Khan, UA and Hasan, N and Ahmad, FJ and Warsi, MH and Ali, AMA and Zafar, A and Jain, GK}, title = {Intranasal Cerium Oxide Nanoparticles Ameliorate Cognitive Function in Rats with Alzheimer's via Anti-Oxidative Pathway.}, journal = {Pharmaceutics}, volume = {14}, number = {4}, pages = {}, pmid = {35456590}, issn = {1999-4923}, support = {TURSP-2020/50//Taif University Researchers Supporting Project number (TURSP-2020/50), Taif University, Taif, Saudi Arabia/ ; }, abstract = {Cerium oxide nanoparticles (CNPs), owing to their antioxidant property, have recently emerged as therapeutic candidate for Alzheimer's disease (AD). However, intravenous CNPs are limited due to their poor physicochemical properties, rapid blood clearance and poor blood-brain penetration. Thus, we developed intranasal CNPs and evaluated its potential in experimental AD. CNPs were synthesized using homogenous precipitation method and optimized through Box-Behnken Design. The formation of CNPs was confirmed by UV spectroscopy and FTIR. The optimized CNP were spherical, small (134.0 ± 3.35 nm), uniform (PDI, 0.158 ± 0.0019) and stable (ZP, -21.8 ± 4.94 mV). The presence of Ce in CNPs was confirmed by energy-dispersive X-ray analysis. Further, the X-ray diffraction spectra revealed that the CNPs were nano-crystalline. The DPPH assay showed that at concentration of 50 µg/mL, the percentage radical scavenging was 95.40 ± 0.006%. Results of the in vivo behavioral studies in the scopolamine-induced Alzheimer rat model showed that intranasal CNPs dose dependently reversed cognitive ability. At dose of 6 mg/kg the morris water maze results (escape latency, path length and dwell time) and passive avoidance results (retention latency) were significantly different from untreated group but not significantly different from positive control group (rivastigmine patch, 13.3 mg/24 h). Further, biochemical estimation showed that intranasal CNP upregulated the levels of SOD and GSH in brain. In conclusion, intranasal CNPs, through its antioxidant effect, could be a prospective therapeutics for the treatment of cognitive impairment in AD.}, }
@article {pmid35454088, year = {2022}, author = {Aguilar-Pineda, JA and Paco-Coralla, SG and Febres-Molina, C and Gamero-Begazo, PL and Shrivastava, P and Vera-López, KJ and Davila-Del-Carpio, G and López-C, P and Gómez, B and Lino Cardenas, CL}, title = {In Silico Analysis of the Antagonist Effect of Enoxaparin on the ApoE4-Amyloid-Beta (Aβ) Complex at Different pH Conditions.}, journal = {Biomolecules}, volume = {12}, number = {4}, pages = {}, doi = {10.3390/biom12040499}, pmid = {35454088}, issn = {2218-273X}, support = {N024-2019-Fondecyt-BM-INC.INV and CONCYTEC- FONDECYT- E038-01//Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica/ ; }, abstract = {Apolipoprotein E4 (ApoE4) is thought to increase the risk of developing Alzheimer's disease. Several studies have shown that ApoE4-Amyloid β (Aβ) interactions can increment amyloid depositions in the brain and that this can be augmented at low pH values. On the other hand, experimental studies in transgenic mouse models have shown that treatment with enoxaparin significantly reduces cortical Aβ levels, as well as decreases the number of activated astrocytes around Aβ plaques. However, the interactions between enoxaparin and the ApoE4-Aβ proteins have been poorly explored. In this work, we combine molecular dynamics simulations, molecular docking, and binding free energy calculations to elucidate the molecular properties of the ApoE4-Aβ interactions and the competitive binding affinity of the enoxaparin on the ApoE4 binding sites. In addition, we investigated the effect of the environmental pH levels on those interactions. Our results showed that under different pH conditions, the closed form of the ApoE4 protein, in which the C-terminal domain folds into the protein, remains stabilized by a network of hydrogen bonds. This closed conformation allowed the generation of six different ApoE4-Aβ interaction sites, which were energetically favorable. Systems at pH5 and 6 showed the highest energetic affinity. The enoxaparin molecule was found to have a strong energetic affinity for ApoE4-interacting sites and thus can neutralize or disrupt ApoE4-Aβ complex formation.}, }
@article {pmid35453314, year = {2022}, author = {Romero-Márquez, JM and Navarro-Hortal, MD and Jiménez-Trigo, V and Muñoz-Ollero, P and Forbes-Hernández, TY and Esteban-Muñoz, A and Giampieri, F and Delgado Noya, I and Bullón, P and Vera-Ramírez, L and Battino, M and Sánchez-González, C and Quiles, JL}, title = {An Olive-Derived Extract 20% Rich in Hydroxytyrosol Prevents β-Amyloid Aggregation and Oxidative Stress, Two Features of Alzheimer Disease, via SKN-1/NRF2 and HSP-16.2 in Caenorhabditis elegans.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {4}, pages = {}, pmid = {35453314}, issn = {2076-3921}, support = {B-AGR-193-UGR18//FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento/ ; PID2019-106778RB-I00//MCIN/AEI/10.13039/501100011033 FEDER "Una manera de hacer Europa"/ ; }, abstract = {Olive milling produces olive oil and different by-products, all of them very rich in different bioactive compounds like the phenolic alcohol hydroxytyrosol. The aim of the present study was to investigate the effects of an olive fruit extract 20% rich in hydroxytyrosol on the molecular mechanisms associated with Alzheimer disease features like Aβ- and tau- induced toxicity, as well as on oxidative stress in Caenorhabditis elegans. Moreover, characterization of the extracts, regarding the profile and content of phenolics, as well as total antioxidant ability, was investigated. The study of lethality, growth, pharyngeal pumping, and longevity in vivo demonstrated the lack of toxicity of the extract. One hundred μg/mL of extract treatment revealed prevention of oxidative stress and a delay in Aβ-induced paralysis related with a lower presence of Aβ aggregates. Indeed, the extract showed the ability to avoid a certain degree of proteotoxicity associated with aggregation of the tau protein. According to RNAi tests, SKN-1/NRF2 transcription factor and the overexpression of HSP-16.2 were mechanistically associated in the observed effects.}, }
@article {pmid35452007, year = {2022}, author = {Høilund-Carlsen, PF and Werner, TJ and Alavi, A and Revheim, ME}, title = {Aducanumab-Related Amyloid-Related Imaging Abnormalities: Paean or Lament?.}, journal = {Clinical nuclear medicine}, volume = {}, number = {}, pages = {}, doi = {10.1097/RLU.0000000000004250}, pmid = {35452007}, issn = {1536-0229}, abstract = {ABSTRACT: When the FDA granted accelerated approval of Biogen's Alzheimer disease drug, aducanumab (marketed as Aduhelm), it deviated from its mission of guaranteeing drug safety and efficacy because the approval was based exclusively on a perceived dose-dependent reduction in brain amyloid deposits and not upon a proven clinical effect. We believe that the amyloid-PET scans, perceived as showing decreasing amyloid deposits, are an expression of increased cerebral cell death due to aducanumab treatment, so that with time one should instead expect a worsening and not an improvement in the treated patients' condition.}, }
@article {pmid35445359, year = {2022}, author = {Pomilio, C and Pérez, NG and Calandri, I and Crivelli, L and Allegri, R and ,  and Sevlever, G and Saravia, F}, title = {Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {35445359}, issn = {2509-2723}, abstract = {We evaluated the effect of the antidiabetic drug metformin on patients enrolled in the ADNI study considering patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Employing data from this observational study, we performed a principal component analysis focusing on the cognitive sphere by evaluating data from neuropsychological tests included in a modified version of the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC). Second, we included the levels of amyloid-β, tau, and phosphorylated tau in CSF. We found that MCI metformin-treated patients were globally characterized as subjects with a better cognitive performance and CSF biomarkers profile than the mean population of MCI patients. On the other hand, control subjects and type 2 diabetes patients (T2D) were paired by age, gender, ApoE allele, and years of education, defining three groups: MCI, MCI + T2D, and MCI + T2D + metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory and learning function. We found that MCI + T2D patients had a worse cognitive performance than MCI patients, but this deleterious effect was not observed in MCI + T2D + metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume. Finally, no differences were found in metabolic plasmatic parameters (glycemia, cholesterol, triglycerides). Our study-employing different strategies for data analysis from the global study ADNI-shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile, and neuroanatomical measures in MCI due to AD patients.}, }
@article {pmid35438756, year = {2022}, author = {Mundal, LJ and Igland, J and Svendsen, K and Holven, KB and Leren, TP and Retterstøl, K}, title = {Association of Familial Hypercholesterolemia and Statin Use With Risk of Dementia in Norway.}, journal = {JAMA network open}, volume = {5}, number = {4}, pages = {e227715}, doi = {10.1001/jamanetworkopen.2022.7715}, pmid = {35438756}, issn = {2574-3805}, mesh = {Aged ; Aged, 80 and over ; *Dementia/drug therapy/epidemiology ; Female ; Humans ; *Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects ; *Hypercholesterolemia/drug therapy/epidemiology ; *Hyperlipoproteinemia Type II/drug therapy/epidemiology ; Male ; Prospective Studies ; }, abstract = {Importance: Hypercholesterolemia, which is a cardiovascular risk factor, may also be associated with dementia risk. The benefit of statin treatment on dementia risk is controversial.<br><br>Objective: To determine whether individuals with familial hypercholesterolemia (FH), who have been exposed to lifelong hypercholesterolemia, have an excess risk of dementia and whether statin use is associated with dementia risk.<br><br>This was a prospective cohort study performed from 2008 to 2018 in Norway. Statistical analysis was performed from January 2021 to February 2022. This study included individuals with genetically verified FH and age-matched and sex-matched controls obtained from the general Norwegian population.<br><br>Exposures: Dementia was defined according to International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes F00-03 and G30.<br><br>Main Outcomes and Measures: Incident cases of total dementia, vascular dementia, Alzheimer disease-dementia in Alzheimer disease, and data on lipid-lowering medication were obtained from the Norwegian Patient Registry, Cause of Death Registry, and the Norwegian Prescription Database. Hazard ratios (HRs) for risk of dementia for individuals with FH vs matched controls were calculated using Cox regression. The cumulative sum of defined daily doses (DDDs) of statins prescribed during study follow-up was calculated for individuals with FH and was analyzed as a time-varying covariate with 3 levels: 1 to 4999 DDDs, 5000 to 10 000 DDDs, and more than 10 000 DDDs.<br><br>Results: Among the 3520 individuals with FH (1863 women [52.9%]; mean [SD] age at the start of follow-up, 51.8 [11.5] years) and the 69 713 controls (36 958 women [53.0%]; mean [SD] age at the start of follow-up, 51.7 [11.5] years), 62 patients with FH (39 women [62.9%]) and 1294 controls (801 women [61.9%]) had developed dementia over the course of 10 years of follow-up. Most dementia cases occurred among individuals aged 70 years and older (39 patients with FH [62.9%] and 870 patients [67.2%] in the control group). We found no excess risk of dementia in patients with FH vs matched controls (HR for total dementia, 0.9; 95% CI, 0.7-1.2). There was no association between cumulative DDDs of statins and total dementia in patients with FH with HRs of 1.2 (95% CI, 0.4-3.8) for cumulative DDDs of 5000 to 10 000 and 1.9 (95% CI, 0.7-5.0) for cumulative DDDs greater than 10 000.<br><br>Conclusions and Relevance: These findings suggest that individuals with FH have no excess risk of dementia compared with age-matched and sex-matched controls and that there is no association between use of statins and risk of dementia in patients with FH.}, }
@article {pmid35435938, year = {2022}, author = {Young, CB and Winer, JR and Younes, K and Cody, KA and Betthauser, TJ and Johnson, SC and Schultz, A and Sperling, RA and Greicius, MD and Cobos, I and Poston, KL and Mormino, EC and , }, title = {Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaneurol.2022.0676}, pmid = {35435938}, issn = {2168-6157}, abstract = {Importance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease.<br><br>Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+).<br><br>This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022.<br><br>Main Outcomes and Measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined.<br><br>Results: The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin.<br><br>Conclusions and Relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.}, }
@article {pmid35431901, year = {2022}, author = {Han, G and Zhen, W and Dai, Y and Yu, H and Li, D and Ma, T}, title = {Dihuang-Yinzi Alleviates Cognition Deficits via Targeting Energy-Related Metabolism in an Alzheimer Mouse Model as Demonstrated by Integration of Metabolomics and Network Pharmacology.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {873929}, pmid = {35431901}, issn = {1663-4365}, abstract = {Energy metabolism disturbance and the consequent reactive oxygen species (ROS) overproduction play a key and pathogenic role in the onset and progression of Alzheimer's disease (AD). Dihuang-Yinzi (DHYZ) is a traditional Chinese herbal prescription clinically applied to treat AD and other neurodegenerative diseases for a long time. However, the systematical metabolic mechanism of DHYZ against AD remains largely unclear. Here we aimed to explore the mechanism of DHYZ in the treatment of AD comprehensively in an in vivo metabolic context by performing metabolomics analysis coupled with network pharmacology study and experimental validation. The network pharmacology was applied to dig out the potential target of DHYZ against AD. The metabolomics analysis based on UPLC-HRMS was carried out to profile the urine of 2× Tg-AD mice treated with DHYZ. By integrating network pharmacology and metabolomics, we found DHYZ could ameliorate 4 key energy-related metabolic pathways, including glycerophospholipid metabolism, nicotinate/nicotinamide metabolism, glycolysis, and tricarboxylic acid cycle. Besides, we identified 5 potential anti-AD targets of DHYZ, including DAO, HIF1A, PARP1, ALDH3B2, and ACHE, and 14 key differential metabolites involved in the 4 key energy-related metabolic pathways. Furthermore, DHYZ depressed the mitochondrial dysfunction and the resultant ROS overproduction through ameliorating glycerophospholipid metabolism disturbance. Thereby DHYZ increased nicotinamide adenine dinucleotide (NAD+) content and promoted glycolysis and tricarboxylic acid (TCA) cycle, and consequently improved oxidative phosphorylation and energy metabolism. In the present study, we provided a novel, comprehensive and systematic insight into investigating the therapeutic efficacy of DHYZ against AD via ameliorating energy-related metabolism.}, }
@article {pmid35431827, year = {2022}, author = {Coker-Ayo, OO and Nathaniel, SI and Poupore, N and Bailey-Taylor, MJ and Roley, LT and Goodwin, RL and McPhail, B and Russ-Sellers, R and Nathaniel, TI}, title = {Sex Differences in Demographic and Pharmacological Factors in Alzheimer Patients With Dementia and Cognitive Impairments.}, journal = {Frontiers in behavioral neuroscience}, volume = {16}, number = {}, pages = {828782}, pmid = {35431827}, issn = {1662-5153}, abstract = {Objective: The current study investigates sex differences associated with pharmacological and demographic characteristics in Alzheimer patients (AD) with dementia (ADD) or mild cognitive impairment (MCI).<br><br>Method: A retrospective analytical approach was used to analyze data from 45,696 AD patients with MCI or ADD. The univariate analysis was used to determine differences in demographic, and pharmacological characteristics for male and female ADD and MCI-AD patients. Multivariate analysis was used to predict specific pharmacological and demographic factors that are associated with male and female MCI and ADD patients.<br><br>Result: In the adjusted analysis for male patients, Hispanics [0.166,0.020 - 1.355, P = 0.094] or African Americans [OR = 2.380, 95% CI,2.120 - 2.674, P < 0.001], were more likely to have MCI-AD and be treated with galantamine [OR = 0.559, 95% CI, 0.382 - 0.818, P = 0.003], donepezil [OR = 1.639, 95% CI,1.503 - 1.787, P < 0.001], rivastigmine [OR = 1.394, 95% CI,1.184 - 1.642, P < 0.001], olanzapine [OR = 2.727, 95% CI,2.315 - 3.212, P < 0.001], risperidone [OR = 2.973, 95% CI,2.506 - 3.526, P < 0.001], present with increasing age [1.075,1.071 - 1.079, P < 0.001], and are on tobacco use [OR = 1.150, 95% CI,1.054 - 1.254, P = 0.002]. For female patients, buspirone [OR = 0.767, 95% CI, 0.683 - 0.861, P < 0.001] and a history of alcohol (ETOH) use [OR = 0.484, 95% CI, 0.442 - 0.529, P < 0.001] were associated with MCI-AD. Increasing age [OR = 1.096, 95% CI, 1.093 - 1.100, P < 0.001], donepezil [OR = 2.185, 95% CI, 2.035 - 2.346, P < 0.001], memantine [OR = 2.283, 95% CI, 2.104 - 2.477, P < 0.001] aripiprazole [OR = 1.807, 95% CI, 1.544 - 2.113, P < 0.001] olanzapine [OR = 2.289, 95% CI, 1.986 - 2.640, P < 0.001] risperidone [OR = 2.548, 95% CI, 2.246 - 2.889, P < 0.001] buspirone [OR = 0.767, 95% CI, 0.683 - 0.861, P < 0.001] escitalopram [OR = 1.213, 95% CI,1.119 - 1.315, P < 0.001] African Americans [OR = 1.395, 95% CI, 1.268 - 1.535, P < 0.001] and tobacco use [OR = 1.150, 95% CI, 1.073 - 1.233, P < 0.001] were associated with ADD.<br><br>Conclusion: Our findings reveal that MCI-AD patients were more likely to be Hispanics or African American males treated with rivastigmine, olanzapine and citalopram. African American females were associated with ADD and more likely to be treated with buspirone and presented with a history of ETOH. This finding suggests the need for a pharmacological treatment approach encompassing sex-sensitive strategies for MCI-AD and ADD patients.}, }
@article {pmid35422230, year = {2022}, author = {Ankul Singh S,  and Chitra V, }, title = {The role of plant-based products in the prevention of neurological complications.}, journal = {Drug metabolism letters}, volume = {}, number = {}, pages = {}, doi = {10.2174/1872312815666220413095159}, pmid = {35422230}, issn = {1874-0758}, abstract = {BACKGROUND: Neurological complications are most likely to be fatal and cause loss of ability to function or care for self. These include Alzheimer's disease and cognitive impairment. The main aim of the review is to determine the effects of various drugs and their cognitive risk with the need to opt for herbal therapy as an adjuvant in treating neurological conditions like Alzheimer's disease with lesser-known side effects. The Methodology: Involved a detailed literature survey which was performed through an online database, such as Science Direct, Google Scholar, Scopus, Cochrane, and PubMed. The study included randomized trials and original research conducted by herbal supplements on animal models to assess expression of upregulation of signalling pathways. Various studies involved in treating dementia, neurological disorders, Alzheimer disease, cognitive dysfunction were included.<br><br>RESULTS: Found that various studies involved plant-based products were showing improvement in prevention of disease and signalling pathways with lesser-known side effects.<br><br>CONCLUSION: It was observed that plant-based products play a major role in the prevention of neurological complications. Herbal medicines could most suitably prevent Alzheimer's risk with less known side effects in contrast with the existing treatment patterns. However, to improve the utility of herbal medicines, more evidences from in vitro, in vivo, and clinical trials need to be addressed.}, }
@article {pmid35422205, year = {2022}, author = {Pomilio, AB and Vitale, AA and Lazarowski, AJ}, title = {Uncommon Noninvasive Biomarkers for the Evaluation and Monitoring of the Etiopathogenesis of Alzheimer's Disease.}, journal = {Current pharmaceutical design}, volume = {}, number = {}, pages = {}, doi = {10.2174/1381612828666220413101929}, pmid = {35422205}, issn = {1873-4286}, abstract = {BACKGROUND: Alzheimer´s disease (AD) is the most widespread dementia in the world, followed by vascular dementia. Since AD is a heterogeneous disease that shows several varied phenotypes, it is not easy to make an accurate diagnosis, so it arises when the symptoms are clear and the disease is already very advanced. Therefore, it is important to find out biomarkers for AD early diagnosis that facilitate treatment or slow down the disease. Classic biomarkers are obtained from cerebrospinal fluid and plasma, along with brain imaging by positron emission tomography. Attempts have been made to discover uncommon biomarkers from other body fluids, which are addressed in this update.<br><br>OBJECTIVE: This update aims to describe recent biomarkers from minimally invasive body fluids for the patients, such as saliva, urine, eye fluid or tears.<br><br>METHODS: Biomarkers were determined in patients versus controls by single tandem mass spectrometry, and immunoassays. Metabolites were identified by nuclear magnetic resonance, and microRNAs with genome-wide high-throughput real-time polymerase chain reaction-based platforms.<br><br>RESULTS: Biomarkers from urine, saliva, and eye fluid were described, including peptides/proteins, metabolites, and some microRNAs. The association with AD neuroinflammation and neurodegeneration was analyzed, highlighting the contribution of matrix metalloproteinases, the immune system and microglia, as well as the vascular system.<br><br>CONCLUSION: Unusual biomarkers have been developed, which distinguish each stage and progression of the disease, and are suitable for the early AD diagnosis. An outstanding relationship of biomarkers with neuroinflammation and neurodegeneration was assessed, clearing up concerns of the etiopathogenesis of AD.}, }
@article {pmid35410602, year = {2022}, author = {Samim, KS and Khatik, GL and Datusalia, AK}, title = {Strategies for treatment of disease-associated dementia beyond Alzheimer disease: An update.}, journal = {Current neuropharmacology}, volume = {}, number = {}, pages = {}, doi = {10.2174/1570159X20666220411083922}, pmid = {35410602}, issn = {1875-6190}, abstract = {Memory, cognition, dementia, and neurodegeneration are complexly interlinked processes through various mechanistic pathways leading to a range of clinical outcomes. These are strongly associated with pathological conditions like Alzheimer's disease, Parkinson's disease, schizophrenia, stroke and are a growing concern for their timely diagnosis and management. Several cognition-enhancing interventions for management include non-pharmacological interventions like diet, exercise, and physical activity, while pharmacological interventions include medicinal agents, herbal agents, and nutritional supplements. This review critically analyzed and discussed the currently available agents under different drug development phase designed to target either of the molecular targets including cholinergic receptor, glutamatergic system, GABAergic targets, glycine site, serotonergic targets, histamine receptors, etc. Understanding memory formation and pathways involved therein aids in opening the new gateways to treating cognitive disorders. However, clinical studies suggest that there is still a dearth of knowledge about the pathological mechanism involved in neurological conditions, making the dropouts of agents from initial phases of clinical trial conducive. Hence, better understandings of the molecular basis of the disease biology, mode of drug action, and interlinked mechanistic pathways are required.}, }
@article {pmid35404282, year = {2022}, author = {Gabel, M and Bollinger, RM and Coble, DW and Grill, JD and Edwards, DF and Lingler, JH and Chin, E and Stark, SL}, title = {Retaining Participants in Longitudinal Studies of Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {}, number = {}, pages = {}, doi = {10.3233/JAD-215710}, pmid = {35404282}, issn = {1875-8908}, abstract = {BACKGROUND: Retention of study participants is essential to advancing Alzheimer's disease (AD) research and developing therapeutic interventions. However, recent multi-year AD studies have lost 25% to 39% of participants.<br><br>OBJECTIVE: We surveyed a random sample of 443 participants (Clinical Dementia Rating [CDR]≤1) at four Alzheimer Disease Research Centers to elucidate perceived facilitators and barriers to continued participation in longitudinal AD research.<br><br>METHODS: Reasons for participation were characterized with factor analysis. Effects of perceived fulfillment of one's own goals and complaints on attendance and likelihood of dropout were estimated with logistic regression models. Open-ended responses suggesting study improvements were analyzed with a Latent Dirichlet Allocation topic model.<br><br>RESULTS: Factor analyses revealed two categories, personal benefit and altruism, as drivers of continued participation. Participants with cognitive impairment (CDR > 0) emphasized personal benefits more than societal benefits. Participants with higher trust in medical researchers were more likely to emphasize broader social benefits. A minority endorsed any complaints. Higher perceived fulfillment of one's own goals and fewer complaints were related to higher attendance and lower likelihood of dropout. Facilitators included access to medical center support and/or future treatment, learning about AD and memory concerns, and enjoying time with staff. Participants' suggestions emphasized more feedback about individual test results and AD research.<br><br>CONCLUSION: The results confirmed previously identified facilitators and barriers. Two new areas, improved communication about individual test results and greater feedback about AD research, emerged as the primary factors to improve participation.}, }
@article {pmid35401820, year = {2022}, author = {Chen, S and Gan, D and Lin, S and Zhong, Y and Chen, M and Zou, X and Shao, Z and Xiao, G}, title = {Metformin in aging and aging-related diseases: clinical applications and relevant mechanisms.}, journal = {Theranostics}, volume = {12}, number = {6}, pages = {2722-2740}, pmid = {35401820}, issn = {1838-7640}, mesh = {Aging/pathology ; Cellular Senescence ; Genomic Instability ; Humans ; *Metformin/pharmacology/therapeutic use ; Telomere ; }, abstract = {Aging is a natural process, which plays a critical role in the pathogenesis of a variety of diseases, i.e., aging-related diseases, such as diabetes, osteoarthritis, Alzheimer disease, cardiovascular diseases, cancers, obesity and other metabolic abnormalities. Metformin, the most widely used antidiabetic drug, has been reported to delay aging and display protective effect on attenuating progression of various aging-related diseases by impacting key hallmark events of aging, including dysregulated nutrient sensing, loss of proteostasis, mitochondrial dysfunction, altered intercellular communication, telomere attrition, genomic instability, epigenetic alterations, stem cell exhaustion and cellular senescence. In this review, we provide updated information and knowledge on applications of metformin in prevention and treatment of aging and aging-related diseases. We focus our discussions on the roles and underlying mechanisms of metformin in modulating aging and treating aging-related diseases.}, }
@article {pmid35397630, year = {2022}, author = {Tong, XK and Royea, J and Hamel, E}, title = {Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer's disease.}, journal = {Cell death &amp; disease}, volume = {13}, number = {4}, pages = {325}, pmid = {35397630}, issn = {2041-4889}, support = {MOP-126001//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; }, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; Disease Models, Animal ; Hippocampus/metabolism ; Ki-67 Antigen/metabolism ; Mice ; Neurogenesis/physiology ; Neurons/metabolism ; Simvastatin/pharmacology/therapeutic use ; *Wnt Signaling Pathway ; beta Catenin/metabolism ; }, abstract = {We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.}, }
@article {pmid35394510, year = {2022}, author = {Desai, RJ and Varma, VR and Gerhard, T and Segal, J and Mahesri, M and Chin, K and Horton, DB and Kim, SC and Schneeweiss, S and Thambisetty, M}, title = {Comparative Risk of Alzheimer Disease and Related Dementia Among Medicare Beneficiaries With Rheumatoid Arthritis Treated With Targeted Disease-Modifying Antirheumatic Agents.}, journal = {JAMA network open}, volume = {5}, number = {4}, pages = {e226567}, pmid = {35394510}, issn = {2574-3805}, mesh = {Abatacept/therapeutic use ; Aged ; *Alzheimer Disease/chemically induced/drug therapy/epidemiology ; *Antirheumatic Agents/adverse effects ; *Arthritis, Rheumatoid/chemically induced/drug therapy/epidemiology ; *Cardiovascular Diseases/drug therapy ; Cohort Studies ; Female ; Humans ; Medicare ; Tumor Necrosis Factor Inhibitors ; United States/epidemiology ; }, abstract = {Importance: Cytokine signaling, including tumor necrosis factor (TNF) and interleukin (IL)-6, through the Janus-kinase (JAK)-signal transducer and activator of transcription pathway, was hypothesized to attenuate the risk of Alzheimer disease and related dementia (ADRD) in the Drug Repurposing for Effective Alzheimer Medicines (DREAM) initiative based on multiomics phenotyping.<br><br>Objective: To evaluate the association between treatment with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept and risk of incident ADRD.<br><br>This cohort study was conducted among US Medicare fee-for-service patients with rheumatoid arthritis aged 65 years and older from 2007 to 2017. Patients were categorized into 3 cohorts based on initiation of tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with a common comparator abatacept (a T-cell activation inhibitor). Analyses were conducted from August 2020 to August 2021.<br><br>Main Outcomes and Measures: The main outcome was onset of ADRD based on diagnosis codes evaluated in 4 alternative analysis schemes: (1) an as-treated follow-up approach, (2) an as-started follow-up approach incorporating a 6-month induction period, (3) incorporating a 6-month symptom to diagnosis period to account for misclassification of ADRD onset, and (4) identifying ADRD through symptomatic prescriptions and diagnosis codes. Hazard ratios (HRs) with 95% CIs were calculated from Cox proportional hazard regression after adjustment for 79 preexposure characteristics through propensity score matching.<br><br>Results: After 1:1 propensity score matching to patients using abatacept, a total of 22 569 propensity score-matched patient pairs, including 4224 tofacitinib pairs (mean [SD] age 72.19 [5.65] years; 6945 [82.2%] women), 6369 tocilizumab pairs (mean [SD] age 72.01 [5.46] years; 10 105 [79.4%] women), and 11 976 TNF inhibitor pairs (mean [SD] age 72.67 [5.91] years; 19 710 [82.3%] women), were assessed. Incidence rates of ADRD varied from 2 to 18 per 1000 person-years across analyses schemes. There were no statistically significant associations of ADRD with tofacitinib (analysis 1: HR, 0.90 [95% CI, 0.55-1.51]; analysis 2: HR, 0.78 [95% CI, 0.53-1.13]; analysis 3: HR, 1.29 [95% CI, 0.72-2.33]; analysis 4: HR, 0.50 [95% CI, 0.21-1.20]), tocilizumab (analysis 1: HR, 0.82 [95% CI, 0.55-1.21]; analysis 2: HR, 1.05 [95% CI, 0.81-1.35]; analysis 3: HR, 1.21 [95% CI, 0.75-1.96]; analysis 4: HR, 0.78 [95% CI, 0.44-1.39]), or TNF inhibitors (analysis 1: HR, 0.93 [95% CI, 0.72-1.20]; analysis 2: HR, 1.02 [95% CI, 0.86-1.20]; analysis 3: HR, 1.13 [95% CI, 0.86-1.48]; analysis 4: 0.90 [95% CI, 0.60-1.37]) compared with abatacept. Results from prespecified subgroup analysis by age, sex, and baseline cardiovascular disease were consistent except in patients with cardiovascular disease, for whom there was a potentially lower risk of ADRD with TNF inhibitors vs abatacept, but only in analyses 2 and 4 (analysis 1: HR, 0.76 [95% CI, 0.50-1.16]; analysis 2: HR, 0.74 [95% CI, 0.56-0.99]; analysis 3: HR, 1.03 [95% CI, 0.65-1.61]; analysis 4: HR, 0.45 [95% CI, 0.21-0.98]).<br><br>Conclusions and Relevance: This cohort study did not find any association of risk of ADRD in patients treated with tofacitinib, tocilizumab, or TNF inhibitors compared with abatacept.}, }
@article {pmid35382657, year = {2022}, author = {Singh, A and Ujjwal, RR and Naqvi, S and Verma, RK and Tiwari, S and Kesharwani, P and Shukla, R}, title = {Formulation development of tocopherol polyethylene glycol nanoengineered polyamidoamine dendrimer for neuroprotection and treatment of Alzheimer disease.}, journal = {Journal of drug targeting}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/1061186X.2022.2063297}, pmid = {35382657}, issn = {1029-2330}, abstract = {Amyloid-beta (Aβ) aggregates deposition at extra neuronal sites induces neurotoxicity and major hallmarks of Alzheimer's disease (AD). To reduce the Aβ fibril toxicity, multi-functional polyamidoamine (PAMAM) dendrimer was conjugated with tocopheryl polyethylene glycol succinate-1000 (TPGS) which acts as a carrier matrix for the delivery of neuroprotective molecule piperine (PIP). This PIP-TPGS-PAMAM dendrimer was fabricated to mitigate the Aβ1-42 fibril toxicity on SHSY5Y cells. TPGS-PAMAM was fabricated through carbodiimide coupling reaction, and PIP was encapsulated in dendrimer through solvent injection method to prepare PIP-TPGS-PAMAM. Antioxidant assay of PIP-TPGS-PAMAM showed 90.18% inhibition of 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radicals compared to free PIP, which was 28.27%. The SHSY5Y cells showed 37.25% for negative control group and 82.55% cell viability for PIP-TPGS-PAMAM treated group against Aβ1-42 toxicity. PIP-TPGS-PAMAM reduced the ROS activity to 15.21% and 48.5% for free PIP treated in cell group. Similarly, extent of Aβ1-42-induced apoptosis also reduced significantly from 38.2% to 12.36% in PIP-TPGS-PAMAM treated group. In addition, PIP-TPGS-PAMAM also disaggregated the Aβ1-42 fibril in SHSY5Y cells. Our findings suggested that PIP-TPGS-PAMAM showed mitigation of Aβ1-42-induced toxicity in neuronal cells, which can offer excellent prospect of neuroprotection and AD therapy.}, }
@article {pmid35379951, year = {2022}, author = {Aisen, PS and Jimenez-Maggiora, GA and Rafii, MS and Walter, S and Raman, R}, title = {Early-stage Alzheimer disease: getting trial-ready.}, journal = {Nature reviews. Neurology}, volume = {}, number = {}, pages = {}, pmid = {35379951}, issn = {1759-4766}, abstract = {Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention must be initiated at very early (preclinical or prodromal) stages of the disease. Although the methods for such early-stage clinical trials have been developed, identification and recruitment of the required asymptomatic or minimally symptomatic study participants takes many years and requires substantial funds. As an example, in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Trial (the first phase III trial to be performed in preclinical AD), 3.5 years and more than 5,900 screens were required to recruit and randomize 1,169 participants. A new clinical trials infrastructure is required to increase the efficiency of recruitment and accelerate therapeutic progress. Collaborations in North America, Europe and Asia are now addressing this need by establishing trial-ready cohorts of individuals with preclinical and prodromal AD. These collaborations are employing innovative methods to engage the target population, assess risk of brain amyloid accumulation, select participants for biomarker studies and determine eligibility for trials. In the future, these programmes could provide effective tools for pursuing the primary prevention of AD. Here, we review the lessons learned from the AD trial-ready cohorts that have been established to date, with the aim of informing ongoing and future efforts towards efficient, cost-effective trial recruitment.}, }
@article {pmid35372787, year = {2022}, author = {Ren, R and Qi, J and Lin, S and Liu, X and Yin, P and Wang, Z and Tang, R and Wang, J and Huang, Q and Li, J and Xie, X and Hu, Y and Cui, S and Zhu, Y and Yu, X and Wang, P and Zhu, Y and Wang, Y and Huang, Y and Hu, Y and Wang, Y and Li, C and Zhou, M and Wang, G}, title = {The China Alzheimer Report 2022.}, journal = {General psychiatry}, volume = {35}, number = {1}, pages = {e100751}, pmid = {35372787}, issn = {2517-729X}, abstract = {China's population has rapidly aged over the recent decades of social and economic development as neurodegenerative disorders have proliferated, especially Alzheimer's disease (AD) and related dementias (ADRD). AD's incidence rate, morbidity, and mortality have steadily increased to make it presently the fifth leading cause of death among urban and rural residents in China and magnify the resulting financial burdens on individuals, families and society. The 'Healthy China Action' plan of 2019-2030 promotes the transition from disease treatment to health maintenance for this expanding population with ADRD. This report describes related epidemiological trends, evaluates the economic burden of the disease, outlines current clinical diagnosis and treatment status and delineates existing available public health resources. More specifically, it examines the public health impact of ADRD, including prevalence, mortality, costs, usage of care, and the overall effect on caregivers and society. In addition, this special report presents technical guidance and supports for the prevention and treatment of AD, provides expertise to guide relevant governmental healthcare policy development and suggests an information platform for international exchange and cooperation.}, }
@article {pmid35370697, year = {2022}, author = {Vidal-Palencia, L and Ramon-Duaso, C and González-Parra, JA and Busquets-Garcia, A}, title = {Gene Expression Analysis of the Endocannabinoid System in Presymptomatic APP/PS1 Mice.}, journal = {Frontiers in pharmacology}, volume = {13}, number = {}, pages = {864591}, pmid = {35370697}, issn = {1663-9812}, abstract = {Alzheimer's disease (AD) is the most common type of dementia and neurodegeneration. The actual cause of AD progression is still unknown and no curative treatment is available. Recently, findings in human samples and animal models pointed to the endocannabinoid system (ECS) as a promising therapeutic approach against AD. However, the specific mechanisms by which cannabinoid drugs induce potential beneficial effects are still undefined. For this reason, it is required a full characterization of the ECS at different time points of AD progression considering important factors such as sex or the analysis of different brain regions to improve future cannabinoid-dependent therapies in AD. Thus, the main aim of the present study is to expand our knowledge of the status of the ECS in a presymptomatic period (3 months of age) using the AD mouse model APP/PS1 mice. First, we evaluated different behavioral domains including anxiety, cognitive functions, and social interactions in male and female APP/PS1 mice at 4 months of age. Although a mild working memory impairment was observed in male APP/PS1 mice, in most of the behaviors assessed we found no differences between genotypes. At 3 months of age, we performed a characterization of the ECS in different brain regions of the APP/PS1 mice considering the sex variable. We assessed the expression of the ECS components by quantitative Real-Time Polymerase Chain Reaction in the hippocampus, prefrontal cortex, hypothalamus, olfactory bulb, and cerebellum. Interestingly, gene expression levels of the type-1 and type-2 cannabinoid receptors and the anabolic and catabolic enzymes, differed depending on the brain region and the sex analyzed. For example, CB1R expression levels decreased in both hippocampus and prefrontal cortex of male APP/PS1 mice but increased in female mice. In contrast, CB2R expression was decreased in females, whereas males tended to have higher levels. Overall, our data indicated that the ECS is already altered in APP/PS1 mice at the presymptomatic stage, suggesting that it could be an early event contributing to the pathophysiology of AD or being a potential predictive biomarker.}, }
@article {pmid35366787, year = {2022}, author = {Mathew, A and Balaji E, V and Pai, SRK and Kishore, A and Pai, V and Pemmireddy, R and K S, C}, title = {Current Drug Targets in Alzheimer's Associated Memory Impairment: A Comprehensive Review.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1871527321666220401124719}, pmid = {35366787}, issn = {1996-3181}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia among geriatrics. It is a progressive, degenerative neurologic disorder that causes memory and cognition loss. The accumulation of amyloid fibrils and neurofibrillary tangles in the brain of AD patients is a distinguishing feature of the disease. Therefore, most of the current therapeutic goals are targeting inhibition of beta-amyloid synthesis and aggregation as well as tau phosphorylation and aggregation. There is also a loss of the cholinergic neurons in the basal forebrain and first-generation therapeutic agents were primarily focused on compensating for this loss of neurons. However, cholinesterase inhibitors can only alleviate cognitive symptoms of AD and cannot reduce the progression of the disease. Understanding the molecular and cellular changes associated with AD pathology has advanced significantly in recent decades. The etiology of AD is complex with a substantial portion of sporadic AD emerging from unknown reasons and a lesser proportion of early-onset familial AD (FAD) caused by mutation in several genes, such as the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes. Hence, efforts are being made to discover novel strategies for these targets for the AD therapy. A new generation of AChE and BChE inhibitors is currently being explored and evaluated in human clinical trials for AD symptomatic treatment. Other approaches for slowing the progression of AD include serotonergic modulation, H3 receptor antagonism, phosphodiesterase, COX-2, and MAO-B inhibition. The present review provides an insight into the possible therapeutic strategies and their molecular mechanisms enlightening perception on classical and future treatment approaches.}, }
@article {pmid35358850, year = {2022}, author = {Tarafdar, A and Wolska, N and Krisp, C and Schlüter, H and Pula, G}, title = {The amyloid peptide β disrupts intercellular junctions and increases endothelial permeability in a NADPH oxidase 1-dependent manner.}, journal = {Redox biology}, volume = {52}, number = {}, pages = {102287}, doi = {10.1016/j.redox.2022.102287}, pmid = {35358850}, issn = {2213-2317}, abstract = {Alzheimer's disease is the most common form of dementia and is associated with the accumulation of amyloid peptide β in the brain parenchyma. Vascular damage and microvascular thrombosis contribute to the neuronal degeneration and the loss of brain function typical of this disease. In this study, we utilised a murine model of Alzheimer's disease to evaluate the neurovascular effects of this disease. Upon detection of an increase in the phosphorylation of the endothelial surface receptor VE-cadherin, we focused our attention on endothelial cells and utilised two types of human endothelial cells cultured in vitro: 1) human umbilical vein endothelial cells (HUVECs) and 2) human brain microvascular endothelial cells (hBMECs). Using an electrical current impedance system (ECIS) and FITC-albumin permeability assays, we discovered that the treatment of human endothelial cells with amyloid peptide β causes a loss in their barrier function, which is oxidative stress-dependent and similarly to our observation in mouse brain associates with VE-cadherin phosphorylation. The activation of the superoxide anion-generating enzyme NADPH oxidase 1 is responsible for the oxidative stress that leads to the disruption of barrier function in human endothelial cells in vitro. In summary, we have identified a novel molecular mechanism explaining how the accumulation of amyloid peptide β in the brain parenchyma may induce the loss of neurovascular barrier function, which has been observed in patients. Neurovascular leakiness plays an important role in brain inflammation and neuronal degeneration driving the progression of the Alzheimer's disease. Therefore, this study provides a novel and promising target for the development of a pharmacological treatment to protect neurovascular function and reduce the progression of the neurodegeneration in Alzheimer's patients.}, }
@article {pmid35358621, year = {2022}, author = {Ren, Q and Jiang, X and Paudel, YN and Gao, X and Gao, D and Zhang, P and Sheng, W and Shang, X and Liu, K and Zhang, X and Jin, M}, title = {Co-treatment with natural HMGB1 inhibitor Glycyrrhizin exerts neuroprotection and reverses Parkinson's disease like pathology in Zebrafish.}, journal = {Journal of ethnopharmacology}, volume = {292}, number = {}, pages = {115234}, doi = {10.1016/j.jep.2022.115234}, pmid = {35358621}, issn = {1872-7573}, mesh = {1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/therapeutic use ; Animals ; Disease Models, Animal ; Glycyrrhizic Acid/pharmacology/therapeutic use ; *HMGB1 Protein/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Molecular Docking Simulation ; Neuroprotection ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use ; *Parkinson Disease/drug therapy ; RNA, Messenger ; Zebrafish ; }, abstract = {Parkinson's disease (PD) is the second most devastating age-related neurodegenerative diseases after Alzheimer diseases (AD) and is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN) and aggregation of α-synuclein (α-syn). The precise etiology of PD is not yet fully understood and lacks the disease-modifying therapeutic strategies that could reverse the ongoing neurodegeneration. In the quest of exploring novel disease modifying therapeutic strategies, natural compounds from plant sources have gained much attention in recent days. Glycyrrhizin (GL) is the main active ingredient of the roots and rhizomes of licorice (Glycyrrhiza glabra L), which are generally used in the treatment of inflammatory diseases or as a tonifying herbal medicine. In Persia, GL is a conventional neuroprotective agent that are used to treat neurological disorders. The traditional use of GL in Japan is to treat chronic hepatitis B. In addition, GL is a natural inhibitor of high mobility group box 1 (HMGB1) which has exerted neuroprotective effect against several HMGB1 mediated pathological conditions.<br><br>AIM OF THE STUDY: The study is aimed to evaluate therapeutic effect of GL against PD in zebrafish.<br><br>MATERIAL AND METHODS: PD in zebrafish larvae is induced by administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Apoptosis was assessed with TUNEL assay. Gene expression was performed to assess the modulation in genes related to neuroinflammatory and autophagy.<br><br>RESULTS: We observed that GL co-treatment increased the length of DA neurons, decreased the number of apoptotic cells in zebrafish brain, and inhibited the loss of vasculature and disorganized vasculature induced by MPTP. GL co-treatment relieved the MPTP-induced locomotor impairment in zebrafish. GL co-treatment suppressed MPTP-induced upregulated mRNA expression of inflammatory markers such as hmgb1a, tlr4b, nfκb, il1β, and il6. GL co-treatment suppressed the autophagy related genes α-syn and atg5 whereas increased the mRNA expression level of parkin and pink1. In addition, molecular docking study reveals that GL has binding interaction with HMGB1, TLR4, and RAGE.<br><br>CONCLUSION: Hence, the effect of GL co-treatment on MPTP-induced PD-like condition in zebrafish is to alleviate apoptosis and autophagy, as well as suppress inflammatory responses.}, }
@article {pmid35356135, year = {2022}, author = {Kim, SH and Park, SS and Kim, CJ and Kim, TW}, title = {Exercise with 40-Hz light flicker improves hippocampal insulin signaling in Alzheimer disease mice.}, journal = {Journal of exercise rehabilitation}, volume = {18}, number = {1}, pages = {20-27}, pmid = {35356135}, issn = {2288-176X}, abstract = {We examined whether exercise is associated with hippocampus-mediated improvement in insulin signaling and cell differentiation in the triple transgenic mouse model of Alzheimer disease (3xTg AD) murine model following exposure to 40-Hz light flickering and exercise. We subjected 12-month-old 3xTg AD mice to exercise and 40-Hz light flickering for 3 months. The exercise session was proceeded for 12 consecutive weeks with gradual increase of intensity. To investigate insulin signaling proteins, western blot was conducted to detect the ratio of phosphorylated insulin receptor β (p-IRβ)/total IRβ (t-IRβ), phosphorylated insulin receptor substrate 1 (p-IRS-1)/total IRS-1 (t-IRS-1), phosphorylated phosphatidylinositide-3-kinase (p-PI3K)/total PI3K (t-PI3K), phosphorylated 3-phosphoinositide dependent protein kinase-1 (p-PDK1)/total PDK-1 (t-PDK1), phosphorylated protein kinase B (p-Akt)/total-Akt (t-Akt), and phosphorylated glycogen synthase kinase 3 beta (p-GSK3β)/total GSK3β (t-GSK3β). Doublecortin immunohistochemistry was performed for assessing cell differentiation in the hippocampus. Treatments exerted a positive effect. The combination of exercise and 40-Hz light flickering exposure was the most effective treatment enhancing insulin signaling. Increased ratio of p-IRβ/t-IRβ, p-IRS-1/t-IRS-1, p-PI3K/t-PI3K, p-PDK1/t-PDK1, p-Akt/t-Akt, and p-GSK3β/t-GSK3β and enhanced cell differentiation were observed in the 3xTg AD with exercise under 40-Hz light flickering group. Our results indicate that exercise under 40-Hz light flickering most potently improved insulin signaling, thereby promoted cell differentiation.}, }
@article {pmid35351154, year = {2022}, author = {Braun, B and Demling, J and Loew, TH}, title = {Alzheimer's disease: history, ethics and medical humanities in the context of assisted suicide.}, journal = {Philosophy, ethics, and humanities in medicine : PEHM}, volume = {17}, number = {1}, pages = {4}, pmid = {35351154}, issn = {1747-5341}, mesh = {*Alzheimer Disease/therapy ; *Dementia ; *Euthanasia ; Humans ; Quality of Life ; *Suicide, Assisted ; }, abstract = {INTRODUCTION: Dementia diseases, especially Alzheimer's disease (AD), are of considerable importance in terms of social policy and health economics. Moreover, against the background of the current Karlsruhe judgement on the legalisation of assisted suicide, there are also questions to be asked about medical humanities in AD.<br><br>METHODOLOGY: Relevant literature on complementary forms of therapy and prognosis was included and discussed.<br><br>RESULTS: Creative sociotherapeutic approaches (art, music, dance) and validating psychotherapeutic approaches show promise for suitability and efficiency in the treatment of dementia, but in some cases still need to be scientifically tested. Biomarker-based early diagnosis of dementia diseases is increasingly becoming a subject of debate against the background of the Karlsruhe ruling.<br><br>DISCUSSION: Needs-oriented and resource-enhancing approaches can make a significant contribution to improving the quality of life of people with dementia. The discussion on the issue of "assisted suicide" should include questions of the dignity and value of a life with dementia.<br><br>OUTLOOK: The integrative dementia therapy model can be complemented by a religion- and spirituality-based approach. Appropriate forms of psychotherapy should be scientifically evaluated.}, }
@article {pmid35350344, year = {2022}, author = {Shahid Nadeem, M and Azam Khan, J and Kazmi, I and Rashid, U}, title = {Design, Synthesis, and Bioevaluation of Indole Core Containing 2-Arylidine Derivatives of Thiazolopyrimidine as Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B for the Treatment of Alzheimer Disease.}, journal = {ACS omega}, volume = {7}, number = {11}, pages = {9369-9379}, pmid = {35350344}, issn = {2470-1343}, abstract = {In continuation of our previous study to identify multitarget inhibitors of cholinesterases (ChEs) and monoamine oxidase (MAOs) isoforms, we synthesized and evaluated 2-arylidine derivatives of thiazolopyrimidine for the treatment of Alzheimer disease. Three series of compounds with different linker size and target-anchoring functional groups were synthesized. Compounds 34-37 showed excellent to good AChE and BChE inhibition potential at nanomolar to low micromolar concentration. While all the compounds showed excellent MAO-B inhibition and selectivity relative to MAO-A, compounds 25 and 36 emerged as the most potent MAO-B inhibitors of all the series of synthesized compounds with IC50 values of 0.13 μM and 0.10 μM, respectively. Furthermore, kinetic studies of inhibitor 35 showed mixed inhibition mode. Exploration of structure activity relationship (SAR) revealed the role of functionalities and length of linkers on potency. Acute toxicity evaluation showed the safety of tested compounds up to 2000 mg/kg dose. PAMPA-BBB evaluation showed BBB permeability of the tested compounds, while MTT assay performed on neuroblastoma SHSY5Y cells showed that all the tested compounds are non-neurotoxic in the tested concentrations. Docking studies showed a strong correlation with experimental in vitro results via binding orientations and interaction patterns of the synthesized compounds into the binding sites of target enzymes. We have successfully identified safe, non-neurotoxic, and blood brain barrier permeable multitarget lead compounds for the treatment of AD.}, }
@article {pmid35346005, year = {2022}, author = {Prasanna, CAL and Sharma, A}, title = {Pharmacological exploration of triazole based therapeutics for Alzheimer disease: An overview.}, journal = {Current drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1389450123666220328153741}, pmid = {35346005}, issn = {1873-5592}, abstract = {Alzheimer`s disease (AD) is an irreversible progressive neurodegenerative disorder which may account for approximately 60-70% cases of dementia worldwide. AD is characterized by impaired behavioural and cognitive functions including memory, language, conception, attentiveness, judgment, and reasoning problems. The two important hallmarks of AD are the appearance of plaques and tangles of amyloid beta (Aβ) and tau proteins, respectively, in the brain based on the etiology of the disease including cholinergic impairment, metal dyshomeostasis, oxidative stress, and degradation of neurotransmitters. Currently, the used medication only provides alleviation of symptoms but not effective in curing the disease that is creating by an urge to develop new molecules to treat AD. Heterocyclic compounds have proven their ability to be developed as drugs for the treatment of various diseases. The five-membered heterocyclic compound triazole has received foremost fascination for the discovery of new drugs due to the possibility of structural variation and proved its significance in various drug categories. Therefore, this review summarizes mainly the recent advancements in the development of novel 1,2,3-triazole and 1,2,4-triazole based molecules in the drug discovery process for targeting various AD targets such as phosphodiesterase 1 (PDE1) Inhibitors, Apoptosis signal-regulating kinase 1 (ASK1) inhibitors, Somatostatin receptor subtype-4 (SSTR4) agonist, many other druggable targets, molecular modelling studies as well as various methodology for the synthesis of triazoles containing molecules such as Click reaction, Pellizzari and Einhorn-Brunner Reaction.}, }
@article {pmid35344024, year = {2022}, author = {Ross, EL and Weinberg, MS and Arnold, SE}, title = {Cost-effectiveness of Aducanumab and Donanemab for Early Alzheimer Disease in the US.}, journal = {JAMA neurology}, volume = {}, number = {}, pages = {}, pmid = {35344024}, issn = {2168-6157}, abstract = {Importance: Several anti-amyloid monoclonal antibodies have been developed for slowing the progression of Alzheimer disease (AD). Among the furthest developed are aducanumab, which received accelerated approval from the US Food and Drug Administration in 2021, and donanemab, which is currently undergoing phase 3 trials. The cost-effectiveness of these treatments has not been established.<br><br>Objectives: To estimate the cost-effectiveness of aducanumab and donanemab relative to standard care for early AD in the US.<br><br>A decision analytic model was used to estimate the lifetime health and economic outcomes of adults with early AD, from US healthcare sector and societal perspectives. Simulated patients had a mean (SD) age of 75.2 (5.5) years; 65% had mild cognitive impairment and 35% had mild dementia. Analyses were conducted from April 6, 2021, to January 20, 2022.<br><br>Interventions: Standard care, aducanumab (selected inputs including disease progression hazard ratio [HR] of 0.89 [95% CI, 0.63-1.15], annual price of $28 000, and twice-yearly monitoring with magnetic resonance imaging [MRI] of the brain), or donanemab (selected inputs including disease progression HR of 0.68 [95% CI, 0.44-0.99], annual price of $28 000, and twice-yearly monitoring with MRI of the brain and amyloid positron emission tomography [PET] monitoring). Donanemab was switched to placebo after substantial amyloid reduction on PET imaging, which occurred in 27% of patients at 6 months and 55% of patients at 12 months.<br><br>Main Outcomes and Measures: Quality-adjusted life-years (QALYs); costs, in 2020 US dollars; incremental cost-effectiveness ratios (ICERs); and value-based prices, defined as the maximum price at which a treatment would be cost-effective given a cost-effectiveness threshold of ICER of $150 000/QALY.<br><br>Results: Lifetime QALYs increased by 0.133 with aducanumab and 0.408 with donanemab. Total health care sector and societal costs increased by $130 100 and $127 800, respectively, with aducanumab and by $78 700 and $71 600, respectively, with donanemab, driven largely by drug costs ($119 000 for aducanumab and $44 600 for donanemab). Health care sector and societal ICERs relative to standard care were $981 000/QALY and $964 000/QALY, respectively, for aducanumab and $193 000/QALY and $176 000/QALY, respectively, for donanemab. In sensitivity analysis, aducanumab's value-based price remained less than $50 000/y, even when assuming a 90% reduction in disease progression. Donanemab's value-based price surpassed $50 000/y once its efficacy exceeded 50%.<br><br>Conclusions and Relevance: These findings suggest that at current expected prices, neither aducanumab nor donanemab would be cost-effective for early AD in the US. Donanemab's dosing scheme, in which patients suspend treatment on achieving substantial amyloid reductions, may provide a rubric by which sufficiently effective anti-amyloid antibody treatments could be cost-effective even when priced comparably to other biologics.}, }
@article {pmid35338074, year = {2022}, author = {Farrell, ME and Papp, KV and Buckley, RF and Jacobs, HIL and Schultz, AP and Properzi, MJ and Vannini, P and Hanseeuw, BJ and Rentz, DM and Johnson, KA and Sperling, RA}, title = {Association of Emerging β-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults.}, journal = {Neurology}, volume = {98}, number = {15}, pages = {e1512-e1524}, pmid = {35338074}, issn = {1526-632X}, support = {P01 AG036694/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; *Alzheimer Disease/diagnostic imaging/pathology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Cognition ; *Cognitive Dysfunction/pathology ; Humans ; Positron-Emission Tomography ; tau Proteins/metabolism ; }, abstract = {BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of β-amyloid (Aβ) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aβ and tau pathology.<br><br>METHODS: One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aβ (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time.<br><br>RESULTS: Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those <CL20 and expanded to include learning/memory retrieval (FCSRT-FR], Selective Reminding Test Total Recall [SRT-tr], Logical Memory Immediate Recall) in the <CL40 group. FTP had limited effects under CL20, with only rising right IT FTP slope related to declining FCSRT-FR and SRT-tr learning/memory retrieval. When we expanded to include those initially <CL40, rising FTP level or slope was related to declines across all tasks, and PiB slope effects on memory retrieval but not DSST score were reduced. A composite measure of processing speed and memory retrieval tasks provided the strongest prediction of decline under CL40, while PACC score remained optimal at high levels of Aβ (>CL40).<br><br>DISCUSSION: Early, Aβ-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aβ and tau pathology. Composites of these measures may help determine whether anti-Aβ or anti-tau therapies administered at the first signs of pathology might preserve cognitive function.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.}, }
@article {pmid35337343, year = {2022}, author = {Sofranko, A and Wahle, T and Kolling, J and Heusinkveld, HJ and Stahlmecke, B and Rosenbruch, M and Albrecht, C and Schins, RPF}, title = {Effects of subchronic dietary exposure to the engineered nanomaterials SiO2 and CeO2 in C57BL/6J and 5xFAD Alzheimer model mice.}, journal = {Particle and fibre toxicology}, volume = {19}, number = {1}, pages = {23}, pmid = {35337343}, issn = {1743-8977}, mesh = {*Alzheimer Disease/chemically induced/pathology ; Animals ; Brain/pathology ; Dietary Exposure ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; *Nanostructures/toxicity ; Plaque, Amyloid/chemically induced ; Silicon Dioxide/toxicity ; }, abstract = {BACKGROUND: There is an increasing concern about the neurotoxicity of engineered nanomaterials (NMs). To investigate the effects of subchronic oral exposures to SiO2 and CeO2 NMs on Alzheimer's disease (AD)-like pathology, 5xFAD transgenic mice and their C57BL/6J littermates were fed ad libitum for 3 or 14 weeks with control food pellets, or pellets dosed with these respective NMs at 0.1% or 1% (w/w). Behaviour effects were evaluated by X-maze, string suspension, balance beam and open field tests. Brains were analysed for plaque load, beta-amyloid peptide levels, markers of oxidative stress and neuroinflammation.<br><br>RESULTS: No marked behavioural impairments were observed in the mice exposed to SiO2 or CeO2 and neither treatment resulted in accelerated plaque formation, increased oxidative stress or inflammation. In contrast, the 5xFAD mice exposed to 1% CeO2 for 14 weeks showed significantly lower hippocampal Aβ plaque load and improved locomotor activity compared to the corresponding controls.<br><br>CONCLUSIONS: The findings from the present study suggest that long-term oral exposure to SiO2 or CeO2 NMs has no neurotoxic and AD-promoting effects. The reduced plaque burden observed in the mice following dietary CeO2 exposure warrants further investigation to establish the underlying mechanism, given the easy applicability of this administration method.}, }
@article {pmid35328650, year = {2022}, author = {Barrón-González, M and Rosales-Hernández, MC and Abad-García, A and Ocampo-Néstor, AL and Santiago-Quintana, JM and Pérez-Capistran, T and Trujillo-Ferrara, JG and Padilla-Martínez, II and Farfán-García, ED and Soriano-Ursúa, MA}, title = {Synthesis, In Silico, and Biological Evaluation of a Borinic Tryptophan-Derivative That Induces Melatonin-like Amelioration of Cognitive Deficit in Male Rat.}, journal = {International journal of molecular sciences}, volume = {23}, number = {6}, pages = {}, pmid = {35328650}, issn = {1422-0067}, support = {M2143//Instituto Politécnico Nacional/ ; 2143//Consejo Nacional de Ciencia y Tecnología/ ; }, mesh = {Animals ; Cognition ; Male ; *Melatonin/pharmacology/therapeutic use ; Rats ; *Receptor, Melatonin, MT1/agonists ; Receptor, Melatonin, MT2 ; Tryptophan ; }, abstract = {Preclinical and clinical evidence supports melatonin and its analogues as potential treatment for diseases involving cognitive deficit such as Alzheimer's disease. In this work, we evaluated by in silico studies a set of boron-containing melatonin analogues on MT1 and MT2 receptors. Then, we synthesized a compound (borolatonin) identified as potent agonist. After chemical characterization, its evaluation in a rat model with cognitive deficit showed that it induced ameliorative effects such as those induced by equimolar administration of melatonin in behavioral tests and in neuronal immunohistochemistry assays. Our results suggest the observed effects are by means of action on the melatonin system. Further studies are required to clarify the mechanism(s) of action, as the beneficial effects on disturbed memory by gonadectomy in male rats are attractive.}, }
@article {pmid35327020, year = {2022}, author = {Sánchez-Pérez, A and Mendialdua-Canales, D and Hurtado-Pomares, M and Peral-Gómez, P and Juárez-Leal, I and Espinosa-Sempere, C and Fernández-Pires, P and Zango-Martín, I and Abellán-Miralles, I and López-González, P and Valera-Gran, D and Navarrete-Muñoz, EM}, title = {The ATENción Plena en Enfermedad de Alzheimer (ATENEA-Mindfulness in Alzheimer's Disease) Program for Caregivers: Study Protocol for a Randomized Controlled Trial.}, journal = {Healthcare (Basel, Switzerland)}, volume = {10}, number = {3}, pages = {}, pmid = {35327020}, issn = {2227-9032}, support = {Ayudas de difusión de la Ciencia//Miguel Hernández University/ ; }, abstract = {A person affected by Alzheimer's disease (AD) gradually loses the ability to perform activities of daily living and becomes dependent on caregivers, thereby having a negative impact on the caregivers' quality of life. There is evidence that suggests that interventions aimed at caregivers, such as mindfulness, may be effective at reducing this burden and emotional issues, such as depression and anxiety, and improving their quality of life. However, there is a lack of consistency in the findings and conclusions remain tentative. In addition, as neuropsychiatric symptoms (NPSs) of AD are major determinants of the caregiver's burden, these interventions should examine the relationship between these symptoms and caregiver outcomes. Importantly, to improve the design of therapeutic interventions for caregivers and complement the treatment of AD, aspects related to occupational performance and the participation of people with AD and their caregivers should also be considered. Therefore, this study will aim to examine first, the effects of a mindfulness-based program designed for caregivers on NPSs of AD and caregivers' anxiety and depression; second, the effects of this program on patients' functional capacity, cognitive performance, executive functions, and quality of life, and on caregivers' burden, quality of life, occupational balance, executive functions, psychological wellbeing, and self-compassion. We believe that the findings of this study will have significant implications for future healthcare strategies focused on improving the quality of life and wellbeing of caregivers.}, }
@article {pmid35310894, year = {2021}, author = {Kuchta, K and Aritake, K and Urade, Y and Tung, NH and Yuan, CS and Sasaki, Y and Shimizu, K and Shoyama, Y}, title = {Preventing Dementia Using Saffron, The Kampo Medicine, Kamiuntanto, and Their Combination, Kamiuntantokabankoka.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {779821}, pmid = {35310894}, issn = {1663-9812}, abstract = {The objective of this review is to evaluate the anti-dementia activities of saffron and its combination with Kampo medicine. The Kampo formula Kamiuntanto composed of 13 crude drugs is well known for its anti-dementia activity. A significant increase in choline acetyltransferase activity and mRNA levels were observed. Polygala radix was identified as the most essential component drug in Kamiuntanto, probably due to the saponins, tenuifolin, and sinapinic acid. Ginseng was also identified as an essential Kamiuntanto component in terms of its synergistic functions with Polygala radix. Saffron, which was recommended in the Bencao Gangmu for memory and dementia, and is used as an anti-spasmodic, anti-catarrhal, and sedative herbal drug. Saffron and its major constituent, crocin were shown to enhance learning-memory, non-rapid eye movement (rem) sleep, and inhibit depression and neuronal cell death due to strong anti-oxidant and anti-inflammation activities. In addition based on the epidemiological studies such as the treatment of sleeping disorders and the clinical trials of saffron for Alzheimer patients, we demonstrated the indirect and direct anti-dementia activities of crocin and saffron.}, }
@article {pmid35310529, year = {2022}, author = {Marianetti, M and Pinna, S and Venuti, A and Liguri, G}, title = {Olive polyphenols and bioavailable glutathione: Promising results in patients diagnosed with mild Alzheimer's disease.}, journal = {Alzheimer's &amp; dementia (New York, N. Y.)}, volume = {8}, number = {1}, pages = {e12278}, pmid = {35310529}, issn = {2352-8737}, abstract = {Introduction: Recent studies highlighted the role of olive polyphenols in disrupting the ordered structure of highly cytotoxic amyloid beta protofibrils and the efficacy of a derivatized form of glutathione to counteract neuronal oxidative stress affecting specific brain regions at early stages of Alzheimer's disease (AD) pathogenesis. We performed a randomized cross-over clinical trial to evaluate their potential benefits in mild AD.<br><br>Methods: Oleuropein and S-acetyl glutathione were administered as dietary supplement for 6 months to 18 patients diagnosed for probable mild AD according to International Working Group 2 criteria. Patients underwent an extensive cognitive and behavioral neuropsychological test battery at the beginning and end of the study to evaluate cognitive deterioration, memory, visuospatial abilities, attention, language, executive functions, and behavioral disorders. We compared patients receiving treatment to patients receiving no treatment.<br><br>Results: All the measured neurocognitive parameters stabilized or improved after the treatment in all patients.<br><br>Discussion: Dietary supplement with olive polyphenols and bioavailable glutathione could be useful for patients diagnosed with mild AD.}, }
@article {pmid35309883, year = {2022}, author = {Seo, SY and Kim, SJ and Oh, JS and Chung, J and Kim, SY and Oh, SJ and Joo, S and Kim, JS}, title = {Unified Deep Learning-Based Mouse Brain MR Segmentation: Template-Based Individual Brain Positron Emission Tomography Volumes-of-Interest Generation Without Spatial Normalization in Mouse Alzheimer Model.}, journal = {Frontiers in aging neuroscience}, volume = {14}, number = {}, pages = {807903}, pmid = {35309883}, issn = {1663-4365}, abstract = {Although skull-stripping and brain region segmentation are essential for precise quantitative analysis of positron emission tomography (PET) of mouse brains, deep learning (DL)-based unified solutions, particularly for spatial normalization (SN), have posed a challenging problem in DL-based image processing. In this study, we propose an approach based on DL to resolve these issues. We generated both skull-stripping masks and individual brain-specific volumes-of-interest (VOIs-cortex, hippocampus, striatum, thalamus, and cerebellum) based on inverse spatial normalization (iSN) and deep convolutional neural network (deep CNN) models. We applied the proposed methods to mutated amyloid precursor protein and presenilin-1 mouse model of Alzheimer's disease. Eighteen mice underwent T2-weighted MRI and 18F FDG PET scans two times, before and after the administration of human immunoglobulin or antibody-based treatments. For training the CNN, manually traced brain masks and iSN-based target VOIs were used as the label. We compared our CNN-based VOIs with conventional (template-based) VOIs in terms of the correlation of standardized uptake value ratio (SUVR) by both methods and two-sample t-tests of SUVR % changes in target VOIs before and after treatment. Our deep CNN-based method successfully generated brain parenchyma mask and target VOIs, which shows no significant difference from conventional VOI methods in SUVR correlation analysis, thus establishing methods of template-based VOI without SN.}, }
@article {pmid35306635, year = {2022}, author = {Smedinga, M and Bunnik, EM and Richard, E and Schermer, MHN}, title = {Should Doctors Offer Biomarker Testing to Those Afraid to Develop Alzheimer's Dementia? : Applying the Method of Reflective Equilibrium for a Clinical Dilemma.}, journal = {Journal of bioethical inquiry}, volume = {}, number = {}, pages = {}, pmid = {35306635}, issn = {1176-7529}, support = {115952//Innovative Medicines Initiative/ ; 731010012/ZONMW_/ZonMw/Netherlands ; }, abstract = {An increasing number of people seek medical attention for mild cognitive symptoms at older age, worried that they might develop Alzheimer's disease. Some clinical practice guidelines suggest offering biomarker testing in such cases, using a brain scan or a lumbar puncture, to improve diagnostic certainty about Alzheimer's disease and enable an earlier diagnosis. Critics, on the other hand, point out that there is no effective Alzheimer treatment available and argue that biomarker tests lack clinical validity. The debate on the ethical desirability of biomarker testing is currently polarized; advocates and opponents tend to focus on their own line of arguments. In this paper, we show how the method of reflective equilibrium (RE) can be used to systematically weigh the relevant arguments on both sides of the debate to decide whether to offer Alzheimer biomarker testing. In the tradition of RE, we reflect upon these arguments in light of their coherence with other argumentative elements, including relevant facts (e.g. on the clinical validity of the test), ethical principles, and theories on societal ideals or relevant concepts, such as autonomy. Our stance in the debate therefore rests upon previously set out in-depth arguments and reflects a wide societal perspective.}, }
@article {pmid35305135, year = {2022}, author = {Nahálková, J}, title = {Finding New Ways How to Control BACE1.}, journal = {The Journal of membrane biology}, volume = {}, number = {}, pages = {}, pmid = {35305135}, issn = {1432-1424}, abstract = {Recently, all applications of BACE1 inhibitors failed as therapeutical targets for Alzheimer´s disease (AD) due to severe side effects. Therefore, alternative ways for treatment development are a hot research topic. The present analysis investigates BACE1 protein-protein interaction networks and attempts to solve the absence of complete knowledge about pathways involving BACE1. A bioinformatics analysis matched the functions of the non-substrate interaction network with Voltage-gated potassium channels, which also appear as top priority protein nodes. Targeting BACE1 interactions with PS1 and GGA-s, blocking of BACE1 access to APP by BRI3 and RTN-s, activation of Wnt signaling and upregulation of β-catenin, and brain delivery of the extracellular domain of p75NTR, are the main alternatives to the use of BACE 1 inhibitors highlighted by the analysis. The pathway enrichment analysis also emphasized substrates and substrate candidates with essential biological functions, which cleavage must remain controlled. They include ephrin receptors, ROBO1, ROBO2, CNTN-s, CASPR-s, CD147, CypB, TTR, APLP1/APLP2, NRXN-s, and PTPR-s. The analysis of the interaction subnetwork of BACE1 functionally related to inflammation identified a connection to three cardiomyopathies, which supports the hypothesis of the common molecular mechanisms with AD. A lot of potential shows the regulation of BACE1 activity through post-translational modifications. The interaction network of BACE1 and its phosphorylation enzyme CSNK1D functionally match the Circadian clock, p53, and Hedgehog signaling pathways. The regulation of BACE1 glycosylation could be achieved through N-acetylglucosamine transferases, α-(1→6)-fucosyltransferase, β-galactoside α-(2→6)-sialyltransferases, galactosyltransferases, and mannosidases suggested by the interaction network analysis of BACE1-MGAT3. The present analysis proposes possibilities for the alternative control of AD pathology.}, }
@article {pmid35303111, year = {2022}, author = {Doherty, JM and Roe, CM and Murphy, SA and Johnson, AM and Fleischer, E and Toedebusch, CD and Redrick, T and Freund, D and Morris, JC and Schindler, SE and Fagan, AM and Holtzman, DM and Lucey, BP and Babulal, GM}, title = {Adverse driving behaviors are associated with sleep apnea severity and age in cognitively normal older adults at risk for Alzheimer's disease.}, journal = {Sleep}, volume = {}, number = {}, pages = {}, doi = {10.1093/sleep/zsac070}, pmid = {35303111}, issn = {1550-9109}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; R01 AG068183/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG074302/AG/NIA NIH HHS/United States ; R01 AG067428/AG/NIA NIH HHS/United States ; K76 AG054863/AG/NIA NIH HHS/United States ; R01 AG056466/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer disease (AD) pathology accumulates for decades before the onset of cognitive decline. Cognitively normal individuals with biomarker evidence of AD brain pathology (i.e., biomarker+ or preclinical AD) can be differentiated from individuals without AD brain pathology based on naturalistic driving data, such as hard acceleration or braking and speeding, measured using in-vehicle dataloggers. Older adults are at increased risk of injury and death from motor vehicle crashes and driving cessation is also linked to negative health outcomes. Identifying potential modifiable risk factors that increase driving risk may prolong safe driving in old age. Sleep apnea is associated with adverse driving behaviors across the age-span. In this study, we hypothesized that high-risk driving behaviors would be associated with increased sleep apnea severity and AD pathology. We found that higher sleep apnea severity measured by a home sleep apnea test was associated with a higher incidence of adverse driving behaviors even after controlling for multiple confounders (β=0.24±0.09,p<0.01). This association was independent of AD biomarker positivity (i.e., increased t-tau/Aβ42 ratio. Increasing age was associated with a higher likelihood of high-risk driving behaviors in individuals with AD brain pathology (β=0.12±0.04,p<0.01), but a lower likelihood in individuals without AD brain pathology (β=-0.06±0.03,p<0.05). These findings suggest that adverse driving behaviors linked to a higher rate of traffic crashes in older adults are associated with sleep apnea severity and AD pathology even in cognitively unimpaired individuals. Futures studies are needed to determine if treatment of sleep apnea decreases high-risk driving behaviors and therefore motor vehicle crashes.}, }
@article {pmid35298477, year = {2022}, author = {Chen, S and Underwood, BR and Jones, PB and Lewis, JR and Cardinal, RN}, title = {Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study.}, journal = {PLoS medicine}, volume = {19}, number = {3}, pages = {e1003941}, pmid = {35298477}, issn = {1549-1676}, support = {MC_PC_17213/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aged ; *Alzheimer Disease/epidemiology ; Cohort Studies ; *Dementia, Vascular ; Humans ; Incidence ; Lithium ; Male ; Middle Aged ; }, abstract = {BACKGROUND: Dementia is the leading cause of death in elderly Western populations. Preventative interventions that could delay dementia onset even modestly would provide a major public health impact. There are no disease-modifying treatments currently available. Lithium has been proposed as a potential treatment. We assessed the association between lithium use and the incidence of dementia and its subtypes.<br><br>METHODS AND FINDINGS: We conducted a retrospective cohort study comparing patients treated between January 1, 2005 and December 31, 2019, using data from electronic clinical records of secondary care mental health (MH) services in Cambridgeshire and Peterborough NHS Foundation Trust (CPFT), United Kingdom (catchment area population approximately 0.86 million). Eligible patients were those aged 50 years or over at baseline and who had at least 1 year follow-up, excluding patients with a diagnosis of mild cognitive impairment (MCI) or dementia before, or less than 1 year after, their start date. The intervention was the use of lithium. The main outcomes were dementia and its subtypes, diagnosed and classified according to the International Classification of Diseases-10th Revision (ICD-10). In this cohort, 29,618 patients (of whom 548 were exposed to lithium) were included. Their mean age was 73.9 years. A total of 40.2% were male, 33.3% were married or in a civil partnership, and 71.0% were of white ethnicity. Lithium-exposed patients were more likely to be married, cohabiting or in a civil partnership, to be a current/former smoker, to have used antipsychotics, and to have comorbid depression, mania/bipolar affective disorder (BPAD), hypertension, central vascular disease, diabetes mellitus, or hyperlipidemias. No significant difference between the 2 groups was observed for other characteristics, including age, sex, and alcohol-related disorders. In the exposed cohort, 53 (9.7%) patients were diagnosed with dementia, including 36 (6.8%) with Alzheimer disease (AD) and 13 (2.6%) with vascular dementia (VD). In the unexposed cohort, corresponding numbers were the following: dementia 3,244 (11.2%), AD 2,276 (8.1%), and VD 698 (2.6%). After controlling for sociodemographic factors, smoking status, other medications, other mental comorbidities, and physical comorbidities, lithium use was associated with a lower risk of dementia (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.40 to 0.78), including AD (HR 0.55, 95% CI 0.37 to 0.82) and VD (HR 0.36, 95% CI 0.19 to 0.69). Lithium appeared protective in short-term (≤1-year exposure) and long-term lithium users (>5-year exposure); a lack of difference for intermediate durations was likely due to lack of power, but there was some evidence for additional benefit with longer exposure durations. The main limitation was the handling of BPAD, the most common reason for lithium prescription but also a risk factor for dementia. This potential confounder would most likely cause an increase in dementia in the exposed group, whereas we found the opposite, and the sensitivity analysis confirmed the primary results. However, the specific nature of the group of patients exposed to lithium means that caution is needed in extending these findings to the general population. Another limitation is that our sample size of patients using lithium was small, reflected in the wide CIs for results relating to some durations of lithium exposure, although again sensitivity analyses remained consistent with our primary findings.<br><br>CONCLUSIONS: We observed an association between lithium use and a decreased risk of developing dementia. This lends further support to the idea that lithium may be a disease-modifying treatment for dementia and that this is a promising treatment to take forwards to larger randomised controlled trials (RCTs) for this indication.}, }
@article {pmid35289333, year = {2022}, author = {Park, H and Yamanaka, T and Nukina, N}, title = {Proteomic analysis of heat-stable proteins revealed an increased proportion of proteins with compositionally biased regions.}, journal = {Scientific reports}, volume = {12}, number = {1}, pages = {4347}, pmid = {35289333}, issn = {2045-2322}, support = {JP20dm0107140//Japan Agency for Medical Research and Development (AMED)/ ; 17H01564//Ministry of Education, Culture, Sports, Science and Technology (MEXT)/ ; }, abstract = {Intrinsically disordered proteins (IDPs) have been in the spotlight for their unique properties, such as their lack of secondary structures and low sequence complexity. Alpha-synuclein and tau are representative disease-related IDPs with low complexity regions in their sequences, accumulating in the brains of patients with Parkinson disease and Alzheimer disease, respectively. Their heat resistance in particular was what attracted our attention. We assumed that there exist many other unidentified proteins that are resistant to heat-treatment, referred to as heat-stable proteins, which would also have low sequence complexity. In this study, we performed proteomic analysis of heat-stable proteins of mouse brains and found that proteins with compositionally biased regions are abundant in the heat-stable proteins. The proteins related to neurodegeneration are known to undergo different types of post-translational modifications (PTMs) such as phosphorylation and ubiquitination. We then investigated the heat-stability and aggregation properties of phosphorylated synuclein and tau with different phosphorylation sites. We suggest that PTMs can be important factors that determine the heat-stability and aggregation properties of a protein. IDPs identified in the heat-stable proteins of mouse brains would be candidates for the pathogenic proteins for neurodegeneration.}, }
@article {pmid35286990, year = {2022}, author = {Suarez Moreno, A and Nguyen, JP and Calmelet, A and Le Saout, E and Damier, P and de Decker, L and Malineau, C and Nizard, J and Canoui-Poitrine, F and Lefaucheur, JP}, title = {Multi-site rTMS with cognitive training improves apathy in the long term in Alzheimer's disease: A 4-year chart review.}, journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology}, volume = {137}, number = {}, pages = {75-83}, doi = {10.1016/j.clinph.2022.02.017}, pmid = {35286990}, issn = {1872-8952}, mesh = {*Alzheimer Disease/diagnosis ; *Apathy ; Cognition ; *Cognition Disorders ; Humans ; Neuropsychological Tests ; Transcranial Magnetic Stimulation/methods ; }, abstract = {OBJECTIVE: To assess the long-term effects of multi-site repetitive transcranial magnetic stimulation combined with cognitive training (NeuroAD procedure) on cognitive symptoms and apathy in patients with Alzheimer's disease (AD) as part of a 4-year chart review.<br><br>METHODS: The study included the 30 AD patients who underwent NeuroAD treatment between 2015 and 2019 at our center. The clinical evaluation was based on the Mini Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Apathy Inventory (AI). Assessment was performed before treatment (baseline), after an initial 6-week protocol of 30 sessions (M1.5), then 3 months (M3), 1 year (M12), and between 1.5 and 4 years (mean 28 months, M28) after treatment initiation.<br><br>RESULTS: During the first year of follow-up, the AI score improved at all time points (M1.5, M3, M12, p < 0.0001), the ADAS-Cog score improved at the end of the initial procedure (M1.5, p = 0.003) then deteriorated (M12, p = 0.01), while the MMSE score did not change. At final assessment (M28), the AI score was still improved from baseline (p < 0.0001), while the MMSE and ADAS-Cog scores worsened (p < 0.0001). Regarding the ADAS-Cog score, the prolonged improvement at M12 or M28 was correlated with the initial improvement at M1.5.<br><br>CONCLUSION: The NeuroAD procedure produced long-term improvement in apathy and more general cognitive improvement only in patients who responded well to the initial 6-week protocol.<br><br>SIGNIFICANCE: Our results suggest long-term beneficial effects of the NeuroAD procedure on apathy, which need to be confirmed in controlled studies. The criteria for predicting a good outcome before starting the procedure remain to be defined.}, }
@article {pmid35278001, year = {2022}, author = {Imai, A and Matsuoka, T and Kato, Y and Narumoto, J}, title = {Diagnostic performance and neural basis of the combination of free- and pre-drawn Clock Drawing Test.}, journal = {International journal of geriatric psychiatry}, volume = {37}, number = {4}, pages = {}, doi = {10.1002/gps.5699}, pmid = {35278001}, issn = {1099-1166}, abstract = {OBJECTIVES: This study aimed to clarify the diagnostic performance and neural basis of the Clock Drawing Test (CDT) combining free- and pre-drawn methods.<br><br>METHODS: This retrospective study included 165 participants (91 with Alzheimer disease [AD], 52 with amnestic mild cognitive impairment [aMCI], and 22 healthy controls [HC]), who were divided into four groups according to their free- and pre-drawn CDT scores: group 1, could do both; group 2, impaired in both; group 3, impaired in pre-drawn CDT; and group 4, impaired in free-drawn CDT. The diagnostic performances of the free-drawn, pre-drawn, and combination methods were compared using receiver operating characteristics analysis; in voxel-based morphometry analysis, the gray matter (GM) volume of groups 2-4 were compared with that of group 1.<br><br>RESULTS: The area under the curve of the combination method was greater than that of the free- or pre-drawn method alone when comparing AD with HC or aMCI. Group 2 had a significantly smaller GM volume in the bilateral temporal lobes than group 1. Group 3 had a trend toward smaller GM volumes in the right temporal lobe when a liberal threshold was applied. Group 4 had significantly smaller GM volumes in the left temporal lobe than group 1.<br><br>CONCLUSIONS: This study suggests that the combination method may be able to screen for a wider range of brain dysfunction. Combined use of free- and pre-drawn CDT may be useful for screening for AD and its early detection and treatment.}, }
@article {pmid35276233, year = {2022}, author = {Romero-Márquez, JM and Navarro-Hortal, MD and Jiménez-Trigo, V and Vera-Ramírez, L and Forbes-Hernández, TJ and Esteban-Muñoz, A and Giampieri, F and Bullón, P and Battino, M and Sánchez-González, C and Quiles, JL}, title = {An oleuropein rich-olive (Olea europaea L.) leaf extract reduces β-amyloid and tau proteotoxicity through regulation of oxidative- and heat shock-stress responses in Caenorhabditis elegans.}, journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association}, volume = {162}, number = {}, pages = {112914}, doi = {10.1016/j.fct.2022.112914}, pmid = {35276233}, issn = {1873-6351}, abstract = {Olive tree-derived products have been associated with numerous benefits for health. The aim of the present study was to characterize an olive leaf extract enriched in oleuropein (OLE) concerning phenolic content and profile as well as antioxidant capacity. Short-term and long-term toxicity, including oxidative stress, was in vivo evaluated in the experimental model Caenorhabditis elegans. Moreover, the potential therapeutic effect of the extract against Aβ induced- and tau protein induced-toxicity was also evaluated in C. elegans. OLE treatment did not exert toxicity. On the contrary, the extract was able to ameliorate oxidative stress and proteotoxicity related to Aβ and tau aggregation. The potential molecular mechanisms present behind the observed results explored by RNAi technology revealed that DAF-16/FOXO and SKN-1/NRF2, elements of the insulin insulin-like signalling pathway, as well as HSP-16.2 overexpression were involved.}, }
@article {pmid35273492, year = {2021}, author = {Efjestad, AS and Ihle-Hansen, H and Hjellvik, V and Engedal, K and Blix, HS}, title = {Use of Drugs With Risk of Heart Rate-Related Problems is Common in Norwegian Dementia Patients Treated With Acetylcholinesterase Inhibitors: A Prevalence Study Based on the Norwegian Prescription Database.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {791578}, pmid = {35273492}, issn = {1663-9812}, abstract = {Background: Drugs commonly prescribed for heart rate control may induce adverse drug reactions in Alzheimer patients treated with acetylcholinesterase inhibitors (AChEIs). We have studied use of drugs with a known risk of Torsades de pointes (TdP) and drugs used to treat behavioral and psychological symptoms of dementia, as well as a combination of drugs with a known risk of TdP and drugs with a known heart rate-lowering effect, before and after initiating treatment with AChEIs. Methods: The study applied data from the Norwegian Prescription Database for the period 2004-2016. Prescriptions of concomitant use of drugs in persistent users of AChEIs was studied in a follow-up period from 4 years before to 2 years after AChEI initiation in men and women of two age groups: 37-80 and 81-88 years. Results: A small number of patients were prescribed haloperidol (∼1.5% The second year after AChEI initiation), digoxin/digitoxin (∼3%), and verapamil (∼1.3%), while a substantial proportion of the patients were prescribed betablockers (∼28%) and citalopram/escitalopram (∼17%). During follow-up, up to 6% of the study population were prescribed both betablockers and citalopram/citalopram in addition to AChEIs, a combination that increased over the follow-up period and was observed most frequently in women in the oldest age group. Conclusions: A large proportion (∼44%) of patients treated with AChEIs were prescribed drugs that could cause bradycardic and prolonged time from the start of the Q wave to the end of the T wave (QT interval). Thus, action should be taken to reduce the combination of drugs with risk of bradycardia and prolonged QT interval. Medication review on a regular basis could be an option as an important risk-reducing intervention.}, }
@article {pmid35265207, year = {2022}, author = {Yang, L and Wu, C and Parker, E and Li, Y and Dong, Y and Tucker, L and Brann, DW and Lin, HW and Zhang, Q}, title = {Non-invasive photobiomodulation treatment in an Alzheimer Disease-like transgenic rat model.}, journal = {Theranostics}, volume = {12}, number = {5}, pages = {2205-2231}, pmid = {35265207}, issn = {1838-7640}, mesh = {Aged ; *Alzheimer Disease/genetics/radiotherapy ; Amyloid beta-Peptides ; Animals ; Disease Models, Animal ; Humans ; *Neurodegenerative Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Plaque, Amyloid ; Quality of Life ; Rats ; Rats, Transgenic ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia in the elderly, causing neuronal degeneration and cognitive deficits that significantly impair independence and quality of life for those affected and their families. Though AD is a major neurodegenerative disease with vast avenues of investigation, there is no effective treatment to cure AD or slow disease progression. The present work evaluated the therapeutic effect of long-term photobiomodulation (PBM) treatment with continuous-wave low-level laser on AD and its underlying mechanism. Methods: PBM was implemented for 2 min, 3 times per week for 16 months in 2-month-old transgenic AD rats. A battery of behavioral tests was performed to measure the effect of PBM treatment on cognitive dysfunction in AD rats. The effects of PBM therapy on typical AD pathologies, including amyloid plaques, intracellular neurofibrillary tangles, neuronal loss, neuronal injury, neuronal apoptosis, and neurodegeneration, were then assessed. The underlying mechanisms were measured using immunofluorescence staining, western blotting analysis, mass spectrometry, primary cortical and hippocampal cell cultures, and related assay kits. Results: PBM treatment significantly improved the typical AD pathologies of memory loss, amyloid plaques, tau hyperphosphorylation, neuronal degeneration, spine damage, and synaptic loss. PBM treatment had several mechanistic effects which may explain these beneficial effects, including 1) regulation of glial cell polarization and inhibition of neuroinflammation, 2) preservation of mitochondrial dynamics by regulating fission and fusion proteins, and 3) suppression of oxidative damage to DNA, proteins, and lipids. Furthermore, PBM enhanced recruitment of microglia surrounding amyloid plaques by improving the expression of microglial IL-3Rα and astrocytic IL-3, which implies a potential role of PBM in improving Aβ clearance. Finally, our results implicate neuronal hemoglobin in mediating the neuroprotective effect of PBM, as Hbα knockdown abolished the neuroprotective effect of PBM treatment. Conclusion: Collectively, our data supports the potential use of PBM treatment to prevent or slow the progression of AD and provides new insights into the molecular mechanisms of PBM therapy.}, }
@article {pmid35262881, year = {2022}, author = {Estella, F and Suarez, E and Lozano, B and Santamarta, E and Saiz, A and Rojas, F and Rojas, I and Blazquez, M and Nader, L and Sol, J and Seijo, F}, title = {Design and Application of Automated Algorithms for Diagnosis and Treatment Optimization in Neurodegenerative Diseases.}, journal = {Neuroinformatics}, volume = {}, number = {}, pages = {}, pmid = {35262881}, issn = {1559-0089}, abstract = {Neurodegenerative diseases represent a growing healthcare problem, mainly related to an aging population worldwide and thus their increasing prevalence. In particular, Alzheimer's disease (AD) and Parkinson's disease (PD) are leading neurodegenerative diseases. To aid their diagnosis and optimize treatment, we have developed a classification algorithm for AD to manipulate magnetic resonance images (MRI) stored in a large database of patients, containing 1,200 images. The algorithm can predict whether a patient is healthy, has mild cognitive impairment, or already has AD. We then applied this classification algorithm to therapeutic outcomes in PD after treatment with deep brain stimulation (DBS), to assess which stereotactic variables were the most important to consider when performing surgery in this indication. Here, we describe the stereotactic system used for DBS procedures, and compare different planning methods with the gold standard normally used (i.e., neurophysiological coordinates recorded intraoperatively). We used information collected from database of 72 DBS electrodes implanted in PD patients, and assessed the potentially most beneficial ranges of deviation within planning and neurophysiological coordinates from the operating room, to provide neurosurgeons with additional landmarks that may help to optimize outcomes: we observed that x coordinate deviation within CT scan and gold standard intra-operative neurophysiological coordinates is a robust matric to pre-assess positive therapy outcomes- "good therapy" prediction if deviation is higher than 2.5 mm. When being less than 2.5 mm, adding directly calculated variables deviation (on Y and Z axis) would lead to specific assessment of "very good therapy".}, }
@article {pmid35262497, year = {2022}, author = {Cheah, WT and Hwang, JJ and Hong, SY and Fu, LC and Chang, YL and Chen, TF and Chen, IA and Chou, CC}, title = {A Digital Screening System for Alzheimer Disease Based on a Neuropsychological Test and a Convolutional Neural Network: System Development and Validation.}, journal = {JMIR medical informatics}, volume = {10}, number = {3}, pages = {e31106}, pmid = {35262497}, issn = {2291-9694}, abstract = {BACKGROUND: Alzheimer disease (AD) and other types of dementia are now considered one of the world's most pressing health problems for aging people worldwide. It was the seventh-leading cause of death, globally, in 2019. With a growing number of patients with dementia and increasing costs for treatment and care, early detection of the disease at the stage of mild cognitive impairment (MCI) will prevent the rapid progression of dementia. In addition to reducing the physical and psychological stress of patients' caregivers in the long term, it will also improve the everyday quality of life of patients.<br><br>OBJECTIVE: The aim of this study was to design a digital screening system to discriminate between patients with MCI and AD and healthy controls (HCs), based on the Rey-Osterrieth Complex Figure (ROCF) neuropsychological test.<br><br>METHODS: The study took place at National Taiwan University between 2018 and 2019. In order to develop the system, pretraining was performed using, and features were extracted from, an open sketch data set using a data-driven deep learning approach through a convolutional neural network. Later, the learned features were transferred to our collected data set to further train the classifier. The first data set was collected using pen and paper for the traditional method. The second data set used a tablet and smart pen for data collection. The system's performance was then evaluated using the data sets.<br><br>RESULTS: The performance of the designed system when using the data set that was collected using the traditional pen and paper method resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.913 (SD 0.004) when distinguishing between patients with MCI and HCs. On the other hand, when discriminating between patients with AD and HCs, the mean AUROC was 0.950 (SD 0.003) when using the data set that was collected using the digitalized method.<br><br>CONCLUSIONS: The automatic ROCF test scoring system that we designed showed satisfying results for differentiating between patients with AD and MCI and HCs. Comparatively, our proposed network architecture provided better performance than our previous work, which did not include data augmentation and dropout techniques. In addition, it also performed better than other existing network architectures, such as AlexNet and Sketch-a-Net, with transfer learning techniques. The proposed system can be incorporated with other tests to assist clinicians in the early diagnosis of AD and to reduce the physical and mental burden on patients' family and friends.}, }
@article {pmid35255879, year = {2022}, author = {Wang, J and Shi, J and Jia, N and Sun, Q}, title = {Network pharmacology analysis reveals neuroprotection of Gynostemma pentaphyllum (Thunb.) Makino in Alzheimer' disease.}, journal = {BMC complementary medicine and therapies}, volume = {22}, number = {1}, pages = {57}, pmid = {35255879}, issn = {2662-7671}, mesh = {*Alzheimer Disease/drug therapy/genetics ; Aryldialkylphosphatase/therapeutic use ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Gynostemma ; Humans ; Molecular Docking Simulation ; Network Pharmacology ; Neuroprotection ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in the world, but still lack of effective drug treatment. Gynostemma Pentaphyllum (Thunb.) Makino (GpM), a Chinese medicinal herb, plays important roles in anti-inflammation, anti-oxidative stress and anti-tumor, which has been reported to ameliorate cognitive impairment of AD. However, the neuroprotective mechanism of GpM remains unclear. This study aims to investigate the targets and possible signaling pathways of GpM in the treatment of AD.<br><br>METHODS: Active compounds of GpM and their putative target proteins were selected from Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and Analysis Platform. AD-associated targets were identified from GeneCards, the Online Mendelian Inheritance in Man (OMIM) database and the Therapeutic Target Database (TTD). The intersecting targets of GpM and AD were identified and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were carried out to analyze the mechanism of them. Compound-target-pathway (CTP) network and protein-protein interaction (PPI) network were constructed and analyzed to elucidate the correlation between compounds, proteins and pathways. Molecular docking was performed to further demonstrate the possibility of GpM for AD.<br><br>RESULTS: A total of 13 active compounds of GpM, 168 putative target proteins of compounds and 722 AD-associated targets were identified. Eighteen intersecting targets of GpM and AD were found and the epidermal growth factor receptor (EGFR), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), nitric oxide synthase in endothelial (NOS3) and serum paraoxonase/arylesterase 1 (PON1) were selected as the primary targets of GpM in the treatment of AD. The neuroprotective effect of GPM was related to a variety of pathways, including amoebiasis, HIF-1 signaling pathway, cytokine-cytokine receptor interaction and so on.<br><br>CONCLUSIONS: Our findings elucidate the active compounds, targets and pathways of GpM involved in effects of anti-AD. The novel mechanism of GpM against AD provides more treatment options for AD.}, }
@article {pmid35254651, year = {2022}, author = {López-Sánchez, N and Ramón-Landreau, M and Trujillo, C and Garrido-García, A and Frade, JM}, title = {A Mutant Variant of E2F4 Triggers Multifactorial Therapeutic Effects in 5xFAD Mice.}, journal = {Molecular neurobiology}, volume = {59}, number = {5}, pages = {3016-3039}, pmid = {35254651}, issn = {1559-1182}, mesh = {*Alzheimer Disease/drug therapy/therapy ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; *Cognitive Dysfunction ; Disease Models, Animal ; E2F4 Transcription Factor ; Humans ; Mice ; Mice, Transgenic ; }, abstract = {Alzheimer's disease (AD) has a complex etiology, which requires a multifactorial approach for an efficient treatment. We have focused on E2 factor 4 (E2F4), a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brains of Alzheimer's patients and of APPswe/PS1dE9 and 5xFAD transgenic mice. E2F4 contains an evolutionarily conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. In this study, we generated a knock-in mouse strain with neuronal expression of a mouse E2F4 variant lacking this Thr-motif (E2F4DN), which was mated with 5xFAD mice. Here, we show that neuronal expression of E2F4DN in 5xFAD mice potentiates a transcriptional program consistent with the attenuation of the immune response and brain homeostasis. This correlates with reduced microgliosis and astrogliosis, modulation of amyloid-β peptide proteostasis, and blocking of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. We also show that our finding is significant for AD, since E2F4 is expressed in cortical neurons from Alzheimer patients in association with Thr-specific phosphorylation, as evidenced by an anti-E2F4/anti-phosphoThr proximity ligation assay. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD.}, }
@article {pmid35254602, year = {2022}, author = {Pereira, PM and Papy-Garcia, D and Barritault, D and Chiappini, F and Jackisch, R and Schimchowitsch, S and Cassel, JC}, title = {Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration.}, journal = {Glycoconjugate journal}, volume = {39}, number = {1}, pages = {107-130}, pmid = {35254602}, issn = {1573-4986}, support = {ACI NTS 2001/70//Ministère Délégué à la Recherche et aux Nouvelles Technologies/ ; Ja 244/5-2//Deutsche Forschungsgemeinschaft/ ; }, mesh = {*Acetylcholinesterase ; Animals ; Cholinergic Agents/pharmacology ; *Glycosaminoglycans/pharmacology ; Male ; Rats ; Rats, Long-Evans ; Ribosome Inactivating Proteins, Type 1 ; }, abstract = {Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75NTR), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.}, }
@article {pmid35250146, year = {2022}, author = {Punn, NS and Agarwal, S}, title = {Modality specific U-Net variants for biomedical image segmentation: a survey.}, journal = {Artificial intelligence review}, volume = {}, number = {}, pages = {1-45}, pmid = {35250146}, issn = {0269-2821}, abstract = {With the advent of advancements in deep learning approaches, such as deep convolution neural network, residual neural network, adversarial network; U-Net architectures are most widely utilized in biomedical image segmentation to address the automation in identification and detection of the target regions or sub-regions. In recent studies, U-Net based approaches have illustrated state-of-the-art performance in different applications for the development of computer-aided diagnosis systems for early diagnosis and treatment of diseases such as brain tumor, lung cancer, alzheimer, breast cancer, etc., using various modalities. This article contributes in presenting the success of these approaches by describing the U-Net framework, followed by the comprehensive analysis of the U-Net variants by performing (1) inter-modality, and (2) intra-modality categorization to establish better insights into the associated challenges and solutions. Besides, this article also highlights the contribution of U-Net based frameworks in the ongoing pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also known as COVID-19. Finally, the strengths and similarities of these U-Net variants are analysed along with the challenges involved in biomedical image segmentation to uncover promising future research directions in this area.}, }
@article {pmid35244970, year = {2022}, author = {Teles, F and Collman, RG and Mominkhan, D and Wang, Y}, title = {Viruses, periodontitis, and comorbidities.}, journal = {Periodontology 2000}, volume = {89}, number = {1}, pages = {190-206}, doi = {10.1111/prd.12435}, pmid = {35244970}, issn = {1600-0757}, mesh = {Female ; Humans ; *Periodontal Diseases/complications ; Periodontics ; *Periodontitis/complications ; Pregnancy ; Pregnancy Outcome ; *Viruses ; }, abstract = {Seminal studies published in the 1990s and 2000s explored connections between periodontal diseases and systemic conditions, revealing potential contributions of periodontal diseases in the initiation or worsening of systemic conditions. The resulting field of periodontal medicine led to the publication of studies indicating that periodontal diseases can influence the risk of systemic conditions, including adverse pregnancy outcomes, cardiovascular and respiratory diseases, as well as Alzheimer disease and cancers. In general, these studies hypothesized that the periodontal bacterial insult and/or the associated proinflammatory cascade could contribute to the pathogenesis of these systemic diseases. While investigations of the biological basis of the connections between periodontal diseases and systemic conditions generally emphasized the bacteriome, it is also biologically plausible, under an analogous hypothesis, that other types of organisms may have a similar role. Human viruses would be logical "suspects" in this role, given their ubiquity in the oral cavity, association with periodontal diseases, and ability to elicit strong inflammatory response, compromise immune responses, and synergize with bacteria in favor of a more pathogenic microbial consortium. In this review, the current knowledge of the role of viruses in connecting periodontal diseases and systemic conditions is examined. We will also delve into the mechanistic basis for such connections and highlight the importance of those relationships in the management and treatment of patients.}, }
@article {pmid35237315, year = {2022}, author = {Authiat, MM and Gruz-Gibelli, E and Colas, J and Bianchi, E and Garcia-Arauzo, M and Marin, P and Herrmann, FR and Savioz, A}, title = {Preferential Involvement of BRCA1/BARD1, Not Tip60/Fe65, in DNA Double-Strand Break Repair in Presenilin-1 P117L Alzheimer Models.}, journal = {Neural plasticity}, volume = {2022}, number = {}, pages = {3172861}, pmid = {35237315}, issn = {1687-5443}, mesh = {*Alzheimer Disease/genetics ; Animals ; DNA ; *DNA Breaks, Double-Stranded ; DNA Repair ; Mice ; Mice, Inbred C57BL ; Presenilin-1/genetics ; }, abstract = {Recently, we showed that DNA double-strand breaks (DSBs) are increased by the Aβ 42-amyloid peptide and decreased by all-trans retinoic acid (RA) in SH-SY5Y cells and C57BL/6J mice. The present work was aimed at investigating DSBs in cells and murine models of Alzheimer's disease carrying the preseniline-1 (PS1) P117L mutation. We observed that DSBs could hardly decrease following RA treatment in the mutated cells compared to the wild-type cells. The activation of the amyloidogenic pathway is proposed in the former case as Aβ 42- and RA-dependent DSBs changes were reproduced by an α-secretase and a γ-secretase inhibitions, respectively. Unexpectedly, the PS1 P117L cells showed lower DSB levels than the controls. As the DSB repair proteins Tip60 and Fe65 were less expressed in the mutated cell nuclei, they do not appear to contribute to this difference. On the contrary, full-length BRCA1 and BARD1 proteins were significantly increased in the chromatin compartment of the mutated cells, suggesting that they decrease DSBs in the pathological situation. These Western blot data were corroborated by in situ proximity ligation assays: the numbers of BRCA1-BARD1, not of Fe65-Tip60 heterodimers, were increased only in the mutated cell nuclei. RA also enhanced the expression of BARD1 and of the 90 kDa BRCA1 isoform. The increased BRCA1 expression in the mutated cells can be related to the enhanced difficulty to inhibit this pathway by BRCA1 siRNA in these cells. Overall, our study suggests that at earlier stages of the disease, similarly to PS1 P117L cells, a compensatory mechanism exists that decreases DSB levels via an activation of the BRCA1/BARD1 pathway. This supports the importance of this pathway in neuroprotection against Alzheimer's disease.}, }
@article {pmid35232884, year = {2022}, author = {}, title = {CMS Proposes Medicare Coverage Policy for Monoclonal Antibody-Based Alzheimer Treatment.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {63}, number = {3}, pages = {12N}, pmid = {35232884}, issn = {1535-5667}, }
@article {pmid35228741, year = {2022}, author = {De Felice, FG and Gonçalves, RA and Ferreira, ST}, title = {Impaired insulin signalling and allostatic load in Alzheimer disease.}, journal = {Nature reviews. Neuroscience}, volume = {23}, number = {4}, pages = {215-230}, pmid = {35228741}, issn = {1471-0048}, abstract = {The discovery of insulin in 1921 revolutionized the treatment of diabetes and paved the way for numerous studies on hormone signalling networks and actions in peripheral tissues and in the central nervous system. Impaired insulin signalling, a hallmark of diabetes, is now established as a key component of Alzheimer disease (AD) pathology. Here, we review evidence showing that brain inflammation and activation of cellular stress response mechanisms comprise molecular underpinnings of impaired brain insulin signalling in AD and integrate impaired insulin signalling with AD pathology. Further, we highlight that insulin resistance is an important component of allostatic load and that allostatic overload can trigger insulin resistance. This bidirectional association between impaired insulin signalling and allostatic overload favours medical conditions that increase the risk of AD, including diabetes, obesity, depression, and cardiovascular and cerebrovascular diseases. Finally, we discuss how the integration of biological, social and lifestyle factors throughout the lifespan can contribute to the development of AD, underscoring the potential of social and lifestyle interventions to preserve brain health and prevent or delay AD.}, }
@article {pmid35227980, year = {2022}, author = {Yang, A and Liu, C and Zhang, H and Wu, J and Shen, R and Kou, X}, title = {A multifunctional anti-AD approach: Design, synthesis, X-ray crystal structure, biological evaluation and molecular docking of chrysin derivatives.}, journal = {European journal of medicinal chemistry}, volume = {233}, number = {}, pages = {114216}, doi = {10.1016/j.ejmech.2022.114216}, pmid = {35227980}, issn = {1768-3254}, mesh = {Acetylcholinesterase ; Alzheimer Disease/*drug therapy ; Amyloid beta-Peptides ; Butyrylcholinesterase ; Cholinesterase Inhibitors/*chemistry/*pharmacology ; Crystallography, X-Ray ; Drug Design ; Flavonoids/*chemistry/*pharmacology ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Structure-Activity Relationship ; }, abstract = {With the aging of the population intensifying, finding a cure or reasonable treatment for Alzheimer' disease (AD) has become an urgent priority. To target the multi-facets of AD, a class of chrysin derivatives (1-4) were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, which were characterized by 1H NMR, 13C NMR, MS and elemental analysis. 1-4 showed inhibitory activities on reactive oxygen species, Aβ1-42 aggregation (self-, Cu2+-induced, AChE-induced). They were also potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with selectivity toward BuChE. Compound 1 as the most promising candidate exhibited the highest selective BuChE inhibition (SI = 15). Furthermore, the kinetic study suggested compound 1 to be a mixed type inhibitor. The results of docking study were consistent with the in vitro results. In addition, compound 1-4 showed favorable blood-brain barrier (BBB) penetration and drug-like property in silico prediction. The corresponding copper complexes of 1-4 have also been synthesized. 1-4 selectively chelated Cu2+, Fe2+, Zn2+ and Al3+ ions, while had no chelating ability to other biometals. The copper complexes also showed good AChE, BuChE and reactive oxygen species inhibitory activities. Notably, the single crystals of 1-Cu(II) complex [Cu(C19H18NO4)2] were prepared for the first time and characterized by X-ray single crystal diffraction. X-ray crystallography analysis of 1-Cu(II) complex provided a reliable structure-activity insight at the molecular level about the antioxidative and Aβ1-42 disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics.}, }
@article {pmid35220356, year = {2022}, author = {McManus, KR and Lapid, MI and Forester, BP and Mueller, M and Hermida, AP and Nykamp, L and Harper, DG and Seiner, SJ and Sanghani, S and Patrick, R and Gentry, MT and Kung, S and Leal, JC and Johnson, EK and Petrides, G}, title = {Simulated Electroconvulsive Therapy: A Novel Approach to a Control Group in Clinical Trials.}, journal = {The journal of ECT}, volume = {}, number = {}, pages = {}, doi = {10.1097/YCT.0000000000000832}, pmid = {35220356}, issn = {1533-4112}, abstract = {OBJECTIVES: Agitation is the most common behavioral symptom of Alzheimer disease (AD) affecting approximately 40% to 60% of the AD population, yet there are no Food and Drug Administration-approved therapies for the myriad of behavioral or psychological symptoms of dementia. There is growing evidence from naturalistic studies that electroconvulsive therapy (ECT) is a safe and effective treatment for agitation in AD patients who are refractory to pharmacotherapy and behavioral interventions. Despite the existing evidence, ECT remains underused because of stigma, lack of education, and concerns regarding adverse cognitive effects. Randomized controlled clinical trials of ECT are an opportunity to provide high-quality evidence of ECT as a safe and efficacious treatment for agitation in the AD population. We describe the methods for the Electroconvulsive Therapy in Alzheimer's Dementia study, which uses a novel, simulated ECT (S-ECT) control group to conduct a single-blind efficacy study of ECT for the treatment of agitation and aggression in individuals with moderate to severe AD.<br><br>METHODS: We discuss the rationale, study design, methodology, ethical and practical challenges, and management strategies in using an S-ECT group as the comparator arm in this randomized controlled trial of ECT in AD-related treatment refractory agitation and aggression.<br><br>CONCLUSIONS: Validation of the safety and efficacy of ECT in patients with advanced AD with refractory agitation and aggression is necessary. This can be accomplished through creative formulation of S-ECT groups that effectively maintain the blind while providing scientific integrity.}, }
@article {pmid35204750, year = {2022}, author = {Maccioni, RB and Calfío, C and González, A and Lüttges, V}, title = {Novel Nutraceutical Compounds in Alzheimer Prevention.}, journal = {Biomolecules}, volume = {12}, number = {2}, pages = {}, pmid = {35204750}, issn = {2218-273X}, support = {i7819020001//Agencia Nacional de Investigación y Desarrollo/ ; ID19I10301//Agencia Nacional de Investigación y Desarrollo/ ; }, mesh = {*Alzheimer Disease/diagnosis/drug therapy/prevention &amp; control ; Antioxidants/pharmacology ; *Cognitive Dysfunction ; *Diet, Mediterranean ; Dietary Supplements ; Humans ; }, abstract = {Alzheimer's disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean shilajit. Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD.}, }
@article {pmid35204298, year = {2022}, author = {Martinez-Banaclocha, M}, title = {N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204298}, issn = {2076-3921}, abstract = {In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use.}, }
@article {pmid35204177, year = {2022}, author = {Yang, JH and Nguyen, CD and Lee, G and Na, CS}, title = {Insamgobonhwan Protects Neuronal Cells from Lipid ROS and Improves Deficient Cognitive Function.}, journal = {Antioxidants (Basel, Switzerland)}, volume = {11}, number = {2}, pages = {}, pmid = {35204177}, issn = {2076-3921}, support = {21-BR-03-05//Korea Brain Research Institute/ ; }, abstract = {Iron is an essential element in the central nervous system that is involved in many of its important biological processes, such as oxygen transportation, myelin production, and neurotransmitter synthesis. Previous studies have observed the selective accumulation of iron in Aβ aggregates and neurofibrillary tangles in the brains of patients with Alzheimer's disease, and excess of this accumulation is associated with accelerated cognitive decline in Alzheimer's patients. Emerging evidence suggests that ferroptosis, cell death due to iron accumulation, is a potential therapeutic target for treating Alzheimer's disease. Insamgobonhwan (GBH) is a well-regarded traditional medicine from Donguibogam that possess antioxidant properties and has been suggested to slow the aging process. However, the neuroprotective role of GBH against lipid peroxidation-induced ferroptosis and its positive cognitive effects remain unexplored. Here, we investigated the ability of GBH to protect against RSL3-induced ferroptosis in vitro and to suppress amyloid-β-induced cognitive impairment in vivo. First, we treated HT22 cells with RSL3 to induce ferroptosis, which is an inhibitor of glutathione peroxidase 4 (GPX4) and induces lethal lipid hydroperoxide accumulation, reactive oxygen species (ROS) production, and ferroptotic cell death. GBH treatment inhibited cell death and lipid peroxidation, which were increased by RSL3 administration. In addition, GBH restored the expression of ferroptosis marker proteins, such as GPX4, HO-1 and COX-2, which were altered by RSL3. Next, we examined whether the protective ability of GBH in cells was reproduced in animals. We concluded that GBH treatment inhibited Aβ-induced lipid peroxidation and improved Aβ-induced cognitive impairment in mice.}, }
@article {pmid35203506, year = {2022}, author = {Umeda, T and Uekado, R and Shigemori, K and Eguchi, H and Tomiyama, T}, title = {Nasal Rifampicin Halts the Progression of Tauopathy by Inhibiting Tau Oligomer Propagation in Alzheimer Brain Extract-Injected Mice.}, journal = {Biomedicines}, volume = {10}, number = {2}, pages = {}, pmid = {35203506}, issn = {2227-9059}, support = {No. 19K07847//the Ministry of Education, Culture, Sports, Science and Technology of Japan/ ; Not applicable//the Research Foundation for Dementia of Osaka, Japan/ ; Not applicable//the Osaka City University Strategic Research Grant 2020 for young researchers/ ; }, abstract = {The cell-to-cell transmission of tau aggregates is considered a mechanism underlying the intracerebral spreading of tau pathology in Alzheimer's disease (AD) and other tauopathies. Recent studies suggest that tau oligomers, rather than fibrils, participate in this process. We previously showed that intranasal rifampicin inhibits tau oligomer accumulation and improves cognition in tauopathy mice. In the present study, we examined the effects of nasal rifampicin on tau propagation in a new mouse model of tauopathy. A tau oligomer-rich fraction prepared from the brain of an AD patient was injected into a unilateral hippocampus of tau264 mice that express both 3-repeat and 4-repeat wild-type human tau. Rifampicin administration was started one week after the injection and performed three times a week for 24 weeks. Cognitive function and tau pathology were assessed by the Morris water maze test and brain section staining. Rifampicin treatment inhibited the spreading of tau oligomers from the injection site to other brain regions and neurofibrillary tangle formation in the entorhinal cortex. Synapse and neuronal loss in the hippocampus were also prevented, and cognitive function remained normal. These results suggest that intranasal rifampicin could be a promising remedy that halts the progression of tauopathy by inhibiting tau oligomer propagation.}, }
@article {pmid35197360, year = {2022}, author = {Day, GS and Scarmeas, N and Dubinsky, R and Coerver, K and Mostacero, A and West, B and Wessels, SR and Armstrong, MJ}, title = {Aducanumab Use in Symptomatic Alzheimer Disease Evidence in Focus: A Report of the AAN Guidelines Subcommittee.}, journal = {Neurology}, volume = {98}, number = {15}, pages = {619-631}, pmid = {35197360}, issn = {1526-632X}, mesh = {*Alzheimer Disease/drug therapy ; Amyloid/metabolism ; Antibodies, Monoclonal, Humanized/adverse effects ; Brain/metabolism ; Humans ; Practice Guidelines as Topic ; }, abstract = {OBJECTIVE: To identify the class of evidence for aducanumab use for the treatment of Alzheimer disease and present clinical considerations regarding use.<br><br>METHODS: The author panel systematically reviewed available clinical trial data detailing aducanumab use in individuals with early symptomatic Alzheimer disease. Level of evidence statements were assigned in accordance with the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed.<br><br>RESULTS: Data were identified from 4 clinical trials, 1 rated Class I and 3 rated Class II. The Class I study showed that single doses of aducanumab up to 30 mg/kg were safe and well tolerated. All 3 Class II studies provided evidence that aducanumab (3-10 mg/kg) decreased amyloid deposition on brain PET at 1 year vs placebo. Efficacy data in the Class II studies varied by dose and outcome, but aducanumab either had no effect on mean change on the Clinical Dementia Rating Sum of Boxes scores or resulted in less worsening (vs placebo) that was of uncertain clinical importance. Adverse amyloid-related imaging abnormalities occurred in approximately 40% of individuals treated with aducanumab vs 10% receiving placebo.<br><br>CLINICAL CONTEXT: Administration of aducanumab will require expanded clinical infrastructure. Evidence-based guidance is needed to address key questions (e.g., safety in populations not enrolled in phase 3 studies, expected benefits on daily function, treatment duration) and critical issues relating to access to aducanumab (e.g., coverage, costs, burden of monthly infusions) that will inform shared decision making between patients and providers.}, }
@article {pmid35197359, year = {2022}, author = {Grober, E and Lipton, RB and Sperling, RA and Papp, KV and Johnson, KA and Rentz, DM and Veroff, AE and Aisen, PS and Ezzati, A}, title = {Associations of Stages of Objective Memory Impairment With Amyloid PET and Structural MRI: The A4 Study.}, journal = {Neurology}, volume = {98}, number = {13}, pages = {e1327-e1336}, pmid = {35197359}, issn = {1526-632X}, support = {K23 AG063993/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; *Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; *Cognitive Dysfunction/diagnostic imaging/pathology ; Humans ; Magnetic Resonance Imaging ; Male ; Memory Disorders/diagnostic imaging/pathology ; Positron-Emission Tomography/methods ; tau Proteins/metabolism ; }, abstract = {BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.<br><br>METHODS: The FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)-positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.<br><br>RESULTS: Participants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.<br><br>DISCUSSION: Presence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.<br><br>ClinicalTrials.gov identifier: NCT02008357.<br><br>CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes.}, }
@article {pmid35195784, year = {2022}, author = {Singh, A and Gupta, P and Tiwari, S and Mishra, A and Singh, S}, title = {Guanabenz mitigates the neuropathological alterations and cell death in Alzheimer's disease.}, journal = {Cell and tissue research}, volume = {388}, number = {2}, pages = {239-258}, pmid = {35195784}, issn = {1432-0878}, abstract = {Alzheimer's disease (AD) pathology is characterized by cognitive impairment, increased acetylcholinesterase (AChE) activity, and impaired neuronal communication. Clinically, AChE inhibitors are being used to treat AD patients; however, these remain unable to prevent the disease progression. Therefore, further development of new therapeutic molecules is required having broad spectrum effects on AD-related various neurodegenerative events. Since repurposing is a quick mode to search the therapeutic molecules; henceforth, this study was conducted to evaluate the anti-Alzheimer activity of drug guanabenz which is already in use for the management of high blood pressure in clinics. The study was performed employing both cellular and rat models of AD along with donepezil as reference drug. Guanabenz treatment in both the experimental models showed significant protection against AD-specific behavioral and pathological indicators like AChE activity, tau phosphorylation, amyloid precursor protein, and memory retention. In conjunction, guanabenz also attenuated the AD-related oxidative stress, impaired mitochondrial functionality (MMP, cytochrome-c translocation, ATP level, and mitochondrial complex I activity), endoplasmic reticulum stress (GRP78, GADD153, cleaved caspase-12), neuronal apoptosis (Bcl-2, Bax, cleaved caspase-3), and DNA fragmentation. In conclusion, findings suggested the panoptic protective effect of guanabenz on disease-related multiple degenerative markers and signaling. Furthermore, clinical trial may shed light and expedite the availability of new therapeutic anti-Alzheimer's molecule for the wellbeing of AD patients.}, }
@article {pmid35195392, year = {2022}, author = {Singh, JV and Thakur, S and Kumar, N and Singh, H and Mithu, VS and Singh, H and Bhagat, K and Gulati, HK and Sharma, A and Singh, H and Sharma, S and Bedi, PMS}, title = {Donepezil-Inspired Multitargeting Indanone Derivatives as Effective Anti-Alzheimer's Agents.}, journal = {ACS chemical neuroscience}, volume = {13}, number = {6}, pages = {733-750}, doi = {10.1021/acschemneuro.1c00535}, pmid = {35195392}, issn = {1948-7193}, mesh = {*Acetylcholinesterase/metabolism ; *Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; Animals ; Cholinesterase Inhibitors/therapeutic use ; DNA ; Donepezil/therapeutic use ; Indans ; Mice ; Structure-Activity Relationship ; }, abstract = {In continuous efforts to develop anti-Alzheimer's agents, we rationally designed and synthesized a series of multitargeting molecules by incorporating the essential molecular features of the standard drug donepezil. Among the series, compound 4b showed multitargeting properties to act as an anti-Alzheimer's agent, which is better tolerable in vivo than donepezil. Acetylcholinesterase (AChE) inhibition data showed that compound 4b inhibits the enzyme with a half-maximal inhibitory concentration (IC50) value of 0.78 μM and also showed DNA protection, which was confirmed through the DNA nicking assay, suggesting the protective effect of 4b against oxidative DNA damage. Compound 4b also showed 53.04% inhibition against Aβ1-42 aggregations, which was found comparable to that of the standard compound curcumin. Molecular dynamics simulations were performed to check the stability of compound 4b with the enzyme AChE, which showed that the enzyme-ligand complex is stable enough to block the hydrolysis of acetylcholine in the brain. Its higher LD50 cutoff value (50 mg/kg) in comparison to donepezil (LD50: 25 mg/kg) made it safer, suggesting that it can be used in further clinical experiments. To evaluate its anti-Alzheimer property, a mice model with melamine-induced cognitive dysfunction was used, and Morris water maze and Rotarod tests were performed. A significant improvement in memory was observed after the treatment with compound 4b and donepezil. The study postulated that the introduction of important structural features of donepezil (dimethoxyindanone moiety as ring-A) embarked with terminal aromatic ether (ring-B and ring-C) made 4b a multitargeting molecule that offers a way for developing alternative therapeutics in the future against Alzheimer's disease (AD).}, }
@article {pmid35191206, year = {2022}, author = {Pardo, M and Khizroev, S}, title = {Where do we stand now regarding treatment of psychiatric and neurodegenerative disorders? Considerations in using magnetoelectric nanoparticles as an innovative approach.}, journal = {Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology}, volume = {}, number = {}, pages = {e1781}, doi = {10.1002/wnan.1781}, pmid = {35191206}, issn = {1939-0041}, support = {FA9550-18-1-0527//Air Force Office of Scientific Research/ ; N66001-19-C-4019//Defense Advanced Research Projects Agency (DARPA) and Naval Information Warfare Center, Pacific (NIWC Pacific)/ ; ECCS-1810270//National Science Foundation (NSF)/ ; }, abstract = {Almost 1000 million people have recently been diagnosed with a mental health or substance disorder (Ritchie &amp; Roser, 2018). Psychiatric disorders, and their treatment, represent a big burden to the society worldwide, causing about 8 million deaths per year (Walker et al., 2015). Daily progress in science enables continuous advances in methods to treat patients; however, the brain remains to be the most unknown and complex organ of the body. There is a growing demand for innovative approaches to treat psychiatric as well as neurodegenerative disorders, disorders with unknown curability, and treatments mostly designed to slow disease progression. Based on that need and the peculiarity of the central nervous system, in the present review, we highlight the handicaps of the existing approaches as well as discuss the potential of the recently introduced magnetoelectric nanoparticles (MENPs) to become a game-changing tool in future applications for the treatment of brain alterations. Unlike other stimulation approaches, MENPs have the potential to enable a wirelessly controlled stimulation at a single-neuron level without requiring genetic modification of the neural tissue and no toxicity has yet been reported. Their potential as a new tool for targeting the brain is discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Neurological Disease.}, }
@article {pmid35183180, year = {2022}, author = {Bentley, TGK and Castillo, D and Sadeghi, N and Piber, D and Carroll, J and Olmstead, R and Irwin, MR}, title = {Costs associated with treatment of insomnia in Alzheimer's disease caregivers: a comparison of mindfulness meditation and cognitive behavioral therapy for insomnia.}, journal = {BMC health services research}, volume = {22}, number = {1}, pages = {231}, pmid = {35183180}, issn = {1472-6963}, mesh = {*Alzheimer Disease/therapy ; Caregivers ; *Cognitive Behavioral Therapy/methods ; Humans ; *Meditation ; *Mindfulness/methods ; *Sleep Initiation and Maintenance Disorders/therapy ; Treatment Outcome ; }, abstract = {BACKGROUND: Among the over 5 million informal caregivers for patients with Alzheimer's disease (AD) in the United States (US), over 60% experience insomnia. Research on insomnia treatment efficacy in AD caregivers is limited. An ongoing randomized non-inferiority clinical trial, the Caregiver Sleep Research study, is evaluating whether mindfulness meditation is non-inferior to cognitive behavioral therapy for insomnia (CBT-I) in the treatment of insomnia in AD caregivers. The present report examines estimated intervention costs in this ongoing trial.<br><br>METHODS: Micro-costing was used to itemize and abstract costs of the two interventions: a mindfulness-based intervention known as mindful awareness practices for insomnia (MAP-I); and CBT-I. This approach involves collecting detailed data on resources utilized and the unit costs of those resources, thereby revealing actual resource use and economic costs for each treatment arm. Personnel time, patient time, and supplies were inventoried, and unit costs were applied. Caregiver time costs, including travel, were based on US Labor Bureau home-health aide national mean hourly wages; instructor/staff costs were based on hourly wages. Per-participant and program costs were calculated assuming individual- and group-delivery to reflect real-world implementation. Sensitivity analyses evaluated robustness of estimates.<br><br>RESULTS: From the societal perspective, per-participant MAP-I costs were $1884 for individual and $1377 for group delivery; for CBT-I, these costs were $3978 and $1981, respectively. Compared with CBT-I, MAP-I provided cost savings of $2094 (53%) and $604 (30%) per treated caregiver for individual and group delivery, respectively. From the US healthcare system perspective, MAP-I vs. CBT-I participant savings were $1872 (65%) for individual and $382 (44%) for group interventions, respectively. For MAP-I and CBT-I, instructor in-class time was the highest cost component. Results were most sensitive to combined instructor time costs.<br><br>CONCLUSIONS: Treatment of insomnia with MAP-I, compared to CBT-I, yields substantial cost savings for society and the healthcare system. With this potential for cost savings, results of the ongoing non-inferiority trial have critical implications for insomnia treatment dissemination and its benefits to AD caregivers and other community populations with insomnia.}, }
@article {pmid35182016, year = {2022}, author = {Ouyang, Q and Liu, K and Zhu, Q and Deng, H and Le, Y and Ouyang, W and Yan, X and Zhou, W and Tong, J}, title = {Brain-Penetration and Neuron-Targeting DNA Nanoflowers Co-Delivering miR-124 and Rutin for Synergistic Therapy of Alzheimer's Disease.}, journal = {Small (Weinheim an der Bergstrasse, Germany)}, volume = {18}, number = {14}, pages = {e2107534}, doi = {10.1002/smll.202107534}, pmid = {35182016}, issn = {1613-6829}, support = {81870861//National Natural Science Foundation of China/ ; 81471107//National Natural Science Foundation of China/ ; 21804144//National Natural Science Foundation of China/ ; U1903125//National Natural Science Foundation of China/ ; 82073799//National Natural Science Foundation of China/ ; 2021JJ31008//Natural Science Foundation of Hunan province in China/ ; 2021JJ20084//Natural Science Foundation of Hunan province in China/ ; 2021RC3020//Science and Technology Innovation Program of Hunan Province/ ; }, mesh = {*Alzheimer Disease/drug therapy ; Amyloid Precursor Protein Secretases/genetics/metabolism/therapeutic use ; Amyloid beta-Peptides/metabolism ; Animals ; Aspartic Acid Endopeptidases/genetics/metabolism/therapeutic use ; Brain/metabolism ; DNA/metabolism ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; *MicroRNAs/metabolism ; Neurons/metabolism ; Rutin/metabolism/pharmacology/therapeutic use ; }, abstract = {Alzheimer disease (AD) is the leading cause of dementia that affects millions of old people. Despite significant advances in the understanding of AD pathobiology, no disease modifying treatment is available. MicroRNA-124 (miR-124) is the most abundant miRNA in the normal brain with great potency to ameliorate AD-like pathology, while it is deficient in AD brain. Herein, the authors develop a DNA nanoflowers (DFs)-based delivery system to realize exogenous supplementation of miR-124 for AD therapy. The DFs with well-controlled size and morphology are prepared, and a miR-124 chimera is attached via hybridization. The DFs are further modified with RVG29 peptide to simultaneously realize brain-blood barrier (BBB) penetration and neuron targeting. Meanwhile, Rutin, a small molecular ancillary drug, is co-loaded into the DFs structure via its intercalation into the double stranded DNA region. Interestingly, Rutin could synergize miR-124 to suppress the expression of both BACE1 and APP, thus achieving a robust inhibition of amyloid β generation. The nanosystem could pro-long miR-124 circulation in vivo, promote its BBB penetration and neuron targeting, resulting in a significant increase of miR-124 in the hippocampus of APP/PS1 mice and robust therapeutic efficacy in vivo. Such a bio-derived therapeutic system shows promise as a biocompatible nanomedicine for AD therapy.}, }
@article {pmid35180118, year = {2022}, author = {de Paula França Resende, E and Ketelle, R and Karydas, A and Allen, I and Grinberg, LT and Spina, S and Seeley, WW and Perry, DC and Miller, B and Naasan, G}, title = {Late-Onset Alcohol Abuse as a Presenting Symptom of Neurodegenerative Diseases.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {86}, number = {3}, pages = {1073-1080}, doi = {10.3233/JAD-215369}, pmid = {35180118}, issn = {1875-8908}, support = {P30 AG062422/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; *Alcoholism/diagnosis/epidemiology ; *Alzheimer Disease/diagnosis/epidemiology ; Cross-Sectional Studies ; *Frontotemporal Dementia/diagnosis/epidemiology ; Humans ; *Neurodegenerative Diseases/diagnosis/epidemiology ; Neuropsychological Tests ; Retrospective Studies ; }, abstract = {BACKGROUND: The association between lifetime alcohol abuse and a higher risk to develop dementia is well known. However, it is unknown whether older adults who begin abusing alcohol late in life have an underlying neurodegenerative disease.<br><br>OBJECTIVE: Identify the frequency of lifelong alcohol abuse (L-AA), late-onset alcohol abuse (LO-AA), and alcohol abuse as a first symptom of dementia (AA-FS) in patients with neurodegenerative diseases.<br><br>METHODS: Cross-sectional retrospective study of patients evaluated at an academic referral center with a clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD), Alzheimer-type dementia (AD), and semantic variant primary progressive aphasia (svPPA) (n = 1,518). The presence of alcohol abuse was screened with the National Alzheimer's Coordinating Center questionnaire. L-AA was defined as onset < 40 years, LO-AA as onset ≥40 years, and AA-FS was defined when the abuse started within the first three years from symptom onset.<br><br>RESULTS: The frequency of LO-AA was 2.2% (n = 33/1,518). LO-AA was significantly more frequent in patients with bvFTD than AD (7.5%, n = 13/173 versus 1.3%, n = 16/1,254, CI:1.0;11.4%), but not svPPA (4.4%, n = 4/91, CI: -4.4;10.7%). Similarly, AA-FS was more frequent in bvFTD patients than AD (5.7%, n = 10/173 versus 0.7%, n = 9/1,254, CI:0.5%;9.5%), but not svPPA (2.2%, n = 2/91, CI:-2.4;9.1%).<br><br>CONCLUSION: LO-AA can be a presenting symptom of dementia, especially bvFTD. Alcohol abuse onset later in life should prompt a clinical investigation into the possibility of an underlying neurodegenerative process because delay in diagnosis and treatment may increase patient and caregiver burden. The results need to be interpreted with caution due to the limitations of the study.}, }
@article {pmid35179048, year = {2021}, author = {Eratne, D and Janelidze, S and Malpas, CB and Loi, S and Walterfang, M and Merritt, A and Diouf, I and Blennow, K and Zetterberg, H and Cilia, B and Wannan, C and Bousman, C and Everall, I and Zalesky, A and Jayaram, M and Thomas, N and Berkovic, SF and Hansson, O and Velakoulis, D and Pantelis, C and Santillo, A and , }, title = {Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives.}, journal = {The Australian and New Zealand journal of psychiatry}, volume = {}, number = {}, pages = {48674211058684}, doi = {10.1177/00048674211058684}, pmid = {35179048}, issn = {1440-1614}, abstract = {OBJECTIVE: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias.<br><br>METHODS: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59).<br><br>RESULTS: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]).<br><br>CONCLUSION: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.}, }
@article {pmid35171074, year = {2022}, author = {Braz de Oliveira, MP and Moreira Padovez, RFC and Serrão, PRMDS and de Noronha, MA and Cezar, NOC and Andrade, LP}, title = {Effectiveness of physical exercise at improving functional capacity in older adults living with Alzheimer's disease: a systematic review of randomized controlled trials.}, journal = {Disability and rehabilitation}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/09638288.2022.2037744}, pmid = {35171074}, issn = {1464-5165}, abstract = {PURPOSE: To investigate the effects of physical exercise at improving functional capacity in older adults living with Alzheimer's disease (AD).<br><br>METHODS: Medline, Embase, Web of Science, The Cochrane Library, Lilacs, and PEDro were searched from inception until January 2021. Randomized controlled trials (RCTs) that reported functional capacity outcomes were included. The evidence was assessed using the GRADE approach.<br><br>RESULTS: Thirteen RCTs were included, involving 811 older adults living with AD. Multimodal exercise (ME), aerobic exercise (AE), and resistance exercise (RE) were used. The interventions were mainly supervised by caregivers. The evidence was low and with effect for activities of daily living (ADLs), moderate and with no effect for mobility and very low and with no effect for muscle strength, postural balance and flexibility after treatment with ME, moderate and with no effect for cardiorespiratory function and ADLs after treatment with AE. It was not possible to synthesize any type of evidence for RE.<br><br>CONCLUSIONS: Multimodal exercise promotes improvements in functional capacity (ADLs). Therefore, the practice of physical exercise can be recommended for older adults living with AD. The involvement of the caregiver in the physical exercises should also be considered, as it could enhance the benefits of exercise for these older adults.Implications for rehabilitationHealthcare providers with clinical knowledge regarding physical exercise should promote, prescribe and support the daily practice of physical exercises for older adults living with Alzheimer's disease (AD).The involvement of caregivers in home-based physical exercise programs should be considered, as it could enhance the benefits of such programs for these older adults.It is important to consider the degree of cognitive impairment in older adults living with AD when outlining goals for the improvement in functional capacity through physical exercise.Multimodal exercise involving aerobic training, postural balance, muscle strengthening, and flexibility is capable of promoting an improvement in functional capacity (activities of daily living) for these older adults.}, }
@article {pmid35157058, year = {2022}, author = {Zissimopoulos, J and Jacobson, M and Chen, Y and Borson, S}, title = {Knowledge and Attitudes Concerning Aducanumab Among Older Americans After FDA Approval for Treatment of Alzheimer Disease.}, journal = {JAMA network open}, volume = {5}, number = {2}, pages = {e2148355}, pmid = {35157058}, issn = {2574-3805}, support = {P30 AG066589/AG/NIA NIH HHS/United States ; P30 AG043073/AG/NIA NIH HHS/United States ; R01 AG055401/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Drug Approval/legislation &amp; jurisprudence ; Female ; *Health Knowledge, Attitudes, Practice ; Humans ; Male ; Middle Aged ; Patient Acceptance of Health Care/*psychology/*statistics &amp; numerical data ; United States ; United States Food and Drug Administration/legislation &amp; jurisprudence ; }, }
@article {pmid35144097, year = {2022}, author = {Krogsaeter, E and Rosato, AS and Grimm, C}, title = {TRPMLs and TPCs: Targets for lysosomal storage and neurodegenerative disease therapy?.}, journal = {Cell calcium}, volume = {103}, number = {}, pages = {102553}, doi = {10.1016/j.ceca.2022.102553}, pmid = {35144097}, issn = {1532-1991}, abstract = {Neurodegenerative diseases (ND) pose a serious health burden to society and healthcare systems alike, with increasing incidence rates especially within aging populations. Alzheimer's disease (AD) is the most prevalent type of ND or dementia, followed by Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Progressive neurological dysfunction and regional neuronal loss constitute the common characteristics of ND. Many ND are accompanied by accumulation of protein aggregates such as extracellular amyloid-β (in AD), intraneuronal hyper-phosphorylated tau (in AD), or α-synuclein (in PD). Two main systems are responsible for the clearance of damaged, dysfunctional or senescent proteins inside cells: the autophagy-lysosomal pathway and the ubiquitin-proteasome system. The importance of lysosomes in neurodegenerative processes is further highlighted by clinical phenotypes of lysosomal storage disorders (LSDs), comprising more than 70 inheritable diseases caused by mutations in lysosomal enzymes or lysosomal membrane proteins, often resulting in severe neurodegeneration. Dysfunctional lysosomal proteins and enzymes result in the lysosomal accumulation of undigested macromolecules, e.g. lipids, glycoproteins, glycosaminoglycans, or gangliosides. Defects in intracellular transport pathways involving endosomes and lysosomes are increasingly recognized as drivers of neurodegenerative disease pathology including AD and PD. Thus, accumulation of damaged proteins and organelles (e.g. mitochondria) in neurons and glial cells overwhelms the capacity of intracellular recycling and degradation mechanisms, exacerbating disease pathology. Endolysosomal ion channels have recently been established as important regulators of lysosomal exocytosis, ion homeostasis/pH, endolysosomal trafficking, fusion and fission, and autophagy. In particular two non-selective endolysosomal cation channel families, the mucolipin/TRPML/MCOLN channels and the two-pore channels/TPCs will be discussed here as potential pharmacological targets for LSD/ND treatment.}, }
@article {pmid35142986, year = {2022}, author = {Kakoty, V and C, SK and Yang, CH and Kumari, S and Dubey, SK and Taliyan, R}, title = {Neuroprotective Effect of Lentivirus-Mediated FGF21 Gene Delivery in Experimental Alzheimer's Disease is Augmented when Concerted with Rapamycin.}, journal = {Molecular neurobiology}, volume = {59}, number = {5}, pages = {2659-2677}, pmid = {35142986}, issn = {1559-1182}, mesh = {*Alzheimer Disease/complications/drug therapy/genetics ; Amyloid beta-Peptides/metabolism ; Animals ; Fibroblast Growth Factors ; Humans ; Lentivirus/genetics/metabolism ; *Neuroprotective Agents/pharmacology/therapeutic use ; Plaque, Amyloid ; Rats ; Sirolimus/pharmacology/therapeutic use ; }, abstract = {Alzheimer type of dementia is accompanied with progressive loss of cognitive function that directly correlates with accumulation of amyloid beta plaques. It is known that Fibroblast growth factor 21 (FGF21), a metabolic hormone, with strong neuroprotective potential, is induced during oxidative stress in Alzheimer's disease. Interestingly, FGF21 cross-talks with autophagy, a mechanism involved in the clearance of abnormal protein aggregate. Moreover, autophagy activation by Rapamycin delivers neuroprotective role in Alzheimer's disease. However, the synergistic neuroprotective efficacy of overexpressed FGF21 along with Rapamycin is not yet investigated. Therefore, the present study examined whether overexpressed FGF21 along with autophagy activation ameliorated neurodegenerative pathology in Alzheimer's disease. We found that cognitive deficits in rats with intracerebroventricular injection of Amyloid beta1-42 oligomers were restored when injected with FGF21-expressing lentiviral vector combined with Rapamycin. Furthermore, overexpression of FGF21 along with Rapamycin downregulated protein levels of Amyloid beta1-42 and phosphorylated tau and expression of major autophagy proteins along with stabilization of oxidative stress. Moreover, FGF21 overexpressed rats treated with Rapamycin revamped the neuronal density as confirmed by histochemical, cresyl violet and immunofluorescence analysis. These results generate compelling evidence that Alzheimer's disease pathology exacerbated by oligomeric amyloid beta may be restored by FGF21 supplementation combined with Rapamycin and thus present an appropriate treatment paradigm for people affected with Alzheimer's disease.}, }
@article {pmid35133330, year = {2021}, author = {Río, AÁ and Marván, ML}, title = {Ethical dilemmas in the face of the possibility of suffering from Alzheimer's disease or other dementias. An exploratory study.}, journal = {Gaceta medica de Mexico}, volume = {157}, number = {4}, pages = {404-410}, doi = {10.24875/GMM.M21000582}, pmid = {35133330}, issn = {0016-3813}, mesh = {Adult ; Advance Directives ; *Alzheimer Disease/diagnosis ; Cross-Sectional Studies ; Decision Making ; Humans ; Surveys and Questionnaires ; }, abstract = {INTRODUCTION: In Mexico, efforts have been made to increase understanding of Alzheimer's disease (AD) and other dementias, as well as to improve the care of patients with these diseases and that of their caregivers. However, people's interest in making decisions and facing the ethical dilemmas regarding the possibility of living with mental diseases has not been investigated.<br><br>OBJECTIVE: To know the opinions of mature adults on some ethical dilemmas related to the possibility of living with AD or other dementias.<br><br>METHODS: Observational, cross-sectional, correlational study. Participants answered a self-administered questionnaire.<br><br>RESULTS: 134 mature adults answered the questionnaire; 70.9% had thought about the possibility of suffering from some dementia and the vast majority would like to know their diagnosis; approximately, half the participants had informed their families of their wishes about medical treatment in the future; 39.6% did not approve artificially feeding a patient who can no longer eat or decide; 37.3% did approve this.<br><br>CONCLUSIONS: There is interest in advance decisions in the face of the possibility of suffering from dementia. To answer unanswered questions in this regard, it is important for research on the subject to continue, as well as to solve some ethical dilemmas and promote the use of advance directives.}, }
@article {pmid35131314, year = {2022}, author = {Arbo, BD and Schimith, LE and Goulart Dos Santos, M and Hort, MA}, title = {Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation.}, journal = {European journal of pharmacology}, volume = {919}, number = {}, pages = {174800}, doi = {10.1016/j.ejphar.2022.174800}, pmid = {35131314}, issn = {1879-0712}, mesh = {Clinical Trials as Topic ; Drug Evaluation, Preclinical ; Drug Repositioning ; Humans ; Neurodegenerative Diseases/*drug therapy ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, are characterized by the progressive loss of neuronal cells, resulting in different clinical symptoms according to the affected brain region. Although there are drugs available for the treatment of these diseases, they present relatively low efficacy and are not capable of modifying the course of the disease or stopping its progression. In the field of drug development, drug repurposing could be an interesting strategy to search new therapeutic options against neurodegenerative diseases, since it involves lower costs and time for development. In this review, we discuss the search of new treatments for Alzheimer's and Parkinson's disease through drug repurposing. A focus was given to drugs that modulate neuroinflammation, since it represents a common point among neurodegenerative diseases and has been explored as a target for drug action.}, }
@article {pmid35111364, year = {2022}, author = {Botchway, BO and Okoye, FC and Chen, Y and Arthur, WE and Fang, M}, title = {Alzheimer Disease: Recent Updates on Apolipoprotein E and Gut Microbiome Mediation of Oxidative Stress, and Prospective Interventional Agents.}, journal = {Aging and disease}, volume = {13}, number = {1}, pages = {87-102}, pmid = {35111364}, issn = {2152-5250}, abstract = {Alzheimer's disease (AD) is a current public health challenge and will remain until the development of an effective intervention. However, developing an effective treatment for the disease requires a thorough understanding of its etiology, which is currently lacking. Although several studies have shown the association between oxidative damage and AD, only a few have clarified the specific mechanisms involved. Herein, we reviewed recent preclinical and clinical studies that indicated the significance of oxidative damage in AD, as well as potential antioxidants. Although several factors regulate oxidative stress in AD, we centered our investigation on apolipoprotein E and the gut microbiome. Apolipoprotein E, particularly apolipoprotein E-ε4, can impair the structural facets of the mitochondria. This, in turn, can minimize the mitochondrial functionality and result in the progressive build-up of free radicals, eventually leading to oxidative stress. Similarly, the gut microbiome can influence oxidative stress to a significant degree via its metabolite, trimethylamine N-oxide. Given the various roles of these two factors in modulating oxidative stress, we also discuss the possible relationship between them and provide future research directions.}, }
@article {pmid35104759, year = {2022}, author = {Wongpun, J and Chanmanee, T and Tocharus, C and Chokchaisiri, R and Chantorn, S and Pabuprapap, W and Suksamrarn, A and Tocharus, J}, title = {The effects of festidinol treatment on the D-galactose and aluminum chloride-induced Alzheimer-like pathology in mouse brain.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {98}, number = {}, pages = {153925}, doi = {10.1016/j.phymed.2022.153925}, pmid = {35104759}, issn = {1618-095X}, abstract = {BACKGROUND: Festidinol is a flavan-3-ol which has been shown to reduce advanced glycation end products (AGEs) and reactive oxygen species, both of which play a crucial role in the pathology of many neurodegenerative diseases.<br><br>PURPOSE: This study aimed to investigate the effects of festidinol on oxidative stress, amyloidogenesis, phosphorylated tau (pTau) expression, synaptic function, and cognitive impairment, and the potential mechanisms involved, in a mouse model with an Alzheimer-like pathology.<br><br>METHODS: D-galactose (150 mg/kg) and aluminum chloride (10 mg/kg) were injected intraperitoneally into 40 mice for 90 days to generate an AD mouse model with cognitive impairment. Festidinol (30 mg/kg) and donepezil (5 mg/kg) were then administered orally for 90 days after which behavior and molecular changes in the brain were measured.<br><br>RESULTS: The aluminum accumulated and the expression of the cell senescence marker P16 increased after exposure to D-galactose and AlCl3 (2.5 ± 0.5 mg/kg, 149.1 ± 28.1% of control, respectively). Festidinol markedly decreased the escape latency (8.7 ± 4.3 s) and increased the number of platform crossings (8 ± 1.4 time) in the Morris water maze test. Superoxide dismutase activity was significantly elevated after festidinol administration, however there were significant reductions in the levels of 4‑hydroxy-2-nonenal, receptor for advanced glycation end products, phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (pNF-κB), and nuclear factor of activated T cells 1 (NFAT1). Festidinol attenuated amyloid beta production by reducing the mRNA of beta-site APP cleaving enzyme 1 (BACE1). Festidinol also significantly decreased the expression of pTau and phosphorylated glycogen synthase kinase 3 (148.6 ± 37.6% of control, 125.3 ± 22.6% of control, respectively).<br><br>CONCLUSION: Festidinol can ameliorate learning and memory impairments by modulating amyloidogenesis, tau hyperphosphorylation, cholinergic activity, neuroinflammation, and oxidative stress, and by regulating the brain-derived neurotrophic factor signaling pathway.}, }
@article {pmid35101010, year = {2022}, author = {Naseem, S and Ismail, H}, title = {In vitro and in vivo evaluations of antioxidative, anti-Alzheimer, antidiabetic and anticancer potentials of hydroponically and soil grown Lactuca sativa.}, journal = {BMC complementary medicine and therapies}, volume = {22}, number = {1}, pages = {30}, pmid = {35101010}, issn = {2662-7671}, mesh = {Alzheimer Disease/*drug therapy ; Animals ; Antineoplastic Agents/*pharmacology ; Antioxidants/*pharmacology ; Diabetes Mellitus, Experimental/*drug therapy ; Hypoglycemic Agents/*pharmacology ; *Lettuce ; Lipid Peroxidation/drug effects ; Male ; Maze Learning ; Morris Water Maze Test ; Pakistan ; Plant Extracts/*pharmacology ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; }, abstract = {BACKGROUND: Lactuca sativa is an edible plant commonly used by local communities to manage diabetes and stomach problems.<br><br>METHODS: This work aimed to investigate the anti-oxidant, anticancer, antidiabetic and Anti-Alzheimer effects of hydroponically (HyL) and soil-grown (SoL) Lactuca sativa. Streptozotocin-induced diabetes and AlCl3-induced Alzheimer's disease model was used to evaluate the medicinal effects of Lactuca sativa.<br><br>RESULTS: HyL showed significant activity in lipid peroxidation assay, DPPH and DNA protection assay, while SoL extract showed moderated activity, respectively. A similar activity response was quantified for α-glucosidase, α-amylase, acetylcholinesterase and butyrylcholinesterase inhibition assays. The cytotoxic potential of HyL and SoL extracts against MCF7, and HePG2 cancer cell lines exhibited significant activity. HyL and SoL showed a substantial decrease in blood glucose levels in streptozotocin-induced diabetic rats. Diabetes-related liver/kidney biomarkers and anti-oxidant enzyme trends moved toward normal after HyL and SoL treatment. In Anti-Alzheimer's based Morris water and elevated plus maze tests, HyL and SoL displayed memory-enhancing response and anti-anxiety behaviour, respectively. HPLC quantification of dopamine and serotonin revealed a moderate but significant (p<0.05) increase in the level of these neurotransmitters in HyL and SoL groups.<br><br>CONCLUSION: Overall, the study revealed that hydroponic Lactuca sativa possesses the therapeutic potential to treat diseases like Alzheimer's and diabetes.}, }
@article {pmid35099507, year = {2022}, author = {Filippi, M and Cecchetti, G and Spinelli, EG and Vezzulli, P and Falini, A and Agosta, F}, title = {Amyloid-Related Imaging Abnormalities and β-Amyloid-Targeting Antibodies: A Systematic Review.}, journal = {JAMA neurology}, volume = {79}, number = {3}, pages = {291-304}, doi = {10.1001/jamaneurol.2021.5205}, pmid = {35099507}, issn = {2168-6157}, abstract = {Importance: After more than a decade of research and development of clinical trials testing anti-β-amyloid monoclonal antibodies (mAbs), extensive experience has been gained regarding the effects of these treatments in patients with Alzheimer disease (AD). On the verge of an expected large-scale introduction in the clinical setting after the recent US Food and Drug Administration approval of aducanumab, shared knowledge regarding amyloid-related imaging abnormalities (ARIAs) is of paramount importance.<br><br>Objective: To summarize available evidence on ARIAs from randomized clinical trials (RCTs) testing anti-β-amyloid mAbs in patients with AD and to provide a comprehensive update about risk factors, clinical correlates, and implications for withholding and reinitiating treatment.<br><br>Evidence Review: In this systematic review, a literature search of MEDLINE/PubMed, Embase, and Cochrane Library and a search of ClinicalTrials.gov were conducted through September 15, 2021. Publications describing RCTs, secondary analyses of RCT data, and case reports of ARIAs were included. Strengths of clinical data were graded according to the Oxford Centre for Evidence-Based Medicine.<br><br>Findings: Twenty-two RCTs, 11 secondary analyses of RCTs, and 1 case report, including in total 15 508 adult patients (8483 women [54.7%]; mean [SD] age, 69.6 [8.3] years) were selected for inclusion. Signal alterations that included parenchymal edema and sulcal effusion leading to transient hyperintensities on fluid-attenuated inversion recovery and T2-weighted sequences were termed ARIA-E, whereas those consisting of hemosiderin deposits, including parenchymal microhemorrhages and leptomeningeal superficial siderosis, were termed ARIA-H. Apolipoprotein E (ApoE) ε4 genotype was the main risk factor for both ARIA types; ARIA-E incidence was further associated with treatment dose, affecting the 55% of ApoE ε4 carriers in the high-dose aducanumab treatment group. Both ARIA types manifested early during study course, and symptomatic cases accounted for the 6.1% to 39.3% of ARIA-E cases at higher treatment doses across RCTs, whereas ARIA-H cases were generally asymptomatic. Most ARIA-E cases resolved with treatment withholding, although corticosteroid administration was required anecdotally. ARIA-E recurrence after dose reinitiation or adjustment varied from 13.8% to 25.6% across RCTs.<br><br>Conclusions and Relevance: Evidence suggests that ARIAs are frequent, mostly asymptomatic collateral events of amyloid-modifying therapies, highlighting the need for standardized clinical and neuroradiological management protocols in real-world clinical settings.}, }
@article {pmid35090935, year = {2022}, author = {Peng, X and Chen, L and Wang, Z and He, Y and Ruganzu, JB and Guo, H and Zhang, X and Ji, S and Zheng, L and Yang, W}, title = {Tanshinone IIA regulates glycogen synthase kinase-3β-related signaling pathway and ameliorates memory impairment in APP/PS1 transgenic mice.}, journal = {European journal of pharmacology}, volume = {918}, number = {}, pages = {174772}, doi = {10.1016/j.ejphar.2022.174772}, pmid = {35090935}, issn = {1879-0712}, mesh = {Abietanes/*pharmacology ; Alzheimer Disease/metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Behavior, Animal/drug effects ; Cognition/drug effects ; Disease Models, Animal ; Glycogen Synthase Kinase 3 beta/metabolism ; *Memory Disorders/drug therapy/metabolism ; Mice ; Mice, Transgenic ; Nootropic Agents/pharmacology ; Phosphatidylinositol 3-Kinases/*metabolism ; Proto-Oncogene Proteins c-akt/*metabolism ; *Salvia miltiorrhiza ; Signal Transduction/drug effects ; }, abstract = {Our previous findings indicated that tanshinone IIA (tan IIA), a natural component extracted from the root and rhizome of danshen, significantly attenuated β-amyloid accumulation, neuroinflammation, and endoplasmic reticulum stress, as well as improved learning and memory deficits in APP/PS1 transgenic mouse model of Alzheimer's disease (AD). However, whether tan IIA can ameliorate tau pathology and the underlying mechanism in APP/PS1 mice remains unclear. In the current study, tan IIA (15 mg/kg and 30 mg/kg) or saline was intraperitoneally administered to the 5-month-old APP/PS1 mice once daily for 4 weeks. The open-field test, novel object recognition test, Y-maze test, and Morris water maze test were performed to assess the cognitive function. Nissl staining, immunohistochemistry, TUNEL, and western blotting were conducted to explore tau hyperphosphorylation, neuronal injury, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3β (GSK-3β) signaling pathway. The activity of GSK-3β, acetylcholinesterase (AChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) were measured using commercial kits. Our results revealed that tan IIA treatment significantly ameliorated behavioral deficits and improved spatial learning and memory ability of APP/PS1 mice. Additionally, tan IIA markedly attenuated tau hyperphosphorylation and prevented neuronal loss and apoptosis in the parietal cortex and hippocampus. Simultaneously, tan IIA reversed cholinergic dysfunction and reduced oxidative stress. Furthermore, tan IIA activated the PI3K/Akt signaling pathway and suppressed GSK-3β. Taken together, the above findings suggested that tan IIA improves cognitive decline and tau pathology may through modulation of PI3K/Akt/GSK-3β signaling pathway.}, }
@article {pmid35090160, year = {2022}, author = {de Souza, NAP and de Oliveira, F and de Carvalho, RLS and Dourado, MCN}, title = {The Relationship Between Decision-making Capacity and the Domains of Awareness in Alzheimer Disease.}, journal = {Alzheimer disease and associated disorders}, volume = {36}, number = {1}, pages = {58-63}, doi = {10.1097/WAD.0000000000000484}, pmid = {35090160}, issn = {1546-4156}, mesh = {*Alzheimer Disease/psychology ; Awareness ; Caregivers/psychology ; Cognition ; Cross-Sectional Studies ; Decision Making ; Humans ; Quality of Life/psychology ; }, abstract = {People with Alzheimer dementia (PwAD) who are aware of their overall cognitive function and diagnosis are more likely to be judged competent in decision-making capacity. Therefore, we aimed to investigate the relationship between decision-making capacity and the different domains of awareness and the relationship between decision-making capacity and the cognitive and clinical impairment of the PwAD. Using a cross-sectional design, we included 121 PwAD and their caregivers. Awareness was assessed across domains, including cognitive functioning and health condition, functional activity impairments, emotional state, social functioning, and interpersonal relationships. The MacArthur Competence Assessment Tool for Treatment was adopted to gather information about decision-making abilities. We found that decision-making capacity is related to the cognitive and functional domains of awareness and relatively independent of the emotional functioning and the relationship domains. Our finding highlighted that PwAD who are unaware of the disease or the cognitive and functional impairments might be unlikely to appreciate the personal benefits of a proposed health treatment or to understand and judge the personal consequences of a decision accurately.}, }
@article {pmid35080744, year = {2022}, author = {Kaniowska, D and Wenk, K and Rademacher, P and Weiss, R and Fabian, C and Schulz, I and Guthardt, M and Lange, F and Greiser, S and Schmidt, M and Braumann, UD and Emmrich, F and Koehl, U and Jaimes, Y}, title = {Extracellular Vesicles of Mesenchymal Stromal Cells Can be Taken Up by Microglial Cells and Partially Prevent the Stimulation Induced by β-amyloid.}, journal = {Stem cell reviews and reports}, volume = {18}, number = {3}, pages = {1113-1126}, pmid = {35080744}, issn = {2629-3277}, support = {100312141//high-performance center for chemical and biosystems. ministry of saxony/ ; 601241//fraunhofer cluster of excellence for immune-mediated diseases cimd./ ; 990101-113//medizinische fakultät, leipzig./ ; }, mesh = {*Alzheimer Disease/genetics/metabolism/therapy ; Amyloid beta-Peptides/metabolism ; Animals ; *Extracellular Vesicles/metabolism ; Inflammation/pathology ; *Mesenchymal Stem Cells ; Mice ; Microglia/pathology ; }, abstract = {Mesenchymal stromal/stem cells (MSCs) have great capacity for immune regulation. MSCs provide protective paracrine effects, which are partially exerted by extracellular vesicles (EVs). It has been reported that MSCs-derived EVs (MSC-EVs) contain soluble factors, such as cytokines, chemokines, growth factors and even microRNAs, which confer them similar anti-inflammatory and regenerative effects to MSCs. Moreover, MSCs modulate microglia activation through a dual mechanism of action that relies both on cell contact and secreted factors. Microglia cells are the central nervous system immune cells and the main mediators of the inflammation leading to neurodegenerative disorders. Here, we investigated whether MSC-EVs affect the activation of microglia cells by β-amyloid aggregates. We show that the presence of MSC-EVs can prevent the upregulation of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and nitric oxide (NO). Both are up-regulated in neurodegenerative diseases representing chronic inflammation, as in Alzheimer's disease. We demonstrate that MSC-EVs are internalized by the microglia cells. Further, our study supports the use of MSC-EVs as a promising therapeutic tool to treat neuroinflammatory diseases.Significance StatementIt has been reported that mesenchymal stromal/stem cells and MSC-derived small extracellular vesicles have therapeutic effects in the treatment of various degenerative and inflammatory diseases. Extracellular vesicles are loaded with proteins, lipids and RNA and act as intercellular communication mediators. Here we show that extracellular vesicles can be taken up by murine microglial cells. In addition, they partially reduce the activation of microglial cells against β-amyloid aggregates. This inhibition of microglia activation may present an effective strategy for the control/therapy of neurodegenerative diseases such as Alzheimer's disease.}, }
@article {pmid35077620, year = {2021}, author = {Vakilian, A and Ahmadi, AM and Heidari, M and Jalali, N and Nazer, M and Bidaki, MZ and Hashemi, SM and Mirabzadeh, M and Rezaei, A and Amirteimoury, M and Najmaddini, P}, title = {Vitamin B12 Administration Facilitates The Antipsychotic And Pain-Relieving Effects Of Quetiapine, In The Alzheimer Patients With Psychotic Symptoms.}, journal = {Journal of Ayub Medical College, Abbottabad : JAMC}, volume = {33(Suppl 1)}, number = {4}, pages = {S744-S751}, pmid = {35077620}, issn = {1819-2718}, mesh = {*Alzheimer Disease/drug therapy ; *Antipsychotic Agents/therapeutic use ; Humans ; Pain/drug therapy ; Quetiapine Fumarate/therapeutic use ; Treatment Outcome ; Vitamin B 12 ; }, abstract = {Background: Psychotic symptoms in Alzheimer's disease (AD) patients are a problem in medicine. The efficacy of the vitamin B12 on the treatment of the psychotic symptoms of the AD patients in the association with antipsychotic drugs Quetiapine and Risperidone, was evaluated in this Study.<br><br>Methods: The effects of vitamin B12 along with two other drugs were studied on the Mini-Mental State Examination (MMSE), Clinical Global Impression (CGI), Brief Psychiatric Rating Scale (BPRS) and pain Visual Analogue Scale (VAS) in 47 AD patients with psychotic symptoms, including 4 groups, psychotic AD patients treated with Risperidone, Risperidone plus vitamin B12, Quetiapine and Quetiapine plus vitamin B12 .<br><br>Results: The results showed that Quetiapine improved all of the psychotic criteria, while Quetiapine plus vitamin B12 had better results on BPRS after 2 weeks, VAS score and MMSE. Risperidone also improves all of the criteria except MMSE and drug efficacy index, while, vitamin B12 neutralize the effects of the Risperidone on the BPRS, VAS, and severity of illness.<br><br>Conclusion: Due to these results, Quetiapine is the preferred antipsychotics drug and Vitamin B12 plays an effective role in treatment as an adjunct therapy.}, }
@article {pmid35074893, year = {2022}, author = {van de Beek, M and Ooms, FAH and Ebenau, JL and Barkhof, F and Scheltens, P and Teunissen, CE and van Harten, AC and van der Flier, WM and Lemstra, AW}, title = {Association of the ATN Research Framework With Clinical Profile, Cognitive Decline, and Mortality in Patients With Dementia With Lewy Bodies.}, journal = {Neurology}, volume = {98}, number = {12}, pages = {e1262-e1272}, doi = {10.1212/WNL.0000000000200048}, pmid = {35074893}, issn = {1526-632X}, mesh = {*Alzheimer Disease/pathology ; Amyloid beta-Peptides ; Biomarkers ; *Cognitive Dysfunction/etiology ; Disease Progression ; Female ; Humans ; *Lewy Body Disease/complications/pathology ; Male ; tau Proteins ; }, abstract = {BACKGROUND AND OBJECTIVES: The ATN framework has been developed to categorize biological processes within the Alzheimer disease (AD) continuum. Because AD pathology often coincides with dementia with Lewy bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN profiles in DLB with prognosis.<br><br>METHODS: We included 202 patients with DLB from the Amsterdam Dementia Cohort (68±7 years; 19% female; Mini-Mental State Examination 24 ± 3; abnormal DAT-SPECT 105/119). Patients were classified into 8 profiles according to the ATN framework, using CSF β-amyloid (Aβ)42 (A), CSF p-tau (T), and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2 years for n = 139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on the 8 profiles as well as 3 clustered categories (normal AD biomarkers, non-AD pathologic change, and AD continuum).<br><br>RESULTS: Fifty (25%) patients with DLB had normal AD biomarkers (A-T-N-), 37 (18%) had non-AD pathologic change (A-T+N- 10%, A-T-N+ 6%, A-T+N+ 3%), and 115 (57%) were classified within the AD continuum (A+T-N- 20%, A+T+N- 16%, A+T-N+ 10%, A+T+N+ 9%). A+T+N+ patients were older and least often had REM sleep behavior disorder symptoms. Parkinsonism was more often present in A+T- compared to A-T+ patients (independent of N). Compared to patients with normal AD biomarkers, patients in A+ categories showed steeper decline on memory tests and higher mortality risk. Cognitive decline and mortality did not differ between non-AD pathologic change and normal AD biomarkers.<br><br>DISCUSSION: In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within patients with DLB aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies (for example, AD-modifying treatment). Expanding the framework by incorporating markers for α-synucleinopathy would improve the use of the framework to characterize patients with dementia with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.}, }
@article {pmid35049930, year = {2022}, author = {Lima, E and Medeiros, J}, title = {Marine Organisms as Alkaloid Biosynthesizers of Potential Anti-Alzheimer Agents.}, journal = {Marine drugs}, volume = {20}, number = {1}, pages = {}, pmid = {35049930}, issn = {1660-3397}, mesh = {Alzheimer Disease/*drug therapy ; Animals ; *Aquatic Organisms ; Biological Products ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {The incidence of neurodegenerative diseases, such as Alzheimer's disease (AD), increases continuously demanding the urgent development of anti-Alzheimer's agents. Marine organisms (MO) have to create their own defenses due to the adverse environment where they live and so synthesize several classes of compounds, such as akaloids, to defend themselves. Therefore, the identification of marine natural products with neuroprotective effects is a necessity. Being that AD is not only a genetic but also an environmental complex disease, a treatment for AD remains to discover. As the major clinical indications (CI) of AD are extracellular plaques formed by β-amyloid (Aβ) protein, intracellular neurofibrillary tangles (NFTs) formed by hyper phosphorylated τ-protein, uncommon inflammatory response and neuron apoptosis and death caused by oxidative stress, alkaloids that may decrease CI, might be used against AD. Most of the alkalolids with those properties are derivatives of the amino acid tryptophan mainly with a planar indole scaffold. Certainly, alkaloids targeting more than one CI, multitarget-directed ligands (MTDL), have the potential to become a lead in AD treatment. Alkaloids to have a maximum of activity against CI, should be planar and contain halogens and amine quaternization.}, }
@article {pmid35034721, year = {2022}, author = {Azzaz, F and Yahi, N and Di Scala, C and Chahinian, H and Fantini, J}, title = {Ganglioside binding domains in proteins: Physiological and pathological mechanisms.}, journal = {Advances in protein chemistry and structural biology}, volume = {128}, number = {}, pages = {289-324}, doi = {10.1016/bs.apcsb.2021.08.003}, pmid = {35034721}, issn = {1876-1631}, mesh = {Amyloid beta-Peptides ; *COVID-19 ; Gangliosides ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; }, abstract = {Gangliosides are anionic lipids that form condensed membrane clusters (lipid rafts) and exert major regulatory functions on a wide range of proteins. In this review, we propose a new view of the structural features of gangliosides with special emphasis on emerging properties associated with protein binding modes. We analyze the different possibilities of molecular associations of gangliosides in lipid rafts and the role of cholesterol in this organization. We are particularly interested in amide groups of N-acetylated sugars which make it possible to neutralize the negative charge of the carboxylate group of sialic acids. We refer to this effect as "NH trick" and we demonstrate that it is operative in GM1, GD1a, GD1b and GT1b gangliosides. The NH trick is key to understand the different topologies adopted by gangliosides (chalice-like at the edge of lipid rafts, condensed clusters in central areas) and their impact on protein binding. We define three major types of ganglioside-binding domains (GBDs): α-helical, loop shaped, and large flat surface. We describe the mode of interaction of each GBD with typical reference proteins: synaptotagmin, 5HT1A receptor, cholera and botulinum toxins, HIV-1 surface envelope glycoprotein gp120, SARS-CoV-2 spike protein, cellular prion protein, Alzheimer's β-amyloid peptide and Parkinson's disease associated α-synuclein. We discuss the common mechanisms and peculiarities of protein binding to gangliosides in the light of physiological and pathological conditions. We anticipate that innovative ganglioside-based therapies will soon show an exponential growth for the treatment of cancer, microbial infections, and neurodegenerative diseases.}, }
@article {pmid35022306, year = {2022}, author = {Whittington, MD and Campbell, JD and Rind, D and Fluetsch, N and Lin, GA and Pearson, SD}, title = {Cost-Effectiveness and Value-Based Pricing of Aducanumab for Patients With Early Alzheimer Disease.}, journal = {Neurology}, volume = {98}, number = {9}, pages = {e968-e977}, doi = {10.1212/WNL.0000000000013314}, pmid = {35022306}, issn = {1526-632X}, mesh = {*Alzheimer Disease/drug therapy ; Antibodies, Monoclonal, Humanized/therapeutic use ; Cost-Benefit Analysis ; Humans ; Quality-Adjusted Life Years ; }, abstract = {BACKGROUND AND OBJECTIVES: Aducanumab was granted accelerated approval with a conflicting evidence base, near-unanimous Food and Drug Administration Advisory Committee vote to reject approval, and a widely criticized launch price of $56,000 per year. The objective of this analysis was to estimate its cost-effectiveness.<br><br>METHODS: We developed a Markov model to compare aducanumab in addition to supportive care to supportive care alone over a lifetime horizon. Results were presented from both the health system and modified societal perspective. The model tracked the severity of disease and the care setting. Incremental cost-effectiveness ratios were calculated and a threshold analysis was conducted to estimate at what price aducanumab would meet commonly used cost-effectiveness thresholds.<br><br>RESULTS: Using estimates of effectiveness based on pooling of data from both pivotal trials, patients treated with aducanumab spent 4 more months in earlier stages of Alzheimer disease. Over the lifetime time horizon, treating a patient with aducanumab results in 0.154 more quality-adjusted life-years (QALYs) gained per patient and 0.201 equal value of life-years gained (evLYG) per patient from the health care system perspective, with additional costs of approximately $204,000 per patient. The incremental outcomes were similar for the modified societal perspective. At the launch price of $56,000 per year, the cost-effectiveness ranged from $1.02 million per evLYG to $1.33 million per QALY gained from the health care system perspective and from $938,000 per evLYG to $1.27 million per QALY gained in the modified societal perspective. The annual price to meet commonly used cost-effectiveness thresholds ranged from $2,950 to $8,360, which represents a discount of 85%-95% off from the annual launch price set by the manufacturer. Using estimates of effectiveness based only on the trial that suggested a benefit, the mean incremental cost was greater than $400,000 per QALY gained.<br><br>CONCLUSION: Patients treated with aducanumab received minimal improvements in health outcomes at considerable cost. This resulted in incremental cost-effectiveness ratios that far exceeded commonly used value thresholds, even under optimistic treatment effectiveness assumptions. These findings are subject to the substantial uncertainty regarding whether aducanumab provides any true net health benefit, but evidence available currently suggests that an annual price of aducanumab of $56,000 is not in reasonable alignment with its clinical benefits.}, }
@article {pmid35019804, year = {2022}, author = {Qin, Y and Zhang, F and Zhang, M and Zhu, W}, title = {Effects of repetitive transcranial magnetic stimulation combined with cognitive training on resting-state brain activity in Alzheimer's disease.}, journal = {The neuroradiology journal}, volume = {}, number = {}, pages = {19714009211067409}, doi = {10.1177/19714009211067409}, pmid = {35019804}, issn = {2385-1996}, abstract = {OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is a promising tool to modulate brain plasticity, but the neural basis has been little addressed. The purpose was to investigate the effects of rTMS on resting-state brain activity in patients with Alzheimer's disease (AD).<br><br>METHODS: Seventeen patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS combined with cognitive training (real group, n = 9); (2) sham rTMS with cognitive training (sham group, n = 8). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex and then the left lateral temporal lobe for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment and resting-state functional magnetic resonance imaging (rsfMRI) before and after treatment. The fractional amplitude of low frequency fluctuation (fALFF) of rsfMRI data in real group were: (1) compared to sham; (2) correlated with rTMS-induced cognitive alterations.<br><br>RESULTS: Significantly increased fALFF in right cerebellum/declive, left lingual/cuneus and left cingulate gyrus, as well as decreased fALFF in left middle frontal gyrus were found after 10 Hz rTMS, but not after sham stimulation. Using these suprathreshold regions, we found that rTMS increased functional connectivity between the right cerebellum/declive and left precentral/postcentral gyrus. The fALFF increase in left lingual/cuneus and right cerebellum/declive was associated with significant improvement in cognitive function.<br><br>CONCLUSIONS: rTMS combined with cognitive training induced increased low frequency fluctuation neural oscillations and functional connectivity in brain regions subserving cognition, suggesting a possible neuronal mechanism of the beneficial effects of rTMS.}, }
@article {pmid35008528, year = {2021}, author = {Sierri, G and Dal Magro, R and Vergani, B and Leone, BE and Formicola, B and Taiarol, L and Fagioli, S and Kravicz, M and Tremolizzo, L and Calabresi, L and Re, F}, title = {Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs.}, journal = {International journal of molecular sciences}, volume = {23}, number = {1}, pages = {}, pmid = {35008528}, issn = {1422-0067}, support = {2017PFYK27//PRIN Research Italy/ ; }, mesh = {ATP Binding Cassette Transporter 1/*metabolism ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/*metabolism ; Apolipoprotein A-I/metabolism ; Astrocytes/*metabolism ; Biological Transport/physiology ; Biomimetics/methods ; Blood-Brain Barrier/metabolism ; Brain/metabolism ; Cell Line ; Cholesterol/*metabolism ; Humans ; Lipoproteins, HDL/*metabolism ; }, abstract = {The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins' synthesis and lipoproteins' assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins' levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood-brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.}, }
@article {pmid35005289, year = {2021}, author = {Adhikari, UK and Sakiz, E and Habiba, U and Mikhael, M and Senesi, M and David, MA and Guillemin, GJ and Ooi, L and Karl, T and Collins, S and Tayebi, M}, title = {Treatment of microglia with Anti-PrP monoclonal antibodies induces neuronal apoptosis in vitro.}, journal = {Heliyon}, volume = {7}, number = {12}, pages = {e08644}, pmid = {35005289}, issn = {2405-8440}, abstract = {Previous reports highlighted the neurotoxic effects caused by some motif-specific anti-PrPC antibodies in vivo and in vitro. In the current study, we investigated the detailed alterations of the proteome with liquid chromatography-mass spectrometry following direct application of anti-PrPC antibodies on mouse neuroblastoma cells (N2a) and mouse primary neuronal (MPN) cells or by cross-linking microglial PrPC with anti-PrPC antibodies prior to co-culture with the N2a/MPN cells. Here, we identified 4 (3 upregulated and 1 downregulated) and 17 (11 upregulated and 6 downregulated) neuronal apoptosis-related proteins following treatment of the N2a and N11 cell lines respectively when compared with untreated cells. In contrast, we identified 1 (upregulated) and 4 (2 upregulated and 2 downregulated) neuronal apoptosis-related proteins following treatment of MPN cells and N11 when compared with untreated cells. Furthermore, we also identified 3 (2 upregulated and 1 downregulated) and 2 (1 upregulated and 1 downregulated) neuronal apoptosis-related related proteins following treatment of MPN cells and N11 when compared to treatment with an anti-PrP antibody that lacks binding specificity for mouse PrP. The apoptotic effect of the anti-PrP antibodies was confirmed with flow cytometry following labelling of Annexin V-FITC. The toxic effects of the anti-PrP antibodies was more intense when antibody-treated N11 were co-cultured with the N2a and the identified apoptosis proteome was shown to be part of the PrPC-interactome. Our observations provide a new insight into the prominent role played by microglia in causing neurotoxic effects following treatment with anti-PrPC antibodies and might be relevant to explain the antibody mediated toxicity observed in other related neurodegenerative diseases such as Alzheimer.}, }
@article {pmid35000424, year = {2022}, author = {Kivipelto, M and Palmer, K and Hoang, TD and Yaffe, K}, title = {Trials and Treatments for Vascular Brain Health: Risk Factor Modification and Cognitive Outcomes.}, journal = {Stroke}, volume = {53}, number = {2}, pages = {444-456}, doi = {10.1161/STROKEAHA.121.032614}, pmid = {35000424}, issn = {1524-4628}, mesh = {*Brain ; COVID-19 ; Cerebrovascular Disorders/*prevention &amp; control/psychology ; Cognitive Dysfunction/*prevention &amp; control/psychology ; *Health ; Humans ; Pandemics ; Randomized Controlled Trials as Topic ; Risk Reduction Behavior ; Stroke/*prevention &amp; control/psychology ; Treatment Outcome ; }, abstract = {There is robust evidence linking vascular health to brain health, cognition, and dementia. In this article, we present evidence from trials of vascular risk factor treatment on cognitive outcomes. We summarize findings from randomized controlled trials of antihypertensives, lipid-lowering medications, diabetes treatments (including antidiabetic drugs versus placebo, and intensive versus standard glycemic control), and multidomain interventions (that target several domains simultaneously such as control of vascular and metabolic factors, nutrition, physical activity, and cognitive stimulation etc). We report that evidence on the efficacy of vascular risk reduction interventions is promising, but not yet conclusive, and several methodological limitations hamper interpretation. Evidence mainly comes from high-income countries and, as cognition and dementia have not been the primary outcomes of many trials, evaluation of cognitive changes have often been limited. As the cognitive aging process occurs over decades, it is unclear whether treatment during the late-life window is optimal for dementia prevention, yet older individuals have been the target of most trials thus far. Further, many trials have not been powered to explore interactions with modifiers such as age, race, and apolipoprotein E, even though sub-analyses from some trials indicate that the success of interventions differs depending on patient characteristics. Due to the complex multifactorial etiology of dementia, and variations in risk factors between individuals, multidomain interventions targeting several risk factors and mechanisms are likely to be needed and the long-term sustainability of preventive interventions will require personalized approaches that could be facilitated by digital health tools. This is especially relevant during the COVID-19 pandemic, where intervention strategies will need to be adapted to the new normal, when face-to-face engagement with participants is limited and public health measures may create changes in lifestyle that affect individuals' vascular risk profiles and subsequent risk of cognitive decline.}, }
@article {pmid34992853, year = {2021}, author = {N'Go, PK and Ahami, OTA and El Hessni, A and Azzaoui, FZ and Aboussaleh, Y and Tako, AN}, title = {Neuroprotective effects of the Chrysophyllum perpulchrum extract against an Alzheimer-like rat model of β amyloid1-40 intrahippocampal injection.}, journal = {Translational neuroscience}, volume = {12}, number = {1}, pages = {545-560}, pmid = {34992853}, issn = {2081-3856}, abstract = {Objective: Alzheimer's disease (AD) is a threatening disease for African populations in the upcoming years because of the increase in their expectancy of life. Here, we investigated whether natural products from Chrysophyllum perpulchrum as catechin and two dimeric procyanidins (catechin + hexose) could prevent progression of oxidative stress and cognitive changes using an AD-like rat model induced by Aβ1-40 injection into the hippocampal CA1 subfield.<br><br>Methodology: Adult male Wistar rats were either microinjected with 1% ammonia as a vehicle (10 µL) or aggregated Aβ1-40 at 10 µg bilateral hippocampus. On the 14th day of post-surgery, some Aβ rats were treated with melatonin (10 mg/kg i.p.) or with the Chrysophyllum perpulchrum extract (300 mg/kg p.o.), and some sham-operated rats received the extract alone. Cognitive abilities were tested with Y-maze, object recognition test and Morris Water Maze. Oxidative stress markers as well as the level of activated microglial cells were assayed in the brain.<br><br>Results: Aβ rats exhibited significant deficits of recognition memory and spatial learning. This was associated with an increase of microglia Iba 1 immunoreactivity as well as nitric oxide (NO), malondialdehyde and superoxide dismutase levels but not to the thiol content in the hippocampus, prefrontal cortex and septum of AD-like rats. The Chrysophyllum perpulchrum extract treatment mitigated Aβ-induced cognitive impairments and reversed microglia overactivation and subsequent generation of oxidative stress markers. Interestingly, the neuroprotective actions of the Chrysophyllum perpulchrum extract seem to be comparable to the control drug melatonin used albeit with some more beneficial effects.<br><br>Conclusion: These findings are preliminary and should be strengthened by more pharmacological studies of bioactive compounds of Chrysophyllum perpulchrum before being proposed as a promising drug against AD.}, }
@article {pmid34983978, year = {2022}, author = {Ismail, Z and Creese, B and Aarsland, D and Kales, HC and Lyketsos, CG and Sweet, RA and Ballard, C}, title = {Psychosis in Alzheimer disease - mechanisms, genetics and therapeutic opportunities.}, journal = {Nature reviews. Neurology}, volume = {18}, number = {3}, pages = {131-144}, pmid = {34983978}, issn = {1759-4766}, mesh = {Aged ; *Alzheimer Disease/complications/drug therapy/genetics ; Humans ; Neurocognitive Disorders ; *Neurodegenerative Diseases ; Neuroimaging ; *Psychotic Disorders/etiology/genetics ; }, abstract = {Psychosis is a common and distressing symptom in people with Alzheimer disease, and few safe and effective treatments are available. However, new approaches to symptom assessment and treatment are beginning to drive the field forward. New nosological perspectives have been provided by incorporating the emergence of psychotic symptoms in older adults - even in advance of dementia - into epidemiological and neurobiological frameworks as well as into diagnostic and research criteria such as the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders, the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) research criteria for psychosis in neurodegenerative disease, and the ISTAART criteria for mild behavioural impairment. Here, we highlight the latest findings in genomics, neuroimaging and neurobiology that are informing approaches to drug discovery and repurposing. Current pharmacological and non-pharmacological treatment options are discussed, with a focus on safety and precision medicine. We also explore trial data for pimavanserin, a novel agent that shows promise for the treatment of psychosis in people with dementia, and discuss existing agents that might be useful but need further exploration such as escitalopram, lithium, cholinesterase inhibitors and vitamin D. Although the assessment and management of psychosis in people with dementia remain challenging, new opportunities are providing direction and hope to the field.}, }
@article {pmid34980874, year = {2022}, author = {Cao, K and Xiang, J and Dong, YT and Xu, Y and Guan, ZZ}, title = {Activation of α7 Nicotinic Acetylcholine Receptor by its Selective Agonist Improved Learning and Memory of Amyloid Precursor Protein/Presenilin 1 (APP/PS1) Mice via the Nrf2/HO-1 Pathway.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {28}, number = {}, pages = {e933978}, pmid = {34980874}, issn = {1643-3750}, mesh = {*Alzheimer Disease/drug therapy/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Benzamides/*pharmacology ; Bridged Bicyclo Compounds/*pharmacology ; Disease Models, Animal ; Heme Oxygenase-1/*metabolism ; Learning/drug effects/physiology ; Maze Learning/drug effects ; Membrane Proteins/*metabolism ; *Memory/drug effects/physiology ; Mice ; Mice, Transgenic ; NF-E2-Related Factor 2/*metabolism ; Neuronal Plasticity/drug effects/physiology ; Nicotinic Agonists/pharmacology ; Presenilin-1/metabolism ; Signal Transduction/drug effects ; *alpha7 Nicotinic Acetylcholine Receptor/agonists/metabolism ; }, abstract = {BACKGROUND To reveal the mechanism underlying the effect of alpha7 nicotinic acetylcholine receptor (nAChR) on neurodegeneration in Alzheimer disease (AD), the influence of the receptor on recognition in APP/PS1 mice was evaluated by using its selective agonist (PNU-282987). MATERIAL AND METHODS APP/PS1 and wild-type (WT) mice were treated with PNU or saline, respectively, for 7 days at the ages of 6 and 10 months. RESULTS Morris water maze analysis showed that both at 6 and 10 months of age, PNU treatment enhanced the learning and memory of APP/PS1 mice. However, PNU treatment did not alter the number of senile plaques. Furthermore, a higher protein expression of Nrf2/HO-1, ADAM10, SYP, and SNAP-25, and a lower level of oxidative stress, were observed in the hippocampus of APP/PS1 mice treated with PNU compared with the control group. CONCLUSIONS The results indicated that the activation of alpha7 nAChR by PNU improved the learning and memory of mice carrying the APP/PS1 mutation, regulated the levels of enzymes that mediate APP metabolization to reduce ß-amyloid peptide damage, and decreased the level of oxidative stress and maintained synaptic plasticity, in which the mechanism might be enhancement of the Nrf2/HO-1 pathway.}, }
@article {pmid34975502, year = {2021}, author = {Zeng, P and Su, HF and Ye, CY and Qiu, SW and Tian, Q}, title = {Therapeutic Mechanism and Key Alkaloids of Uncaria rhynchophylla in Alzheimer's Disease From the Perspective of Pathophysiological Processes.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {806984}, pmid = {34975502}, issn = {1663-9812}, abstract = {Presently, there is a lack of effective disease-modifying drugs for the treatment of Alzheimer's disease (AD). Uncaria rhynchophylla (UR) and its predominant active phytochemicals alkaloids have been studied to treat AD. This study used a novel network pharmacology strategy to identify UR alkaloids against AD from the perspective of AD pathophysiological processes and identified the key alkaloids for specific pathological process. The analysis identified 10 alkaloids from UR based on high-performance liquid chromatography (HPLC) that corresponded to 127 targets correlated with amyloid-β (Aβ) pathology, tau pathology and Alzheimer disease pathway. Based on the number of targets correlated with AD pathophysiological processes, angustoline, angustidine, corynoxine and isocorynoxeine are highly likely to become key phytochemicals in AD treatment. Among the 127 targets, JUN, STAT3, MAPK3, CCND1, MMP2, MAPK8, GSK3B, JAK3, LCK, CCR5, CDK5 and GRIN2B were identified as core targets. Based on the pathological process of AD, angustoline, angustidine and isocorynoxeine were identified as the key UR alkaloids regulating Aβ production and corynoxine, isocorynoxeine, dihydrocorynatheine, isorhynchophylline and hirsutine were identified as key alkaloids that regulate tau phosphorylation. The findings of this study contribute to a more comprehensive understanding of the key alkaloids and mechanisms of UR in the treatment of AD, as well as provide candidate compounds for drug research and development for specific AD pathological processes.}, }
@article {pmid34973014, year = {2021}, author = {Ben Abdessalem, H and Ai, Y and Marulasidda Swamy, KS and Frasson, C}, title = {Virtual Reality Zoo Therapy for Alzheimer's Disease Using Real-Time Gesture Recognition.}, journal = {Advances in experimental medicine and biology}, volume = {1338}, number = {}, pages = {97-105}, pmid = {34973014}, issn = {0065-2598}, mesh = {Aged ; *Alzheimer Disease/therapy ; Anxiety Disorders ; Gestures ; Humans ; *Virtual Reality ; *Virtual Reality Exposure Therapy ; }, abstract = {Alzheimer's disease affects almost ten million people every year. Negative emotions such as frustration and anxiety can have impact on brain capability in terms of memory functions. Alzheimer's patients experience more negative emotions than healthy older adults. Non-pharmacological treatment such as animal therapy could help Alzheimer patient but has restrictions and requirements. We propose a Virtual Reality Zoo Therapy system in which the patients are immersed in a virtual environment and can interact with animals using their hands. With the immersive experience of virtual reality (VR), patients feel that they are in a real therapy room and can freely interact with animals. This system is controlled by an intelligent agent which tracks the patients' emotions using electroencephalography and commands the animals according to their hand gesture and emotions. Experiments have been done and preliminary results show that it is possible to predict patients' hand gesture and interpret them in order to interact with virtual animals and the Zoo Therapy system can reduce the negative emotions.}, }
@article {pmid34970718, year = {2022}, author = {Vecchio, F and Quaranta, D and Miraglia, F and Pappalettera, C and Di Iorio, R and L'Abbate, F and Cotelli, M and Marra, C and Rossini, PM}, title = {Neuronavigated Magnetic Stimulation combined with cognitive training for Alzheimer's patients: an EEG graph study.}, journal = {GeroScience}, volume = {44}, number = {1}, pages = {159-172}, pmid = {34970718}, issn = {2509-2723}, mesh = {Aged ; *Alzheimer Disease/diagnosis ; Cognition/physiology ; *Cognition Disorders ; Electroencephalography ; Humans ; Transcranial Magnetic Stimulation/methods ; }, abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder in elderly subjects. Recent studies verified the effects of cognitive training combined with repetitive transcranial magnetic stimulation (rTMS-COG) in AD patients. Here, we analyzed neuropsychological and neurophysiological data, derived from electroencephalography (EEG), to evaluate the effects of a 6-week protocol of rTMS-COG in 72 AD. We designed a randomized, double-blind, sham-controlled trial to evaluate efficacy of rTMS on 6 brain regions obtained by an individual MRI combined with COG related to brain areas to stimulate (i.e., syntax and grammar tasks, comprehension of lexical meaning and categorization tasks, action naming, object naming, spatial memory, spatial attention). Patients underwent neuropsychological and EEG examination before (T0), after treatment (T1), and after 40 weeks (T2), to evaluate the effects of rehabilitation therapy. "Small World" (SW) graph approach was introduced allowing us to model the architecture of brain connectivity in order to correlate it with cognitive improvements. We found that following 6 weeks of intensive daily treatment the immediate results showed an improvement in cognitive scales among AD patients. SW present no differences before and after the treatment, whereas a crucial SW modulation emerges at 40-week follow-up, emphasizing the importance of rTMS-COG rehabilitation treatment for AD. Additional results demonstrated that the delta and alpha1 SW seem to be diagnostic biomarkers of AD, whereas alpha2 SW might represent a prognostic biomarker of cognitive recovery. Derived EEG parameters can be awarded the role of diagnostic and predictive biomarkers of AD progression, and rTMS-COG can be regarded as a potentially useful treatment for AD.}, }
@article {pmid34967389, year = {2021}, author = {Cheng, X and Wang, H and Zheng, Z and Feng, K and Tang, S and Liu, Y and Chen, K and Bi, C and Gao, M and Ji, L}, title = {Alzheimer disease effects of different stages on intestinal flora: A protocol for systematic review and meta-analysis.}, journal = {Medicine}, volume = {100}, number = {52}, pages = {e28462}, pmid = {34967389}, issn = {1536-5964}, support = {81373528//Innovative Research Group Project of the National Natural Science Foundation of China/ ; }, mesh = {*Alzheimer Disease ; *Cognitive Dysfunction ; *Gastrointestinal Microbiome ; Humans ; Meta-Analysis as Topic ; Research Design ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND: Alzheimer disease (AD) is a common degenerative disease of the central nervous system that can be divided into 3 stages, according to the degree of cognitive impairment. The clinical manifestations are cognitive dysfunction and memory loss, impacting the daily activities of the affected individuals. In recent years, studies have demonstrated a relationship between intestinal flora and AD. However, no meta-analysis has documented the correlation between AD and intestinal flora, to the best of our knowledge. Herein, we sought to assess the correlation between different stages of AD and intestinal flora. A systematic and comprehensive understanding of this relationship is of great significance for developing prevention and treatment strategies against AD.<br><br>METHODS: A comprehensive search of the medical literature in Chinese and English language was performed in databases, such as PubMed, EBSCO, CNKI, web of science, WanFang, Cochrane Library, and CBM databases. Pre-defined search strategies were used to retrieve clinical studies of Alzheimer disease and gut microbiota. The included studies were independently analyzed by the 2 researchers who extracted the data. The quality of the data was evaluated according to the "Cochrane system evaluator manual." Finally, Endnote and RevMan software were used for systematic regression and meta-analysis of evidence.<br><br>RESULTS: We documented the intestinal flora changes in the 3 stages of Alzheimer disease, according to currently available clinical evidence, and revealed the correlation between the abundance and diversity of flora and treatment efficacy. These findings are essential for developing new strategies for the prevention and treatment of Alzheimer disease.<br><br>INPLASY REGISTRATION NUMBER: INPLASY2021100093.<br><br>ETHICS AND DISSEMINATION: Since all data utilized in this systematic review and meta-analysis are published, ethical approval was not needed.}, }
@article {pmid34967131, year = {2022}, author = {Li, S and Li, Y and Wang, Y and Li, R and Niu, H and Liu, C and Zhang, Y}, title = {Ionic-liquid-based ultrasound-assisted extraction combined with countercurrent chromatography and semipreparative LC for the preparation of monoamine oxidase B inhibitors from Pueraria thomsonii.}, journal = {Journal of separation science}, volume = {45}, number = {5}, pages = {1116-1127}, doi = {10.1002/jssc.202100799}, pmid = {34967131}, issn = {1615-9314}, support = {31870336//National Natural Science Foundation of China/ ; 20200201114JC//Jilin Provincial Science and Technology Department/ ; 2020C036-8//Jilin Province Development and Reform Commission/ ; [2020] 011//Natural Science Foundation of Changchun Normal University/ ; 20200201114JC//Natural Science Foundation of Jilin Province/ ; }, mesh = {Chromatography, High Pressure Liquid/methods ; Countercurrent Distribution/methods ; *Ionic Liquids ; Monoamine Oxidase ; *Pueraria/chemistry ; }, abstract = {A simple and efficient method was developed for the rapid screening and identification of ligands for monoamine oxidase B. A new ionic-liquid-based ultrasound-assisted extraction method for medicinal herbs was also developed and validated. In addition, the hyphenated technique of countercurrent chromatography and semipreparative-LC was developed and applied to the isolation of the chemical constituents for Pueraria thomsonii Benth. Three potent monoamine oxidase B inhibitors, namely, daidzein-4',7-diglucoside (42.2 mg), puerarin 6''-O-xyloside (88.3 mg), and 3'-hydroxypuerarin (48.5 mg) with purities of 98.2, 96.3, and 97.1%, respectively, were obtained from 500 g of P. thomsonii raw material using semi-preparative high-performance liquid chromatography, whereas 3'-methoxypuerarin (76.2 mg), daidzein-8-C-apiosyl (1→6) glucoside (84.2 mg), and tectorigenin (75.1 mg) with purities of 98.5, 96.4, and 96.8%, respectively, were obtained from 500 g raw material via countercurrent chromatography using a two-phase solvent system comprising n-hexane-ethyl acetate-methanol-water at a volume ratio of 1.85:1.00:0.86:3.69 (v/v/v/v). Then, the anti-Alzheimer activity of the phytochemicals was assessed using a PC12 cell model. Treatment with tectorigenin, daidzein-4',7-diglucoside, puerarin 6''-O-xyloside, 3'-hydroxypuerarin, 3'-methoxypuerarin, and daidzein-8-C-apiosyl (1→6) glucoside (100 μg/mL), resulted in cell viabilities of 69.00, 65.81, 59.69, 57.90, 55.61, and 54.59%, respectively (p < 0.001). The protocol was proved to be very accurate and efficient.}, }
@article {pmid34963433, year = {2021}, author = {Turkez, H and Arslan, ME and Barboza, JN and Kahraman, CY and de Sousa, DP and Mardinoğlu, A}, title = {Therapeutic Potential of Ferulic Acid in Alzheimer's Disease.}, journal = {Current drug delivery}, volume = {}, number = {}, pages = {}, doi = {10.2174/1567201819666211228153801}, pmid = {34963433}, issn = {1875-5704}, abstract = {Alzheimer's Disease (AD) is one of the most important neurodegenerative diseases and it covers 60% of whole dementia cases. AD is a constantly progressing neurodegenerative disease as a result of the production of β-amyloid (Aβ) protein and the accumulation of hyper-phosphorylated Tau protein; it causes breakages in the synaptic bonds and neuronal deaths to a large extent. Millions of people worldwide suffer from AD because there is no definitive drug for disease prevention, treatment or slowdown. Over the last decade, multiple target applications have been developed for AD treatments. These targets include Aβ accumulations, hyper-phosphorylated Tau proteins, mitochondrial dysfunction, and oxidative stress resulting in toxicity. Various natural or semisynthetic antioxidant formulations have been shown to protect brain cells from Aβ induced toxicity and provide promising potentials for AD treatment. Ferulic acid (FA), a high-capacity antioxidant molecule, is naturally synthesized from certain plants. FA has been shown to have different substantial biological properties, such as anticancer, antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and cardioprotective actions, etc. Furthermore, FA exerted neuroprotection via preventing Aβ-fibril formation, acting as an anti-inflammatory agent, and inhibiting free radical generation and acetylcholinesterase (AChE) enzyme activity. In this review, we present key biological roles of FA and several FA derivatives in Aβ-induced neurotoxicity, protection against free radical attacks, and enzyme inhibitions and describe them as possible therapeutic agents for the treatment of AD.}, }
@article {pmid34959619, year = {2021}, author = {Viel, C and Brandtner, AT and Weißhaar, A and Lehto, A and Fuchs, M and Klein, J}, title = {Effects of Magnesium Orotate, Benfotiamine and a Combination of Vitamins on Mitochondrial and Cholinergic Function in the TgF344-AD Rat Model of Alzheimer's Disease.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {12}, pages = {}, pmid = {34959619}, issn = {1424-8247}, support = {0815//Wörwag Pharma (Germany)/ ; }, abstract = {Glucose hypometabolism, mitochondrial dysfunction, and cholinergic deficits have been reported in early stages of Alzheimer's disease (AD). Here, we examine these parameters in TgF344-AD rats, an Alzheimer model that carries amyloid precursor protein and presenilin-1 mutations, and of wild type F344 rats. In mitochondria isolated from rat hippocampi, we found reductions of complex I and oxidative phosphorylation in transgenic rats. Further impairments, also of complex II, were observed in aged (wild-type and transgenic) rats. Treatment with a "cocktail" containing magnesium orotate, benfotiamine, folic acid, cyanocobalamin, and cholecalciferol did not affect mitochondrial activities in wild-type rats but restored diminished activities in transgenic rats to wild-type levels. Glucose, lactate, and pyruvate levels were unchanged by age, genetic background, or treatment. Using microdialysis, we also investigated extracellular concentrations of acetylcholine that were strongly reduced in transgenic animals. Again, ACh levels in wild-type rats did not change upon treatment with nutrients, whereas the cocktail increased hippocampal acetylcholine levels under physiological stimulation. We conclude that TgF344-AD rats display a distinct mitochondrial and cholinergic dysfunction not unlike the findings in patients suffering from AD. This dysfunction can be partially corrected by the application of the "cocktail" which is particularly active in aged rats. We suggest that the TgF344-AD rat is a promising model to further investigate mitochondrial and cholinergic dysfunction and potential treatment approaches for AD.}, }
@article {pmid34957899, year = {2021}, author = {Salehi, S and Nourbakhsh, MS and Yousefpour, M and Rajabzadeh, G and Sahab-Negah, S}, title = {Chitosan-coated niosome as an efficient curcumin carrier to cross the blood-brain barrier: an animal study.}, journal = {Journal of liposome research}, volume = {}, number = {}, pages = {1-9}, doi = {10.1080/08982104.2021.2019763}, pmid = {34957899}, issn = {1532-2394}, abstract = {This study aims to improve the curcumin bio-stability and brain permeability by loading in bare niosome (BN) and chitosan-coated niosome (ChN). Span 60, tween 60, and cholesterol were optimized as niosome shell components to attain the highest encapsulation efficiency (EE), besides the lowest particle size, using the mixture design method. The resulting optimized BN had a mean diameter of 80 ± 0.2 nm and surface charge of -31 ± 0.1 mv, which changed to 85 ± 0.15 nm and 35 ± 0.12 mv, respectively, after applying the chitosan layer. The EE% in bare niosome were about 80 ± 0.2, which changed to 82 ± 0.21 in ChN. The optimized formulation displayed sustained release, following the Hixson-Crowell model.Wistar rats were subjected to intraperitoneal injection (i.p.) of BN and ChN to evaluate the blood-brain barrier permeability of the curcumin. In this regard, ChN significantly increased curcumin concentration in different parts of the liver, plasma, and central nervous system (cerebral cortex, cerebellum, and stratum), compared with BN. Altogether, our results showed that ChN could be used as a promising delivery system for the treatment of some neurological diseases such as Alzheimer's.}, }
@article {pmid34952254, year = {2022}, author = {Lithgow, BJ and Dastgheib, Z and Moussavi, Z}, title = {Baseline Prediction of rTMS efficacy in Alzheimer patients.}, journal = {Psychiatry research}, volume = {308}, number = {}, pages = {114348}, doi = {10.1016/j.psychres.2021.114348}, pmid = {34952254}, issn = {1872-7123}, mesh = {*Alzheimer Disease/psychology/therapy ; Cognition ; Discriminant Analysis ; Humans ; *Transcranial Magnetic Stimulation/methods ; Treatment Outcome ; }, abstract = {Repetitive transcranial magnetic stimulation (rTMS) with extensive 2-6-week protocols are applied to improve cognition and/or slow the cognitive decline seen in Alzheimer's Disease (AD). To date, there are no means to predict the response of a patient to rTMS treatment at baseline. Electrovestibulography (EVestG) biomarkers can be used to predict, at baseline, the efficacy of rTMS when applied to AD individuals. In a population of 27 AD patients (8 with significant cerebrovascular symptomatology, labelled ADcvd) EVestG signals were measured before and after rTMS treatment, and then compared with 16 age-matched healthy controls. MoCA was measured at baseline, whilst ADAS-Cog was the primary outcome measure. AD severity and comorbid cerebrovascular disease were treated as covariates. Using ADAS-Cog total score change, 13/27 AD/ADcvd patients improved with rTMS and 14/27 showed no-improvement. Leave-one-out-cross-validated linear-discriminant-analysis using two EVestG features yielded a blind accuracy of 75% for separating the improved and non-improved populations. Three-way separation of improved/non-improved/control accuracy was 91.9% using MoCA (67% alone) and one EVestG feature (66% alone). AD severity affects the rTMS treatment efficacy. The effect of existing significant cerebrovascular symptomatology on the efficacy of rTMS treatment remains unresolved. Baseline EVestG features can be predictive of the efficacy of rTMS treatment.}, }
@article {pmid34951386, year = {2021}, author = {Todri, J and Lena, O and Todri, A and Fuentes, JM}, title = {Does the Global Postural Re-Education Affect the Psychological and Postural Aspects of Alzheimer Disease Patients? A Six Months Quasi-Experimental Study.}, journal = {Current Alzheimer research}, volume = {18}, number = {13}, pages = {1057-1065}, doi = {10.2174/1567205019666211223094811}, pmid = {34951386}, issn = {1875-5828}, mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/therapy ; Cognition ; Female ; Humans ; Male ; Mental Status and Dementia Tests ; Quality of Life ; Treatment Outcome ; }, abstract = {OBJECTIVE: To study the implementation of Global Postural Re-education as a rehabilitative alternative in residence facilities for seniors with Alzheimer, and to verify its effect on psychological and cognitive symptoms.<br><br>METHODS: A quasi-experimental design was employed using month-follow-up assessments at 1,3, and 6 months respectively. Ninety elderly people participated in the composition of the study sample: 69 women and 21 men aged from 67 to 89 years (80.2 ±5.5), grouped in two phases: mild and moderate, according to Alzheimer severity. Patients in both groups received the same treatment twice a week for consecutively 24 weeks. Three follow-up medium-long term assessments were performed at intervals of 1, 3, and 6 months. Outcome measures included Mini-Mental State Examination, Geriatric Depression Scale, Quality of Life in Alzheimer Disease, Barthel Index, and Tinetti Scale.<br><br>RESULTS: The severity of groups therapy interaction showed significant changes in four outcome measures as cognition [F(1,88)=60.26; p=.000; partial η2= 0.406], depression [F(1,88)=8.24; p=.005; partial η2= 0.086], life quality [F(1,88)= 10.45; p=.002; partial η2= 0.106] and equilibrium [F(1,88)= 6.96; p=.010; partial η2= 0.073]. No changes were found for autonomy [F(1,88)= 1.10; p=.297; partial η2= 0.012]. These changes between the two groups were observed at the sixth month follow-up assessment.<br><br>CONCLUSION: Global postural reeducation could be useful as a complementary rehabilitation treatment in Alzheimer patients.}, }
@article {pmid34950896, year = {2021}, author = {Hainsworth, AH and Elahi, FM and Corriveau, RA}, title = {An introduction to therapeutic approaches to vascular cognitive impairment.}, journal = {Cerebral circulation - cognition and behavior}, volume = {2}, number = {}, pages = {100033}, pmid = {34950896}, issn = {2666-2450}, support = {MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MR/R005567/1/MRC_/Medical Research Council/United Kingdom ; MR/T033371/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Vascular cognitive impairment (VCI), encompassing vascular dementia, has been claimed as the "second-most common dementia" after Alzheimer Disease. Whether or not this is true, the clinical picture of most dementia in older people includes vascular disease. There are no validated pharmacological targets for prevention or treatment of VCI. This has inspired a multitude of potential treatment approaches, reflected by the articles in this Special Issue. These include in vitro testing of the novel oral anticoagulant dabigatran for protection against β-amyloid neurotoxicity, and an overview of neuroinflammation in VCI and the role of circulating markers (PIGF, VEGF-D) identified by the MarkVCID study. There are reviews of potential therapeutics, including adrenomedullin and nootropic preparations (exemplified by cerebrolysin). The role of sleep is reviewed, with possible therapeutic targets (5HT2A receptors). There is a clinical study protocol (INVESTIGATE-SVD) and a feasibility analysis for a secondary prevention trial in small vessel disease. Clinical data include secondary analyses of blood pressure and cerebral blood flow from a longitudinal clinical trial (NILVAD), differences between methylphenidate and galantamine responders and non-responders (STREAM-VCI), appraisal of treatment approaches in India, and primary outcomes from a randomised trial of Argentine tango dancing to preserve cognition in African American women (ACT). Treating vascular disease has great potential to improve global cognitive health, with public health impacts alongside individual benefit. Vascular disease burden varies across populations, offering the possibility of proactively addressing health inequity in dementia using vascular interventions. The next 5-10 years will witness cost-effective lifestyle interventions, repurposed drugs and novel therapeutics.}, }
@article {pmid34950895, year = {2021}, author = {Ruchoux, MM and Kalaria, RN and Román, GC}, title = {The pericyte: A critical cell in the pathogenesis of CADASIL.}, journal = {Cerebral circulation - cognition and behavior}, volume = {2}, number = {}, pages = {100031}, pmid = {34950895}, issn = {2666-2450}, support = {G0400074/MRC_/Medical Research Council/United Kingdom ; G0502157/MRC_/Medical Research Council/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; G1100540/MRC_/Medical Research Council/United Kingdom ; }, abstract = {Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease presenting with migraine, mood and cognitive disorders, focal neurological deficits, recurrent ischemic attacks, lacunar infarcts and brain white matter changes. As they age, CADASIL patients invariably develop cognitive impairment and subcortical dementia. CADASIL is caused by missense mutations in the NOTCH3 gene resulting in a profound cerebral vasculopathy affecting primarily arterial vascular smooth muscle cells, which target the microcirculation and perfusion. Based on a thorough review of morphological lesions in arteries, veins, and capillaries in CADASIL, we surmise that arteriolar and capillary pericyte damage or deficiency appears a key feature in the pathogenesis of the disease. This may affect critical pericyte-endothelial interactions causing stroke injury and vasomotor disturbances. Changes in microvascular permeability due to perhaps localized blood-brain barrier alterations and pericyte secretory dysfunction likely contribute to delayed neuronal as well as glial cell death. Moreover, pericyte-mediated cerebral venous insufficiency may explain white matter lesions and the dilatation of Virchow-Robin perivascular spaces typical of CADASIL. The postulated central role of the pericyte offers some novel approaches to the study and treatment of CADASIL and enable elucidation of other forms of cerebral small vessel diseases and subcortical vascular dementia.}, }
@article {pmid34944489, year = {2021}, author = {Soto-Mercado, V and Mendivil-Perez, M and Velez-Pardo, C and Jimenez-Del-Rio, M}, title = {(-)-Epigallocatechin-3-Gallate Diminishes Intra-and Extracellular Amyloid-Induced Cytotoxic Effects on Cholinergic-like Neurons from Familial Alzheimer's Disease PSEN1 E280A.}, journal = {Biomolecules}, volume = {11}, number = {12}, pages = {}, pmid = {34944489}, issn = {2218-273X}, mesh = {Alzheimer Disease/drug therapy/*genetics/metabolism ; Amyloid beta-Peptides/*chemistry/drug effects/toxicity ; Catechin/*analogs &amp; derivatives/pharmacology ; Cells, Cultured ; Cholinergic Neurons/*cytology/drug effects/metabolism ; Female ; Gene Regulatory Networks/drug effects ; Humans ; Hydrogen Peroxide/metabolism ; Microscopy, Fluorescence ; Models, Biological ; Mutation ; Presenilin-1/*genetics ; Protein Aggregates/drug effects ; }, abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disease characterized by functional disruption, death of cholinergic neurons (ChNs) because of intracellular and extracellular Aβ aggregates, and hyperphosphorylation of protein TAU (p-TAU). To date, there are no efficient therapies against AD. Therefore, new therapies for its treatment are in need. The goal of this investigation was to evaluate the effect of the polyphenol epigallocatechin-3-gallate (EGCG) on cholinergic-like neurons (ChLNs) bearing the mutation E280A in PRESENILIN 1 (PSEN1 E280A). To this aim, wild-type (WT) and PSEN1 E280A ChLNs were exposed to EGCG (5-50 μM) for 4 days. Untreated or treated neurons were assessed for biochemical and functional analysis. We found that EGCG (50 μM) significantly inhibited the aggregation of (i)sAPPβf, blocked p-TAU, increased ∆Ψm, decreased oxidation of DJ-1 at residue Cys106-SH, and inhibited the activation of transcription factor c-JUN and P53, PUMA, and CASPASE-3 in mutant ChLNs compared to WT. Although EGCG did not reduce (e)Aβ42, the polyphenol reversed Ca2+ influx dysregulation as a response to acetylcholine (ACh) stimuli in PSEN1 E280A ChLNs, inhibited the activation of transcription factor NF-κB, and reduced the secretion of pro-inflammatory IL-6 in wild-type astrocyte-like cells (ALCs) when exposed to mutant ChLNs culture supernatant. Taken together, our findings suggest that the EGCG might be a promising therapeutic approach for the treatment of FAD.}, }
@article {pmid34941464, year = {2022}, author = {Katsenos, AP and Davri, AS and Simos, YV and Nikas, IP and Bekiari, C and Paschou, SA and Peschos, D and Konitsiotis, S and Vezyraki, P and Tsamis, KI}, title = {New treatment approaches for Alzheimer's disease: preclinical studies and clinical trials centered on antidiabetic drugs.}, journal = {Expert opinion on investigational drugs}, volume = {31}, number = {1}, pages = {105-123}, doi = {10.1080/13543784.2022.2022122}, pmid = {34941464}, issn = {1744-7658}, mesh = {*Alzheimer Disease/drug therapy ; *Diabetes Mellitus, Type 2/drug therapy/epidemiology ; Glucagon-Like Peptide-1 Receptor/agonists ; Humans ; Hypoglycemic Agents/pharmacology/therapeutic use ; Randomized Controlled Trials as Topic ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; }, abstract = {INTRODUCTION: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) represent two major chronic diseases that affect a large percentage of the population and share common pathogenetic mechanisms, including oxidative stress and inflammation. Considering their common mechanistic aspects, and given the current lack of effective therapies for AD, accumulating research has focused on the therapeutic potential of antidiabetic drugs in the treatment or prevention of AD.<br><br>AREAS COVERED: This review examines the latest preclinical and clinical evidence on the potential of antidiabetic drugs as candidates for AD treatment. Numerous approved drugs for T2DM, including insulin, metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium glucose cotransporter 2 inhibitors (SGLT2i), are in the spotlight and may constitute novel approaches for AD treatment.<br><br>EXPERT OPINION: Among other pharmacologic agents, GLP-1 RA and SGLT2i have so far exhibited promising results as novel treatment approaches for AD, while current research has centered on deciphering their action on the central nervous system (CNS). Further investigation is crucial to reveal the most effective pharmacological agents and their optimal combinations, maximize their beneficial effects on neurons, and find ways to increase their distribution to the CNS.}, }
@article {pmid34939734, year = {2022}, author = {Yu, ZY and Chen, DW and Tan, CR and Zeng, GH and He, CY and Wang, J and Bu, XL and Wang, YJ}, title = {Physiological clearance of Aβ by spleen and splenectomy aggravates Alzheimer-type pathogenesis.}, journal = {Aging cell}, volume = {21}, number = {1}, pages = {e13533}, pmid = {34939734}, issn = {1474-9726}, mesh = {Alzheimer Disease/*pathology ; Amyloid beta-Peptides/*adverse effects ; Animals ; Disease Models, Animal ; Female ; Humans ; Mice ; Mice, Transgenic ; Spleen/*pathology ; Splenectomy/*methods ; }, abstract = {BACKGROUND: A previous study demonstrated that nearly 40%-60% of brain Aβ flows out into the peripheral system for clearance. However, where and how circulating Aβ is cleared in the periphery remains unclear. The spleen acts as a blood filter and an immune organ. The aim of the present study was to investigate the role of the spleen in the clearance of Aβ in the periphery.<br><br>METHODS: We investigated the physiological clearance of Aβ by the spleen and established a mouse model of AD and spleen excision by removing the spleens of APP/PS1 mice to investigate the effect of splenectomy on AD mice.<br><br>RESULTS: We found that Aβ levels in the splenic artery were higher than those in the splenic vein, suggesting that circulating Aβ is cleared when blood flows through the spleen. Next, we found that splenic monocytes/macrophages could take up Aβ directly in vivo and in vitro. Splenectomy aggravated behaviour deficits, brain Aβ burden and AD-related pathologies in AD mice.<br><br>CONCLUSION: Our study reveals for the first time that the spleen exerts a physiological function of clearing circulating Aβ in the periphery. Our study also suggests that splenectomy, which is a routine treatment for splenic rupture and hypersplenism, might accelerate the development of AD.}, }
@article {pmid34933129, year = {2022}, author = {Mahaman, YAR and Embaye, KS and Huang, F and Li, L and Zhu, F and Wang, JZ and Liu, R and Feng, J and Wang, X}, title = {Biomarkers used in Alzheimer's disease diagnosis, treatment, and prevention.}, journal = {Ageing research reviews}, volume = {74}, number = {}, pages = {101544}, doi = {10.1016/j.arr.2021.101544}, pmid = {34933129}, issn = {1872-9649}, mesh = {*Alzheimer Disease/diagnosis/therapy ; Amyloid beta-Peptides ; Biomarkers ; Humans ; *Neurodegenerative Diseases ; Neurofibrillary Tangles ; Plaque, Amyloid ; tau Proteins ; }, abstract = {Alzheimer's disease (AD), being the number one in terms of dementia burden, is an insidious age-related neurodegenerative disease and is presently considered a global public health threat. Its main histological hallmarks are the Aβ senile plaques and the P-tau neurofibrillary tangles, while clinically it is marked by a progressive cognitive decline that reflects the underlying synaptic loss and neurodegeneration. Many of the drug therapies targeting the two pathological hallmarks namely Aβ and P-tau have been proven futile. This is probably attributed to the initiation of therapy at a stage where cognitive alterations are already obvious. In other words, the underlying neuropathological changes are at a stage where these drugs lack any therapeutic value in reversing the damage. Therefore, there is an urgent need to start treatment in the very early stage where these changes can be reversed, and hence, early diagnosis is of primordial importance. To this aim, the use of robust and informative biomarkers that could provide accurate diagnosis preferably at an earlier phase of the disease is of the essence. To date, several biomarkers have been established that, to a different extent, allow researchers and clinicians to evaluate, diagnose, and more specially exclude other related pathologies. In this study, we extensively reviewed data on the currently explored biomarkers in terms of AD pathology-specific and non-specific biomarkers and highlighted the recent developments in the diagnostic and theragnostic domains. In the end, we have presented a separate elaboration on aspects of future perspectives and concluding remarks.}, }
@article {pmid34930444, year = {2021}, author = {Schneider, LS and Qiu, Y and Thomas, RG and Evans, C and Jacobs, DM and Jin, S and Kaye, JA and LaCroix, AZ and Messer, K and Salmon, DP and Sano, M and Schafer, K and Feldman, HH}, title = {Impact of potential modifications to Alzheimer's disease clinical trials in response to disruption by COVID-19: a simulation study.}, journal = {Alzheimer's research &amp; therapy}, volume = {13}, number = {1}, pages = {201}, pmid = {34930444}, issn = {1758-9193}, support = {R01 AG057684/NH/NIH HHS/United States ; R01 AG051346/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; U19 AG010483/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/drug therapy ; *COVID-19 ; Computer Simulation ; Humans ; Pandemics ; SARS-CoV-2 ; }, abstract = {BACKGROUND: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made.<br><br>METHODS: We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.<br><br>RESULTS: Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.<br><br>DISCUSSION: These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials' validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.}, }
@article {pmid34919633, year = {2021}, author = {Xhima, K and Markham-Coultes, K and Kofoed, RH and Saragovi, HU and Hynynen, K and Aubert, I}, title = {Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies.}, journal = {Brain : a journal of neurology}, volume = {}, number = {}, pages = {}, doi = {10.1093/brain/awab460}, pmid = {34919633}, issn = {1460-2156}, abstract = {Early degeneration of basal forebrain cholinergic neurons (BFCNs) contributes substantially to cognitive decline in Alzheimer's disease (AD). Evidence from preclinical models of neuronal injury and aging support a pivotal role for nerve growth factor (NGF) in neuroprotection, resilience, and cognitive function. However, whether NGF can provide therapeutic benefit in the presence of AD-related pathologies remains unresolved. Perturbations in the NGF signaling system in AD may render neurons unable to benefit from NGF administration. Additionally, challenges related to brain delivery remain for clinical translation of NGF-based therapies in AD. To be safe and efficient, NGF-related agents should stimulate the NGF receptor, tropomyosin receptor kinase A (TrkA), avoid activation through the p75 neurotrophin receptor (p75NTR), and be delivered non-invasively to targeted brain areas using real-time monitoring. We addressed these limitations using MRI-guided focused ultrasound (MRIgFUS) to increase blood-brain barrier (BBB) permeability locally and transiently, allowing an intravenously administered TrkA agonist that does not activate p75NTR, termed D3, to enter targeted brain areas. Here, we report the therapeutic potential of selective TrkA activation in a transgenic mouse model that recapitulates numerous AD-associated pathologies. Repeated MRIgFUS-mediated delivery of D3 (D3/FUS) improved cognitive function in the TgCRND8 model of AD. Mechanistically, D3/FUS treatment effectively attenuated cholinergic degeneration and promoted functional recovery. D3/FUS treatment also resulted in widespread reduction of brain amyloid pathology and dystrophic neurites surrounding amyloid plaques. Furthermore, D3/FUS markedly enhanced hippocampal neurogenesis in TgCRND8 mice, implicating TrkA agonism as a novel therapeutic target to promote neurogenesis in the context of AD-related pathology. Thus, this study provides evidence that selective TrkA agonism confers neuroprotection to effectively counteract AD-related vulnerability. Recent clinical trials demonstrate that non-invasive BBB modulation using MRIgFUS is safe, feasible and reversible in AD patients. TrkA receptor agonists coupled with MRIgFUS delivery constitute a promising disease-modifying strategy to foster brain health and counteract cognitive decline in AD.}, }
@article {pmid34917297, year = {2021}, author = {Jameie, SB and Pirasteh, A and Naseri, A and Jameie, MS and Farhadi, M and Babaee, JF and Elyasi, L}, title = {β-Amyloid Formation, Memory, and Learning Decline Following Long-term Ovariectomy and Its Inhibition by Systemic Administration of Apigenin and β-Estradiol.}, journal = {Basic and clinical neuroscience}, volume = {12}, number = {3}, pages = {383-394}, pmid = {34917297}, issn = {2008-126X}, abstract = {Introduction: The increasing cases of Alzheimer Disease (AD) has caused numerous problems. The risk of developing AD increases in menopausal women, too. Apigenin and β-estradiol are effective antioxidant and neuroprotective agents. We conducted the present study to explore their combined effects on β-amyloid plaque formation, memory, and learning in ovariectomized rats.<br><br>Methods: Forty-two Wistar rats were randomly assigned into 6 groups: 1) ovariectomized (OVX), 2) OVX + apigenin, 3) OVX + β-estradiol, 4) OVX + apigenin + β-estradiol, 5 &amp;6) vehicle shams for E2 and API, and 7) surgical sham. Treatment was done with apigenin and β-estradiol. Then, we studied the formation of β-amyloid plaques, neuronal density in the hippocampus area, apoptosis, memory, and learning.<br><br>Results: Findings showed the significant formation of β-amyloid plaques in the hippocampus of OVX animals and their memory impairment. Apigenin and β-estradiol significantly reduced the number of β-amyloid plaques, as well as the symptoms of memory impairment and learning, and decreased the expression of caspase-3 in treated animals.<br><br>Conclusion: Accordingly, β-estradiol and apigenin could have more potent therapeutic effects on AD.}, }
@article {pmid34915100, year = {2022}, author = {Lai, X and Hu, J and Liu, H and Lan, L and Long, Y and Gao, X and Deng, J}, title = {A short peptide from sAPPα binding to BACE1-APP action site rescues Alzheimer-like pathology.}, journal = {Neuroscience letters}, volume = {770}, number = {}, pages = {136397}, doi = {10.1016/j.neulet.2021.136397}, pmid = {34915100}, issn = {1872-7972}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Amyloid Precursor Protein Secretases/antagonists &amp; inhibitors/*metabolism ; Amyloid beta-Peptides/chemistry/*metabolism ; Animals ; Aspartic Acid Endopeptidases/antagonists &amp; inhibitors/*metabolism ; Binding Sites ; Blood-Brain Barrier/metabolism ; Cell Line, Tumor ; Humans ; Male ; Mice ; Neuroprotective Agents/pharmacology/*therapeutic use ; Peptide Fragments/chemistry/pharmacology/*therapeutic use ; Protease Inhibitors/pharmacology/*therapeutic use ; Protein Binding ; Proteolysis/drug effects ; }, abstract = {Amyloid β-peptide (Aβ) is the driven force of Alzheimer's disease (AD), and reducing Aβ production could be a potential therapeutic strategy for AD. sAPPα appears to have the ability to specifically inhibit β-cleavage of APP without inhibiting BACE1 completely, direct administration of sAPPα may not be clinically applicable due to the low permeability of blood-brain barrier (BBB). In this study, we investigated the neuroprotective effects of a short peptide generated from sAPPα, which could specifically bind to BACE1 at the BACE1-APP action site. We found that this peptide significantly reduced Aβ production both in vivo and in vitro, thus further attenuated Aβ deposition, Tau hyperphosphorylation, neuroinflammation et al. and rescued behavioral deficits. Therefore, this short peptide may hold promise for the treatment of AD due to its neuroprotective effects, low molecular weight to cross BBB, and less safety concerns. The anti-neurodegenerative capacity of sAPPα may not result solely from direct inhibition of BACE1.}, }
@article {pmid34913091, year = {2021}, author = {Stazi, M and Lehmann, S and Sakib, MS and Pena-Centeno, T and Büschgens, L and Fischer, A and Weggen, S and Wirths, O}, title = {Long-term caffeine treatment of Alzheimer mouse models ameliorates behavioural deficits and neuron loss and promotes cellular and molecular markers of neurogenesis.}, journal = {Cellular and molecular life sciences : CMLS}, volume = {79}, number = {1}, pages = {55}, pmid = {34913091}, issn = {1420-9071}, support = {20021//Alzheimer Forschung Initiative/ ; WI 3472/10-1//Deutsche Forschungsgemeinschaft/ ; }, mesh = {Alzheimer Disease/*drug therapy ; Amyloid beta-Peptides/metabolism ; Animals ; Biomarkers/metabolism ; Caffeine/*pharmacology ; Cells, Cultured ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Neurogenesis/*drug effects ; Neurons/*drug effects/pathology ; Plaque, Amyloid/*drug therapy ; }, abstract = {Epidemiological studies indicate that the consumption of caffeine, the most commonly ingested psychoactive substance found in coffee, tea or soft drinks, reduces the risk of developing Alzheimer's disease (AD). Previous treatment studies with transgenic AD mouse models reported a reduced amyloid plaque load and an amelioration of behavioral deficits. It has been further shown that moderate doses of caffeine have the potential to attenuate the health burden in preclinical mouse models of a variety of brain disorders (reviewed in Cunha in J Neurochem 139:1019-1055, 2016). In the current study, we assessed whether long-term caffeine consumption affected hippocampal neuron loss and associated behavioral deficits in the Tg4-42 mouse model of AD. Treatment over a 4-month period reduced hippocampal neuron loss, rescued learning and memory deficits, and ameliorated impaired neurogenesis. Neuron-specific RNA sequencing analysis in the hippocampus revealed an altered expression profile distinguished by the up-regulation of genes linked to synaptic function and processes, and to neural progenitor proliferation. Treatment of 5xFAD mice, which develop prominent amyloid pathology, with the same paradigm also rescued behavioral deficits but did not affect extracellular amyloid-β (Aβ) levels or amyloid precursor protein (APP) processing. These findings challenge previous assumptions that caffeine is anti-amyloidogenic and indicate that the promotion of neurogenesis might play a role in its beneficial effects.}, }
@article {pmid34909647, year = {2021}, author = {Bhat, A and Dalvi, H and Jain, H and Rangaraj, N and Singh, SB and Srivastava, S}, title = {Perspective insights of repurposing the pleiotropic efficacy of statins in neurodegenerative disorders: An expository appraisal.}, journal = {Current research in pharmacology and drug discovery}, volume = {2}, number = {}, pages = {100012}, pmid = {34909647}, issn = {2590-2571}, abstract = {Neurodegenerative disorders which affects a larger population pose a great clinical challenge. These disorders impact the quality of life of an individual by damaging the neurons, which are the unit cells of the brain. Clinicians are faced with the grave challenge of inhibiting the progression of these diseases as available treatment options fail to meet the clinical demand. Thus, treating the disease/disorder symptomatically is the Hobson's choice. The goal of the researchers is to introduce newer therapies in this segment and introducing a new molecule will take long years of development. Hence, drug repurposing/repositioning can be a better substitute in comparison to time consuming and expensive drug discovery and development cycle. Presently, a paradigm shift towards the re-purposing of drugs can be witnessed. Statins which have been previously approved as anti-hyperlipidemic agents are in the limelight of research for re-purposed drugs. Owing to their anti-inflammatory and antioxidant nature, statins act as neuroprotective in several brain disorders. Further they attenuate the amyloid plaques and protein aggregation which are the triggering factors in the Alzheimer's and Parkinson's respectively. In case of Huntington disease and Multiple sclerosis they help in improving the psychomotor symptoms and stimulate remyelination thus acting as neuroprotective. This article reviews the potential of statins in treating neurodegenerative disorders along with a brief discussion on the safety concerns associated with use of statins and human clinical trial data linked with re-tasking statins for neurodegenerative disorders along with the regulatory perspectives involved with the drug repositioning.}, }
@article {pmid34906893, year = {2022}, author = {Chauhan, BS and Kumar, R and Kumar, P and Kumar, P and Sinha, S and Mishra, SK and Kumar, P and Tiwari, KN and Critchley, AT and Prithiviraj, B and Srikrishna, S}, title = {Neuroprotective potential of flavonoid rich Ascophyllum nodosum (FRAN) fraction from the brown seaweed on an Aβ42 induced Alzheimer's model of Drosophila.}, journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology}, volume = {95}, number = {}, pages = {153872}, doi = {10.1016/j.phymed.2021.153872}, pmid = {34906893}, issn = {1618-095X}, mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; Animals ; *Ascophyllum ; Disease Models, Animal ; Drosophila ; Drosophila melanogaster ; Flavonoids/pharmacology ; Neuroprotection ; Peptide Fragments ; *Seaweed ; }, abstract = {BACKGROUND: In Alzheimer Disease (AD) pathogenesis, aggregation of Aβ42 fibrils strongly correlates with memory dysfunction and neurotoxicity. Till date, no promising cures for AD. Report shows that flavonoids contributed anti-oxidant, anti-cancer and neuroprotection activity by regulating the mitochondrial machinery. Here, we first report the identification of flavonoids from Ascophyllum nodosum as having the ability to dissolve Aβ42 fibrils in an AD model of Drosophila. FRAN could be superior anti-AD agents for neuroprotection, their underlying mechanism and how they collectively halted amyloidogenesis is currently being investigated.<br><br>PURPOSE: This study aimed to investigate the neuroprotective role of FRAN in the Aβ42 expressing AD model of Drosophila.<br><br>METHODS: Drosophila stocks: OregonR+, ey-GAL4/CyO, elavc155-GAL4, UAS-mitoGFP, UAS-mcherry.mito.OMM, UAS-Aβ42/CyO were used, cultured at 28±1 °C in a BOD incubator. Ascophyllum extract rich in flavonoids as revealed by LC-MS study and employed against the AD flies. The validation of Aβ42 expression was done by immunostaining and q-RT PCR. The eye roughness of AD flies was scored in a dose-dependent manner. Further, In vivo and in silico studies of FRAN extract was executed against Aβ42 induced neurotoxicity.<br><br>RESULTS: In order to determine the most effective lethal dose of FRAN extract concentration 1, 2, 5, 10 mg/ml were screened using OregonR+flies. Extract 1 and 2 mg/ml did not show any lethality. Hence, extract 2 mg/ml was employed on AD flies and a ≥ 50% rescue in the eye phenotype was observed using SEM images. This dose had a strong effect on cell apoptosis, viability, longevity, mitochondrial dysfunction and oxidative stress by regulating mitochondrial dynamic markers in comparable to control. Extract also scavenging free radicals in order to maintain in situ cellular ROS and prevent Aβ42-induced neurotoxicity in vivo and in silico. Hence, we suggest its great potential as a future therapeutic agent for AD treatment.<br><br>CONCLUSION: In conclusion, FRAN extract rich in flavonoids as having largest neuroprotective activity against Aβ42 aggregation in eye tissue of Drosophila. Extract shows strong effect against Aβ42-induced neurotoxicity by altering the various cellular and molecular events. So, it could be considered as strong anti-AD agents for neuroprotection.}, }
@article {pmid34900398, year = {2021}, author = {He, C and Zhao, X and Lei, Y and Nie, J and Lu, X and Song, J and Wang, L and Li, H and Liu, F and Zhang, Y and Niu, Q}, title = {Whole-transcriptome analysis of aluminum-exposed rat hippocampus and identification of ceRNA networks to investigate neurotoxicity of Al.}, journal = {Molecular therapy. Nucleic acids}, volume = {26}, number = {}, pages = {1401-1417}, pmid = {34900398}, issn = {2162-2531}, abstract = {Aluminum is a known neurotoxin that can induce Aβ deposition and abnormal phosphorylation of tau protein, leading to Alzheimer disease (AD)-like damages such as neuronal damage and decreased learning and memory functions. In this study, we constructed a rat model of subchronic aluminum maltol exposure, and the whole-transcriptome sequencing was performed on the hippocampus of the control group and the middle-dose group. A total of 167 miRNAs, 37 lncRNAs, 256 mRNAs, and 64 circRNAs expression changed. The Kyoto Encyclopedia of Genes and Genomes showed that PI3K/AKT pathway was the most enriched pathway of DEGs, and IRS1 was the core molecule in the PPI network. circRNA/lncRNA-miRNA-mRNA networks of all DEGs, DEGs in the PI3K/AKT pathway, and IRS1 were constructed by Cytoscape. Molecular experiment results showed that aluminum inhibited the IRS1/PI3K/AKT pathway and increased the content of Aβ and tau. In addition, we also constructed an AAV intervention rat model, proving that inhibition of miR-96-5p expression might resist aluminum-induced injury by upregulating expression of IRS1. In general, these results suggest that the ceRNA networks are involved in the neurotoxic process of aluminum, providing a new strategy for studying the toxicity mechanism of aluminum and finding biological targets for the prevention and treatment of AD.}, }
@article {pmid34896396, year = {2022}, author = {Shobo, A and James, N and Dai, D and Röntgen, A and Black, C and Kwizera, JR and Hancock, MA and Huy Bui, K and Multhaup, G}, title = {The amyloid-β1-42-oligomer interacting peptide D-AIP possesses favorable biostability, pharmacokinetics, and brain region distribution.}, journal = {The Journal of biological chemistry}, volume = {298}, number = {1}, pages = {101483}, doi = {10.1016/j.jbc.2021.101483}, pmid = {34896396}, issn = {1083-351X}, abstract = {We have previously developed a unique 8-amino acid Aβ42 oligomer-Interacting Peptide (AIP) as a novel anti-amyloid strategy for the treatment of Alzheimer's disease. Our lead candidate has successfully progressed from test tubes (i.e., in vitro characterization of protease-resistant D-AIP) to transgenic flies (i.e., in vivo rescue of human Aβ42-mediated toxicity via D-AIP-supplemented food). In the present study, we examined D-AIP in terms of its stability in multiple biological matrices (i.e., ex-vivo mouse plasma, whole blood, and liver S9 fractions) using MALDI mass spectrometry, pharmacokinetics using a rapid and sensitive LC-MS method, and blood brain barrier (BBB) penetrance in WT C57LB/6 mice. D-AIP was found to be relatively stable over 3 h at 37 °C in all matrices tested. Finally, label-free MALDI imaging showed that orally administered D-AIP can readily penetrate the intact BBB in both male and female WT mice. Based upon the favorable stability, pharmacokinetics, and BBB penetration outcomes for orally administered D-AIP in WT mice, we then examined the effect of D-AIP on amyloid "seeding" in vitro (i.e., freshly monomerized versus preaggregated Aβ42). Complementary biophysical assays (ThT, TEM, and MALDI-TOF MS) showed that D-AIP can directly interact with synthetic Aβ42 aggregates to disrupt primary and/or secondary seeding events. Taken together, the unique mechanistic and desired therapeutic potential of our lead D-AIP candidate warrants further investigation, that is, testing of D-AIP efficacy on the altered amyloid/tau pathology in transgenic mouse models of Alzheimer's disease.}, }
@article {pmid34877187, year = {2021}, author = {Alkasabera, A and Onyali, CB and Anim-Koranteng, C and Shah, HE and Ethirajulu, A and Bhawnani, N and Mostafa, JA}, title = {The Effect of Type-2 Diabetes on Cognitive Status and the Role of Anti-diabetes Medications.}, journal = {Cureus}, volume = {13}, number = {11}, pages = {e19176}, pmid = {34877187}, issn = {2168-8184}, abstract = {Type-2 diabetes mellitus prevalence is constantly increasing; this is explained by the increase of its risk factors and the amelioration of its management. Therefore, people are living longer with diabetes mellitus, which, in turn, has revealed new complications of the disease. Dementia is represented mainly by Alzheimer's disease and is an interesting topic of study. Accordingly, statistics have shown that dementia incidence is doubled in diabetic patients. The establishment of a relation between type-2 diabetes mellitus was studied on several levels in both humans and animal subjects. First, insulin receptors were found in the brain, especially the hippocampus, and insulin transport to the brain is mainly accomplished through the blood-brain barrier. Secondly, several studies showed that insulin affects multiple neurotransmitters in favor of promoting memory and cognition status. Thirdly, multiple pathological studies showed that insulin and Alzheimer's disease share many common lesions in the brain, such as beta-amyloid plaques, amylin-Aβ plaques, hyper-phosphorylated tau protein, and brain atrophy, especially in the hippocampus. After recognizing the positive effect of insulin on cognitive status, and the harmful effect of insulin resistance on cognitive status, multiple studies were focused on the role of anti-diabetes medications in fighting dementia. Consequently, these studies showed a positive impact of oral anti-diabetes medication, as well as insulin in limiting the progression of dementia and promoting cognitive status. Moreover, their effects were also noticed on limiting the pathological lesions of Alzheimer's disease. Accordingly, we can consider type-2 diabetes mellitus as a risk factor for dementia and Alzheimer's disease. Therefore, this can be used on the pharmaceutical level by the promising implication of antidiabetics as a treatment of dementia and Alzheimer's disease or at least to limit its progression. However, multiple clinical studies should be dedicated to proving the true benefits of anti-diabetes medications in treating dementia before they can be used in reality.}, }
@article {pmid34870910, year = {2021}, author = {Teplyshova, AM and Datieva, VK}, title = {[Alzheimer disease and epilepsy].}, journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova}, volume = {121}, number = {10. Vyp. 2}, pages = {23-29}, doi = {10.17116/jnevro202112110223}, pmid = {34870910}, issn = {1997-7298}, mesh = {*Alzheimer Disease/diagnosis/drug therapy/epidemiology ; Animals ; Anticonvulsants/therapeutic use ; *Cognitive Dysfunction/diagnosis/epidemiology/etiology ; *Epilepsy/drug therapy/epidemiology ; Humans ; Seizures/drug therapy ; }, abstract = {Alzheimer Disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory, difficulty in thinking, changes in behavior and personality disorders. The risk of developing epileptic seizures (ES) in patients with AD increases significantly. Animal and human studies have shown a close relationship between the pathogenesis of ES and AD. The exact prevalence of ES in AD remains unclear due to methodological difficulties, in particular, detection of ES in patients with cognitive impairment. EP types differ in sporadic and hereditary forms of AD. Antiepileptic therapy in AD has its own characteristics. Certain antiepileptic drugs can have a positive effect on cognitive function.}, }
@article {pmid34867298, year = {2021}, author = {Lemon, N and Canepa, E and Ilies, MA and Fossati, S}, title = {Carbonic Anhydrases as Potential Targets Against Neurovascular Unit Dysfunction in Alzheimer's Disease and Stroke.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {772278}, pmid = {34867298}, issn = {1663-4365}, support = {R01 AG062572/AG/NIA NIH HHS/United States ; R01 NS104127/NS/NINDS NIH HHS/United States ; }, abstract = {The Neurovascular Unit (NVU) is an important multicellular structure of the central nervous system (CNS), which participates in the regulation of cerebral blood flow (CBF), delivery of oxygen and nutrients, immunological surveillance, clearance, barrier functions, and CNS homeostasis. Stroke and Alzheimer Disease (AD) are two pathologies with extensive NVU dysfunction. The cell types of the NVU change in both structure and function following an ischemic insult and during the development of AD pathology. Stroke and AD share common risk factors such as cardiovascular disease, and also share similarities at a molecular level. In both diseases, disruption of metabolic support, mitochondrial dysfunction, increase in oxidative stress, release of inflammatory signaling molecules, and blood brain barrier disruption result in NVU dysfunction, leading to cell death and neurodegeneration. Improved therapeutic strategies for both AD and stroke are needed. Carbonic anhydrases (CAs) are well-known targets for other diseases and are being recently investigated for their function in the development of cerebrovascular pathology. CAs catalyze the hydration of CO2 to produce bicarbonate and a proton. This reaction is important for pH homeostasis, overturn of cerebrospinal fluid, regulation of CBF, and other physiological functions. Humans express 15 CA isoforms with different distribution patterns. Recent studies provide evidence that CA inhibition is protective to NVU cells in vitro and in vivo, in models of stroke and AD pathology. CA inhibitors are FDA-approved for treatment of glaucoma, high-altitude sickness, and other indications. Most FDA-approved CA inhibitors are pan-CA inhibitors; however, specific CA isoforms are likely to modulate the NVU function. This review will summarize the literature regarding the use of pan-CA and specific CA inhibitors along with genetic manipulation of specific CA isoforms in stroke and AD models, to bring light into the functions of CAs in the NVU. Although pan-CA inhibitors are protective and safe, we hypothesize that targeting specific CA isoforms will increase the efficacy of CA inhibition and reduce side effects. More studies to further determine specific CA isoforms functions and changes in disease states are essential to the development of novel therapies for cerebrovascular pathology, occurring in both stroke and AD.}, }
@article {pmid34865098, year = {2022}, author = {Wang, W and Gu, XH and Li, M and Cheng, ZJ and Tian, S and Liao, Y and Liu, X}, title = {MicroRNA-155-5p Targets SKP2, Activates IKKβ, Increases Aβ Aggregation, and Aggravates a Mouse Alzheimer Disease Model.}, journal = {Journal of neuropathology and experimental neurology}, volume = {81}, number = {1}, pages = {16-26}, doi = {10.1093/jnen/nlab116}, pmid = {34865098}, issn = {1554-6578}, mesh = {Alzheimer Disease/*pathology ; Animals ; Disease Models, Animal ; HEK293 Cells ; Humans ; I-kappa B Kinase/*metabolism ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*metabolism ; S-Phase Kinase-Associated Proteins/*metabolism ; }, abstract = {The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase β (IKKβ) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKβ-mediated Aβ aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aβ deposition was determined by histological examination. sh-IKKβ plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aβ1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKβ was assessed by co-immunoprecipitation. IKKβ knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aβ deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aβ deposition in the mice. SKP2 regulated the stability of IKKβ protein via ubiquitination. MiR-155-5p regulates Aβ deposition and the expression of Aβ generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKβ axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.}, }
@article {pmid34864127, year = {2022}, author = {Li, F and Li, Y and Deng, ZP and Zhu, XJ and Zhang, ZG and Zhang, XD and Tian, JL and Li, W and Zhao, P}, title = {Traditional uses, phytochemistry, pharmacology and clinical applications of Cortex Juglandis Mandshuricae: A comprehensive review.}, journal = {Journal of ethnopharmacology}, volume = {285}, number = {}, pages = {114887}, doi = {10.1016/j.jep.2021.114887}, pmid = {34864127}, issn = {1872-7573}, mesh = {Animals ; Drugs, Chinese Herbal/chemistry/*pharmacology ; Humans ; Juglans/*chemistry ; Phytochemicals ; *Phytotherapy ; Plant Extracts/chemistry/*pharmacology ; }, abstract = {ETHNOPHARMALOGICAL RELEVANCE: Cortex Juglandis Mandshuricae (CJM) is the dry branch or stem bark of the Juglans mandshurica Maxim. and is widely used as a traditional Chinese medicine in Asia and Africa. Its use was first recorded in Kaibao Bencao.<br><br>AIM OF THE STUDY: The present review provides a deeper insight, better awareness and detailed knowledge of phytochemistry, pharmacology, quality control, along with clinical applications of Cortex Juglandis Mandshuricae.<br><br>METHODS: The relevant information of Cortex Juglandis Mandshuricae was obtained from several databases including Web of Science, PubMed, and CNKI. The medical books, PhD and MSc dissertations in Chinese were also used to perform this work.<br><br>RESULTS: CJM has been traditionally used against a wide range of diseases, including dysentery, acute conjunctivitis, bacterial infections, and cancer. A total of 249 compounds have been isolated from CJM; they mainly include quinones and their derivatives, flavonoids, tannins, diarylheptanoids, triterpenoids, coumarins, phenylpropanoids, and volatile oils. These compounds exert anti-tumor, anti-oxidant, anti-inflammatory, bacteriostatic, anti-complement, immunomodulatory, anti-parasitic activities. Specifically, the effects of juglone, alkaloids and unsaturated fatty acid CJM components against hepatic cancer occur through exertion of apoptosis through a mitochondria-dependent pathway. In addition, taxifolin and several tannins have been found to have anti-HIV activity, and (±)-juglanaloid A and (±)-juglanaloid B target Alzheimer disease. Quality control is monitored through identification of juglone, quercetin, and volatile oils. A clinical preparation of CJM, Compound Muji Granules, is used in the treatment of various liver diseases with good therapeutic effect.<br><br>CONCLUSION: While CJM has been used extensively as a folk medicine, the relationships between structure and activity remain unclear. More in vivo models are needed to study the pharmacological mechanisms of action and to assess potential toxic components, in addition to which the evidence used to demonstrate the quality standards of medicinal materials is clearly inadequate. Therefore, more in-depth research is needed to provide a reasonable scientific basis improve its clinical utilization.}, }
@article {pmid34856171, year = {2022}, author = {Chen, CLH and Lu, Q and Moorakonda, RB and Kandiah, N and Tan, BY and Villaraza, SG and Cano, J and Venketasubramanian, N}, title = {Alzheimer's Disease THErapy With NEuroaid (ATHENE): A Randomized Double-Blind Delayed-Start Trial.}, journal = {Journal of the American Medical Directors Association}, volume = {23}, number = {3}, pages = {379-386.e3}, doi = {10.1016/j.jamda.2021.10.018}, pmid = {34856171}, issn = {1538-9375}, mesh = {Acetylcholinesterase/therapeutic use ; *Alzheimer Disease/drug therapy ; Cholinesterase Inhibitors/therapeutic use ; Double-Blind Method ; Drugs, Chinese Herbal/*therapeutic use ; Humans ; *Time-to-Treatment ; Treatment Outcome ; }, abstract = {OBJECTIVES: Preclinical and clinical studies indicate a role for MLC901 (NeuroAiD II) in Alzheimer's disease (AD). The primary aim was to investigate its safety as add-on therapy to standard treatment and the secondary aims its effect on cognition and slowing disease progression.<br><br>DESIGN: Randomized double-blind placebo-controlled delayed-start study.<br><br>SETTING AND PARTICIPANT: Patients with mild to moderate probable AD by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n = 125), were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months when all patients received MLC901, in a delayed-start design (clinical trial registration: ClinicalTrials.gov, NCT03038035).<br><br>METHODS: The primary outcome measure was occurrence of serious adverse events (SAEs) at 6 months. Secondary outcomes included the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and other assessment scales.<br><br>RESULTS: There was no significant difference in the risk of SAEs between early and delayed starters at month (M) 6 (22.6% vs 27.0%, risk difference -4.4%, 90% CI -16.9% to 8.3%). Similarly, there was no significant difference in the risk of adverse events and the occurrence of stroke or vascular events between early and delayed starters throughout the 12-month study period. Early starters did not differ significantly on ADAS-Cog from delayed starters at M6 [mean difference (MD) -1.0, 95% CI -3.3 to 1.3] and M12 (MD -2.35, 95% CI -5.45 to 0.74) on intention-to-treat analysis. Other cognitive assessment scales did not show significant differences.<br><br>CONCLUSIONS AND IMPLICATIONS: This study of 125 persons with dementia found no evidence of a significant increase in adverse events between MLC901 and placebo, thus providing support for further studies on both efficacy and safety. Analyses suggest the potential of MLC901 in slowing down AD progression, but this requires further confirmation in larger and longer studies using biomarkers for AD.}, }
@article {pmid34856086, year = {2021}, author = {Balázs, N and Bereczki, D and Kovács, T}, title = {Cholinesterase inhibitors and memantine for the treatment of Alzheimer and non-Alzheimer dementias.}, journal = {Ideggyogyaszati szemle}, volume = {74}, number = {11-12}, pages = {379-387}, doi = {10.18071/isz.74.0379}, pmid = {34856086}, issn = {0019-1442}, mesh = {*Alzheimer Disease/drug therapy ; Caregivers ; Cholinesterase Inhibitors/therapeutic use ; Humans ; *Memantine/therapeutic use ; Quality of Life ; }, abstract = {In aging societies, the morbidity and mortality of dementia is increasing at a significant rate, thereby imposing burden on healthcare, economy and the society as well. Patients' and caregivers' quality of life and life expectancy are greatly determined by the early diagnosis and the initiation of available symptomatic treatments. Cholinesterase inhibitors and memantine have been the cornerstones of Alzheimer's therapy for approximately two decades and over the years, more and more experience has been gained on their use in non-Alzheimer's dementias too. The aim of our work was to provide a comprehensive summary about the use of cholinesterase inhibitors and memantine for the treatment of Alzheimer's and non-Alzheimers's dementias.}, }
@article {pmid34854749, year = {2022}, author = {Lonergan, PE and Washington, SL and Cowan, JE and Zhao, S and Broering, JM and Cooperberg, MR and Carroll, PR}, title = {Androgen Deprivation Therapy and the Risk of Dementia after Treatment for Prostate Cancer.}, journal = {The Journal of urology}, volume = {207}, number = {4}, pages = {832-840}, doi = {10.1097/JU.0000000000002335}, pmid = {34854749}, issn = {1527-3792}, mesh = {Aged ; Androgen Antagonists/*therapeutic use ; Antineoplastic Agents, Hormonal/*therapeutic use ; Dementia/diagnosis/*etiology ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Propensity Score ; Proportional Hazards Models ; Prostatic Neoplasms/*drug therapy/*psychology ; Retrospective Studies ; Risk Factors ; Sensitivity and Specificity ; }, abstract = {PURPOSE: The association between androgen deprivation therapy (ADT) and dementia in men with prostate cancer remains inconclusive. We assessed the association between cumulative ADT exposure and the onset of dementia in a nationwide longitudinal registry of men with prostate cancer.<br><br>MATERIALS AND METHODS: A retrospective analysis of men aged ≥50 years from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) registry was performed. The primary outcome was onset of dementia after primary treatment. ADT exposure was expressed as a time-varying independent variable of total ADT exposure. The probability of receiving ADT was estimated using a propensity score. Cox proportional hazards regression was performed to determine the association between ADT exposure and dementia with competing risk of death, adjusted for propensity score and clinical covariates among men receiving various treatments.<br><br>RESULTS: Of 13,570 men 317 (2.3%) were diagnosed with dementia after a median of 7.0 years (IQR 3.0-12.0) of followup. Cumulative ADT use was significantly associated with dementia (HR 2.02; 95% CI 1.40-2.91; p <0.01) after adjustment. In a subset of 8,506 men, where propensity score matched by whether or not they received ADT, there was also an association between ADT use and dementia (HR 1.59; 95% CI 1.03-2.44; p=0.04). There was no association between primary treatment type and onset of dementia in the 8,489 men in the cohort who did not receive ADT.<br><br>CONCLUSIONS: Cumulative ADT exposure was associated with dementia. This increased risk should be accompanied by a careful discussion of the needs and benefits of ADT in those being considered for treatment.}, }
@article {pmid34851866, year = {2021}, author = {Bago Rožanković, P and Rožanković, M and Badžak, J and Stojić, M and Šušak Sporiš, I}, title = {Impact of Donepezil and Memantine on Behavioral and Psychological Symptoms of Alzheimer Disease: Six-month Open-label Study.}, journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology}, volume = {34}, number = {4}, pages = {288-294}, pmid = {34851866}, issn = {1543-3641}, mesh = {*Alzheimer Disease/complications/drug therapy ; Behavioral Symptoms/drug therapy ; Donepezil/therapeutic use ; Humans ; Indans/therapeutic use ; *Memantine/therapeutic use ; Piperidines/therapeutic use ; Prospective Studies ; Treatment Outcome ; }, abstract = {BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) are common in individuals with Alzheimer disease (AD). Donepezil and memantine are both widely used for the treatment of moderate AD.<br><br>OBJECTIVE: To evaluate the effects of donepezil and memantine in relieving BPSD in individuals with moderate AD.<br><br>METHOD: We conducted a prospective, randomized, 6-month clinical trial involving 85 individuals with moderate AD divided into two groups: group 1 (n = 42) was treated with donepezil; group 2 (n = 43) was treated with memantine. We used the Neuropsychiatric Inventory (NPI) to assess the prevalence and severity of BPSD at baseline and after 6 months of treatment with donepezil or memantine.<br><br>RESULTS: The two groups' baseline characteristics, including age, sex, mean length of education, and disease duration, were comparable, as were their baseline Mini-Mental State Examination scores. The NPI Total score improved from baseline to month 6 in both groups (P < 0.0001). Analyses of the NPI subdomains revealed that both donepezil treatment and memantine treatment produced statistically significant improvement in all of the NPI domains except euphoria and apathy, for which no improvement was observed after memantine treatment. Both treatments were well tolerated, with mostly mild and transient adverse effects.<br><br>CONCLUSION: Specific drugs for AD, including donepezil and memantine, may be effective in treating BPSD in individuals with moderate AD, with a favorable safety profile.}, }
@article {pmid34850970, year = {2021}, author = {Edmans, BG and Wolverson, E and Dunning, R and Slann, M and Russell, G and Crowther, G and Hall, D and Yates, R and Albert, M and Underwood, BR}, title = {Inpatient psychiatric care for patients with dementia at four sites in the United Kingdom.}, journal = {International journal of geriatric psychiatry}, volume = {37}, number = {2}, pages = {}, doi = {10.1002/gps.5658}, pmid = {34850970}, issn = {1099-1166}, }
@article {pmid34839794, year = {2021}, author = {Tuerxun, M and Muhda, A and Yin, L}, title = {The molecular mechanisms of signal pathway activating effect of E2F-1/NF-κB/GSK-3β on cognitive dysfunction of Alzheimer rats.}, journal = {Bioengineered}, volume = {12}, number = {2}, pages = {10000-10008}, pmid = {34839794}, issn = {2165-5987}, mesh = {Alzheimer Disease/*complications ; Animals ; Cognitive Dysfunction/*etiology/*metabolism ; E2F1 Transcription Factor/*metabolism ; Glycogen Synthase Kinase 3 beta/*metabolism ; Hippocampus/metabolism ; Morris Water Maze Test ; NF-kappa B/*metabolism ; Phosphorylation ; Rats, Sprague-Dawley ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction ; tau Proteins/metabolism ; }, abstract = {Alzheimer disease (AD) seriously harms human health and its onset is insidious. Therefore, it is of great significance to find out the pathogenesis of AD disease for improving the prevention and treatment effect of the disease. The study drew attention to the influence of E2F-1/NF-κB/GSK-3β signaling pathway on cognitive dysfunction of Alzheimer rats. 60 specific pathogen-free (SPF) SD rats were selected as research subjects. The, the AD model was created by injecting Aβ1-42 into hippocampus CA1 region of AD rats using a microscopic syringe. Besides, Morris water maze test and Western blot were performed to detect the cognitive function, the levels of destination protein and active oxidation products in the brain of rats. Compared to the Sham group, the escape latency and the distance of the model group significantly increased (P < 0.05), and the number of times to pass the target quadrant was significantly reduced (P < 0.05); the expression levels of E2F-1 and NF-κB protein in the hippocampus and the phosphorylation levels of Tau231, Tau262, Tau396, Tau404 and T216-GSK-3β protein of the model group were significantly increased (P < 0.05); the ROS/RNS value in the hippocampus of the model group significantly increased (P < 0.05). AD model rats exhibit obvious cognitive dysfunction, which is associated with the activation of E2F-1/NF-κB/GSK-3β signaling pathway and the heightened Tau protein phosphorylation level.}, }
@article {pmid34836972, year = {2021}, author = {Chang, CH and Liu, CY and Chen, SJ and Tsai, HC}, title = {Effect of N-methyl-D-aspartate receptor enhancing agents on cognition in dementia: an exploratory systematic review and meta-analysis of randomized controlled trials.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {22996}, pmid = {34836972}, issn = {2045-2322}, mesh = {Cognition Disorders/*drug therapy/etiology/pathology ; Dementia/*complications ; Humans ; Randomized Controlled Trials as Topic/*statistics &amp; numerical data ; Receptors, N-Methyl-D-Aspartate/*agonists ; }, abstract = {Multiple N-methyl-D-aspartate (NMDA) receptor enhancing agents have had promising effects on cognition among patients with dementia. However, the results remain inconsistent. This exploratory meta-analysis investigated the effectiveness of NMDA receptor enhancing agents for cognitive function. PubMed, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews were searched for randomized controlled trials (RCTs). Controlled trials assessing add-on NMDA receptor enhancing agent treatment in patients with dementia and using cognition rating scales were eligible and pooled using a random-effect model for comparisons. The standardized mean difference (SMD) was calculated in each study from the effect size; positive values indicated that NMDA receptor enhancing agent treatment improved cognitive function. Funnel plots and the I2 statistic were evaluated for statistical heterogeneity. Moderators were evaluated using meta-regression. We identified 14 RCTs with 2224 participants meeting the inclusion criteria. Add-on NMDA receptor enhancing agents had small positive significant effects on overall cognitive function among patients with dementia (SMD = 0.1002, 95% CI 0.0105-0.1900, P = 0.02860). Subgroup meta-analysis showed patients with Alzheimer's Disease and trials using the Alzheimer Disease Assessment Scale-cognitive subscale as the primary outcome had small positive significant effects (SMD = 0.1042, 95% CI 0.0076-0.2007, P = 0.03451; SMD = 0.1267, 95% CI 0.0145-0.2388, P = 0.2686). This exploratory meta-analysis showed a very small, positive, and significant effect on overall cognition function in patients with dementia. Studies with larger samples are needed to evaluate different cognitive domains and phases of dementia.}, }
@article {pmid34833381, year = {2021}, author = {Anninos, P and Adamopoulos, A and Anninou, N and Tsagas, N}, title = {Analyzing the Effect of Weak External Transcranial Magnetic Stimulation on the Primary Dominant Frequencies of Alzheimer Patients Brain by Using MEG Recordings.}, journal = {Medicina (Kaunas, Lithuania)}, volume = {57}, number = {11}, pages = {}, pmid = {34833381}, issn = {1648-9144}, support = {80623//General Secretariat for Research and Technology/ ; 80623//ERGO AEBE INC, GR/ ; }, mesh = {*Alzheimer Disease/therapy ; Brain/diagnostic imaging ; Humans ; *Magnetoencephalography ; Transcranial Magnetic Stimulation ; }, abstract = {Backround and Objectives: Alternative, non-invasive, and non-pharmaceutical options are gaining place in the battle of Alzheimer's Disease treatment control. Lately, the magnetic stimulation of the brain is the most prevalent technique with encouraging results. The aim of this study is to establish any possible change on the Primary Dominant Frequencies (PDF) (range 2-7 Hz) of the affected brain regions in Alzheimer Disease (AD) patients after applying extremely weak Transcranial Magnetic Stimulation. Materials and Methods: For this purpose, all AD patients were scanned with the use of MagnetoEncephaloGraphy (MEG) recordings through a whole-head 122-channel MEG system. Results: Our results exerted statistically significant PDF changes due to weak TMS accompanied by rabid attenuation of clinical symptoms. Conclusion: Thus, this is the first time that a positive therapeutic effect is being demonstrated even at pico-Tesla range magnetic fields in a small clinical group of studies for AD.}, }
@article {pmid34824332, year = {2021}, author = {Mosaferi, B and Jand, Y and Salari, AA}, title = {Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {22941}, pmid = {34824332}, issn = {2045-2322}, support = {64.1D.1463//Maragheh University of Medical Sciences/ ; }, mesh = {Adrenocorticotropic Hormone/metabolism ; Alzheimer Disease/drug therapy/*microbiology/physiopathology/psychology ; Amyloid beta-Peptides ; Animals ; Anti-Bacterial Agents/*pharmacology ; Anxiety/microbiology/physiopathology/*prevention &amp; control/psychology ; Behavior, Animal/*drug effects ; *Brain-Gut Axis ; Depression/microbiology/physiopathology/*prevention &amp; control/psychology ; Disease Models, Animal ; Dysbiosis ; Gastrointestinal Microbiome/*drug effects ; Hypothalamo-Hypophyseal System/metabolism/*physiopathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress ; Oxytocin/metabolism ; Peptide Fragments ; }, abstract = {The gut-microbiota-brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer's disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1-42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic-pituitary-adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.}, }
@article {pmid34824314, year = {2021}, author = {Arredondo, SB and Reyes, DT and Herrera-Soto, A and Mardones, MD and Inestrosa, NC and Varela-Nallar, L}, title = {Andrographolide promotes hippocampal neurogenesis and spatial memory in the APPswe/PS1ΔE9 mouse model of Alzheimer's disease.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {22904}, pmid = {34824314}, issn = {2045-2322}, mesh = {Alzheimer Disease/*drug therapy/genetics/pathology/psychology ; Amyloid beta-Protein Precursor/genetics ; Animals ; Behavior, Animal/*drug effects ; Cell Proliferation/*drug effects ; Dentate Gyrus/*drug effects/pathology ; Disease Models, Animal ; Diterpenes/*pharmacology ; Female ; Genetic Predisposition to Disease ; Mice, Transgenic ; Neural Stem Cells/*drug effects/pathology ; Neurogenesis/*drug effects ; Neurons/*drug effects/pathology ; Nootropic Agents/*pharmacology ; Presenilin-1/genetics ; Spatial Memory/*drug effects ; }, abstract = {In Alzheimer´s disease (AD) there is a reduction in hippocampal neurogenesis that has been associated to cognitive deficits. Previously we showed that Andrographolide (ANDRO), the main bioactive component of Andrographis paniculate, induces proliferation in the hippocampus of the APPswe/PSEN1ΔE9 (APP/PS1) mouse model of AD as assessed by staining with the mitotic marker Ki67. Here, we further characterized the effect of ANDRO on hippocampal neurogenesis in APP/PS1 mice and evaluated the contribution of this process to the cognitive effect of ANDRO. Treatment of 8-month-old APP/PS1 mice with ANDRO for 4 weeks increased proliferation in the dentate gyrus as evaluated by BrdU incorporation. Although ANDRO had no effect on neuronal differentiation of newborn cells, it strongly increased neural progenitors, neuroblasts and newborn immature neurons, cell populations that were decreased in APP/PS1 mice compared to age-matched wild-type mice. ANDRO had no effect on migration or in total dendritic length, arborization and orientation of immature neurons, suggesting no effects on early morphological development of newborn neurons. Finally, ANDRO treatment improved the performance of APP/PS1 mice in the object location memory task. This effect was not completely prevented by co-treatment with the anti-mitotic drug TMZ, suggesting that other effects of ANDRO in addition to the increase in neurogenesis might underlie the observed cognitive improvement. Altogether, our data indicate that in APP/PS1 mice ANDRO stimulates neurogenesis in the hippocampus by inducing proliferation of neural precursor cells and improves spatial memory performance.}, }
@article {pmid34810243, year = {2022}, author = {Bown, CW and Carare, RO and Schrag, MS and Jefferson, AL}, title = {Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain.}, journal = {Neurology}, volume = {98}, number = {3}, pages = {107-117}, pmid = {34810243}, issn = {1526-632X}, support = {F32 AG022773/AG/NIA NIH HHS/United States ; F31 AG066358/AG/NIA NIH HHS/United States ; T32 AG058524/AG/NIA NIH HHS/United States ; R01 AG034962/AG/NIA NIH HHS/United States ; R01 AG056534/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; R01 NS100980/NS/NINDS NIH HHS/United States ; S10 OD032380/OD/NIH HHS/United States ; }, mesh = {Aging ; *Alzheimer Disease/complications/diagnostic imaging ; Biomarkers ; Brain/diagnostic imaging ; *Cerebral Small Vessel Diseases/complications/diagnostic imaging ; Humans ; Magnetic Resonance Imaging/methods ; }, abstract = {Perivascular spaces (PVS) are fluid-filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on MRI. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as 2 possible mechanisms that drive ePVS formation. We describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the 2 most prominent theoretical views and review ePVS associations with other common small vessel disease markers. Because ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.}, }
@article {pmid34807243, year = {2022}, 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 = {79}, number = {1}, pages = {13-21}, doi = {10.1001/jamaneurol.2021.4161}, pmid = {34807243}, issn = {2168-6157}, mesh = {Aged ; Alzheimer Disease/*diagnostic imaging/*drug therapy/pathology ; Amyloid beta-Peptides/*metabolism ; Antibodies, Monoclonal, Humanized/*therapeutic use ; Clinical Trials as Topic ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Treatment Outcome ; }, 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 {pmid34797294, year = {2021}, author = {Zhang, J and Kuang, X and Tang, C and Xu, N and Xiao, S and Xiao, L and Wang, S and Dong, Y and Lu, L and Zhang, L}, title = {Acupuncture for amnestic mild cognitive impairment: A pilot multicenter, randomized, parallel controlled trial.}, journal = {Medicine}, volume = {100}, number = {46}, pages = {e27686}, pmid = {34797294}, issn = {1536-5964}, support = {No. 81303043//National Outstanding Youth Science Fund Project of National Natural Science Foundation of China/ ; XK2018001//Key Construction Project of Double First Class University Plan of Guangzhou University of Chinese Medicine/ ; 2017TQ04R627//the Young Top Talent Project of Scientific and Technological Innovation in Special Support Plan for Training High-level Talents in Guangdong/ ; 2019QNPY02//the Youth Research and Cultivation Project of Guangzhou University of Chinese Medicine/ ; }, mesh = {Acupuncture Therapy/*methods ; Alzheimer Disease/diagnosis/*therapy ; Amnesia/therapy ; Cognitive Dysfunction/diagnosis/*therapy ; Diagnostic and Statistical Manual of Mental Disorders ; Feasibility Studies ; Humans ; Mental Status and Dementia Tests ; Pilot Projects ; Treatment Outcome ; }, abstract = {INTRODUCTION: Patients with amnesic mild cognitive impairment (aMCI) are more likely to develop Alzheimer disease than corresponding age normal population. Because Alzheimer disease is irreversible, early intervention for aMCI patients seems important and urgent. We have designed a pilot multicenter, randomized, parallel controlled trial to assess the efficacy and safety of acupuncture on aMCI, explore the feasibility of acupuncture in the treatment of aMCI, so as to provide a reference for large-sample clinical trials in the next stage.<br><br>METHOD: We designed a pilot multicenter, randomized, parallel controlled trial. This trial aims to test the feasibility of carrying out a large-sample clinical trial. In this trial, 50 eligible patients with aMCI will be included and allocated to acupuncture group (n = 25) or sham acupuncture group (n = 25) at random. Subjects will accept treatment 2 times a week for 12 weeks continuously, with a total of 24 treatment sessions. We will select 6 acupoints (GV20, GV14, bilateral BL18, bilateral BL23). For the clinical outcomes, the primary outcome is Montreal cognitive assessment, which will be assessed from baseline to the end of this trial. And the secondary outcomes are Mini-mental State Examination, Delayed Story Recall, Clinical Dementia Rating scale, Global Deterioration Scale, Activity of Daily Life, Alzheimer Disease Assessment Scale-Cognitive Section, brain magnetic resonance imaging, brain functional magnetic resonance imaging, and event-related potential P300, which will be assessed before and after treatment. In addition, we will assess the safety outcomes from baseline to the end of this trial and feasibility outcome after treatment. We will evaluate neuropsychological assessment scale (Montreal cognitive assessment, Mini-mental State Examination, Alzheimer Disease Assessment Scale-Cognitive Section) at 3 months and 6 months after treatment.<br><br>DISCUSSION: This pilot trial aims to explore the feasibility of the trial, verify essential information of its efficacy and safety. This pilot study will provide a preliminary basis for carrying out a larger clinical trial of acupuncture on aMCI in near future.}, }
@article {pmid34775786, year = {2022}, author = {Lee, CJ and Lee, JY and Han, K and Kim, DH and Cho, H and Kim, KJ and Kang, ES and Cha, BS and Lee, YH and Park, S}, title = {Blood Pressure Levels and Risks of Dementia: a Nationwide Study of 4.5 Million People.}, journal = {Hypertension (Dallas, Tex. : 1979)}, volume = {79}, number = {1}, pages = {218-229}, doi = {10.1161/HYPERTENSIONAHA.121.17283}, pmid = {34775786}, issn = {1524-4563}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/epidemiology/physiopathology ; Antihypertensive Agents/therapeutic use ; Blood Pressure/*physiology ; Comorbidity ; Dementia/*epidemiology/physiopathology ; Dementia, Vascular/epidemiology/physiopathology ; Female ; Humans ; Hypertension/drug therapy/*epidemiology/physiopathology ; Incidence ; Male ; Middle Aged ; Risk ; }, abstract = {There are inconsistent results on the impacts of controlling blood pressure (BP) on the risk of dementia. We investigated the association between BP and risk of dementia subtypes by antihypertensive treatment and comorbidities. Using the Korean National Health Insurance Service-Health Screening Database from 2009 to 2012, a total of 4 522 447 adults aged 60+ years without a history of dementia were analyzed and followed up for a mean of 5.4 years. Individuals were classified according to their baseline systolic BP (SBP) and diastolic BP; SBP 130 to <140 mm Hg and diastolic BP 80 to <90 mm Hg were used as reference groups. The risk of overall dementia and probable Alzheimer disease was significantly higher in the SBP≥160 and lower SBP groups. These U-shaped associations were consistent regardless of antihypertensive use or comorbidities. The risk of probable vascular dementia (VaD) was not higher among lower SBP groups and increased gradually as SBP increased. Although there was a linear association between SBP and the risk of probable VaD in individuals not taking antihypertensives or without comorbidities, there was a U-shaped association in individuals taking antihypertensives or with comorbidities. Patterns of association between diastolic BP and risk of probable Alzheimer disease or probable VaD were similar to those with SBP, except for the risk of probable VaD in individuals taking antihypertensives. In conclusion, risks of probable Alzheimer disease and probable VaD were different among lower BP groups. Although the risk of dementia appears higher in people with lower BP receiving antihypertensives, this finding may be affected by comorbidities.}, }
@article {pmid34775673, year = {2021}, author = {He, K and Nie, L and Ali, T and Wang, S and Chen, X and Liu, Z and Li, W and Zhang, K and Xu, J and Liu, J and Yu, ZJ and Yang, X and Li, S}, title = {Adiponectin alleviated Alzheimer-like pathologies via autophagy-lysosomal activation.}, journal = {Aging cell}, volume = {20}, number = {12}, pages = {e13514}, pmid = {34775673}, issn = {1474-9726}, mesh = {Adiponectin/*metabolism ; Animals ; Autophagy/*genetics ; Humans ; Lysosomes/*metabolism ; Male ; Mice ; Proteomics/*methods ; }, abstract = {Adiponectin (APN) deficiency has also been associated with Alzheimer-like pathologies. Recent studies have illuminated the importance of APN signaling in reducing Aβ accumulation, and the Aβ elimination mechanism remains rudimentary. Therefore, we aimed to elucidate the APN role in reducing Aβ accumulation and its associated abnormalities by targeting autophagy and lysosomal protein changes. To assess, we performed a combined pharmacological and genetic approach while using preclinical models and human samples. Our results demonstrated that the APN level significantly diminished in the plasma of patients with dementia and 5xFAD mice (6 months old), which positively correlated with Mini-Mental State Examination (MMSE), and negatively correlated with Clinical Dementia Rating (CDR), respectively. APN deficiency accelerated cognitive impairment, Aβ deposition, and neuroinflammation in 5xFAD mice (5xFAD*APN KO), which was significantly rescued by AdipoRon (AR) treatment. Furthermore, AR treatment also markedly reduced Aβ deposition and attenuated neuroinflammation in APP/PS1 mice without altering APP expression and processing. Interestingly, AR treatment triggered autophagy by mediating AMPK-mTOR pathway signaling. Most importantly, APN deficiency dysregulated lysosomal enzymes level, which was recovered by AR administration. We further validated these changes by proteomic analysis. These findings reveal that APN is the negative regulator of Aβ deposition and its associated pathophysiologies. To eliminate Aβ both extra- and intracellular deposition, APN contributes via the autophagic/lysosomal pathway. It presents a therapeutic avenue for AD therapy by targeting autophagic and lysosomal signaling.}, }
@article {pmid34775332, year = {2022}, author = {He, X and Hui, Z and Xu, L and Bai, R and Gao, Y and Wang, Z and Xie, T and Ye, XY}, title = {Medicinal chemistry updates of novel HDACs inhibitors (2020 to present).}, journal = {European journal of medicinal chemistry}, volume = {227}, number = {}, pages = {113946}, doi = {10.1016/j.ejmech.2021.113946}, pmid = {34775332}, issn = {1768-3254}, mesh = {Chemistry, Pharmaceutical ; Histone Deacetylase Inhibitors/chemistry/*pharmacology ; Histone Deacetylases/*metabolism ; Humans ; Molecular Structure ; }, abstract = {Epigentic enzymes histone deacetylases (HDACs) catalyze the removal of acetyl groups from the ε-N-acetylated lysine residues of various protein substrates including both histone and non-histone proteins. Different HDACs have distinct biological functions and are recruited to specific regions of the genome. Due to their important biological functions, HDACs have been validated in clinics for anticancer therapy, and are being explored for potential treatment of several other diseases such as Alzheimer disease (AD), metabolic disease, viral infection, and multiple sclerosis, etc. Besides five approved drugs, there are more than thirty HDACs inhibitors currently being investigated in clinical trials. Centering on the advances of drug discovery programs in this field since 2020, this review discusses HDACs inhibitors from the aspects of the structure-based rational design, isoform selectivity, pharmacology, and toxicology of the compounds of interest. The hope is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in this area.}, }
@article {pmid34768981, year = {2021}, author = {El-Battari, A and Rodriguez, L and Chahinian, H and Delézay, O and Fantini, J and Yahi, N and Di Scala, C}, title = {Gene Therapy Strategy for Alzheimer's and Parkinson's Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells.}, journal = {International journal of molecular sciences}, volume = {22}, number = {21}, pages = {}, pmid = {34768981}, issn = {1422-0067}, support = {//H2020 SME Phase 1/ ; }, mesh = {Alzheimer Disease/*drug therapy/*metabolism ; Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloidogenic Proteins/metabolism ; Brain/drug effects/metabolism ; Calcium/metabolism ; Cell Line ; Cell Membrane/drug effects/metabolism ; Gangliosides/metabolism ; Genetic Therapy/methods ; Humans ; Parkinson Disease/*drug therapy/*metabolism ; Peptide Fragments/*metabolism ; }, abstract = {We present here a gene therapy approach aimed at preventing the formation of Ca2+-permeable amyloid pore oligomers that are considered as the most neurotoxic structures in both Alzheimer's and Parkinson's diseases. Our study is based on the design of a small peptide inhibitor (AmyP53) that combines the ganglioside recognition properties of the β-amyloid peptide (Aβ, Alzheimer) and α-synuclein (α-syn, Parkinson). As gangliosides mediate the initial binding step of these amyloid proteins to lipid rafts of the brain cell membranes, AmyP53 blocks, at the earliest step, the Ca2+ cascade that leads to neurodegeneration. Using a lentivirus vector, we genetically modified brain cells to express the therapeutic coding sequence of AmyP53 in a secreted form, rendering these cells totally resistant to oligomer formation by either Aβ or α-syn. This protection was specific, as control mCherry-transfected cells remained fully sensitive to these oligomers. AmyP53 was secreted at therapeutic concentrations in the supernatant of cultured cells, so that the therapy was effective for both transfected cells and their neighbors. This study is the first to demonstrate that a unique gene therapy approach aimed at preventing the formation of neurotoxic oligomers by targeting brain gangliosides may be considered for the treatment of two major neurodegenerative disorders, Alzheimer's and Parkinson's diseases.}, }
@article {pmid34766133, year = {2021}, author = {Sajan, MP and Hansen, BC and Acevedo-Duncan, M and Kindy, MS and Cooper, DR and Farese, RV}, title = {Roles of hepatic atypical protein kinase C hyperactivity and hyperinsulinemia in insulin-resistant forms of obesity and type 2 diabetes mellitus.}, journal = {MedComm}, volume = {2}, number = {1}, pages = {3-16}, pmid = {34766133}, issn = {2688-2663}, support = {R01 ES016774/ES/NIEHS NIH HHS/United States ; R21 AG043718/AG/NIA NIH HHS/United States ; }, abstract = {Diet-induced obesity, the metabolic syndrome, type 2 diabetes (DIO/MetS/T2DM), and their adverse sequelae have reached pandemic levels. In mice, DIO/MetS/T2DM initiation involves diet-dependent increases in lipids that activate hepatic atypical PKC (aPKC) and thereby increase lipogenic enzymes and proinflammatory cytokines. These or other hepatic aberrations, via adverse liver-to-muscle cross talk, rapidly impair postreceptor insulin signaling to glucose transport in muscle. The ensuing hyperinsulinemia further activates hepatic aPKC, which first blocks the ability of Akt to suppress gluconeogenic enzyme expression, and later impairs Akt activation, further increasing hepatic glucose production. Recent findings suggest that hepatic aPKC also increases a proteolytic enzyme that degrades insulin receptors. Fortunately, all hepatic aberrations and muscle impairments are prevented/reversed by inhibition or deficiency of hepatic aPKC. But, in the absence of treatment, hyperinsulinemia induces adverse events, some by using "spare receptors" to bypass receptor defects. Thus, in brain, hyperinsulinemia increases Aβ-plaque precursors and Alzheimer risk; in kidney, hyperinsulinemia activates the renin-angiotensin-adrenal axis, thus increasing vasoconstriction, sodium retention, and cardiovascular risk; and in liver, hyperinsulinemia increases lipogenesis, obesity, hepatosteatosis, hyperlipidemia, and cardiovascular risk. In summary, increases in hepatic aPKC are critically required for development of DIO/MetS/T2DM and its adverse sequelae, and therapeutic approaches that limit hepatic aPKC may be particularly effective.}, }
@article {pmid34763094, year = {2021}, author = {Kshirsagar, S and Sawant, N and Morton, H and Reddy, AP and Reddy, PH}, title = {Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.}, journal = {Pharmacological research}, volume = {174}, number = {}, pages = {105973}, pmid = {34763094}, issn = {1096-1186}, support = {R56 AG066347/AG/NIA NIH HHS/United States ; R03 AG063162/AG/NIA NIH HHS/United States ; R01 AG042178/AG/NIA NIH HHS/United States ; R01 AG069333/AG/NIA NIH HHS/United States ; R56 AG060767/AG/NIA NIH HHS/United States ; R01 AG047812/AG/NIA NIH HHS/United States ; R01 NS105473/NS/NINDS NIH HHS/United States ; }, mesh = {Alzheimer Disease/*metabolism ; Animals ; Catechin/*analogs &amp; derivatives/pharmacology ; Cell Line ; Coumarins/*pharmacology ; DNA-Binding Proteins/genetics/metabolism ; High Mobility Group Proteins/genetics/metabolism ; Hippocampus/cytology ; Mice ; Mitochondria/drug effects/ultrastructure ; Mitochondrial Dynamics/drug effects ; Mitophagy/*drug effects ; NF-E2-Related Factor 2/genetics/metabolism ; Neurons/metabolism ; Nuclear Respiratory Factor 1/genetics/metabolism ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics/metabolism ; Phosphorylation ; Synapses/drug effects ; Synaptophysin/metabolism ; tau Proteins/genetics/*metabolism ; }, abstract = {The purpose of our study is to determine the protective effects of mitophagy enhancers against phosphorylated tau (P-tau)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Mitochondrial abnormalities, including defective mitochondrial dynamics, biogenesis, axonal transport and impaired clearance of dead mitochondria are linked to P-tau in AD. Mitophagy enhancers are potential therapeutic candidates to clear dead mitochondria and improve synaptic and cognitive functions in AD. We recently optimized the doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. In the current study, we treated mutant Tau expressed in HT22 (mTau-HT22) cells with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial/synaptic genes, cell survival and mitochondrial respiration. We also assessed mitochondrial morphology in mTau-HT22 cells treated and untreated with mitophagy enhancers. Mutant Tau-HT22 cells showed increased fission, decreased fusion, synaptic &amp; mitophagy genes, reduced cell survival and defective mitochondrial respiration. However, these events were reversed in mitophagy enhancers treated mTau-HT22 cells. Cell survival was increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mTau-HT22 cells. Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.}, }
@article {pmid34761857, year = {2022}, author = {Álvarez-Fernández, B and Bernal-López, MR and Gómez-Huelgas, R}, title = {Role of aripiprazole in the management of behavioural and psychological symptoms of dementia: a narrative review.}, journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society}, volume = {22}, number = {1}, pages = {137-144}, doi = {10.1111/psyg.12787}, pmid = {34761857}, issn = {1479-8301}, support = {CB06/03/0018//Centros de Investigación En Red/ ; C1- 0005-2020//Fondo Europeo de Desarrollo Regional-FEDER and Nicolás Monardes Program/ ; CPII/00014//Miguel Servet Type II Program, Fondo Europeo de Desarrollo Regional-FEDER/ ; }, mesh = {Aggression ; *Antipsychotic Agents/therapeutic use ; Aripiprazole/therapeutic use ; *Dementia/drug therapy ; Humans ; Quality of Life ; }, abstract = {Behavioural and psychological symptoms of dementia affect in a great way quality of life of both patients and their caregivers, which increases the risk of patient institutionalisation when such symptoms are poorly controlled. One of the drugs that are used for controlling behavioural and psychological symptoms of dementia (BPSD) is aripiprazole. This narrative review aims to solve three basic questions. Is aripiprazole useful for the management of these symptoms? Does aripiprazole play a substantial role regarding safety and efficacy, compared with the other pharmacological options available for the same purpose? Has aripiprazole gained importance in treatment regimens of these symptoms, in current clinical practice? We conclude that aripiprazole is effective to manage BPSD. Moreover, it has shown a good safety profile compared with other antipsychotics in advanced disease and frail patients. Thus, aripiprazole has gained importance in current management algorithms for dementia patients mainly due to its efficacy regarding rapid control of agitation and aggressiveness.}, }
@article {pmid34755432, year = {2022}, author = {Parveen, S and Mehra, A and Kumar, K and Grover, S}, title = {Knowledge and attitude of caregivers of people with dementia.}, journal = {Geriatrics &amp; gerontology international}, volume = {22}, number = {1}, pages = {19-25}, doi = {10.1111/ggi.14304}, pmid = {34755432}, issn = {1447-0594}, mesh = {Aged ; *Alzheimer Disease ; *Caregivers ; Family ; Female ; Humans ; Male ; }, abstract = {AIM: This study aimed to evaluate the knowledge and attitude of caregivers of people with dementia towards the disease (Alzheimer disease). The secondary objective of the study was to assess the association of attitude and knowledge towards dementia.<br><br>METHODS: In total, 50 patients with dementia and their caregivers were included in the present study. Caregivers were evaluated on the Dementia Attitude Scale and Alzheimer's Disease Knowledge Scale (ADKS) to assess the level of knowledge and attitude.<br><br>RESULTS: The mean age of patients was 72.2 years, and the majority of them were men, married, from joint/extended family setup, urban background, and upper or upper-middle socioeconomic status. The mean age of the caregivers was 48.04 years, and the majority was educated more than the matric level. Nearly half of the caregivers were children, and about one-third were the spouse of the person with dementia. The mean duration of the caregiver role was 3.6 ± 3.0 years, while the average time spent in caregiving was 7.4 ± 2.9 h/day. Using the Alzheimer's Disease Knowledge Scale, the mean knowledge score for the caregivers was 16.9 ± 2.7. In terms of individual items on the knowledge scale, most of the caregivers were aware of most aspects of dementia. In terms of the mean weighted score, the maximum score was for the domains of course and symptoms and this was followed by the domain of "treatment and management." The lowest score was obtained for the domain of assessment and diagnosis on ADKS. On the Dementia Attitude Scale, the mean total score was 76.4 ± 18.4. The mean total score for the knowledge domain was higher than the support domain.<br><br>CONCLUSION: The current study suggests that most caregivers with dementia have a reasonable level of knowledge about dementia. However, in terms of attitude, caregivers of people with dementia have a less positive attitude towards dementia. The study's finding suggests that there is a need to evaluate the knowledge and attitude of the caregivers of people with dementia and the gaps must be addressed to improve the outcome, both for the people with dementia and their caregivers. Geriatr Gerontol Int 2022; 22: 19-25.}, }
@article {pmid34753171, year = {2022}, author = {Ben-Hassen, C and Helmer, C and Berr, C and Jacqmin-Gadda, H}, title = {Five-Year Dynamic Prediction of Dementia Using Repeated Measures of Cognitive Tests and a Dependency Scale.}, journal = {American journal of epidemiology}, volume = {191}, number = {3}, pages = {453-464}, doi = {10.1093/aje/kwab269}, pmid = {34753171}, issn = {1476-6256}, abstract = {The progression of dementia prevalence over the years and the lack of efficient treatments to stop or reverse the cognitive decline make dementia a major public health challenge in the developed world. Identifying people at high risk of developing dementia could improve the treatment of these patients and help select the target population for preventive clinical trials. We used joint modeling to build a dynamic prediction tool of dementia based on the change over time of 2 neurocognitive tests (the Mini-Mental State Examination and the Isaacs Set Tests) as well as an autonomy scale (the Instrumental Activities of Daily Living). The model was estimated with data from the French cohort Personnes Agées QUID (1988-2015) and validated both by cross-validation and externally with data from the French Three City cohort (1999-2018). We evaluated its predictive abilities through area under the receiver operating characteristics curve and Brier score, accounting for right censoring and competing risk of death, and obtained an average area under the curve value of 0.95 for the risk of dementia in the next 5 or 10 years. This tool is able to discriminate a high-risk group of people from the rest of the population. This could be of help in clinical practice and research.}, }
@article {pmid34750588, year = {2022}, author = {Blanchard, JW and Victor, MB and Tsai, LH}, title = {Dissecting the complexities of Alzheimer disease with in vitro models of the human brain.}, journal = {Nature reviews. Neurology}, volume = {18}, number = {1}, pages = {25-39}, pmid = {34750588}, issn = {1759-4766}, mesh = {Alzheimer Disease/genetics/*pathology/physiopathology ; Animals ; Brain/*pathology/physiology/physiopathology ; Genetic Predisposition to Disease ; Humans ; *Models, Anatomic ; *Models, Neurological ; }, abstract = {Alzheimer disease (AD) is the most prevalent type of dementia. It is marked by severe memory loss and cognitive decline, and currently has limited effective treatment options. Although individuals with AD have common neuropathological hallmarks, emerging data suggest that the disease has a complex polygenic aetiology, and more than 25 genetic loci have been linked to an elevated risk of AD and dementia. Nevertheless, our ability to decipher the cellular and molecular mechanisms that underlie genetic susceptibility to AD, and its progression and severity, remains limited. Here, we discuss ongoing efforts to leverage genomic data from patients using cellular reprogramming technologies to recapitulate complex brain systems and build in vitro discovery platforms. Much attention has already been given to methodologies to derive major brain cell types from pluripotent stem cells. We therefore focus on technologies that combine multiple cell types to recreate anatomical and physiological properties of human brain tissue in vitro. We discuss the advances in the field for modelling four domains that have come into view as key contributors to the pathogenesis of AD: the blood-brain barrier, myelination, neuroinflammation and neuronal circuits. We also highlight opportunities for the field to further interrogate the complex genetic and environmental factors of AD using in vitro models.}, }
@article {pmid34740367, year = {2021}, author = {Park, SH and Baik, K and Jeon, S and Chang, WS and Ye, BS and Chang, JW}, title = {Extensive frontal focused ultrasound mediated blood-brain barrier opening for the treatment of Alzheimer's disease: a proof-of-concept study.}, journal = {Translational neurodegeneration}, volume = {10}, number = {1}, pages = {44}, pmid = {34740367}, issn = {2047-9158}, mesh = {*Alzheimer Disease/diagnostic imaging/therapy ; *Blood-Brain Barrier/diagnostic imaging ; Humans ; Plaque, Amyloid ; Prospective Studies ; Tomography, X-Ray Computed ; }, abstract = {BACKGROUND: Focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening has shown efficacy in removal of amyloid plaque and improvement of cognitive functions in preclinical studies, but this is rarely reported in clinical studies. This study was conducted to evaluate the safety, feasibility and potential benefits of repeated extensive BBB opening.<br><br>METHODS: In this open-label, prospective study, six patients with Alzheimer's disease (AD) were enrolled at Severance Hospital in Korea between August 2020 and September 2020. Five of them completed the study. FUS-mediated BBB opening, targeting the bilateral frontal lobe regions over 20 cm3, was performed twice at three-month intervals. Magnetic resonance imaging, 18F-Florbetaben (FBB) positron emission tomography, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI) and comprehensive neuropsychological tests were performed before and after the procedures.<br><br>RESULTS: FUS targeted a mean volume of 21.1 ± 2.7 cm3 and BBB opening was confirmed at 95.7% ± 9.4% of the targeted volume. The frontal-to-other cortical region FBB standardized uptake value ratio at 3 months after the procedure showed a slight decrease, which was statistically significant, compared to the pre-procedure value (- 1.6%, 0.986 vs1.002, P = 0.043). The CGA-NPI score at 2 weeks after the second procedure significantly decreased compared to baseline (2.2 ± 3.0 vs 8.6 ± 6.0, P = 0.042), but recovered after 3 months (5.2 ± 5.8 vs 8.6 ± 6.0, P = 0.89). No adverse effects were observed.<br><br>CONCLUSIONS: The repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD. In addition, the BBB opening is potentially beneficial for amyloid removal in AD patients.}, }
@article {pmid34733087, year = {2021}, author = {Faraj, J and Takanti, V and Tavakoli, HR}, title = {The Gut-Brain Axis: Literature Overview and Psychiatric Applications.}, journal = {Federal practitioner : for the health care professionals of the VA, DoD, and PHS}, volume = {38}, number = {8}, pages = {356-362}, pmid = {34733087}, issn = {1078-4497}, abstract = {Importance: Literature exploring the relationship between the intestinal microbiome and its effects on general health and well-being has grown significantly in recent years, and our knowledge of this subject continues to grow. Mounting evidence indicates that the intestinal microbiome is a potential target for therapeutic intervention in psychiatric illness and in neurodegenerative disorders such as Alzheimer disease. It is reasonable to consider modulating not just a patient's neurochemistry, behavior, or cognitive habits, but also their intestinal microbiome in an effort to improve psychiatric symptoms.<br><br>Observations: In this review paper, we show that intestinal microbiota possess the ability to directly influence both physical and mental well-being; therefore, should be included in future discussions regarding psychiatric treatment.<br><br>Conclusions: Clinicians are encouraged to consider patients' gut health when evaluating and treating psychiatric conditions, such as anxiety and depression. Optimization and diversification of gut flora through the use of psychobiotics-probiotics that confer mental health benefits-may soon become standard practice in conjunction with traditional psychiatric treatment modalities such as pharmacotherapy and psychotherapy.}, }
@article {pmid34722519, year = {2021}, author = {Sorenson, CM and Song, YS and Zaitoun, IS and Wang, S and Hanna, BA and Darjatmoko, SR and Gurel, Z and Fisk, DL and McDowell, CM and McAdams, RM and Sheibani, N}, title = {Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities.}, journal = {Frontiers in cell and developmental biology}, volume = {9}, number = {}, pages = {737426}, pmid = {34722519}, issn = {2296-634X}, support = {P30 CA014520/CA/NCI NIH HHS/United States ; P30 EY016665/EY/NEI NIH HHS/United States ; R01 EY026078/EY/NEI NIH HHS/United States ; R01 EY030076/EY/NEI NIH HHS/United States ; }, abstract = {Adenosine receptors (AR) are widely expressed in a variety of tissues including the retina and brain. They are involved in adenosine-mediated immune responses underlying the onset and progression of neurodegenerative diseases. The expression of AR has been previously demonstrated in some retinal cells including endothelial cells and retinal pigment epithelial cells, but their expression in the choroid and choroidal cells remains unknown. Caffeine is a widely consumed AR antagonist that can influence inflammation and vascular cell function. It has established roles in the treatment of neonatal sleep apnea, acute migraine, and post lumbar puncture headache as well as the neurodegenerative diseases such as Parkinson and Alzheimer. More recently, AR antagonism with caffeine has been shown to protect preterm infants from ischemic retinopathy and retinal neovascularization. However, whether caffeine impacts the development and progression of ocular age-related diseases including neovascular age-related macular degermation remains unknown. Here, we examined the expression of AR in retinal and choroidal tissues and cells. We showed that antagonism of AR with caffeine or istradefylline decreased sprouting of thoracic aorta and choroid/retinal pigment epithelium explants in ex vivo cultures, consistent with caffeine's ability to inhibit endothelial cell migration in culture. In vivo studies also demonstrated the efficacy of caffeine in inhibition of choroidal neovascularization and mononuclear phagocyte recruitment to the laser lesion sites. Istradefylline, a specific AR 2A antagonist, also decreased choroidal neovascularization. Collectively, our studies demonstrate an important role for expression of AR in the choroid whose antagonism mitigate choroidal inflammatory and angiogenesis activities.}, }
@article {pmid34719771, year = {2022}, author = {Pathak, N and Vimal, SK and Tandon, I and Agrawal, L and Hongyi, C and Bhattacharyya, S}, title = {Neurodegenerative Disorders of Alzheimer, Parkinsonism, Amyotrophic Lateral Sclerosis and Multiple Sclerosis: An Early Diagnostic Approach for Precision Treatment.}, journal = {Metabolic brain disease}, volume = {37}, number = {1}, pages = {67-104}, pmid = {34719771}, issn = {1573-7365}, mesh = {Aged ; *Alzheimer Disease/diagnosis ; *Amyotrophic Lateral Sclerosis/diagnosis/pathology ; Humans ; *Multiple Sclerosis ; *Neurodegenerative Diseases/diagnosis/drug therapy ; *Parkinson Disease ; }, abstract = {Neurodegenerative diseases (NDs) are characterised by progressive dysfunction of synapses, neurons, glial cells and their networks. Neurodegenerative diseases can be classified according to primary clinical features (e.g., dementia, parkinsonism, or motor neuron disease), anatomic distribution of neurodegeneration (e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations), or principal molecular abnormalities. The most common neurodegenerative disorders are amyloidosis, tauopathies, a-synucleinopathy, and TAR DNA-binding protein 43 (TDP-43) proteopathy. The protein abnormalities in these disorders have abnormal conformational properties along with altered cellular mechanisms, and they exhibit motor deficit, mitochondrial malfunction, dysfunctions in autophagic-lysosomal pathways, synaptic toxicity, and more emerging mechanisms such as the roles of stress granule pathways and liquid-phase transitions. Finally, for each ND, microglial cells have been reported to be implicated in neurodegeneration, in particular, because the microglial responses can shift from neuroprotective to a deleterious role. Growing experimental evidence suggests that abnormal protein conformers act as seed material for oligomerization, spreading from cell to cell through anatomically connected neuronal pathways, which may in part explain the specific anatomical patterns observed in brain autopsy sample. In this review, we mention the human pathology of select neurodegenerative disorders, focusing on how neurodegenerative disorders (i.e., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis) represent a great healthcare problem worldwide and are becoming prevalent because of the increasing aged population. Despite many studies have focused on their etiopathology, the exact cause of these diseases is still largely unknown and until now with the only available option of symptomatic treatments. In this review, we aim to report the systematic and clinically correlated potential biomarker candidates. Although future studies are necessary for their use in early detection and progression in humans affected by NDs, the promising results obtained by several groups leads us to this idea that biomarkers could be used to design a potential therapeutic approach and preclinical clinical trials for the treatments of NDs.}, }
@article {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 {pmid34704025, year = {2021}, author = {Powell, F and Tosun, D and Raj, A and , }, title = {Network-constrained technique to characterize pathology progression rate in Alzheimer's disease.}, journal = {Brain communications}, volume = {3}, number = {3}, pages = {fcab144}, pmid = {34704025}, issn = {2632-1297}, support = {R01 EB022717/EB/NIBIB NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; R01 NS092802/NS/NINDS NIH HHS/United States ; RF1 AG062196/AG/NIA NIH HHS/United States ; R56 AG064873/AG/NIA NIH HHS/United States ; }, abstract = {Current methods for measuring the chronic rates of cognitive decline and degeneration in Alzheimer's disease rely on the sensitivity of longitudinal neuropsychological batteries and clinical neuroimaging, particularly structural magnetic resonance imaging of brain atrophy, either at a global or regional scale. There is particular interest in approaches predictive of future disease progression and clinical outcomes using a single time point. If successful, such approaches could have great impact on differential diagnosis, therapeutic treatment and clinical trial inclusion. Unfortunately, it has proven quite challenging to accurately predict clinical and degeneration progression rates from baseline data. Specifically, a key limitation of the previously proposed approaches for disease progression based on the brain atrophy measures has been the limited incorporation of the knowledge from disease pathology progression models, which suggest a prion-like spread of disease pathology and hence the neurodegeneration. Here, we present a new metric for disease progression rate in Alzheimer that uses only MRI-derived atrophy data yet is able to infer the underlying rate of pathology transmission. This is enabled by imposing a spread process driven by the brain networks using a Network Diffusion Model. We first fit this model to each patient's longitudinal brain atrophy data defined on a brain network structure to estimate a patient-specific rate of pathology diffusion, called the pathology progression rate. Using machine learning algorithms, we then build a baseline data model and tested this rate metric on data from longitudinal Alzheimer's Disease Neuroimaging Initiative study including 810 subjects. Our measure of disease progression differed significantly across diagnostic groups as well as between groups with different genetic risk factors. Remarkably, hierarchical clustering revealed 3 distinct clusters based on CSF profiles with >90% accuracy. These pathological clusters exhibit progressive atrophy and clinical impairments that correspond to the proposed rate measure. We demonstrate that a subject's degeneration speed can be best predicted from baseline neuroimaging volumetrics and fluid biomarkers for subjects in the middle of their degenerative course, which may be a practical, inexpensive screening tool for future prognostic applications.}, }
@article {pmid34703895, year = {2021}, author = {Kim, T and Chi, SI and Kim, H and Seo, KS}, title = {Analysis of behavioral management for dental treatment in patients with dementia using the Korean National Health Insurance data.}, journal = {Journal of dental anesthesia and pain medicine}, volume = {21}, number = {5}, pages = {461-469}, pmid = {34703895}, issn = {2383-9309}, abstract = {Background: The global population is aging rapidly, and accordingly, the number of patients with dementia is increasing every year. Although the need for dental treatment increases for various reasons in patients with dementia, they cannot cooperate during dental treatment. Therefore, behavioral management, including sedation (SED) or general anesthesia (GA), is required for patients with dementia. Thus, this study aimed to investigate the trends and effects of SED or GA in patients with dementia undergoing dental treatment in South Korea based on the Korean National Health Insurance claims data.<br><br>Methods: This study utilized customized health information data provided by the Health Insurance Review and Assessment Service. Among patients with records of using sedative drugs during dental treatment from January 2007 to September 2019, patients with the International Classification of Diseases-10 code for dementia (F00, F01, F02, F03, and G30) were selected. We then analyzed the full insurance claims data for dental care. Age, sex, sedative use, and dental treatment of patients were analyzed yearly. In addition, the number of cases of GA or SED per year was analyzed, and changes in behavioral management methods with increasing age were investigated.<br><br>Results: Between January 2007 and September 2019, a total of 4,383 (male, 1,454; female, 2,929) patients with dementia received dental treatment under SED or GA. The total number of SED and GA cases were 1,515 (male, 528 ; female, 987) and 3,396 (male, 1,119 ; female, 2,277) cases, respectively. The total number of cases of dental treatment for 4,383 patients with dementia was 153,051 cases, of which 2.22% were under GA and 0.98% were under SED. Midazolam was the most commonly used drug for SED.<br><br>Conclusion: Although gingivitis and pulpitis were the most common reasons for patients with dementia to visit the dentist, GA or SED for patients with dementia was frequently used in oral and maxillofacial or periodontal surgery.}, }
@article {pmid34696749, year = {2021}, author = {Wang, XF and Xiao, HH and Wu, YT and Kong, L and Chen, JC and Yang, JX and Hu, XL}, title = {Active constituent of Polygala tenuifolia attenuates cognitive deficits by rescuing hippocampal neurogenesis in APP/PS1 transgenic mice.}, journal = {BMC complementary medicine and therapies}, volume = {21}, number = {1}, pages = {267}, pmid = {34696749}, issn = {2662-7671}, mesh = {Alzheimer Disease/*drug therapy ; Animals ; Disease Models, Animal ; Hippocampus/*drug effects ; Medicine, Chinese Traditional/*methods ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Molecular Structure ; Morris Water Maze Test ; Neural Stem Cells/*drug effects ; Neurogenesis/*drug effects ; Polygala/chemistry ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common dementia worldwide, and there is still no satisfactory drug or therapeutic strategy. Polygala tenuifolia is a traditional Chinese medicine with multiple neuroprotective effects. In present study, we investigated the effects of three active constituents [3,6'-disinapoyl sucrose (DISS), onjisaponin B (OB) and tenuifolin (TEN)] of Polygala tenuifolia (PT) on the proliferation and differentiation of neural stem cells (NSCs) to identify the potential active constituent of PT promoting hippocampal neurogenesis.<br><br>METHODS: NSCs were isolated from hippocampi of newborn C57BL/6 mice, and transfected with mutant amyloid precursor protein (APP) gene to establish an AD cell model (APP-NSCs). 3-(4,5- Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays were performed, and the proliferation and differentiation of NSCs were assessed by neurosphere formation assay, 5-bromo-2'-deoxyuridine (BrdU) incorporation assay and immunofluorescence (IF) staining analysis. APP/PS1 transgenic mice were administrated with the potential active constituent DISS for 4 weeks. Morris water maze (MWM), Nissl staining assay and IF staining assays were carried out to evaluate the cognitive function, neural damages and hippocampal neurogenesis, respectively.<br><br>RESULTS: DISS exerted the optimal ability to strengthen APP-NSCs proliferation and neuronal differentiation, followed by OB and TEN. Furthermore, DISS treatment for 4 weeks strikingly rescued the cognitive deficits, neuronal injures, and neurogenesis disorder in adult APP/PS1 transgenic mice.<br><br>CONCLUSIONS: Our findings demonstrated that DISS is the constituent of PT that triggers the most potent increase of hippocampal neurogenesis in our mouse model of AD.}, }
@article {pmid34689322, year = {2022}, author = {Tournier, M and Pambrun, E and Maumus-Robert, S and Pariente, A and Verdoux, H}, title = {The risk of dementia in patients using psychotropic drugs: Antidepressants, mood stabilizers or antipsychotics.}, journal = {Acta psychiatrica Scandinavica}, volume = {145}, number = {1}, pages = {56-66}, doi = {10.1111/acps.13380}, pmid = {34689322}, issn = {1600-0447}, mesh = {Aged ; Antidepressive Agents/adverse effects ; *Antipsychotic Agents/adverse effects ; Case-Control Studies ; *Dementia/drug therapy/epidemiology ; Humans ; Middle Aged ; Psychotropic Drugs/therapeutic use ; }, abstract = {OBJECTIVE: The risk of dementia associated with the use of psychotropic drugs is not fully understood. A nested case-control study was carried out to assess the risk of dementia broadly defined or Alzheimer's disease associated with antidepressants, mood stabilizers or antipsychotics.<br><br>METHODS: A cohort was formed from healthcare claim databases including all patients aged 50 and over with a first dispensing of the psychotropic drugs concerned between 2006 and 2017. Patients who developed dementia over the study period were considered as cases. The association between drug exposure prior to a five-year lag time and diagnosis of dementia was assessed by conditional logistic regression models.<br><br>RESULTS: No association was found between dementia, either broadly defined or Alzheimer disease, and antidepressant or mood stabilizers. Findings were conflicting with regard to antipsychotics. First- and second-generation antipsychotics (FGA and SGA) were not associated with Alzheimer disease. SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (Odds ratio [OR] 2.00; 95%CI 1.06-3.79; p = 0.03). In a sensitivity analysis using a lag time of 3 years, ever use of SGA and SGA treatments of more than 3 months were associated with a higher risk of dementia broadly defined than no use of antipsychotics (OR 1.71; 1.10-2.67; p = 0.02 and OR 1.84; 1.03-3.32; p = 0.04, respectively).<br><br>CONCLUSION: The association between antipsychotics and dementia should be further investigated to establish patients, specific drugs, and patterns of treatment at risk. Prescribers should remain cautious when prescribing them.}, }
@article {pmid34687079, year = {2021}, author = {Bagheri, S and Haddadi, R and Saki, S and Kourosh-Arami, M and Komaki, A}, title = {The effect of sodium channels on neurological/neuronal disorders: A systematic review.}, journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience}, volume = {81}, number = {8}, pages = {669-685}, doi = {10.1002/jdn.10153}, pmid = {34687079}, issn = {1873-474X}, support = {9412257459; IR.UMSHA.REC.1394.582//Hamadan University of Medical Sciences/ ; }, mesh = {Brain/*metabolism ; Epilepsy/*metabolism ; Humans ; Multiple Sclerosis/*metabolism ; Neurons/*metabolism ; Voltage-Gated Sodium Channels/*metabolism ; }, abstract = {Neurological and neuronal disorders are associated with structural, biochemical, or electrical abnormalities in the nervous system. Many neurological diseases have not yet been discovered. Interventions used for the treatment of these disorders include avoidance measures, lifestyle changes, physiotherapy, neurorehabilitation, pain management, medication, and surgery. In the sodium channelopathies, alterations in the structure, expression, and function of voltage-gated sodium channels (VGSCs) are considered as the causes of neurological and neuronal diseases. Online databases, including Scopus, Science Direct, Google Scholar, and PubMed were assessed for studies published between 1977 and 2020 using the keywords of review, sodium channels blocker, neurological diseases, and neuronal diseases. VGSCs consist of one α subunit and two β subunits. These subunits are known to regulate the gating kinetics, functional characteristics, and localization of the ion channel. These channels are involved in cell migration, cellular connections, neuronal pathfinding, and neurite outgrowth. Through the VGSC, the action potential is triggered and propagated in the neurons. Action potentials are physiological functions and passage of impermeable ions. The electrophysiological properties of these channels and their relationship with neurological and neuronal disorders have been identified. Subunit mutations are involved in the development of diseases, such as epilepsy, multiple sclerosis, autism, and Alzheimer's disease. Accordingly, we conducted a review of the link between VGSCs and neurological and neuronal diseases. Also, novel therapeutic targets were introduced for future drug discoveries.}, }
@article {pmid34683848, year = {2021}, author = {Wu, ATH and Lawal, B and Wei, L and Wen, YT and Tzeng, DTW and Lo, WC}, title = {Multiomics Identification of Potential Targets for Alzheimer Disease and Antrocin as a Therapeutic Candidate.}, journal = {Pharmaceutics}, volume = {13}, number = {10}, pages = {}, pmid = {34683848}, issn = {1999-4923}, support = {DP2-110-21121-03-C-09//Ministry of Science and Technology, Taiwan/ ; }, abstract = {Alzheimer's disease (AD) is the most frequent cause of neurodegenerative dementia and affects nearly 50 million people worldwide. Early stage diagnosis of AD is challenging, and there is presently no effective treatment for AD. The specific genetic alterations and pathological mechanisms of the development and progression of dementia remain poorly understood. Therefore, identifying essential genes and molecular pathways that are associated with this disease's pathogenesis will help uncover potential treatments. In an attempt to achieve a more comprehensive understanding of the molecular pathogenesis of AD, we integrated the differentially expressed genes (DEGs) from six microarray datasets of AD patients and controls. We identified ATPase H+ transporting V1 subunit A (ATP6V1A), BCL2 interacting protein 3 (BNIP3), calmodulin-dependent protein kinase IV (CAMK4), TOR signaling pathway regulator-like (TIPRL), and the translocase of outer mitochondrial membrane 70 (TOMM70) as upregulated DEGs common to the five datasets. Our analyses revealed that these genes exhibited brain-specific gene co-expression clustering with OPA1, ITFG1, OXCT1, ATP2A2, MAPK1, CDK14, MAP2K4, YWHAB, PARK2, CMAS, HSPA12A, and RGS17. Taking the mean relative expression levels of this geneset in different brain regions into account, we found that the frontal cortex (BA9) exhibited significantly (p < 0.05) higher expression levels of these DEGs, while the hippocampus exhibited the lowest levels. These DEGs are associated with mitochondrial dysfunction, inflammation processes, and various pathways involved in the pathogenesis of AD. Finally, our blood-brain barrier (BBB) predictions using the support vector machine (SVM) and LiCABEDS algorithm and molecular docking analysis suggested that antrocin is permeable to the BBB and exhibits robust ligand-receptor interactions with high binding affinities to CAMK4, TOMM70, and T1PRL. Our results also revealed good predictions for ADMET properties, drug-likeness, adherence to Lipinskís rules, and no alerts for pan-assay interference compounds (PAINS) Conclusions: These results suggest a new molecular signature for AD parthenogenesis and antrocin as a potential therapeutic agent. Further investigation is warranted.}, }
@article {pmid34677596, year = {2021}, author = {Ito, K and Chapman, R and Pearson, SD and Tafazzoli, A and Yaffe, K and Gurwitz, JH}, title = {Evaluation of the Cost-effectiveness of Drug Treatment for Alzheimer Disease in a Simulation Model That Includes Caregiver and Societal Factors.}, journal = {JAMA network open}, volume = {4}, number = {10}, pages = {e2129392}, pmid = {34677596}, issn = {2574-3805}, mesh = {Alzheimer Disease/*drug therapy/economics ; Caregivers/economics/psychology ; Cohort Studies ; Computer Simulation/*standards/statistics &amp; numerical data ; Cost-Benefit Analysis/*methods/statistics &amp; numerical data ; Humans ; Quality-Adjusted Life Years ; Social Norms ; }, abstract = {Importance: The possibility of widespread use of a novel effective therapy for Alzheimer disease (AD) will present important clinical, policy, and financial challenges.<br><br>Objective: To describe how including different patient, caregiver, and societal treatment-related factors affects estimates of the cost-effectiveness of a hypothetical disease-modifying AD treatment.<br><br>In this economic evaluation, the Alzheimer Disease Archimedes Condition Event Simulator was used to simulate the prognosis of a hypothetical cohort of patients selected from the Alzheimer Disease Neuroimaging Initiative database who received the diagnosis of mild cognitive impairment (MCI). Scenario analyses that varied costs and quality of life inputs relevant to patients and caregivers were conducted. The analysis was designed and conducted from June 15, 2019, to September 30, 2020.<br><br>Exposures: A hypothetical drug that would delay progression to dementia in individuals with MCI compared with usual care.<br><br>Main Outcomes and Measures: Incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life-year (QALY) gained.<br><br>Results: The model included a simulated cohort of patients who scored between 24 and 30 on the Mini-Mental State Examination and had a global Clinical Dementia Rating scale of 0.5, with a required memory box score of 0.5 or higher, at baseline. Using a health care sector perspective, which included only individual patient health care costs, the ICER for the hypothetical treatment was $192 000 per QALY gained. The result decreased to $183 000 per QALY gained in a traditional societal perspective analysis with the inclusion of patient non-health care costs. The inclusion of estimated caregiver health care costs produced almost no change in the ICER, but the inclusion of QALYs gained by caregivers led to a substantial reduction in the ICER for the hypothetical treatment, to $107 000 per QALY gained in the health sector perspective. In the societal perspective scenario, with the broadest inclusion of patient and caregiver factors, the ICER decreased to $74 000 per added QALY.<br><br>Conclusions and Relevance: The findings of this economic evaluation suggest that policy makers should be aware that efforts to estimate and include the effects of AD treatments outside those on patients themselves can affect the results of the cost-effectiveness analyses that often underpin assessments of the value of new treatments. Further research and debate on including these factors in assessments that will inform discussions on fair pricing for new treatments are needed.}, }
@article {pmid34664858, year = {2021}, author = {Jeong, JH and Jung, C and Kim, J and Kim, JY and Kim, HS and Park, YC and Lee, JH and Jung, IC}, title = {Investigation of combined treatment of acupuncture and neurofeedback for improving cognitive function in mild neurocognitive disorder: A randomized, assessor-blind, pilot study.}, journal = {Medicine}, volume = {100}, number = {37}, pages = {e27218}, pmid = {34664858}, issn = {1536-5964}, support = {KSN2021240, HB16C0044//Korea National Institute of Health/ ; }, mesh = {Acupuncture Therapy/*methods/standards/statistics &amp; numerical data ; Aged ; Cognition/*drug effects ; Cognitive Dysfunction/physiopathology/*therapy ; Combined Modality Therapy/methods/*standards/statistics &amp; numerical data ; Female ; Humans ; Male ; Middle Aged ; Neurofeedback/*methods ; Pilot Projects ; Republic of Korea ; }, abstract = {BACKGROUND: Mild neurocognitive disorder (MND) is an intermediate state that can progress to dementia, and the cognitive reserve of MND is an important task in preventing dementia. Acupuncture and neurofeedback (NF) training have been used to improve cognitive function and treat MND or dementia, but their effectiveness remains controversial. In this trial, we will evaluate the efficacy and safety of combined NF-acupuncture treatment in comparison with single acupuncture treatment.<br><br>METHODS AND DESIGN: This study is a randomized, assessor-blind, pilot trial. It is designed in accordance with the Standards for Reporting Interventions in Controlled Trials of Acupuncture. A total of 44 MND participants who meet the inclusion and exclusion criteria will be enrolled, and each will be randomly assigned to 1 of 2 groups of 22 subjects. Each subject will visit 24 times over 12 weeks and receive either acupuncture or NF-acupuncture combined treatment. At visit 25 (week 13), a follow-up evaluation will be performed, and then the investigator will analyze the results. The primary outcome is defined by the Korean version of the Montreal Cognitive Assessment score from screening to visit 25. The secondary outcome includes the following: change in Alzheimer Disease Assessment Scale-Cognitive, the Korean version of the Beck Depression Inventory, Body Awareness Questionnaire, delayed matching to sample task scores, and functional near-infrared spectroscopy values, from visit 1 to visit 25; heart rate variability values from visit 1 to visit 5, visit 9, visit 13, visit 21, visit 25; breath per minute values from visit 1 to visit 1 to 25.<br><br>DISCUSSION: We will evaluate the effectiveness and safety of combined NF-acupuncture therapy, and expect that it will serve as the basis for the use of NF together with acupuncture in the clinical setting.<br><br>TRIAL REGISTRATION NUMBER: KCT0004972 (registered in Clinical Research Information Service of the Republic of Korea, https://cris.nih.go.kr/cris/search/detailSearch.do/16239).}, }
@article {pmid34657891, year = {2021}, author = {Høilund-Carlsen, PF and Alavi, A}, title = {Aducanumab (Marketed as Aduhelm) Approval Is Likely Based on Misinterpretation of PET Imaging Data.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {84}, number = {4}, pages = {1457-1460}, doi = {10.3233/JAD-215275}, pmid = {34657891}, issn = {1875-8908}, mesh = {Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/*therapeutic use ; *Data Interpretation, Statistical ; Drug Approval ; Humans ; Plaque, Amyloid/*metabolism ; *Positron-Emission Tomography ; United States ; United States Food and Drug Administration ; }, abstract = {According to the FDA, aducanumab (Aduhelm), the recently approved anti-Alzheimer drug, reduces the level of cerebral amyloid plaques-a hallmark finding in patients with Alzheimer's disease-and this will result in a reduction in clinical decline. The authors of this article are not convinced that amyloid deposits are a hallmark of Alzheimer's disease and are of the opinion that the apparent reduction in amyloid accumulation following aducanumab treatment is likely instead a result of continued and advanced cerebral cell death and, thus, not a sign of improvement but of an even more advanced disease.}, }
@article {pmid34654436, year = {2021}, author = {Hoyer-Kimura, C and Konhilas, JP and Mansour, HM and Polt, R and Doyle, KP and Billheimer, D and Hay, M}, title = {Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia.}, journal = {Journal of neuroinflammation}, volume = {18}, number = {1}, pages = {236}, pmid = {34654436}, issn = {1742-2094}, support = {P30 ES006694/ES/NIEHS NIH HHS/United States ; U01 AG066623/AG/NIA NIH HHS/United States ; NIA U01AG066623-01/AG/NIA NIH HHS/United States ; }, mesh = {Angiotensin I/*agonists/*metabolism/therapeutic use ; Animals ; Biomarkers/metabolism ; Cognitive Dysfunction/drug therapy/*metabolism/pathology ; Cytokines/*metabolism ; Dementia, Vascular/drug therapy/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Neurofilament Proteins/*metabolism ; Peptide Fragments/*agonists/*metabolism/therapeutic use ; Prognosis ; Stroke Volume/physiology ; }, abstract = {BACKGROUND: Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1-7 (Ang-(1-7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1-7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model.<br><br>METHODS: VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1-7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05.<br><br>RESULTS: Treatment with Ang-(1-7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain.<br><br>CONCLUSIONS: These data show that treatment with Ang-(1-7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.}, }
@article {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 {pmid34619465, year = {2021}, author = {Li, Y and Sang, S and Ren, W and Pei, Y and Bian, Y and Chen, Y and Sun, H}, title = {Inhibition of Histone Deacetylase 6 (HDAC6) as a therapeutic strategy for Alzheimer's disease: A review (2010-2020).}, journal = {European journal of medicinal chemistry}, volume = {226}, number = {}, pages = {113874}, doi = {10.1016/j.ejmech.2021.113874}, pmid = {34619465}, issn = {1768-3254}, mesh = {Acetamides/chemical synthesis/chemistry/*pharmacology ; Alzheimer Disease/*drug therapy/metabolism ; Histone Deacetylase 6/*antagonists &amp; inhibitors/metabolism ; Histone Deacetylase Inhibitors/chemical synthesis/chemistry/*pharmacology ; Humans ; Hydroxamic Acids/chemical synthesis/chemistry/*pharmacology ; Models, Molecular ; Molecular Structure ; Neuroprotective Agents/chemical synthesis/chemistry/*pharmacology ; }, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which is characterized by the primary risk factor, age. Several attempts have been made to treat AD, while most of them end in failure. However, with the deepening study of pathogenesis of AD, the expression of HDAC6 in the hippocampus, which plays a major role of the memory formation, is becoming worth of notice. Neurofibrillary tangles (NFTs), a remarkable lesion in AD, has been characterized in association with the abnormal accumulation of hyperphosphorylated Tau, which is mainly caused by the high expression of HDAC6. On the other hand, the hypoacetylated tubulin induced by HDAC6 is also fatal for the neuronal transport, which is the key impact of the formation of axons and dendrites. Overall, the significantly increased expression of HDAC6 in brain regions is deleterious to neuron survival in AD patients. Based on the above research, the inhibition of HDAC6 seems to be a potential therapeutic method for the treatment of AD. Up to now, various types of HDAC6 inhibitors have been discovered. This review mainly analyzes the HDAC6 inhibitors reported amid 2010-2020 in terms of their structure, selectivity and pharmacological impact towards AD. And we aim at facilitating the design and development of better HDAC6 inhibitors in the future.}, }
@article {pmid34609493, year = {2021}, author = {Zacharias, HU and Weihs, A and Habes, M and Wittfeld, K and Frenzel, S and Rashid, T and Stubbe, B and Obst, A and Szentkirályi, A and Bülow, R and Berger, K and Fietze, I and Penzel, T and Hosten, N and Ewert, R and Völzke, H and Grabe, HJ}, title = {Association Between Obstructive Sleep Apnea and Brain White Matter Hyperintensities in a Population-Based Cohort in Germany.}, journal = {JAMA network open}, volume = {4}, number = {10}, pages = {e2128225}, pmid = {34609493}, issn = {2574-3805}, support = {P30 AG066546/AG/NIA NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aging/physiology ; Cohort Studies ; Cross-Sectional Studies ; Female ; Germany/epidemiology ; Humans ; Magnetic Resonance Imaging/methods/statistics &amp; numerical data ; Male ; Middle Aged ; Sleep Apnea, Obstructive/*complications/diagnostic imaging/epidemiology ; White Matter/abnormalities/*physiopathology ; }, abstract = {Importance: Underlying pathomechanisms of brain white matter hyperintensities (WMHs), commonly observed in older individuals and significantly associated with Alzheimer disease and brain aging, have not yet been fully elucidated. One potential contributing factor to WMH burden is chronic obstructive sleep apnea (OSA), a disorder highly prevalent in the general population with readily available treatment options.<br><br>Objective: To investigate potential associations between OSA and WMH burden.<br><br>Analyses were conducted in 529 study participants of the Study of Health in Pomerania-Trend baseline (SHIP-Trend-0) study with complete WMH, OSA, and important clinical data available. SHIP-Trend-0 is a general population-based, cross-sectional, observational study to facilitate the investigation of a large spectrum of common risk factors, subclinical disorders, and clinical diseases and their relationships among each other with patient recruitment from Western Pomerania, Germany, starting on September 1, 2008, with data collected until December 31, 2012. Data analysis was performed from February 1, 2019, to January 31, 2021.<br><br>Exposures: The apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) were assessed during a single-night, laboratory-based polysomnography measurement.<br><br>Main Outcomes and Measures: The primary outcome was WMH data automatically segmented from 1.5-T magnetic resonance images.<br><br>Results: Of 529 study participants (mean [SD] age, 52.15 [13.58] years; 282 female [53%]), a total of 209 (40%) or 102 (19%) individuals were diagnosed with OSA according to AHI or ODI criteria (mean [SD] AHI, 7.98 [12.55] events per hour; mean [SD] ODI, 3.75 [8.43] events per hour). Both AHI (β = 0.024; 95% CI, 0.011-0.037; P <.001) and ODI (β = 0.033; 95% CI, 0.014-0.051; P <. 001) were significantly associated with brain WMH volumes. These associations remained even in the presence of additional vascular, metabolic, and lifestyle WMH risk factors. Region-specific WMH analyses found the strongest associations between periventricular frontal WMH volumes and both AHI (β = 0.0275; 95% CI, 0.013-0.042, P < .001) and ODI (β = 0.0381; 95% CI, 0.016-0.060, P < .001) as well as periventricular dorsal WMH volumes and AHI (β = 0.0165; 95% CI, 0.004-0.029, P = .008).<br><br>Conclusions and Relevance: This study found significant associations between OSA and brain WMHs, indicating a novel, potentially treatable WMH pathomechanism.}, }
@article {pmid34607546, year = {2021}, author = {Rema, J and Novais, F and Telles-Correia, D}, title = {Precision Psychiatry: Machine learning as a tool to find new pharmacological targets.}, journal = {Current topics in medicinal chemistry}, volume = {}, number = {}, pages = {}, doi = {10.2174/1568026621666211004095917}, pmid = {34607546}, issn = {1873-4294}, abstract = {There is an increasing amount of data arising from neurobehavioral sciences and medical records that cannot be adequately analyzed by traditional research methods. New drugs develop at a slow rate and seem unsatisfactory for the majority of neurobehavioral disorders. Machine learning (ML) techniques, instead, can incorporate psychopathological, computational, cognitive, and neurobiological underpinning knowledge leading to a refinement of detection, diagnosis, prognosis, treatment, research, and support. Machine and deep learning methods are currently used to accelerate the process of discovering new pharmacological targets and drugs.<br><br>OBJECTIVE: The present work reviews current evidence regarding the contribution of machine learning to the discovery of new drug targets.<br><br>METHODS: Scientific articles from PubMed, SCOPUS, EMBASE, and Web of Science Core Collection published until May 2021 were included in this review.<br><br>RESULTS: The most significant areas of research are schizophrenia, depression and anxiety, Alzheimer´s disease, and substance use disorders. ML techniques have pinpointed target gene candidates and pathways, new molecular substances, and several biomarkers regarding psychiatric disorders. Drug repositioning studies using ML have identified multiple drug candidates as promising therapeutic agents.<br><br>CONCLUSION: Next-generation ML techniques and subsequent deep learning may power new findings regarding the discovery of new pharmacological agents by bridging the gap between biological data and chemical drug information.}, }
@article {pmid34598900, year = {2022}, author = {Guo, W and Zeng, Z and Xing, C and Zhang, J and Bi, W and Yang, J and Shah, R and Wang, D and Li, Y and Zhang, X and Bian, Y and Du, H}, title = {Stem cells from human exfoliated deciduous teeth affect mitochondria and reverse cognitive decline in a senescence-accelerated mouse prone 8 model.}, journal = {Cytotherapy}, volume = {24}, number = {1}, pages = {59-71}, doi = {10.1016/j.jcyt.2021.07.018}, pmid = {34598900}, issn = {1477-2566}, mesh = {Aging ; *Alzheimer Disease/therapy ; Animals ; *Cognitive Dysfunction/therapy ; Disease Models, Animal ; Humans ; Maze Learning ; Mice ; Mitochondria ; Stem Cells ; Tooth, Deciduous ; }, abstract = {BACKGROUND AIMS: Stem cell therapy is a novel therapy being explored for AD. The molecular mechanism of its effect is still unclear. The authors investigated the effects and mechanism by injection of SHEDs into an AD mouse model.<br><br>METHODS: SHEDs were cultured in vitro and injected into AD SAMP8 mice by caudal vein, and SHEDs labeled via synthetic dye showed in vivo migration to the head. The cognitive ability of SAMP8 mice was evaluated via Barnes maze and new object recognition. The pathological indicators of AD, including Tau, amyloid plaques and inflammatory factors, were examined at the protein or RNA level. Next, macro-proteomics analysis and weighted gene co-expression network analysis (WGCNA) based on protein groups and behavioral data were applied to discover the important gene cluster involved in the improvement of AD by SHEDs, which was further confirmed in an AD model in both mouse and cell lines.<br><br>RESULTS: SHED treatment improved the cognitive ability and pathological symptoms of SAMP8 mice. Proteomics analysis indicated that these improvements were tightly related to the mitochondria, which was proved through examination of the shape and function of mitochondria both in vivo (SAMP8 brain) and in vitro (SH-SY5Y cells). Finally, the core targets of SHEDs in the mitochondrial pathway, Hook3, Mic13 and MIF, were screened out and confirmed in vivo.<br><br>CONCLUSIONS: SHED treatment significantly relieved AD symptoms, improved cognitive ability and reversed memory loss in an AD mouse model, possibly through the recovery of dysfunctional mitochondria. These results raise the possibility that SHED may ease the symptoms of AD by targeting the mitochondria.}, }
@article {pmid34585216, year = {2021}, author = {Costa, N and Mounié, M and Pagès, A and Derumeaux, H and Rapp, T and Guyonnet, S and Coley, N and Cantet, C and Carrié, I and Andrieu, S and Molinier, L}, title = {The Cost-Effectiveness of Three Prevention Strategies in Alzheimer's Disease: Results from the Multidomain Alzheimer Preventive Trial (MAPT).}, journal = {The journal of prevention of Alzheimer's disease}, volume = {8}, number = {4}, pages = {425-435}, doi = {10.14283/jpad.2021.47}, pmid = {34585216}, issn = {2426-0266}, mesh = {Aged ; *Alzheimer Disease/drug therapy/prevention &amp; control ; Cognition/*physiology ; Cost-Benefit Analysis/*economics ; Docosahexaenoic Acids/*administration &amp; dosage ; Exercise/*physiology ; Female ; France ; Humans ; Independent Living ; Male ; Monaco ; Research Design ; }, abstract = {BACKGROUND: To date, no curative treatment is available for Alzheimer's disease (AD). Therefore, efforts should focus on prevention strategies to improve the efficiency of healthcare systems.<br><br>OBJECTIVE: Our aim was to assess the cost-effectiveness of three preventive strategies for AD compared to a placebo.<br><br>DESIGN: The Multidomain Alzheimer Preventive Trial (MAPT) study was a multicenter, randomized, placebo-controlled superiority trial with four parallel groups, including three intervention groups (one group with Multidomain Intervention (MI) plus a placebo, one group with Polyunsaturated Fatty Acids (PFA), one group with a combination of PFA and MI) and one placebo group.<br><br>SETTING: Participants were recruited and included in 13 memory centers in France and Monaco.<br><br>PARTICIPANTS: Community-dwelling subject aged 70 years and older were followed during 3 years.<br><br>INTERVENTIONS: We used data from the MAPT study which aims to test the efficacy of a MI along PFA, the MI plus a placebo, PFA alone, or a placebo alone.<br><br>MEASUREMENT: Direct medical and non-medical costs were calculated from a payer's perspective during the 3 years of follow-up. The base case incremental Cost-Effectiveness Ratio (ICER) represents the cost per improved cognitive Z-score point. Sensitivity analyses were performed using different interpretation of the effectiveness criteria.<br><br>RESULTS: Analyses were conducted on 1,525 participants. The ICER at year 3 that compares the MI + PFA and the MI alone to the placebo amounted to €21,443 and €21,543 respectively, per improved Z score point. PFA alone amounted to €111,720 per improved Z score point.<br><br>CONCLUSION: Our study shows that ICERS of PFA combined with MI and MI alone amounted to €21,443 and €21,543 respectively per improved Z score point compared to the placebo and are below the WTP of €50,000 while the ICER of PFA alone amounted to €111,720 per improved Z score point. This information may help decision makers and serve as a basis for the implementation of a lifetime decision analytic model.}, }
@article {pmid34570180, year = {2021}, author = {Mintzer, J and Lanctôt, KL and Scherer, RW and Rosenberg, PB and Herrmann, N and van Dyck, CH and Padala, PR and Brawman-Mintzer, O and Porsteinsson, AP and Lerner, AJ and Craft, S and Levey, AI and Burke, W and Perin, J and Shade, D and , }, title = {Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {78}, number = {11}, pages = {1324-1332}, doi = {10.1001/jamaneurol.2021.3356}, pmid = {34570180}, issn = {2168-6157}, support = {P30 AG066507/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; UL1 TR001863/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*complications ; Apathy/*drug effects ; Central Nervous System Stimulants/*therapeutic use ; Female ; Humans ; Male ; Methylphenidate/*therapeutic use ; }, abstract = {Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality.<br><br>Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease.<br><br>This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included.<br><br>Interventions: Ten milligrams of methylphenidate, twice daily, vs matching placebo.<br><br>Main Outcomes and Measures: The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life.<br><br>Results: Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups.<br><br>Conclusions and Relevance: This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02346201.}, }
@article {pmid34570177, year = {2021}, author = {Vossel, K and Ranasinghe, KG and Beagle, AJ and La, A and Ah Pook, K and Castro, M and Mizuiri, D and Honma, SM and Venkateswaran, N and Koestler, M and Zhang, W and Mucke, L and Howell, MJ and Possin, KL and Kramer, JH and Boxer, AL and Miller, BL and Nagarajan, SS and Kirsch, HE}, title = {Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity: A Randomized Clinical Trial.}, journal = {JAMA neurology}, volume = {78}, number = {11}, pages = {1345-1354}, doi = {10.1001/jamaneurol.2021.3310}, pmid = {34570177}, issn = {2168-6157}, support = {K23 AG038357/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/complications/*drug therapy ; Anticonvulsants/*therapeutic use ; Cognition/*drug effects ; Cross-Over Studies ; Double-Blind Method ; Executive Function/drug effects ; Female ; Humans ; Levetiracetam/*therapeutic use ; Male ; Middle Aged ; *Seizures/etiology ; }, abstract = {Importance: Network hyperexcitability may contribute to cognitive dysfunction in patients with Alzheimer disease (AD).<br><br>Objective: To determine the ability of the antiseizure drug levetiracetam to improve cognition in persons with AD.<br><br>The Levetiracetam for Alzheimer's Disease-Associated Network Hyperexcitability (LEV-AD) study was a phase 2a randomized double-blinded placebo-controlled crossover clinical trial of 34 adults with AD that was conducted at the University of California, San Francisco, and the University of Minnesota, Twin Cities, between October 16, 2014, and July 21, 2020. Participants were adults 80 years and younger who had a Mini-Mental State Examination score of 18 points or higher and/or a Clinical Dementia Rating score of less than 2 points. Screening included overnight video electroencephalography and a 1-hour resting magnetoencephalography examination.<br><br>Interventions: Group A received placebo twice daily for 4 weeks followed by a 4-week washout period, then oral levetiracetam, 125 mg, twice daily for 4 weeks. Group B received treatment using the reverse sequence.<br><br>Main Outcomes and Measures: The primary outcome was the ability of levetiracetam treatment to improve executive function (measured by the National Institutes of Health Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research [NIH-EXAMINER] composite score). Secondary outcomes were cognition (measured by the Stroop Color and Word Test [Stroop] interference naming subscale and the Alzheimer's Disease Assessment Scale-Cognitive Subscale) and disability. Exploratory outcomes included performance on a virtual route learning test and scores on cognitive and functional tests among participants with epileptiform activity.<br><br>Results: Of 54 adults assessed for eligibility, 11 did not meet study criteria, and 9 declined to participate. A total of 34 adults (21 women [61.8%]; mean [SD] age, 62.3 [7.7] years) with AD were enrolled and randomized (17 participants to group A and 17 participants to group B). Thirteen participants (38.2%) were categorized as having epileptiform activity. In total, 28 participants (82.4%) completed the study, 10 of whom (35.7%) had epileptiform activity. Overall, treatment with levetiracetam did not change NIH-EXAMINER composite scores (mean difference vs placebo, 0.07 points; 95% CI, -0.18 to 0.32 points; P = .55) or secondary measures. However, among participants with epileptiform activity, levetiracetam treatment improved performance on the Stroop interference naming subscale (net improvement vs placebo, 7.4 points; 95% CI, 0.2-14.7 points; P = .046) and the virtual route learning test (t = 2.36; Cohen f2 = 0.11; P = .02). There were no treatment discontinuations because of adverse events.<br><br>Conclusions and Relevance: In this randomized clinical trial, levetiracetam was well tolerated and, although it did not improve the primary outcome, in prespecified analysis, levetiracetam improved performance on spatial memory and executive function tasks in patients with AD and epileptiform activity. These exploratory findings warrant further assessment of antiseizure approaches in AD.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02002819.}, }
@article {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 {pmid34558138, year = {2022}, author = {Erekat, NS}, title = {Apoptosis and its therapeutic implications in neurodegenerative diseases.}, journal = {Clinical anatomy (New York, N.Y.)}, volume = {35}, number = {1}, pages = {65-78}, doi = {10.1002/ca.23792}, pmid = {34558138}, issn = {1098-2353}, mesh = {*Alzheimer Disease ; *Amyotrophic Lateral Sclerosis/drug therapy ; Apoptosis ; Humans ; *Huntington Disease ; *Neurodegenerative Diseases/drug therapy ; *Parkinson Disease/drug therapy ; }, abstract = {Neurodegenerative disorders are characterized by progressive loss of particular populations of neurons. Apoptosis has been implicated in the pathogenesis of neurodegenerative diseases, including Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. In this review, we focus on the existing notions relevant to comprehending the apoptotic death process, including the morphological features, mediators and regulators of cellular apoptosis. We also highlight the evidence of neuronal apoptotic death in Parkinson disease, Alzheimer disease, Huntington disease, and amyotrophic lateral sclerosis. Additionally, we present evidence of potential therapeutic agents that could modify the apoptotic pathway in the aforementioned neurodegenerative diseases and delay disease progression. Finally, we review the clinical trials that were conducted to evaluate the use of anti-apoptotic drugs in the treatment of the aforementioned neurodegenerative diseases, in order to highlight the essential need for early detection and intervention of neurodegenerative diseases in humans.}, }
@article {pmid34556089, year = {2021}, author = {Jiang, Z and Shi, Y and Zhao, W and Zhou, L and Zhang, B and Xie, Y and Zhang, Y and Tan, G and Wang, Z}, title = {Association between chronic periodontitis and the risk of Alzheimer's disease: combination of text mining and GEO dataset.}, journal = {BMC oral health}, volume = {21}, number = {1}, pages = {466}, pmid = {34556089}, issn = {1472-6831}, mesh = {*Alzheimer Disease/genetics ; *Chronic Periodontitis/genetics ; Computational Biology ; Data Mining ; Gene Expression Profiling ; Gene Regulatory Networks ; Heat-Shock Proteins ; Humans ; Protein Interaction Maps/genetics ; }, abstract = {BACKGROUND: Although chronic periodontitis has previously been reported to be linked with Alzheimer's disease (AD), the pathogenesis between the two is unclear. The purpose of this study is to analyze and screen the relevant and promising molecular markers between chronic periodontitis and Alzheimer's disease (AD).<br><br>METHODS: In this paper, we analyzed three AD expression datasets and extracted differentially expressed genes (DEGs), then intersected them with chronic periodontitis genes obtained from text mining, and finally obtained integrated DEGs. We followed that by enriching the matching the matching cell signal cascade through DAVID analysis. Moreover, the MCODE of Cytoscape software was employed to uncover the protein-protein interaction (PPI) network and the matching hub gene. Finally, we verified our data using a different independent AD cohort.<br><br>RESULTS: The chronic periodontitis gene set acquired from text abstracting was intersected with the previously obtained three AD groups, and 12 common genes were obtained. Functional enrichment assessment uncovered 12 cross-genes, which were mainly linked to cell morphogenesis involved in neuron differentiation, leading edge membrane, and receptor ligand activity. After PPI network creation, the ten hub genes linked to AD were retrieved, consisting of SPP1, THY1, CD44, ITGB1, HSPB3, CREB1, SST, UCHL1, CCL5 and BMP7. Finally, the function terms in the new independent dataset were used to verify the previous dataset, and we found 22 GO terms and one pathway, "ECM-receptor interaction pathways", in the overlapping functional terms.<br><br>CONCLUSIONS: The establishment of the above-mentioned candidate key genes, as well as the enriched signaling cascades, provides promising molecular markers for chronic periodontitis-related AD, which may help the diagnosis and treatment of AD patients in the future.}, }
@article {pmid34551697, year = {2021}, author = {Mengr, A and Hrubá, L and Exnerová, A and Holubová, M and Popelová, A and Železná, B and Kuneš, J and Maletínská, L}, title = {Palmitoylated Prolactin-releasing Peptide Reduced Aβ Plaques and Microgliosis in the Cerebellum: APP/PS1 Mice Study.}, journal = {Current Alzheimer research}, volume = {18}, number = {8}, pages = {607-622}, doi = {10.2174/1567205018666210922110652}, pmid = {34551697}, issn = {1875-5828}, support = {20-00546S, RVO:61388963, RVO:67958523//Czech Science Foundation/ ; }, mesh = {*Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Animals ; Cerebellum ; *Diabetes Mellitus, Type 2 ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Plaque, Amyloid/pathology ; Presenilin-1/genetics/metabolism ; Prolactin-Releasing Hormone/metabolism/pharmacology ; }, abstract = {BACKGROUND: Prolactin-releasing peptide (PrRP) is a potential drug for the treatment of obesity and associated Type 2 Diabetes Mellitus (T2DM) due to its strong anorexigenic and antidiabetic properties. In our recent study, the lipidized PrRP analog palm11-PrRP31 was proven to exert beneficial effects in APP/PS1 mice, a model of Alzheimer´s Disease (AD)-like amyloid-β (Aβ) pathology, reducing the Aβ plaque load, microgliosis and astrocytosis in the hippocampus and cortex.<br><br>OBJECTIVE: In this study, we focused on the neuroprotective and anti-inflammatory effects of palm11-PrRP31 and its possible impact on synaptogenesis in the cerebellum of APP/PS1 mice, because others have suggested that cerebellar Aβ plaques contribute to cognitive deficits in AD.<br><br>METHODS: APP/PS1 mice were treated subcutaneously with palm11-PrRP31 for 2 months, then immunoblotting and immunohistochemistry were used to quantify pathological markers connected to AD, compared to control mice.<br><br>RESULTS: In the cerebella of 8 months old APP/PS1 mice, we found widespread Aβ plaques surrounded by activated microglia detected by ionized calcium-binding adapter molecule (Iba1), but no increase in astrocytic marker Glial Fibrillary Acidic Protein (GFAP) compared to controls. Interestingly, no difference in both presynaptic markers syntaxin1A and postsynaptic marker spinophilin was registered between APP/PS1 and control mice. Palm11-PrRP31 treatment significantly reduced the Aβ plaque load and microgliosis in the cerebellum. Furthermore, palm11-PrRP31 increased synaptogenesis and attenuated neuroinflammation and apoptosis in the hippocampus of APP/PS1 mice.<br><br>CONCLUSION: These results suggest palm11-PrRP31 is a promising agent for the treatment of neurodegenerative disorders.}, }
@article {pmid34550903, year = {2021}, author = {Jutten, RJ and Sikkes, SAM and Van der Flier, WM and Scheltens, P and Visser, PJ and Tijms, BM and , }, title = {Finding Treatment Effects in Alzheimer Trials in the Face of Disease Progression Heterogeneity.}, journal = {Neurology}, volume = {96}, number = {22}, pages = {e2673-e2684}, pmid = {34550903}, issn = {1526-632X}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; *Disease Progression ; Female ; Humans ; Male ; Middle Aged ; *Models, Statistical ; Neuroprotective Agents/*therapeutic use ; Risk Factors ; *Treatment Outcome ; }, abstract = {OBJECTIVE: To investigate the influence of heterogeneity in disease progression for detecting treatment effects in Alzheimer disease (AD) trials, using a simulation study.<br><br>METHODS: Individuals with an abnormal amyloid PET scan, diagnosis of mild cognitive impairment or dementia, baseline Mini-Mental State Examination (MMSE) score ≥24, global Clinical Dementia Rating (CDR) score of 0.5, and ≥1 follow-up cognitive assessment were selected from the Alzheimer's Disease Neuroimaging Initiative database (n = 302, age 73 ± 6.7; 44% female; 16.1 ± 2.7 years of education; 69% APOE ε4 carrier). We simulated a clinical trial by randomly assigning individuals to a "placebo" and "treatment" group and subsequently computed group differences on the CDR-sum of boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale-13 and MMSE after 18 months follow-up. We repeated this simulation 10,000 times to determine the 95% range of effect sizes. We further studied the influence of known AD risk factors (age, sex, education, APOE ε4 status, CSF total tau levels) on the variability in effect sizes.<br><br>RESULTS: Individual trajectories on all cognitive outcomes were highly variable, and the 95% ranges of possible effect sizes at 18 months were broad (e.g., ranging from 0.35 improvement to 0.35 decline on the CDR-SB). Results of recent anti-amyloid trials mostly fell within these 95% ranges of effect sizes. APOE ε4 carriers and individuals with abnormal baseline tau levels showed faster decline at group level, but also greater within-group variability, as illustrated by broader 95% effect size ranges (e.g., ±0.70 points for the CDR-SB).<br><br>CONCLUSIONS: Individuals with early AD show heterogeneity in disease progression, which increases when stratifying on risk factors associated with progression. We provide guidance for a priori effect sizes on cognitive outcomes for detecting true change, which is crucial for future AD trials.}, }
@article {pmid34542571, year = {2021}, author = {Janelidze, S and Teunissen, CE and Zetterberg, H and Allué, JA and Sarasa, L and Eichenlaub, U and Bittner, T and Ovod, V and Verberk, IMW and Toba, K and Nakamura, A and Bateman, RJ and Blennow, K and Hansson, O}, title = {Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease.}, journal = {JAMA neurology}, volume = {78}, number = {11}, pages = {1375-1382}, doi = {10.1001/jamaneurol.2021.3180}, pmid = {34542571}, issn = {2168-6157}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging/*pathology ; Amyloid beta-Peptides/*analysis ; Biomarkers/analysis ; Brain/diagnostic imaging/*pathology ; Cross-Sectional Studies ; Female ; Humans ; Immunoassay/methods ; Male ; Mass Spectrometry/methods ; Middle Aged ; Peptide Fragments/*analysis ; Positron-Emission Tomography ; }, abstract = {Importance: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials.<br><br>Objective: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD.<br><br>This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays.<br><br>Main Outcomes and Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status.<br><br>Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P < .05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P < .001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P = .16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay.<br><br>Conclusions and Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology.}, }
@article {pmid34542418, year = {2021}, author = {Saredakis, D and Keage, HA and Corlis, M and Ghezzi, ES and Loffler, H and Loetscher, T}, title = {The Effect of Reminiscence Therapy Using Virtual Reality on Apathy in Residential Aged Care: Multisite Nonrandomized Controlled Trial.}, journal = {Journal of medical Internet research}, volume = {23}, number = {9}, pages = {e29210}, pmid = {34542418}, issn = {1438-8871}, mesh = {Aged ; *Apathy ; Australia ; Cognition ; Humans ; *Parkinson Disease ; *Virtual Reality ; }, abstract = {BACKGROUND: Apathy is a frequent and underrecognized neurological disorder symptom. Reduced goal-directed behavior caused by apathy is associated with poor outcomes for older adults in residential aged care. Recommended nonpharmacological treatments include person-centered therapy using information and communication technology. Virtual reality (VR) in the form of head-mounted displays (HMDs) is a fully immersive technology that provides access to a wide range of freely available content. The use of VR as a therapy tool has demonstrated promise in the treatment of posttraumatic stress disorder and anxiety. In addition, VR has been used to improve conditions including depression, anxiety, cognitive function, and balance in older adults with memory deficits, Alzheimer disease, and Parkinson disease. Research using VR for the symptoms of apathy in older adults living in residential aged care facilities is limited.<br><br>OBJECTIVE: This study aims to examine whether using HMDs as a tool for reminiscence therapy improves the symptoms of apathy compared with using a laptop computer and physical items with older adults living in residential aged care.<br><br>METHODS: In this multisite trial, 43 participants were allocated to one of three groups: reminiscence therapy intervention using VR in the form of HMDs, reminiscence therapy using a laptop computer supplemented by physical items if required (active control), and a usual care (passive control) group. The primary outcome was apathy, and the secondary outcomes included cognition and depression. The side effects of using HMDs were also measured in the VR group.<br><br>RESULTS: Mixed model analyses revealed no significant group interaction over time in outcomes between the VR and laptop groups (estimate=-2.24, SE 1.89; t40=-1.18; P=.24). Pooled apathy scores in the two intervention groups compared with the passive control group also revealed no significant group interaction over time (estimate=-0.26, SE 1.66; t40=-0.16; P=.88). There were no significant secondary outcomes. Most participants in the VR group stated that they would prefer to watch content in VR than on a flat screen (Χ22=11.2; P=.004), side effects from HMD use were negligible to minimal according to the Simulator Sickness Questionnaire cutoff scores.<br><br>CONCLUSIONS: Although there were no significant results in outcome measures, this study found that participants engaged in the research and enjoyed the process of reminiscing using both forms of technology. It was found that VR can be implemented in an aged care setting with correct protocols in place. Providing residents in aged care with a choice of technology may assist in increasing participation in activities. We cannot dismiss the importance of immediate effects while the therapy was in progress, and this is an avenue for future research.<br><br>TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12619001510134; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378564.<br><br>RR2-DOI: 10.1136/bmjopen-2020-046030.}, }
@article {pmid34535787, year = {2021}, author = {Liu, KY and Howard, R}, title = {Can we learn lessons from the FDA's approval of aducanumab?.}, journal = {Nature reviews. Neurology}, volume = {17}, number = {11}, pages = {715-722}, pmid = {34535787}, issn = {1759-4766}, support = {MR/S021418/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/pharmacology/*therapeutic use ; Clinical Trials, Phase III as Topic ; *Drug Approval ; Humans ; Middle Aged ; Randomized Controlled Trials as Topic ; Treatment Outcome ; United States ; United States Food and Drug Administration/*organization &amp; administration ; }, abstract = {On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen's shared interpretation of clinical trial data - that high-dose aducanumab was substantially clinically effective - avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA's decision on 7 June 2021 and consider whether any lessons can be learned for the field.}, }
@article {pmid34531308, year = {2021}, author = {Lopez-Grancha, M and Bernardelli, P and Moindrot, N and Genet, E and Vincent, C and Roudieres, V and Krick, A and Sabuco, JF and Machnik, D and Ibghi, D and Pradier, L and Taupin, V}, title = {A Novel Selective PKR Inhibitor Restores Cognitive Deficits and Neurodegeneration in Alzheimer Disease Experimental Models.}, journal = {The Journal of pharmacology and experimental therapeutics}, volume = {378}, number = {3}, pages = {262-275}, doi = {10.1124/jpet.121.000590}, pmid = {34531308}, issn = {1521-0103}, mesh = {*Alzheimer Disease ; Cognition Disorders ; Maze Learning ; Memory Disorders ; }, abstract = {In Alzheimer disease (AD), the double-strand RNA-dependent kinase protein kinase R (PKR)/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2α (eIF2α). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid-β oligomers (AβOs), have been associated with activation of PKR-dependent signaling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models. In ApoE4 human replacement male mice, 1-week oral treatment with SAR439883 rescued short-term memory impairment in the spatial object recognition test and dose-dependently reduced learning and memory deficits in the Barnes maze test. Moreover, in AβO-injected male mice, a 2-week administration of SAR439883 in diet dose-dependently ameliorated the AβO-induced cognitive impairment in both Y-maze and Morris Water Maze, prevented loss of synaptic proteins, and reduced levels of the proinflammatory cytokine interleukin-1β In both mouse models, these effects were associated with a dose-dependent inhibition of brain PKR activity as measured by both PKR occupancy and partial lowering of peIF2α levels. Our results provide evidence that selective pharmacological inhibition of PKR by a small selective molecule can rescue memory deficits and prevent neurodegeneration in animal models of AD-like pathology, suggesting that inhibition of PKR is a potential therapeutic approach for AD. SIGNIFICANCE STATEMENT: This study reports the identification of a new small molecule potent and selective protein kinase R (PKR) inhibitor that can prevent cognitive deficits and neurodegeneration in Alzheimer disease (AD) experimental models, including a mouse model expressing the most prevalent AD genetic risk factor ApoE4. With high potency and selectivity, this PKR inhibitor represents a unique tool for investigating the physiological role of PKR and a starting point for developing new drug candidates for AD.}, }
@article {pmid34531298, year = {2021}, author = {Antolini, L and DiFrancesco, JC and Zedde, M and Basso, G and Arighi, A and Shima, A and Cagnin, A and Caulo, M and Carare, RO and Charidimou, A and Cirillo, M and Di Lazzaro, V and Ferrarese, C and Giossi, A and Inzitari, D and Marcon, M and Marconi, R and Ihara, M and Nitrini, R and Orlandi, B and Padovani, A and Pascarella, R and Perini, F and Perini, G and Sessa, M and Scarpini, E and Tagliavini, F and Valenti, R and Vázquez-Costa, JF and Villarejo-Galende, A and Hagiwara, Y and Ziliotto, N and Piazza, F}, title = {Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy-Related Inflammation: A Multicenter Prospective Longitudinal Cohort Study.}, journal = {Neurology}, volume = {97}, number = {18}, pages = {e1809-e1822}, pmid = {34531298}, issn = {1526-632X}, mesh = {Aged ; *Cerebral Amyloid Angiopathy/complications/diagnostic imaging ; Cerebral Hemorrhage ; Cohort Studies ; Female ; Humans ; Inflammation ; Longitudinal Studies ; Magnetic Resonance Imaging ; Prospective Studies ; }, abstract = {BACKGROUND AND OBJECTIVES: The goal of this work was to investigate the natural history and outcomes after treatment for spontaneous amyloid-related imaging abnormalities (ARIA)-like in cerebral amyloid angiopathy-related inflammation (CAA-ri).<br><br>METHODS: This was a multicenter, hospital-based, longitudinal, prospective observational study of inpatients meeting CAA-ri diagnostic criteria recruited through the Inflammatory Cerebral Amyloid Angiopathy and Alzheimer's Disease βiomarkers International Network from January 2013 to March 2017. A protocol for systematic data collection at first-ever presentation and at subsequent in-person visits, including T1-weighted, gradient recalled echo-T2*, fluid-suppressed T2-weighted (fluid-attenuated inversion recovery), and T1 postgadolinium contrast-enhanced images acquired on 1.5T MRI, was used at the 3-, 6-, 12-, and 24-month follow-up. Centralized reads of MRIs were performed by investigators blinded to clinical, therapeutic, and time-point information. Main outcomes were survival, clinical and radiologic recovery, intracerebral hemorrhage (ICH), and recurrence of CAA-ri.<br><br>RESULTS: The study enrolled 113 participants (10.6% definite, 71.7% probable, and 17.7% possible CAA-ri). Their mean age was 72.9 years; 43.4% were female; 37.1% were APOEε4 carriers; 36.3% had a history of Alzheimer disease; and 33.6% had a history of ICH. A history of ICH and the occurrence of new ICH at follow-up were more common in patients with cortical superficial siderosis at baseline (52.6% vs 14.3%, p < 0.0001 and 19.3% vs 3.6%, p < 0.009, respectively). After the first-ever presentation of CAA-ri, 70.3% (95% confidence interval [CI] 61.6%-78.5%) and 84.1% (95% CI 76.2%-90.6%) clinically recovered within 3 and 12 months, followed by radiologic recovery in 45.1% (95% CI 36.4%-54.8%) and 77.4% (95% CI 67.7%-85.9%), respectively. After clinicoradiologic resolution of the first-ever episode, 38.3% (95% CI 22.9%-59.2%) had at least 1 recurrence within the following 24 months. Recurrence was more likely if IV high-dose corticosteroid pulse therapy was suddenly stopped compared to slow oral tapering off (hazard ratio 4.68, 95% CI 1.57-13.93; p = 0.006).<br><br>DISCUSSION: These results from the largest longitudinal cohort registry of patients with CAA-ri support the transient and potentially relapsing inflammatory nature of the clinical-radiologic acute manifestations of the disease and the effectiveness of slow oral tapering off after IV corticosteroid pulse therapy in preventing recurrences. Our results highlight the importance of differential diagnosis for spontaneous ARIA-like events in β-amyloid-driven diseases, including treatment-related ARIA in patients with Alzheimer disease exposed to immunotherapy drugs.}, }
@article {pmid34530925, year = {2021}, author = {Marazuela, P and Solé, M and Bonaterra-Pastra, A and Pizarro, J and Camacho, J and Martínez-Sáez, E and Kuiperij, HB and Verbeek, MM and de Kort, AM and Schreuder, FHBM and Klijn, CJM and Castillo-Ribelles, L and Pancorbo, O and Rodríguez-Luna, D and Pujadas, F and Delgado, P and Hernández-Guillamon, M}, title = {MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy.}, journal = {Acta neuropathologica communications}, volume = {9}, number = {1}, pages = {154}, pmid = {34530925}, issn = {2051-5960}, support = {R01 NS104147/NS/NINDS NIH HHS/United States ; }, mesh = {Aged ; Animals ; Antigens, Surface/*biosynthesis/genetics ; Biomarkers/metabolism ; Brain/*metabolism/*pathology ; Cells, Cultured ; Cerebral Amyloid Angiopathy/genetics/*metabolism/*pathology ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Milk Proteins/*biosynthesis/genetics ; }, abstract = {Brain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.}, }
@article {pmid34530113, year = {2021}, author = {Gao, F and Liu, T and Tuo, M and Chi, S}, title = {The role of orexin in Alzheimer disease: From sleep-wake disturbance to therapeutic target.}, journal = {Neuroscience letters}, volume = {765}, number = {}, pages = {136247}, doi = {10.1016/j.neulet.2021.136247}, pmid = {34530113}, issn = {1872-7972}, mesh = {Alzheimer Disease/complications/*drug therapy/pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Cognition/drug effects ; Cognitive Dysfunction/drug therapy/etiology ; Disease Models, Animal ; Humans ; Orexin Receptor Antagonists/pharmacology/*therapeutic use ; Orexins/antagonists &amp; inhibitors/*metabolism ; Sleep Wake Disorders/drug therapy/*etiology/pathology ; Sleep, REM/drug effects ; }, abstract = {Accumulating evidence has shown that sleep disturbance is a common symptom in Alzheimer's disease (AD), which is regarded as a modifiable risk factor for AD. Orexin is a key modulator of the sleep-wake cycle and has been found to be dysregulated in AD patients. The increased orexin in cerebrospinal fluid (CSF) is associated with decreased sleep efficiency and REM sleep, as well as cognitive impairment in AD patients. The orexin system has profuse projections to brain regions that are implicated in arousal and cognition and has been found to participate in the progression of AD pathology. Conversely the orexin receptor antagonists are able to consolidate sleep and reduce AD pathology. Therefore, improved understanding of the mechanisms linking orexin system, sleep disturbance and AD could make orexin receptor antagonists a promising target for the prevention or treatment of AD.}, }
@article {pmid34526539, year = {2021}, author = {Benseny-Cases, N and Álvarez-Marimon, E and Aso, E and Carmona, M and Klementieva, O and Appelhans, D and Ferrer, I and Cladera, J}, title = {In situ identification and G4-PPI-His-Mal-dendrimer-induced reduction of early-stage amyloid aggregates in Alzheimer's disease transgenic mice using synchrotron-based infrared imaging.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {18368}, pmid = {34526539}, issn = {2045-2322}, mesh = {Alzheimer Disease/*drug therapy ; Amyloid beta-Peptides/genetics/metabolism ; Animals ; Cerebral Cortex/diagnostic imaging/drug effects/metabolism ; Dendrimers/administration &amp; dosage/*therapeutic use ; Histidine/chemistry ; Maltose/chemistry ; Mice ; Mice, Inbred C57BL ; Polypropylenes/administration &amp; dosage/*therapeutic use ; Spectroscopy, Fourier Transform Infrared ; }, abstract = {Amyloid plaques composed of Aβ amyloid peptides and neurofibrillary tangles are a pathological hallmark of Alzheimer Disease. In situ identification of early-stage amyloid aggregates in Alzheimer's disease is relevant for their importance as potential targets for effective drugs. Synchrotron-based infrared imaging is here used to identify early-stage oligomeric/granular aggregated amyloid species in situ in the brain of APP/PS1 transgenic mice for the first time. Also, APP/PS1 mice show fibrillary aggregates at 6 and 12 months. A significant decreased burden of early-stage aggregates and fibrillary aggregates is obtained following treatment with poly(propylene imine) dendrimers with histidine-maltose shell (a neurodegenerative protector) in 6-month-old APP/PS1 mice, thus demonstrating their putative therapeutic properties of in AD models. Identification, localization, and characterization using infrared imaging of these non-fibrillary species in the cerebral cortex at early stages of AD progression in transgenic mice point to their relevance as putative pharmacological targets. No less important, early detection of these structures may be useful in the search for markers for non-invasive diagnostic techniques.}, }
@article {pmid34524654, year = {2022}, author = {Parker, K and Vincent, B and Rhee, Y and Choi, BJ and Robinson-Lane, SG and Hamm, JM and Klawitter, L and Jurivich, DA and McGrath, R}, title = {The estimated prevalence of no reported dementia-related diagnosis in older Americans living with possible dementia by healthcare utilization.}, journal = {Aging clinical and experimental research}, volume = {34}, number = {2}, pages = {359-365}, pmid = {34524654}, issn = {1720-8319}, support = {K01 AG065420/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; *Cognitive Dysfunction ; *Dementia/diagnosis/epidemiology ; *Home Care Services ; Humans ; Patient Acceptance of Health Care ; Prevalence ; United States/epidemiology ; }, abstract = {BACKGROUND: Screening for dementia in relevant healthcare settings may help in identifying low cognitive functioning for comprehensive cognitive assessments and subsequent dementia treatment after diagnosis.<br><br>AIMS: This study sought to estimate the prevalence of no reported dementia-related diagnosis in a nationally-representative sample of older Americans with a cognitive impairment consistent with dementia (CICD) by healthcare utilization.<br><br>METHODS: The unweighted analytical sample included 1514 Americans aged ≥ 65 years that were identified as having a CICD without history of stroke, cancers, neurological conditions, or brain damage who participated in at least one-wave of the 2010-2016 waves of the Health and Retirement Study. An adapted Telephone Interview of Cognitive Status assessed cognitive functioning. Those with scores ≤ 6 had a CICD. Dementia-related diagnosis was self-reported. Respondents indicated if they visited a physician, received home healthcare, or experienced an overnight nursing home stay in the previous two years.<br><br>RESULTS: The prevalence of no reported dementia-related diagnosis in persons with a CICD who visited a physician was 89.9% (95% confidence interval (CI): 85.4%-93.1%). Likewise, the prevalence of no reported diagnosis in those with a CICD who received home healthcare was 84.3% (CI: 75.1-90.5%). For persons with a CICD that had an overnight nursing home stay, the prevalence of no reported dementia-related diagnosis was 83.0% (CI: 69.1-91.4%).<br><br>DISCUSSION: Although the prevalence of no reported dementia-related diagnosis in individuals with a CICD differed across healthcare settings, the prevalence was generally high nonetheless.<br><br>CONCLUSIONS: We recommend increased awareness and efforts be given to dementia screenings in various clinical settings.}, }
@article {pmid34521342, year = {2021}, author = {Wen, J and Zhao, M and Sun, W and Cheng, X and Yu, L and Cao, D and Li, P}, title = {Uptake of Aβ by OATPs might be a new pathophysiological mechanism of Alzheimer disease.}, journal = {BMC neuroscience}, volume = {22}, number = {1}, pages = {53}, pmid = {34521342}, issn = {1471-2202}, mesh = {Alzheimer Disease/chemically induced/*metabolism/*physiopathology ; Amyloid beta-Peptides/*metabolism/toxicity ; HEK293 Cells ; Humans ; Liver-Specific Organic Anion Transporter 1/*metabolism ; Peptide Fragments/*metabolism/toxicity ; }, abstract = {BACKGROUND: The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD), at the same time, it is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABC1B1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. In the preliminary study, we found that the protein expression of organic anion transporting Polypeptide 1a4 (OATP1B1) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp1a4 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD.<br><br>RESULTS: In this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport of Aβ1-42. Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK293T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATPs may act as an important "carrier" for the transport of Aβ1-42 from the blood to the tissues, including liver and brain.<br><br>CONCLUSIONS: This is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.}, }
@article {pmid34515788, year = {2021}, author = {Schwartz, JB and Weintraub, S}, title = {Treatment for Alzheimer Disease-Sex and Gender Effects Need to Be Explicitly Analyzed and Reported in Clinical Trials.}, journal = {JAMA network open}, volume = {4}, number = {9}, pages = {e2124386}, doi = {10.1001/jamanetworkopen.2021.24386}, pmid = {34515788}, issn = {2574-3805}, mesh = {*Alzheimer Disease/drug therapy/epidemiology ; Gender Identity ; Humans ; Sex Factors ; }, }
@article {pmid34512506, year = {2021}, author = {Tsolaki, M and Tsatali, M and Gkioka, M and Poptsi, E and Tsolaki, A and Papaliagkas, V and Tabakis, IM and Lazarou, I and Makri, M and Kazis, D and Papagiannopoulos, S and Kiryttopoulos, A and Koutsouraki, E and Tegos, T}, title = {Memory Clinics and Day Care Centers in Thessaloniki, Northern Greece: 30 Years of Clinical Practice and Experience.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {683131}, pmid = {34512506}, issn = {1664-2295}, abstract = {Background: This review describes the diagnostic and interventional procedures conducted in two university memory clinics (established network of G. Papanikolaou Hospital: 1988-2017 and AHEPA hospital: 2017-today) and 2 day care centers (established network of DCCs: 2005-today) in North Greece and their contribution in the scientific field of dementia. The aims of this work are (1) to provide a diagnosis and treatment protocol established in the network of memory clinics and DCCs and (2) to present further research conducted in the aforementioned network during the last 30 years of clinical practice. Methods: The guidelines to set a protocol demand a series of actions as follows: (1) set the diagnosis criteria, neuropsychological assessment, laboratory examinations, and examination of neurophysiological, neuroimaging, cerebrospinal fluid, blood, and genetic markers; and (2) apply non-pharmacological interventions according to the needs and specialized psychosocial interventions of the patient to the caregivers of the patient. Results: In addition to the guidelines followed in memory clinics at the 1st and 3rd Department of Neurology and two DCCs, a database of patients, educational programs, and further participation in international research programs, including clinical trials, make our contribution in the dementia field strong. Conclusion: In the current paper, we provide useful guidelines on how major and minor neurocognitive disorders are being treated in Thessaloniki, Greece, describing successful practices which have been adapted in the last 30 years.}, }
@article {pmid34508753, year = {2021}, author = {Baldinotti, R and Fronza, MG and Fetter, J and Silva, L and Bender, CB and Lüdtke, DS and Seixas, FK and Collares, T and Alves, D and Savegnago, L}, title = {Protective effects of octylseleno-xylofuranoside in a streptozotocin-induced mouse model of Alzheimer's disease.}, journal = {European journal of pharmacology}, volume = {910}, number = {}, pages = {174499}, doi = {10.1016/j.ejphar.2021.174499}, pmid = {34508753}, issn = {1879-0712}, mesh = {Alzheimer Disease/chemically induced/pathology/*prevention &amp; control ; Animals ; Cerebral Cortex/drug effects/pathology ; Disease Models, Animal ; Glycosides/*pharmacology/therapeutic use ; Hippocampus/drug effects/pathology ; Humans ; Infusions, Intraventricular ; Lipid Peroxidation/drug effects ; Male ; Mice ; Organoselenium Compounds/*pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Streptozocin/administration &amp; dosage/toxicity ; }, abstract = {Octylseleno-xylofuranoside (OSX) is an organic selenium compound which has previously shown antioxidant and antidepressant-like activities, trough the modulation of monoaminergic system and synaptic plasticity pathways. Since recent studies have suggested Major Depressive Disorder (MDD) as a potential risk factor or condition that precedes and correlates with Alzheimer's Disease (AD), this study aimed to evaluate the protective effects of OSX in an AD mouse model induced by intracerebroventricular injection of streptozotocin (STZ). To address this protective effect, mice were pre-treated with intragastrical OSX (0.1 mg/kg) or vehicle for 20 days. After the pre-treatment, mice were submitted to two alternated intracerebroventricular infusions of STZ (days 21 and 23) or saline. 15 days after the last STZ injection, cognitive and memory skills of the treated mice were evaluated on object recognition test, Y-maze, stepdown passive avoidance and social recognition paradigms. Added to that, measurements of oxidative stress markers and gene expression were evaluated in brain samples of the same mice groups. Mice pre-treatment with OSX protected mice from cognitive and memory decline elicited by STZ. This effect was attributed to the prevention of lipid peroxidation and modulation of acetylcholinesterase and monoamine oxidase activities in cerebral cortices and hippocampi by OSX treatment. Furthermore, OSX treatment demonstrated reduction of amyloidogenic pathway genes expression when compared to the control groups. Besides that, OSX treatment showed no hepatic and renal toxicity in the protocol used for treatment. Considering the antidepressant-like effect of OSX, together with the ability to prevent memory and cognitive impairment, this new compound may be an interesting strategy for targeting the comorbidity between MDD and AD, in a multitarget drug paradigm.}, }
@article {pmid34507318, year = {2021}, author = {Brenowitz, WD and Xiang, Y and McEvoy, CT and Yang, C and Yaffe, K and Le, WD and Leng, Y}, title = {Current Alzheimer disease research highlights: evidence for novel risk factors.}, journal = {Chinese medical journal}, volume = {134}, number = {18}, pages = {2150-2159}, pmid = {34507318}, issn = {2542-5641}, support = {K01 AG062722/AG/NIA NIH HHS/United States ; R00 AG056598/AG/NIA NIH HHS/United States ; }, mesh = {*Alzheimer Disease/epidemiology/etiology ; Amyloid ; Amyloid beta-Peptides ; Humans ; Risk Factors ; tau Proteins ; }, abstract = {ABSTRACT: Alzheimer disease (AD) is the most common type of dementia characterized by the progressive cognitive and social decline. Clinical drug targets have heavily focused on the amyloid hypothesis, with amyloid beta (Aβ), and tau proteins as key pathophysiologic markers of AD. However, no effective treatment has been developed so far, which prompts researchers to focus on other aspects of AD beyond Aβ, and tau proteins. Additionally, there is a mounting epidemiologic evidence that various environmental factors influence the development of dementia and that dementia etiology is likely heterogenous. In the past decades, new risk factors or potential etiologies have been widely studied. Here, we review several novel epidemiologic and clinical research developments that focus on sleep, hypoxia, diet, gut microbiota, and hearing impairment and their links to AD published in recent years. At the frontiers of AD research, these findings and updates could be worthy of further attention.}, }
@article {pmid34506904, year = {2022}, author = {Sanders, OD and Rajagopal, L and Rajagopal, JA}, title = {The oxidatively damaged DNA and amyloid-β oligomer hypothesis of Alzheimer's disease.}, journal = {Free radical biology &amp; medicine}, volume = {179}, number = {}, pages = {403-412}, doi = {10.1016/j.freeradbiomed.2021.08.019}, pmid = {34506904}, issn = {1873-4596}, mesh = {*Alzheimer Disease/drug therapy ; *Amyloid beta-Peptides/metabolism ; Brain/metabolism ; DNA ; Hippocampus/metabolism ; Humans ; Peptide Fragments ; }, abstract = {The amyloid-β (Aβ) oligomer hypothesis of Alzheimer's disease (AD) still dominates the field, yet the clinical trial evidence does not robustly support it. A falsifiable prediction of the hypothesis is that Aβ oligomer levels should be elevated in the brain regions and at the disease stages where and when neuron death and synaptic protein loss begin and are the most severe, but we review previous evidence to demonstrate that this is not consistently the case. To rescue the Aβ oligomer hypothesis from falsification, we propose the novel ad-hoc hypothesis that the exceptionally vulnerable hippocampus may normally produce Aβ peptides even in healthily aging individuals, and hippocampal oxidatively damaged DNA, pathogen DNA, and metal ions such as zinc may initiate and drive Aβ peptide aggregation into oligomers and spreading, neuron death, synaptic dysfunction, and other aspects of AD neurodegeneration. We highlight additional evidence consistent with the underwhelming efficacy of Aβ oligomer-lowering agents, such as aducanumab, and of antioxidants, such as vitamin E, versus the so far isolated case report that DNase-I treatment for 2 months resulted in a severe AD patient's Mini-Mental State Exam score increasing from 3 to 18, reversing his diagnosis to moderate AD, according to the Mini-Mental State Exam.}, }
@article {pmid34496627, year = {2021}, author = {Lee, SR and Choi, EK and Park, SH and Jung, JH and Han, KD and Oh, S and Lip, GYH}, title = {Comparing Warfarin and 4 Direct Oral Anticoagulants for the Risk of Dementia in Patients With Atrial Fibrillation.}, journal = {Stroke}, volume = {52}, number = {11}, pages = {3459-3468}, doi = {10.1161/STROKEAHA.120.033338}, pmid = {34496627}, issn = {1524-4628}, mesh = {Aged ; Anticoagulants/*therapeutic use ; Atrial Fibrillation/complications/*drug therapy ; Cardiovascular Diseases/etiology/prevention &amp; control ; Cerebrovascular Disorders/etiology/prevention &amp; control ; Dementia/*epidemiology ; Factor Xa Inhibitors/*therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; Warfarin/*therapeutic use ; }, abstract = {Background and Purpose: Atrial fibrillation is a risk factor for dementia, and oral anticoagulant use is associated with a decreased risk of dementia in patients with atrial fibrillation. We aimed to investigate whether the risk of dementia would be different between patients treated with direct oral anticoagulants (DOACs) compared with those with warfarin.<br><br>Methods: Using the Korean nationwide claims database from January 2014 to December 2017, we identified oral anticoagulant–naive nonvalvular atrial fibrillation patients aged ≥40 years. For the comparisons, warfarin and DOAC groups were balanced using the inverse probability of treatment weighting method. The primary outcome was incident dementia.<br><br>Results: Among 72 846 of total study patients, 25 948 were treated with warfarin, and 46 898 were treated with DOAC (17 193 with rivaroxaban, 9882 with dabigatran, 11 992 with apixaban, and 7831 with edoxaban). During mean 1.3±1.1 years of follow-up, crude incidence of dementia was 4.87 per 100 person-years (1.20 per 100 person-years for vascular dementia and 3.30 per 100 person-years for Alzheimer dementia). Compared with warfarin, DOAC showed a comparable risks of dementia, vascular dementia, and Alzheimer dementia. In subgroup analyses, DOAC was associated with a lower risk of dementia than warfarin, particularly in patients aged 65 to 74 years (hazard ratio, 0.815 [95% CI, 0.709–0.936]) and in patients with prior stroke (hazard ratio, 0.891 [95% CI, 0.820–0.968]). When comparing individual DOACs with warfarin, edoxaban was associated with a lower risk of dementia (hazard ratio, 0.830 [95% CI, 0.740–0.931]).<br><br>Conclusions: In this large Asian population with atrial fibrillation, DOAC showed a comparable risk of dementia with warfarin overall. DOACs appeared more beneficial than warfarin, in those aged 65 to 74 years or with a history of stroke. For specific DOACs, only edoxaban was associated with a lower risk of dementia than warfarin.}, }
@article {pmid34489674, year = {2021}, author = {Ou, H and Chien, WC and Chung, CH and Chang, HA and Kao, YC and Wu, PC and Tzeng, NS}, title = {Association Between Antibiotic Treatment of Chlamydia pneumoniae and Reduced Risk of Alzheimer Dementia: A Nationwide Cohort Study in Taiwan.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {701899}, pmid = {34489674}, issn = {1663-4365}, abstract = {Background: Chlamydia pneumoniae (CPn) is a common community-acquired pneumonia. In the literature, CPn infection is demonstrated to exhibit an association with Alzheimer dementia (AD). We executed the present nationwide, population-based research with the goal of probing the association of CPn infection and antibiotic therapy with AD risk. Methods: We conducted a cohort study using a database extracted from Taiwan's National Health Insurance Research Database (NHIRD). All medical conditions for each enrolled individuals were categorized using the International Classification of Diseases, ninth Revision classifications. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between CPn pneumonia-associated hospitalizations and AD were estimated using Fine and Gray's survival analysis and adjusted for comorbidities. The effects of the antibiotics on the HRs for AD in the patients with CPn pneumonia-associated hospitalization were also analyzed. Results: Our analyses included 6,628 individuals, including 1,657 CPn-infected patients, as well as 4,971 controls matched by age, index date, and sex (1:3). In this study, patients hospitalized for CPn pneumonia exhibited a significantly higher AD risk (adjusted HR = 1.599, 95% CI = 1.284-1.971, p < 0.001). We also noted an association of macrolide use (≥15 days) and fluoroquinolone use (≥15 days) with decreased AD risk. Conclusions: We determined CPn pneumonia to be associated with a relatively high AD risk. The result in this study confirmed the findings from previous literatures, by using a large, nationwide, population-based database. Appropriate macrolide and fluoroquinolone treatment may attenuate this risk.}, }
@article {pmid34489627, year = {2021}, author = {Sim, AY and Barua, S and Kim, JY and Lee, YH and Lee, JE}, title = {Role of DPP-4 and SGLT2 Inhibitors Connected to Alzheimer Disease in Type 2 Diabetes Mellitus.}, journal = {Frontiers in neuroscience}, volume = {15}, number = {}, pages = {708547}, pmid = {34489627}, issn = {1662-4548}, abstract = {Alzheimer's disease (AD) is characterized by memory loss and cognitive decline. Additionally, abnormal extracellular amyloid plaques accumulation and nerve damage caused by intracellular neurofibrillary tangles, and tau protein are characteristic of AD. Furthermore, AD is associated with oxidative stress, impaired mitochondrial structure and function, denormalization, and inflammatory responses. Recently, besides the amyloid β hypothesis, another hypothesis linking AD to systemic diseases has been put forth by multiple studies as a probable cause for AD. Particularly, type 2 diabetes mellitus (T2DM) and its features, including hyperinsulinemia, and chronic hyperglycemia with an inflammatory response, have been shown to be closely related to AD through insulin resistance. The brain cannot synthesize or store glucose, but it does require glucose, and the use of glucose in the brain is higher than that in any other organ in the mammalian body. One of the therapeutic drugs for T2DM, dipeptidyl peptidase-4 (DPP-4) inhibitor, suppresses the degradation of incretins, glucagon-like peptides and glucose-dependent insulinotropic peptide. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, recently used in T2DM treatment, have a unique mechanism of action via inhibition of renal glucose reabsorption, and which is different from the mechanisms of previously used medications. This manuscript reviews the pathophysiological relationship between the two diseases, AD and T2DM, and the pharmacological effects of therapeutic T2DM drugs, especially DPP-4 inhibitors, and SGLT2 inhibitors.}, }
@article {pmid34484904, year = {2021}, author = {Mahdavi, KD and Jordan, SE and Barrows, HR and Pravdic, M and Habelhah, B and Evans, NE and Blades, RB and Iovine, JJ and Becerra, SA and Steiner, RA and Chang, M and Kesari, S and Bystritsky, A and O'Connor, E and Gross, H and Pereles, FS and Whitney, M and Kuhn, T}, title = {Treatment of Dementia With Bosutinib: An Open-Label Study of a Tyrosine Kinase Inhibitor.}, journal = {Neurology. Clinical practice}, volume = {11}, number = {3}, pages = {e294-e302}, pmid = {34484904}, issn = {2163-0402}, abstract = {Objective: The pursuit of an effective therapeutic intervention for dementia has inspired interest in the class of medications known as tyrosine kinase inhibitors such as bosutinib.<br><br>Methods: Thirty-one patients with probable Alzheimer dementia or Parkinson spectrum disorder with dementia completed 12 months of bosutinib therapy and an additional 12 months of follow-up. The Clinical Dementia Rating scale (as estimated by the Quick Dementia Rating System [QDRS]) was the primary cognitive status outcome measure. Secondary outcome measures included the Repeatable Battery Assessment of Neuropsychological Status (RBANS) and the Montreal Cognitive Assessment. Cox regression methods were used to compare results with population-based estimates of cognitive decline.<br><br>Results: The present article reports on cognitive outcomes obtained at 12 months for 31 participants and up to 24 months for a 16-participant subset. Safety and tolerability of bosutinib were confirmed among the study population (Mage = 73.7 years, SDage = 14 years). Bosutinib was associated with less worsening in Clinical Dementia Rating (CDR) scores (hazard ratio = -0.62, p < 0.001, 95% confidence interval [CI]: -1.02 to -0.30) and less decline in RBANS performance (hazard ratio = -3.42, p < 0.001, 95% CI: -3.59 to -3.72) during the year of treatment than population-based estimates of decline. In the 24-month follow-up, wherein 16 patients were observed after 1 year postintervention, 31.2% of participants exhibited worsened CDR levels compared with their 12-month performances.<br><br>Conclusions: Results support an overall positive outcome after 1 year of bosutinib. Future studies should explore the relationship between tyrosine kinases and neurodegenerative pathology as well as related avenues of treatment.}, }
@article {pmid34478861, year = {2021}, author = {Taheri, M and Oryan, SH and Eslimi Esfahani, D and Kouchesfahani, HM 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 = {185}, 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 {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}, mesh = {Aged ; *Alzheimer Disease/therapy ; Amyloid beta-Peptides ; Dentists ; Humans ; Porphyromonas gingivalis ; Professional Role ; }, 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 {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 = {78}, number = {10}, pages = {1187-1196}, doi = {10.1001/jamaneurol.2021.2876}, pmid = {34459862}, issn = {2168-6157}, support = {P30 AG066515/AG/NIA NIH HHS/United States ; R01 AG063689/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Aging/*pathology ; Amyloid beta-Peptides/*metabolism ; Brain/metabolism/*pathology ; Cognitive Dysfunction/*pathology ; Cross-Sectional Studies ; Female ; Humans ; Male ; Positron-Emission Tomography ; Sleep/*physiology ; }, 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 {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 = {}, 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}, pmid = {34449462}, issn = {1536-5964}, support = {LY13G030020//natural science foundation of zhejiang province/ ; }, mesh = {Aged ; Alzheimer Disease/*complications ; Cerebral Small Vessel Diseases/*complications ; Cognitive Dysfunction/*etiology/*pathology ; Comorbidity ; Female ; Humans ; Magnetic Resonance Imaging ; Male ; Mental Status and Dementia Tests ; Neuropsychological Tests ; }, 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 {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}, 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}, pmid = {34447243}, issn = {1177-8881}, mesh = {Animals ; Drugs, Chinese Herbal/*chemistry ; Flavonoids/isolation &amp; purification/*pharmacology ; Humans ; Molecular Targeted Therapy ; Nervous System Diseases/*drug therapy/physiopathology ; Network Pharmacology ; Protein Interaction Maps ; }, 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 {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 = {}, pmid = {34445613}, issn = {1422-0067}, support = {VT2019-2021//UHK/ ; }, mesh = {Animals ; Cognition Disorders/*drug therapy ; Humans ; Muscarinic Agonists/*pharmacology ; Neurodegenerative Diseases/*drug therapy ; *Neuropharmacology ; Pharmaceutical Preparations/*administration &amp; dosage ; Quinuclidines/*pharmacology ; Thiophenes/*pharmacology ; }, 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 {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}, support = {K99 AG061281/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; RF1 AG058501/AG/NIA NIH HHS/United States ; RF1 AG053303/AG/NIA NIH HHS/United States ; K99 AG062723/AG/NIA NIH HHS/United States ; R01 AG044546/AG/NIA NIH HHS/United States ; U01 AG058922/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*genetics/metabolism/therapy ; Amyloid beta-Peptides/metabolism ; Biomarkers/metabolism ; Humans ; }, 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 {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}, mesh = {*Alzheimer Disease ; *Aminoacyltransferases ; Double-Blind Method ; Humans ; Treatment Outcome ; }, 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 = {2021}, 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}, pmid = {34425652}, issn = {2008-823X}, mesh = {Amyloid beta-Peptides/*toxicity ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Cyclic AMP Response Element-Binding Protein/metabolism ; Humans ; Inflammation Mediators/metabolism ; Interleukin-6/*metabolism ; Linagliptin/*pharmacology ; Neuroblastoma/metabolism/*pathology ; Neuroprotective Agents/*pharmacology ; Phosphorylation/drug effects ; Protein Kinase C-epsilon/metabolism ; Wnt1 Protein/*metabolism ; }, abstract = {Background: Alzheimer’s disease is one of the neurodegenerative disorders typified by the aggregate of amyloid-β (Aβ) and phosphorylated tau protein. Oxidative stress and neuroinflammation, because of Aβ peptides, are strongly involved in the pathophysiology of Alzheimer’s disease (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 {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}, mesh = {Anti-Inflammatory Agents/pharmacology ; *Antioxidants/pharmacology ; *Flavonoids/pharmacology ; Prenylation ; Structure-Activity Relationship ; }, 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 = {110}, number = {12}, pages = {3953-3962}, doi = {10.1016/j.xphs.2021.08.013}, pmid = {34403652}, issn = {1520-6017}, mesh = {ATP-Binding Cassette Transporters/metabolism ; *Alzheimer Disease/genetics/metabolism ; Animals ; Cerebral Cortex/metabolism ; Disease Models, Animal ; Inflammation/metabolism ; Mice ; Mice, Transgenic ; Proteomics ; Receptors, Ionotropic Glutamate/metabolism ; }, 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 {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 = {10}, number = {2}, pages = {905-917}, 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 {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}, 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 {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 = {176}, number = {}, pages = {8-17}, doi = {10.1016/j.brainresbull.2021.08.004}, pmid = {34391822}, issn = {1873-2747}, mesh = {Alzheimer Disease/*metabolism ; Animals ; Anti-Bacterial Agents/*pharmacology ; Brain/drug effects/metabolism ; Brain-Derived Neurotrophic Factor/metabolism ; Cognition/drug effects ; Disease Models, Animal ; Gastrointestinal Microbiome/*drug effects ; Interleukin-6/metabolism ; Male ; Maze Learning/drug effects ; Mice ; Recognition, Psychology/*drug effects ; Spatial Memory/*drug effects ; Tumor Necrosis Factor-alpha/metabolism ; }, 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.}, }
@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}, 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 {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}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Autophagy ; Genistein/pharmacology/therapeutic use ; *Huntington Disease ; *Neurodegenerative Diseases/drug therapy ; }, 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 {pmid34378237, year = {2021}, author = {Gove, D and Nielsen, TR and Smits, C and Plejert, C and Rauf, MA and Parveen, S and Jaakson, S and Golan-Shemesh, D and Lahav, D and Kaur, R and Herz, MK and Monsees, J and Thyrian, JR 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 = {36}, number = {12}, pages = {1823-1828}, doi = {10.1002/gps.5614}, pmid = {34378237}, issn = {1099-1166}, mesh = {Aged ; *Dementia/diagnosis/therapy ; *Ethnicity ; Europe ; Health Personnel ; Humans ; Minority Groups ; }, 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.}, }
@article {pmid34370647, year = {2022}, author = {Dorman, G and Flores, I and Gutiérrez, C and Castaño, RF and Aldecoa, M and Kim, L}, title = {Medicinal Herbs and Nutritional Supplements for Dementia Therapy: Potential Targets and Clinical Evidence.}, journal = {CNS &amp; neurological disorders drug targets}, volume = {21}, number = {1}, pages = {26-51}, doi = {10.2174/1871527320666210809121230}, pmid = {34370647}, issn = {1996-3181}, mesh = {Alzheimer Disease/drug therapy ; Antioxidants/therapeutic use ; Cognition/drug effects ; Cognition Disorders/drug therapy ; Dementia/*drug therapy ; *Dietary Supplements ; Humans ; *Plants, Medicinal ; }, abstract = {Spices and herbs have been used for medicinal purposes for centuries. Also, in the last decades, the use of different nutritional supplements has been implemented to treat all kinds of diseases, including those that present an alteration in cognitive functioning. Dementia is a clinical syndrome in which a person's mental and cognitive capacities gradually decline. As the disease progresses, the person's autonomy diminishes. As there is not an effective treatment to prevent progressive deterioration in many of these pathologies, nutritional interventions have been, and still are, one of the most widely explored therapeutic possibilities. In this review, we have discussed a great number of potentially interesting plants, nutritional derivatives, and probiotics for the treatment of dementia around the world. Their action mechanisms generally involve neuroprotective effects via anti-inflammatory, antioxidant, anti-apoptotic, b-amyloid, and tau anti-aggregate actions; brain blood flow improvement, and effects on synaptic cholinergic and dopaminergic neurotransmission, which may optimize cognitive performance in patients with cognitive impairment. As for their efficacy in patients with cognitive impairment and/or dementias, evidence is still scarce andthe outcomes are controversial. We consider that many of these substances have promising therapeutic properties. Therefore, the scientific community has to continue with a complete research focused on both identifying possible action mechanisms and carrying out clinical trials, preferably randomized, double-blind ones, with a greater number of patients, a long-term follow-up, dose standardization, and the use of current diagnostic criteria.}, }
@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}, pmid = {34367470}, issn = {1942-0994}, mesh = {Alzheimer Disease/*diagnosis/genetics ; Biomarkers/*analysis ; Case-Control Studies ; *Gene Expression Profiling ; *Gene Regulatory Networks ; Humans ; Microarray Analysis ; Prognosis ; *Protein Interaction Maps ; ROC Curve ; }, 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 {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}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/cerebrospinal fluid/*diagnostic imaging/*drug therapy ; Cognitive Dysfunction/cerebrospinal fluid/*diagnostic imaging/*drug therapy ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Immunoglobulins, Intravenous/*administration &amp; dosage ; Male ; Middle Aged ; Time Factors ; Treatment Outcome ; tau Proteins/cerebrospinal fluid ; }, 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 {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 = {}, pmid = {34361099}, issn = {1422-0067}, mesh = {Adenosine Triphosphate/*metabolism ; Alzheimer Disease/drug therapy/*metabolism/pathology ; Autophagy ; Coumarins/*pharmacology ; Energy Metabolism ; Humans ; Membrane Potential, Mitochondrial ; Mitochondria/drug effects/*metabolism ; Neuroblastoma/drug therapy/*metabolism/pathology ; *Organelle Biogenesis ; Reactive Oxygen Species/metabolism ; Tumor Cells, Cultured ; }, 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 {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}, mesh = {*Alzheimer Disease/diagnosis ; *Apathy ; Caregivers ; Humans ; Observational Studies as Topic ; Quality of Life ; Surveys and Questionnaires ; }, 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 {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 = {}, 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/ ; }, mesh = {Alzheimer Disease/*blood/microbiology ; *Biological Monitoring ; Chromatography, Liquid ; Humans ; Mycotoxins/analysis/*blood/metabolism ; Neurodegenerative Diseases ; Ochratoxins ; Parkinson Disease/*blood/metabolism ; Sterigmatocystin/analysis ; Tandem Mass Spectrometry ; Trichothecenes ; Zearalenone/analysis ; }, 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 {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 = {21}, number = {8}, pages = {843-849}, doi = {10.1080/14737175.2021.1960823}, pmid = {34338566}, issn = {1744-8360}, mesh = {*Albumins ; *Alzheimer Disease/therapy ; Amyloid beta-Peptides ; Biomarkers ; Cognitive Dysfunction ; Disease Progression ; Humans ; *Plasma Exchange ; }, 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.<br><br>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.<br><br>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 {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 = {19}, number = {38}, pages = {8264-8271}, doi = {10.1039/d1ob00814e}, pmid = {34338277}, issn = {1477-0539}, mesh = {*Diglycerides ; }, 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 {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}, mesh = {*Alzheimer Disease/drug therapy ; Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides/metabolism ; Animals ; Aspartic Acid Endopeptidases ; Brain Diseases/*drug therapy ; Cell Line ; *Diabetes Mellitus, Experimental/chemically induced/drug therapy ; Glycogen Synthase Kinase 3 beta ; Hippocampus/drug effects/metabolism ; PPAR gamma ; Phosphorylation ; Rats ; Spirostans/*pharmacology ; tau Proteins/metabolism ; }, 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 {pmid34329605, year = {2021}, author = {Procter, TV and Williams, A and Montagne, A}, title = {Interplay between Brain Pericytes and Endothelial Cells in Dementia.}, journal = {The American journal of pathology}, volume = {191}, number = {11}, pages = {1917-1931}, doi = {10.1016/j.ajpath.2021.07.003}, pmid = {34329605}, issn = {1525-2191}, support = {MR/T015594/1/MRC_/Medical Research Council/United Kingdom ; 203913/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Alzheimer Disease/metabolism/pathology ; Animals ; Blood-Brain Barrier/*metabolism/pathology ; Brain/metabolism/pathology ; Cell Communication/*physiology ; Cerebral Small Vessel Diseases/metabolism/pathology ; Dementia/*metabolism/pathology ; Endothelial Cells/*metabolism/pathology ; Humans ; Pericytes/*metabolism/pathology ; }, abstract = {Prevalence of dementia continues to increase because of the aging population and limited treatment options. Cerebral small vessel disease and Alzheimer disease are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit, in particular the blood-brain barrier (BBB), is required for maintaining brain homeostasis. A complex interaction exists among the endothelial cells, which line the blood vessels and pericytes, which surround them in the neurogliovascular unit. Disruption of the BBB in dementia precipitates cognitive decline. This review highlights how dysfunction of the endothelial-pericyte crosstalk contributes to dementia, and focuses on cerebral small vessel disease and Alzheimer disease. It also examines loss of pericyte coverage and subsequent downstream changes. Furthermore, it examines how disruption of the intimate crosstalk between endothelial cells and pericytes leads to alterations in cerebral blood flow, transcription, neuroinflammation, and transcytosis, contributing to breakdown of the BBB. Finally, this review illustrates how cumulation of loss of endothelial-pericyte crosstalk is a major driving force in dementia pathology.}, }
@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}, 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 {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 = {14}, pages = {18993-19012}, pmid = {34315132}, issn = {1945-4589}, mesh = {Alzheimer Disease/*drug therapy ; Cell Line ; Drugs, Chinese Herbal/chemistry/*pharmacology ; Flavones/*pharmacology ; Ginkgo biloba/*chemistry ; Humans ; Molecular Docking Simulation ; Plant Extracts/chemistry/pharmacology ; Signal Transduction/drug effects ; }, 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 {pmid34299575, year = {2021}, author = {Huang, Y and Chang, Y and Liu, L and Wang, J}, title = {Nanomaterials for Modulating the Aggregation of β-Amyloid Peptides.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {14}, pages = {}, pmid = {34299575}, issn = {1420-3049}, support = {22076221//National Natural Science Foundation of China/ ; 21IRTSTHN005//Program for Innovative Research Team of Science and Technology in the University of Henan Province/ ; }, mesh = {Alzheimer Disease/metabolism/*therapy ; Amyloid beta-Peptides/chemistry/*metabolism ; Animals ; Humans ; Nanomedicine ; Nanostructures/chemistry/*therapeutic use ; Photothermal Therapy ; Protein Aggregation, Pathological/metabolism/*therapy ; }, abstract = {The aberrant aggregation of amyloid-β (Aβ) peptides in the brain has been recognized as the major hallmark of Alzheimer's disease (AD). Thus, the inhibition and dissociation of Aβ aggregation are believed to be effective therapeutic strategiesforthe prevention and treatment of AD. When integrated with traditional agents and biomolecules, nanomaterials can overcome their intrinsic shortcomings and boost their efficiency via synergistic effects. This article provides an overview of recent efforts to utilize nanomaterials with superior properties to propose effective platforms for AD treatment. The underlying mechanismsthat are involved in modulating Aβ aggregation are discussed. The summary of nanomaterials-based modulation of Aβ aggregation may help researchers to understand the critical roles in therapeutic agents and provide new insight into the exploration of more promising anti-amyloid agents and tactics in AD theranostics.}, }
@article {pmid34297074, year = {2021}, author = {Insel, PS and Mohlenhoff, BS and Neylan, TC and Krystal, AD and Mackin, RS}, title = {Association of Sleep and β-Amyloid Pathology Among Older Cognitively Unimpaired Adults.}, journal = {JAMA network open}, volume = {4}, number = {7}, pages = {e2117573}, pmid = {34297074}, issn = {2574-3805}, support = {R01 AG063689/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Amyloid beta-Peptides/*analysis ; Aniline Compounds ; Brain/diagnostic imaging/*pathology ; Cognitive Dysfunction/diagnostic imaging/etiology ; Cross-Sectional Studies ; Ethylene Glycols ; Female ; Geriatric Assessment ; Humans ; Male ; Mental Status and Dementia Tests ; Plaque, Amyloid/diagnostic imaging/etiology ; Positron-Emission Tomography/*methods ; *Sleep ; Sleep Initiation and Maintenance Disorders/diagnostic imaging/*pathology/psychology ; }, abstract = {Importance: Disrupted sleep commonly occurs with progressing neurodegenerative disease. Large, well-characterized neuroimaging studies of cognitively unimpaired adults are warranted to clarify the magnitude and onset of the association between sleep and emerging β-amyloid (Aβ) pathology.<br><br>Objective: To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults.<br><br>In this cross-sectional study, screening data were collected between April 1, 2014, and December 31, 2017, from healthy, cognitively unimpaired adults 65 to 85 years of age who underwent florbetapir F 18 positron emission tomography (PET), had APOE genotype information, scored between 25 and 30 on the Mini-Mental State Examination, and had a Clinical Dementia Rating of 0 for the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study. Data analysis was performed from December 1, 2019, to May 10, 2021.<br><br>Exposures: Self-reported daytime and nighttime sleep duration.<br><br>Main Outcomes and Measures: Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio.<br><br>Results: Amyloid PET and sleep duration information was acquired on 4425 cognitively unimpaired participants (mean [SD] age, 71.3 [4.7] years; 2628 [59.4%] female; 1509 [34.1%] tested Aβ positive). Each additional hour of nighttime sleep was associated with a 0.005 reduction of global Aβ standardized uptake value ratio (F1, 4419 = 5.0; P = .03), a 0.009 reduction of medial orbitofrontal Aβ (F1, 4419 = 17.4; P < .001), and a 0.011 reduction of anterior cingulate Aβ (F1, 4419 = 15.9; P < .001). When restricting analyses to participants who tested Aβ negative, nighttime sleep was associated with a 0.006 reduction of medial orbitofrontal Aβ (F1,2910 = 16.9; P < .001) and a 0.005 reduction of anterior cingulate Aβ (F1,2910 = 7.6; P = .03). Daytime sleep was associated with a 0.013 increase of precuneus Aβ (F1,2910 = 7.3; P = .03) and a 0.024 increase of posterior cingulate Aβ (F1,2910 = 14.2; P = .001) in participants who tested Aβ negative.<br><br>Conclusions and Relevance: In this cross-sectional study, the increased risk of Aβ deposition with reduced nighttime sleep duration occurred early, before cognitive impairment or significant Aβ deposition. Daytime sleep may be associated with an increase in risk for early Aβ accumulation and did not appear to be corrective for loss of nighttime sleep, demonstrating a circadian rhythm dependence of sleep in preventing Aβ accumulation. Treatments that improve sleep may reduce early Aβ accumulation and aid in delaying the onset of cognitive dysfunction associated with early Alzheimer disease.}, }
@article {pmid34295207, year = {2021}, author = {Kwan, KKL and Yun, H and Dong, TTX and Tsim, KWK}, title = {Ginsenosides attenuate bioenergetics and morphology of mitochondria in cultured PC12 cells under the insult of amyloid beta-peptide.}, journal = {Journal of ginseng research}, volume = {45}, number = {4}, pages = {473-481}, pmid = {34295207}, issn = {1226-8453}, abstract = {BACKGROUND: Mitochondrial dysfunction is one of the significant reasons for Alzheimer's disease (AD). Ginsenosides, natural molecules extracted from Panax ginseng, have been demonstrated to exert essential neuroprotective functions, which can ascribe to its anti-oxidative effect, enhancing central metabolism and improving mitochondrial function. However, a comprehensive analysis of cellular mitochondrial bioenergetics after ginsenoside treatment under Aβ-oxidative stress is missing.<br><br>METHODS: The antioxidant activities of ginsenoside Rb1, Rd, Re, Rg1 were compared by measuring the cell survival and reactive oxygen species (ROS) formation. Next, the protective effects of ginsenosides of mitochondrial bioenergetics were examined by measuring oxygen consumption rate (OCR) in PC12 cells under Aβ-oxidative stress with an extracellular flux analyzer. Meanwhile, mitochondrial membrane potential (MMP) and mitochondrial dynamics were evaluated by confocal laser scanning microscopy.<br><br>RESULTS: Ginsenoside Rg1 possessed the strongest anti-oxidative property, and which therefore provided the best protective function to PC12 cells under the Aβ oxidative stress by increasing ATP production to 3 folds, spare capacity to 2 folds, maximal respiration to 2 folds and non-mitochondrial respiration to 1.5 folds, as compared to Aβ cell model. Furthermore, ginsenoside Rg1 enhanced MMP and mitochondrial interconnectivity, and simultaneously reduced mitochondrial circularity.<br><br>CONCLUSION: In the present study, these results demonstrated that ginsenoside Rg1 could be the best natural compound, as compared with other ginsenosides, by modulating the OCR of cultured PC12 cells during oxidative phosphorylation, in regulating MMP and in improving mitochondria dynamics under Aβ-induced oxidative stress.}, }
@article {pmid34294612, year = {2021}, author = {Chiang, TI and Yu, YH and Lin, CH and Lane, HY}, title = {Novel Biomarkers of Alzheimer's Disease: Based Upon N-methyl-D-aspartate Receptor Hypoactivation and Oxidative Stress.}, journal = {Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology}, volume = {19}, number = {3}, pages = {423-433}, pmid = {34294612}, issn = {1738-1088}, abstract = {Early detection and prevention of Alzheimer's disease (AD) is important. The current treatment for early AD is acetylcholine esterase inhibitors (AChEIs); however, the efficacy is poor. Besides, AChEI did not show efficacy in mild cognitive impairment (MCI). Beta-amyloid (A) deposits have been regarded to be highly related to the pathogenesis of AD. However, many clinical trials aiming at the clearance of A deposits failed to improve the cognitive decline of AD, even at its early phase. There should be other important mechanisms unproven in the course of AD and MCI. Feasible biomarkers for the diagnosis and treatment response of AD are lacking to date. The N-methyl-D-aspartate receptor (NMDAR) activation plays an important role in learning and memory. On the other hand, oxidative stress has been regarded to contribute to aging with the assumption that free radicals damage cell constituents and connective tissues. Our recent study found that an NMDAR enhancer, sodium benzoate (the pivotal inhibitor of D-amino acid oxidase [DAAO]), improved the cognitive and global function of patients with early-phase AD. Further, we found that peripheral DAAO levels were higher in patients with MCI and AD than healthy controls. We also found that sodium benzoate was able to change the activity of antioxidant. These pieces of evidence suggest that the NMDAR function is associated with anti-oxidation, and have potential to be biomarkers for the diagnosis and treatment response of AD.}, }
@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 {pmid34282704, year = {2021}, author = {Sanders, OD and Rajagopal, L and Rajagopal, JA}, title = {Does oxidatively damaged DNA drive amyloid-β generation in Alzheimer's disease? A hypothesis.}, journal = {Journal of neurogenetics}, volume = {35}, number = {4}, pages = {351-357}, doi = {10.1080/01677063.2021.1954641}, pmid = {34282704}, issn = {1563-5260}, mesh = {*Alzheimer Disease/genetics ; *Amyloid Precursor Protein Secretases ; Amyloid beta-Peptides ; Aspartic Acid Endopeptidases ; DNA ; Humans ; Intracellular Signaling Peptides and Proteins ; Protein Serine-Threonine Kinases ; }, abstract = {In Alzheimer's disease (AD), amyloid-β (Aβ) generation and upstream β-secretase 1 (BACE1) expression appear to be driven by oxidative stress via c-Jun N-terminal kinase (JNK), p38, and Interferon-Induced, Double-Stranded RNA-Activated Protein Kinase (PKR). In addition, inflammatory molecules, including lipopolysaccharide (LPS), induce genes central to Aβ genesis, such as BACE1, via nuclear factor-κB (NFκB). However, additional triggers of Aβ generation remain poorly understood and might represent novel opportunities for therapeutic intervention. Based on mechanistic studies and elevated ectopic oxidatively damaged DNA (oxoDNA) levels in preclinical AD, mild cognitive impairment, and AD patients, we hypothesize oxoDNA contributes to β-amyloidosis starting from the earliest stages of AD through multiple pathways. OxoDNA induces mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), thereby sensitizing the brain to oxidative stress-induced JNK activation and BACE1 transcription. It also induces myeloid differentiation primary response 88 (MyD88) and activates protein kinase CK2, thereby increasing NFκB activation and BACE1 induction. OxoDNA increases oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) ectopic localization, likely augmenting JNK-mediated BACE1 induction. OxoDNA likely also promotes β-amyloidosis via absent in melanoma 2 (AIM2) induction. Falsifiable predictions of this hypothesis include that deoxyribonuclease treatment should decrease Aβ and possibly slow cognitive decline in AD patients. While formal testing of this hypothesis remains to be performed, a case report has found deoxyribonuclease I treatment improved a severely demented AD patient's Mini-Mental Status Exam score from 3 to 18 at 2 months. There is preliminary preclinical and clinical evidence suggesting that ectopic oxidatively damaged DNA may act as an inflammatory damage-associated molecular pattern contributing to Aβ generation in AD, and deoxyribonuclease I should be formally evaluated to test whether it can decrease Aβ levels and slow cognitive decline in AD patients.}, }
@article {pmid34276768, year = {2021}, author = {Liu, Z and Li, H and Pan, S}, title = {Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer's Disease.}, journal = {Frontiers in genetics}, volume = {12}, number = {}, pages = {658323}, pmid = {34276768}, issn = {1664-8021}, abstract = {BACKGROUND: As the most common neurodegenerative disease, Alzheimer's disease (AD) leads to progressive loss of cognition and memory. Presently, the underlying pathogenic genes of AD patients remain elusive, and effective disease-modifying therapy is not available. This study explored novel biomarkers that can affect diagnosis and treatment in AD based on immune infiltration.<br><br>METHODS: The gene expression profiles of 139 AD cases and 134 normal controls were obtained from the NCBI GEO public database. We applied the computational method CIBERSORT to bulk gene expression profiles of AD to quantify 22 subsets of immune cells. Besides, based on the use of the Least Absolute Shrinkage Selection Operator (LASSO), this study also applied SVM-RFE analysis to screen key genes. GO-based semantic similarity and logistic regression model analyses were applied to explore hub genes further.<br><br>RESULTS: There was a remarkable significance in the infiltration of immune cells between the subgroups. The proportions for monocytes, M0 macrophages, and dendritic cells in the AD group were significantly higher than those in the normal group, while the proportion of some cells was lower than that of the normal group, such as NK cell resting, T-cell CD4 naive, T-cell CD4 memory activation, and eosinophils. Additionally, seven genes (ABCA2, CREBRF, CD72, CETN2, KCNG1, NDUFA2, and RPL36AL) were identified as hub genes. Then we performed the analysis of immune factor correlation, gene set enrichment analysis (GSEA), and GO based on seven hub genes. The AUC of ROC prediction model in test and validation sets were 0.845 and 0.839, respectively. Eventually, the mRNA expression analysis of ABCA2, NDUFA2, CREBRF, and CD72 revealed significant differences among the seven hub genes and then was confirmed by RT-PCR.<br><br>CONCLUSION: A model based on immune cell infiltration might be used to forecast AD patients' diagnosis, and it provided a new perspective for AD treatment targets.}, }
@article {pmid34276536, year = {2021}, author = {Song, Y and Chen, S and Gao, J and Lu, J and Xu, W and Lin, X and Chen, J}, title = {Case Report: Coexistence of Anti-AMPA Receptor Encephalitis and Positive Biomarkers of Alzheimer's Disease.}, journal = {Frontiers in neurology}, volume = {12}, number = {}, pages = {673347}, pmid = {34276536}, issn = {1664-2295}, abstract = {Anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis is a rare autoimmune disease that is characterized by acute cognitive impairment, mental symptoms, and seizures. The high comorbidity rate between anti-AMPA receptor (AMPAR) encephalitis and other somatic diseases, such as malignancy, has revealed the possibility of potential copathogenesis. However, there have not yet been reports about anti-AMPAR encephalitis with concomitant cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer disease (AD). Herein, we present the case of an elderly male patient with autoimmune encephalitis (AE) presenting with anti-AMPA1-R and anti-AMPA2-R antibodies, as well as CSF biomarkers of AD. The patient was hospitalized with acute memory decline for 1 week. Anti-AMPA1-R and anti-AMPA2-R antibodies were positively detected in CSF, and the anti-AMPA2-R antibody was also present in the serum. Additionally, the biomarkers of AD were concurrently present in CSF (Aβ1-42 = 245.70 pg/mL, t-Tau = 894.48 pg/mL, p-Tau = 78.66 pg/mL). After administering a combined treatment of intravenous immunoglobulin and glucocorticoids, the patient recovered significantly, and his cognitive function achieved a sustained remission during 2 months' follow-up. This case raises the awareness of a possible interaction between AE and changes of CSF biomarkers. We speculated that the existence of AMPAR antibodies can induce changes of CSF, and other pathological alterations. This present report highlights that a potential relationship exists among AE and provides a warning when making the diagnosis of AD.}, }
@article {pmid34274727, year = {2021}, author = {Ritwiset, A and Khajonrit, J and Krongsuk, S and Maensiri, S}, title = {Molecular insight on the formation structure and dynamics of melatonin in an aqueous solution and at the Water-Air interface: A molecular dynamics study.}, journal = {Journal of molecular graphics &amp; modelling}, volume = {108}, number = {}, pages = {107983}, doi = {10.1016/j.jmgm.2021.107983}, pmid = {34274727}, issn = {1873-4243}, mesh = {*COVID-19 ; Humans ; *Melatonin ; Molecular Dynamics Simulation ; Molecular Structure ; SARS-CoV-2 ; Water ; }, abstract = {Melatonin is a natural hormone that has been shown highly antioxidant effects. Consequently, it has been extensively studied for its therapeutic potential in several diseases such as insomnia, cardiovascular, Alzheimer, and certain types of cancers. Recently, it has been used to adjuvant treatment for COVID-19 patients. It is well-known that melatonin is highly hydrophobic, resulting in lower solubility. However, the molecular structure and dynamic behavior of the formation of melatonin in an aqueous solution and at the water-air interface have not yet been clearly explained. This information is necessary for the melatonin formulation in drug delivery systems. The present work focuses on the molecular structure and dynamics of melatonin molecules in the aqueous solution and at the water-air interface based on using a molecular dynamics simulation study. The results showed that most melatonin molecules were aggregated in an aqueous solution while they were formed a self-assembled monolayer with the ordered structure at the water-air interface. The strong interaction of melatonin depends on their functional group which showed a similar trend for both systems and was sequenced as follows: carbonyl O > indole NH > amide NH > methoxy OA, respectively. However, the carbonyl O and the indole NH groups exhibit strong interactions with water molecules at the interface. Consequently, the two preferred orientations of the melatonin head group can be observed at the water-air interface (i.e., one is to turn the head group to the water surface with the tilted angle of ~40°-60° and the second one is to turn the head group away from the water surface with the tilted angle of ~130°). The longer lifetime of hydrogen bonds formed between melatonin themselves in the bulk water reveals that the stability of melatonin aggregation in an aqueous solution is more stable. Therefore, melatonin has less soluble in an aqueous solution.}, }
@article {pmid34268646, year = {2022}, author = {Ousta, A and Piao, L and Fang, YH and Vera, A and Nallamothu, T and Garcia, AJ and Sharp, WW}, title = {Microglial Activation and Neurological Outcomes in a Murine Model of Cardiac Arrest.}, journal = {Neurocritical care}, volume = {36}, number = {1}, pages = {61-70}, pmid = {34268646}, issn = {1556-0961}, support = {R01 HL133675/HL/NHLBI NIH HHS/United States ; R01 NS107421/NS/NINDS NIH HHS/United States ; T32 HL007381/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Cardiopulmonary Resuscitation ; Disease Models, Animal ; Female ; *Heart Arrest/complications ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/metabolism ; }, abstract = {BACKGROUND: Neurological injury following successful resuscitation from sudden cardiac arrest (CA) is common. The pathophysiological basis of this injury remains poorly understood, and treatment options are limited. Microglial activation and neuroinflammation are established contributors to many neuropathologies, such as Alzheimer disease and traumatic brain injury, but their potential role in post-CA injury has only recently been recognized. Here, we hypothesize that microglial activation that occurs following brief asystolic CA is associated with neurological injury and represents a potential therapeutic target.<br><br>METHODS: Adult C57BL/6 male and female mice were randomly assigned to 12-min, KCl-induced asystolic CA, under anesthesia and ventilation, followed by successful cardiopulmonary resuscitation (n = 19) or sham intervention (n = 11). Neurological assessments of mice were performed using standardized neurological scoring, video motion tracking, and sensory/motor testing. Mice were killed at 72 h for histological studies; neuronal degeneration was assessed using Fluoro-Jade C staining. Microglial characteristics were assessed by immunohistochemistry using the marker of ionized calcium binding adaptor molecule 1, followed by ImageJ analyses for cell integrity density and skeletal analyses.<br><br>RESULTS: Neurological injury in post-cardiopulmonary-resuscitation mice vs. sham mice was evident by poorer neurological scores (difference of 3.626 ± 0.4921, 95% confidence interval 2.618-4.634), sensory and motor functions (worsened by sixfold and sevenfold, respectively, compared with baseline), and locomotion (75% slower with a 76% decrease in total distance traveled). Post-CA brains demonstrated evidence of neurodegeneration and neuroinflammatory microglial activation.<br><br>CONCLUSIONS: Extensive microglial activation and neurodegeneration in the CA1 region and the dentate gyrus of the hippocampus are evident following brief asystolic CA and are associated with severe neurological injury.}, }
@article {pmid34262831, year = {2021}, author = {Qi, X and Nizamutdinov, D and Berman, MH and Dougal, G and Chazot, PL and Wu, E and Stevens, AB and Yi, SS and Huang, JH}, title = {Gender Differences of Dementia in Response to Intensive Self-Administered Transcranial and Intraocular Near-Infrared Stimulation.}, journal = {Cureus}, volume = {13}, number = {7}, pages = {e16188}, pmid = {34262831}, issn = {2168-8184}, abstract = {Background Transcranial near-infrared (tNIR) stimulation was proven to be a safe, reliable, and effective treatment for cognitive and behavioral symptoms of dementia. Dementia patients of different genders differ in terms of gross anatomy, biochemistry, genetic profile, clinical presentations, and socio-psychological status. Studies of the tNIR effect on dementia have thus far been gender-neutral, with dementia subjects being grouped based on diagnoses or dementia severity. This trial hereby investigated how dementia subjects of different sex respond to tNIR treatment. Methods A total of 60 patient-caregiver dyads were enrolled and randomized to this double-blind, sham-controlled clinical trial. The tNIR light has a wavelength of 1,060 nm to 1,080 nm and was delivered via a photobiomodulation (PBM) unit. The active PBM unit emits near-infrared (NIR) light while the sham unit does not. The treatment consists of a six-minute tNIR light stimulation session twice daily for eight weeks. Neuropsychological assessments conducted at baseline (week 0) and endline (week 8) were compared within the female and male group and between different sex, respectively. Results Over the course of treatment, active-arm female subjects had a 20.2% improvement in Mini-Mental State Exam (MMSE) (mean 4.8 points increase, p < 0.001) and active-arm male cohort had 19.3% improvement (p < 0.001). Control-arm female subjects had a 6.5% improvement in MMSE (mean 1.5 points increase, p < 0.03) and control-arm male subjects had 5.9% improvement (p = 0.35) with no significant differences in the mean MMSE between female and male subjects in both arms respectively. Other comparison of assessments including Clock Copying and Drawing Test, Logical Memory Test - immediate and delayed recall yielded nominal but not statistically significant differences. No significant differences were observed in the mean MMSE between female and male subjects in both arms respectively before treatment implementation (active arm, p = 0.12; control arm, p = 0.50) at week 0, or after treatment completion (active arm, p = 0.11; control arm, p = 0.74) at week 8. Conclusion Despite differences between female and male dementia subjects, the response to tNIR light stimulation does not demonstrate gender-based differences. Further studies are warranted to refine the tNIR treatment protocol for subjects suffering from dementia or dementia-related symptoms.}, }
@article {pmid34258377, year = {2021}, author = {Keret, O and Staffaroni, AM and Ringman, JM and Cobigo, Y and Goh, SM and Wolf, A and Allen, IE and Salloway, S and Chhatwal, J and Brickman, AM and Reyes-Dumeyer, D and Bateman, RJ and Benzinger, TLS and Morris, JC and Ances, BM and Joseph-Mathurin, N and Perrin, RJ and Gordon, BA and Levin, J and Vöglein, J and Jucker, M and la Fougère, C and Martins, RN and Sohrabi, HR and Taddei, K and Villemagne, VL and Schofield, PR and Brooks, WS and Fulham, M and Masters, CL and Ghetti, B and Saykin, AJ and Jack, CR and Graff-Radford, NR and Weiner, M and Cash, DM and Allegri, RF and Chrem, P and Yi, S and Miller, BL and Rabinovici, GD and Rosen, HJ and , }, title = {Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.}, journal = {Alzheimer's &amp; dementia (Amsterdam, Netherlands)}, volume = {13}, number = {1}, pages = {e12197}, pmid = {34258377}, issn = {2352-8729}, support = {P30 AG066444/AG/NIA NIH HHS/United States ; U01 AG068057/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; R01 AG055121/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P01 AG012435/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG057739/AG/NIA NIH HHS/United States ; R01 AG068193/AG/NIA NIH HHS/United States ; U19 AG032438/AG/NIA NIH HHS/United States ; R01 LM013463/LM/NLM NIH HHS/United States ; }, abstract = {INTRODUCTION: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.<br><br>METHODS: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.<br><br>RESULTS: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.<br><br>DISCUSSION: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.}, }
@article {pmid34255194, year = {2022}, author = {Isik, AT and Erken, N and Yavuz, I and Kaya, D and Ontan, MS and Ates Bulut, E and Dost, FS}, title = {Orthostatic hypotension in patients with Alzheimer's disease: a meta-analysis of prospective studies.}, journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology}, volume = {43}, number = {2}, pages = {999-1006}, pmid = {34255194}, issn = {1590-3478}, mesh = {Aged ; *Alzheimer Disease/complications/epidemiology ; *Autonomic Nervous System Diseases ; Cross-Sectional Studies ; Humans ; *Hypotension, Orthostatic/epidemiology ; Prospective Studies ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Orthostatic hypotension (OH) is a clinical sign associated with severe adverse health outcomes in older adults. It has been reported to be common in patients with Alzheimer's disease (AD). The present meta-analysis aimed to investigate the prevalence and risk of OH in AD patients.<br><br>METHODS: English-language articles published from January 1990 to August 2020 were searched in PubMed, ScienceDirect, Cochrane, and Web of Science with the keywords "Alzheimer" and "autonomic dysfunction" or "dysautonomia" or "postural hypotension" or "orthostatic hypotension." All prospective clinical studies (case-control, cohort, and cross-sectional studies, and randomized controlled trials) that were regarded as pertinent were included in this study. For quality assessment, the Newcastle-Ottawa Scale was used. Odds ratios (OR) and risk ratios (RR) were extracted with 95% confidence intervals (CI) and combined using the random effects model after logarithmic transformation. The prevalence in the AD patients was also combined using the random effects model.<br><br>RESULTS: The meta-analysis involved 11 studies (7 case-control and 4 case series) to assess the risk of OH in AD. It was found that AD increased the risk of OH with an RR of 1.98 (95% CI: 0.97-4.04) and an OR of 2.53 (95% CI:1.10-5.86) compared to healthy controls, and OH was present in 28% (95% CI: 0.17-0.40) of 500 AD patients.<br><br>CONCLUSION: There is an elevated risk of OH in AD by nearly 2.5-fold. Therefore, the evaluation of postural blood pressure changes should definitely be among the follow-up and treatment goals of AD.}, }
@article {pmid34254991, year = {2021}, author = {Steinbrook, R}, title = {The Accelerated Approval of Aducanumab for Treatment of Patients With Alzheimer Disease.}, journal = {JAMA internal medicine}, volume = {181}, number = {10}, pages = {1281}, doi = {10.1001/jamainternmed.2021.4622}, pmid = {34254991}, issn = {2168-6114}, mesh = {*Alzheimer Disease/drug therapy ; Antibodies, Monoclonal, Humanized ; Drug Approval ; Humans ; }, }
@article {pmid34251396, year = {2021}, author = {Mitchell, SL and D'Agata, EMC and Hanson, LC and Loizeau, AJ and Habtemariam, DA and Tsai, T and Anderson, RA and Shaffer, ML}, title = {The Trial to Reduce Antimicrobial Use in Nursing Home Residents With Alzheimer Disease and Other Dementias (TRAIN-AD): A Cluster Randomized Clinical Trial.}, journal = {JAMA internal medicine}, volume = {181}, number = {9}, pages = {1174-1182}, doi = {10.1001/jamainternmed.2021.3098}, pmid = {34251396}, issn = {2168-6114}, mesh = {Aged, 80 and over ; Alzheimer Disease/*complications ; Anti-Bacterial Agents/*therapeutic use ; Dementia/*complications ; Female ; Follow-Up Studies ; Humans ; Male ; Nursing Homes/*statistics &amp; numerical data ; Palliative Care/*methods ; *Patient Care Planning ; Respiratory Tract Infections/*drug therapy/etiology ; Retrospective Studies ; }, abstract = {Importance: Antimicrobials are extensively prescribed to nursing home residents with advanced dementia, often without evidence of infection or consideration of the goals of care.<br><br>Objective: To test the effectiveness of a multicomponent intervention to improve the management of suspected urinary tract infections (UTIs) and lower respiratory infections (LRIs) for nursing home residents with advanced dementia.<br><br>A cluster randomized clinical trial of 28 Boston-area nursing homes (14 per arm) and 426 residents with advanced dementia (intervention arm, 199 residents; control arm, 227 residents) was conducted from August 1, 2017, to April 30, 2020.<br><br>Interventions: The intervention content integrated best practices from infectious diseases and palliative care for management of suspected UTIs and LRIs in residents with advanced dementia. Components targeting nursing home practitioners (physicians, physician assistants, nurse practitioners, and nurses) included an in-person seminar, an online course, management algorithms (posters, pocket cards), communication tips (pocket cards), and feedback reports on prescribing of antimicrobials. The residents' health care proxies received a booklet about infections in advanced dementia. Nursing homes in the control arm continued routine care.<br><br>Main Outcomes and Measures: The primary outcome was antimicrobial treatment courses for suspected UTIs or LRIs per person-year. Outcomes were measured for as many as 12 months. Secondary outcomes were antimicrobial courses for suspected UTIs and LRIs when minimal criteria for treatment were absent per person-year and burdensome procedures used to manage these episodes (bladder catherization, chest radiography, venous blood sampling, or hospital transfer) per person-year.<br><br>Results: The intervention arm had 199 residents (mean [SD] age, 87.7 [8.0] years; 163 [81.9%] women; 36 [18.1%] men), of which 163 (81.9%) were White and 27 (13.6%) were Black. The control arm had 227 residents (mean [SD] age, 85.3 [8.6] years; 190 [83.7%] women; 37 [16.3%] men), of which 200 (88.1%) were White and 22 (9.7%) were Black. There was a 33% (nonsignificant) reduction in antimicrobial treatment courses for suspected UTIs or LRIs per person-year in the intervention vs control arm (adjusted marginal rate difference, -0.27 [95% CI, -0.71 to 0.17]). This reduction was primarily attributable to reduced antimicrobial use for LRIs. The following secondary outcomes did not differ significantly between arms: antimicrobials initiated when minimal criteria were absent, bladder catheterizations, venous blood sampling, and hospital transfers. Chest radiography use was significantly lower in the intervention arm (adjusted marginal rate difference, -0.56 [95% CI, -1.10 to -0.03]). In-person or online training was completed by 88% of the targeted nursing home practitioners.<br><br>Conclusions and Relevance: This cluster randomized clinical trial found that despite high adherence to the training, a multicomponent intervention promoting goal-directed care for suspected UTIs and LRIs did not significantly reduce antimicrobial use among nursing home residents with advanced dementia.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT03244917.}, }
@article {pmid34246109, year = {2021}, author = {Moghadam, B and Ashouri, M and Roohi, H and Karimi-Jafari, MH}, title = {Computational evidence of new putative allosteric sites in the acetylcholinesterase receptor.}, journal = {Journal of molecular graphics &amp; modelling}, volume = {107}, number = {}, pages = {107981}, doi = {10.1016/j.jmgm.2021.107981}, pmid = {34246109}, issn = {1873-4243}, mesh = {*Acetylcholinesterase/metabolism ; Allosteric Site ; Binding Sites ; *Cholinesterase Inhibitors/pharmacology ; Molecular Docking Simulation ; }, abstract = {Acetylcholinesterase (AChE), with a rigid structure and buried active site at the end of a deep narrow gorge, is interesting enough to solve the paradox between high catalytic activity and unavailability of the active site in treatment of Alzheimer's disease (AD). In this way, the blind docking process is performed on an ensemble of AChE structures created with molecular dynamics (MD) simulations to survey the whole space of AChE to find multiple access pathways to the active site and ranking them based on their affinity scores. Our results show that there are other allosteric binding sites in the protein structure whose inhibition, can affect protein function by disrupting the release of the Acetylcholine (AC) degradation products. In this study, inhibitory activities of Hybride14 and two natural compounds (Papaverine and Palmatine) were evaluated for all possible allosteric sites via docking method. The results confirmed the non-competitive inhibition mechanism. The best binding mode for these inhibitors and efficacy of hydrogen bonds and hydrophobic interactions on inhibitory activities of ligands were also disclosed. Furthermore, our studies provide significant molecular insight for AChE inhibition that could aid in the development of new drugs for AD's treatment.}, }
@article {pmid34245772, year = {2021}, author = {Patwardhan, AG and Belemkar, S}, title = {An update on Alzheimer's disease: Immunotherapeutic agents, stem cell therapy and gene editing.}, journal = {Life sciences}, volume = {282}, number = {}, pages = {119790}, doi = {10.1016/j.lfs.2021.119790}, pmid = {34245772}, issn = {1879-0631}, mesh = {Alzheimer Disease/genetics/immunology/*therapy ; Animals ; Gene Editing/methods ; Genetic Therapy/methods ; Humans ; Immunotherapy/methods ; Stem Cell Transplantation/methods ; }, abstract = {Alzheimer's disease is a chronic lifestyle ailment whose occurrence has come to light with the increasing life expectancy due to better healthcare. The patient burden for AD is set to double by the year 2060 and advancement in research is of utmost importance to combat this problem. AD is characterized by the pathological hallmarks of amyloid plaques and neurofibrillary tangles. The disease has been implicated to have a genetic predisposition. The current treatment strategies are at best ameliorative in nature and offer no substantive cure. Immunotherapeutic approaches employed have shown few therapeutic benefits but the accelerated approval of aducanumab by the US-FDA shows clinical benefit merit. In addition, newer therapeutic approaches are the need of the hour. This review aims to highlight the pathology of the disease, followed by an insight into newer approaches like stem cell therapy and gene editing, focusing on possible CRISPR mediated targets.}, }
@article {pmid34242671, year = {2021}, author = {Ilieva, K and Atanasova, M and Atanasova, D and Kortenska, L and Tchekalarova, J}, title = {Chronic agomelatine treatment alleviates icvAβ-induced anxiety and depressive-like behavior through affecting Aβ metabolism in the hippocampus in a rat model of Alzheimer's disease.}, journal = {Physiology &amp; behavior}, volume = {239}, number = {}, pages = {113525}, doi = {10.1016/j.physbeh.2021.113525}, pmid = {34242671}, issn = {1873-507X}, mesh = {Acetamides ; *Alzheimer Disease/chemically induced/complications/drug therapy ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Anxiety ; Disease Models, Animal ; Hippocampus/metabolism ; Rats ; }, abstract = {Recently, we reported that the atypical antidepressant agomelatine (Ago) exerted a beneficial impact on behavioral changes and concomitant neuropathological events in icvSTZ rat model of sporadic Alzheimer diseases (AD). In the present study, we aimed to explore the effect of Ago (40 mg/kg, i.p. for 30 days) on beta-amyloid (Aβ) metabolism in icvAβ1-42 rat model of AD. The melatonin analogue was administered either simultaneously with Aβ1-42 (AβAgo1) or 30 days later during the late stage of the progression of AD (AβAgo2). Treatment with Ago in the early stage of AD attenuated anxiety and depressive-like responses but was inefficient against Aβ-induced impairment of hippocampus-dependent spatial memory. The melatonin analogue, administered both during the early and the late stage of AD, corrected to control level the elevated Aβ1-42 in the frontal cortex (FC) and the hippocampus. The concentration of α-secretase was enhanced by AβAgo1 compared to the sham- and Aβ-veh groups in the hippocampus. No changes in the concentration of β-secretase in the FC and the hippocampus as well as of γ-secretase in the FC were observed among groups. Both the AβAgo1 and AβAgo2 attenuated to control level the Aβ-induced increased concentration of γ-secretase in the hippocampus. AβAgo1 exerted also structure-specific neuroprotection observed mainly in the CA1, septal CA3b subfield of the dorsal hippocampus and septo-temporal piriform cortex (Pir) and partially in the temporal CA3c, septal and temporal Pir. These findings suggest that Ago treatment in the early stage of AD can exert beneficial effects on concomitant behavioral impairments and neuroprotection in associated brain structures. The antidepressant administration both in the early stage and after the progression of AD affected Aβ metabolism via decreasing of γ-secretase concentration in the hippocampus.}, }
@article {pmid34238525, year = {2021}, author = {Jorge, C and Cetó, M and Arias, A and Blasco, E and Gil, MP and López, R and Dakterzada, F and Purroy, F and Piñol-Ripoll, G}, title = {Level of understanding of Alzheimer disease among caregivers and the general population.}, journal = {Neurologia (Barcelona, Spain)}, volume = {36}, number = {6}, pages = {426-432}, doi = {10.1016/j.nrleng.2018.03.004}, pmid = {34238525}, issn = {2173-5808}, mesh = {*Alzheimer Disease/diagnosis ; *Caregivers ; Disease Progression ; Humans ; }, abstract = {INTRODUCTION: Understanding of Alzheimer disease (AD) is fundamental for early diagnosis and to reduce caregiver burden. The objective of this study is to evaluate the degree of understanding of AD among informal caregivers and different segments of the general population through the Alzheimer's Disease Knowledge Scale (ADKS).<br><br>PATIENTS AND METHODS: We assessed the knowledge of caregivers in different follow-up periods (less than one year, between 1 and 5 years, and over 5 years since diagnosis) and individuals from the general population. ADKS scores were grouped into different items: life impact, risk factors, symptoms, diagnosis, treatment, disease progression, and caregiving.<br><br>RESULTS: A total of 419 people (215 caregivers and 204 individuals from the general population) were included in the study. No significant differences were found between groups for overall ADKS score (19.1 vs 18.8, P = .9). There is a scarce knowledge of disease risk factors (49.3%) or the care needed (51.2%), while symptoms (78.6%) and course of the disease (77.2%) were the best understood aspects. Older caregiver age was correlated with worse ADKS scores overall and for life impact, symptoms, treatment, and disease progression (P < .05). Time since diagnosis improved caregivers' knowledge of AD symptoms (P = .00) and diagnosis (P = .05).<br><br>CONCLUSION: Assessing the degree of understanding of AD is essential to the development of health education strategies both in the general population and among caregivers.}, }
@article {pmid34238048, year = {2021}, author = {He, Y and Li, H and Huang, J and Huang, S and Bai, Y and Li, Y and Huang, W}, title = {Efficacy of antidepressant drugs in the treatment of depression in Alzheimer disease patients: A systematic review and network meta-analysis.}, journal = {Journal of psychopharmacology (Oxford, England)}, volume = {35}, number = {8}, pages = {901-909}, doi = {10.1177/02698811211030181}, pmid = {34238048}, issn = {1461-7285}, mesh = {Alzheimer Disease/*drug therapy/psychology ; Antidepressive Agents/*administration &amp; dosage/adverse effects ; Cognition/drug effects ; Depression/*drug therapy/etiology ; Humans ; Mirtazapine/administration &amp; dosage/adverse effects ; Network Meta-Analysis ; Randomized Controlled Trials as Topic ; Sertraline/administration &amp; dosage/adverse effects ; }, abstract = {BACKGROUND: Depression is considered as one of the most common neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) patients. Prescription of antidepressants is a current clinical practice well-established as the first-line treatment for such patients. Our study was aimed at systematically examining the evidence on the efficacy of antidepressants in the treatment of depression in AD patients.<br><br>METHODS: We conducted a network meta-analysis of randomized controlled trials retrieved by systematic search of the Cochrane Central Register of Controlled Trials, PubMed, Embase, and CNKI databases. Primary outcomes included mean depression score and safety. Secondary outcomes were cognition. The surface under the cumulative ranking curve was performed to estimate a ranking probability for different treatments.<br><br>RESULTS: A total of 25 studies including 14 medications met the inclusion criteria. Compared with placebo, only mirtazapine (standard mean deviation [SMD], -1.94; 95% confidence interval [CI], -3.53 to -0.36; p < 0.05) and sertraline (SMD, -1.16; 95% CI, -2.17 to -0.15; p < 0.05) showed a slightly better effect in treating symptoms of depression. Clomipramine increased risk of adverse events than placebo (odds ratio, 3.01; 95% CI, 1.45 to 4.57; p < 0.05). In terms of cognitive function, there was no statistically significant difference between antidepressants and placebo.<br><br>CONCLUSION: Overall, in the short-term treatment, these data suggest that commonly used antidepressants sertraline and mirtazapine should be considered as an alternative treatment for depression in AD patients. However, more high-quality trials with large samples and longer following-up are proposed.}, }
@article {pmid34224891, year = {2021}, author = {Lin, F and Zhang, H and Bao, J and Li, L}, title = {Identification of Potential Diagnostic miRNAs Biomarkers for Alzheimer Disease Based on Weighted Gene Coexpression Network Analysis.}, journal = {World neurosurgery}, volume = {153}, number = {}, pages = {e315-e328}, doi = {10.1016/j.wneu.2021.06.118}, pmid = {34224891}, issn = {1878-8769}, mesh = {Alzheimer Disease/*genetics ; *Biomarkers ; Databases, Genetic ; Gene Expression Profiling/*methods ; Gene Regulatory Networks ; Humans ; MicroRNAs/*analysis ; }, abstract = {BACKGROUND: Alzheimer disease (AD) is an age-related neurodegenerative disease that accounts for nearly three fourths of dementia cases. Searching for potential biomarkers will help clinicians in the early diagnosis and treatment of AD.<br><br>METHODS: Firstly, we downloaded detailed AD data from the Gene Expression Omnibus (GEO) database for identification of differentially expressed microribonucleic acids (DEmiRNAs) and differentially expressed messenger ribonucleic acids (DEmRNAs). Secondly, functional enrichment analysis was used to identify the biological functions of DEmRNAs. Thirdly, weighted gene coexpression network analysis was used to identify important modules and hub miRNAs. In addition, the miRNA-mRNA regulatory network was constructed. Fourthly, the GSE120584 dataset was used for electronic expression verification and diagnostic analysis. Finally, real-time polymerase chain reaction in vitro verification was performed.<br><br>RESULTS: We obtained 1005 DEmiRNAs and 97 DEmRNAs, respectively. Functional enrichment found that DEmRNAs was enriched in the N-glycan biosynthesis pathway, which was associated with AD. In the weighted gene coexpression network analysis, we found that the brown module was the optimal module. Moreover, 11 hub miRNAs were identified. A total of 216 negatively regulated miRNA-mRNA regulation effects are involved. Hub miRNAs were found to have potential diagnostic value in the receiver operating characteristic analysis.<br><br>CONCLUSION: Eleven hub miRNAs were identified, and DEmRNAs was found to be significantly enriched in the N-glycan biosynthesis pathway, which contributes to the early diagnosis and treatment of AD.}, }
@article {pmid34224083, year = {2022}, author = {Chen, X and Li, L and Sharma, A and Dhiman, G and Vimal, S}, title = {The Application of Convolutional Neural Network Model in Diagnosis and Nursing of MR Imaging in Alzheimer's Disease.}, journal = {Interdisciplinary sciences, computational life sciences}, volume = {14}, number = {1}, pages = {34-44}, pmid = {34224083}, issn = {1867-1462}, mesh = {Algorithms ; *Alzheimer Disease/diagnostic imaging/nursing ; Humans ; Magnetic Resonance Imaging/methods ; *Neural Networks, Computer ; Support Vector Machine ; }, abstract = {The disease Alzheimer is an irrepressible neurologicalbrain disorder. Earlier detection and proper treatment of Alzheimer's disease can help for brain tissue damage prevention. The study was intended to explore the segmentation effects of convolutional neural network (CNN) model on Magnetic Resonance (MR) imaging for Alzheimer's diagnosis and nursing. Specifically, 18 Alzheimer's patients admitted to Indira Gandhi Medical College (IGMC) hospital were selected as the experimental group, with 18 healthy volunteers in the Ctrl group. Furthermore, the CNN model was applied to segment the MR imaging of Alzheimer's patients, and its segmentation effects were compared with those of the fully convolutional neural network (FCNN) and support vector machine (SVM) algorithms. It was found that the CNN model demonstrated higher segmentation precision, and the experimental group showed a higher clinical dementia rating (CDR) score and a lower mini-mental state examination (MMSE) score (P < 0.05). The size of parahippocompalgyrus and putamen was bigger in the Ctrl (P < 0.05). In experimental group, the amplitude of low-frequency fluctuation (ALFF) was positively correlated with the MMSE score in areas of bilateral cingulum gyri (r = 0.65) and precuneus (r = 0.59). In conclusion, the grey matter structure is damaged in Alzheimer's patients, and hippocampus ALFF and regional homogeneity (ReHo) is involved in the neuronal compensation mechanism of hippocampal damage, and the caregivers should take an active nursing method.}, }
@article {pmid34221150, year = {2021}, author = {Cotoban, AG and Udroiu, CA and Vina, R and Vinereanu, D}, title = {Antithrombotic Strategies in Invasively Managed Patients with Non-ST Elevation Acute Coronary Syndromes and Non-Valvular Atrial Fibrillation in Romania.}, journal = {Maedica}, volume = {16}, number = {1}, pages = {6-15}, pmid = {34221150}, issn = {1841-9038}, abstract = {Introduction: Concomitant atrial fibrillation (AF) in non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients complicates the decision-making process regarding short- and long-term antithrombotic strategies. Patient profiles and usage rates of different antithrombotic combinations in this patient subgroup in Romania are poorly described. Premises and objectives: To describe the characteristics of invasively managed NSTE-ACS patients with AF (either known or newly diagnosed) compared to patients with no oral anticoagulation (OAC) indications, and analyze the rates and factors that influence the different antithrombotic regimens at discharge in AF patients. Material and methods: The Romanian National NSTE-ACS Registry allows the enrollment of invasively managed NSTE-ACS patients admitted in 11 interventional centers. Patients with non-valvular AF and no other OAC indication were identified and compared with patients with no indication for OAC. The antithrombotic strategy at discharge was analyzed based on demographic, clinical, and invasive management characteristics. Outcomes:A total of 1418 patients were enrolled between 2016 and 2019 out of which, 175 AF subjects and 1159 patients with no OAC indication were included in the analysis. Subjects with AF were older (70 ± 8.3 vs 62.9 ± 10.4 years, p <0.001) and more likely to have a GRACE score >140 (aOR 2.28, 95% CI 1.58-3.31, p<0.001), a history of heart failure (aOR 3.07, 95% CI 2.14-4.41, p <0.001), dementia or Alzheimer disease (aOR 3.45, 95% CI 1.11-10.68, p 0.032), and non-fatal major cardiovascular (CV) events during admission (aOR 6.71, 95% CI 1.61-27.94, p 0.009). Globally, triple antithrombotic therapy (TAT) was used in 52.5% of AF patients. 69% of PCI patients received TAT. One in four patients with AF did not receive OAC at discharge. Prior treatment with OAC was the strongest predictor for OAC usage at discharge (aOR 12.34, 95% CI 3.21-47.61, p<0.001). Conclusion: More than one in 10 NSTE-ACS patients have a concomitant non-valvular AF diagnosis. These patients are significantly older and are more likely to have significant CV and non-CV disease. Triple antithrombotic therapy is the most used antithrombotic strategy, especially in the PCI subgroup. One in four NSTE-ACS AF patients do not receive OAC at discharge.}, }
@article {pmid34210995, year = {2021}, author = {Aarsland, D and Batzu, L and Halliday, GM and Geurtsen, GJ and Ballard, C and Ray Chaudhuri, K and Weintraub, D}, title = {Parkinson disease-associated cognitive impairment.}, journal = {Nature reviews. Disease primers}, volume = {7}, number = {1}, pages = {47}, pmid = {34210995}, issn = {2056-676X}, mesh = {Aged ; Biomarkers ; *Cognitive Dysfunction/diagnosis/epidemiology/etiology ; Humans ; *Parkinson Disease/complications/diagnosis/epidemiology ; Risk Factors ; }, abstract = {Parkinson disease (PD) is the second most common neurodegenerative disorder, affecting >1% of the population ≥65 years of age and with a prevalence set to double by 2030. In addition to the defining motor symptoms of PD, multiple non-motor symptoms occur; among them, cognitive impairment is common and can potentially occur at any disease stage. Cognitive decline is usually slow and insidious, but rapid in some cases. Recently, the focus has been on the early cognitive changes, where executive and visuospatial impairments are typical and can be accompanied by memory impairment, increasing the risk for early progression to dementia. Other risk factors for early progression to dementia include visual hallucinations, older age and biomarker changes such as cortical atrophy, as well as Alzheimer-type changes on functional imaging and in cerebrospinal fluid, and slowing and frequency variation on EEG. However, the mechanisms underlying cognitive decline in PD remain largely unclear. Cortical involvement of Lewy body and Alzheimer-type pathologies are key features, but multiple mechanisms are likely involved. Cholinesterase inhibition is the only high-level evidence-based treatment available, but other pharmacological and non-pharmacological strategies are being tested. Challenges include the identification of disease-modifying therapies as well as finding biomarkers to better predict cognitive decline and identify patients at high risk for early and rapid cognitive impairment.}, }
@article {pmid34207410, year = {2021}, author = {Bures, J and Tacheci, I and Kvetina, J and Radochova, V and Kohoutova, D and Valis, M and Rejchrt, S and Knoblochova, V and Zdarova Karasova, J}, title = {Dextran Sodium Sulphate-Induced Gastrointestinal Injury Further Aggravates the Impact of Galantamine on the Gastric Myoelectric Activity in Experimental Pigs.}, journal = {Pharmaceuticals (Basel, Switzerland)}, volume = {14}, number = {6}, pages = {}, pmid = {34207410}, issn = {1424-8247}, support = {18-13283S//Grantová Agentura České Republiky/ ; }, abstract = {Galantamine has been used as a treatment for Alzheimer disease. It has a unique, dual mode of action (inhibitor of acetylcholinesterase and allosteric modulator of nicotinic acetylcholine receptors). Nausea (in about 20%), vomiting (10%) and diarrhoea (5-7%) are the most common side effects. The aim of this study was to assess the effect of galantamine on porcine gastric myoelectric activity without (Group A) and with (Group B) dextran sodium sulphate (DSS)-induced gastrointestinal injury. Galantamine hydrobromide was administrated to twelve pigs as a single intragastric dose (24 mg). Gastric myoelectric activity was investigated by electrogastrography (EGG). Basal (15 min before galantamine administration) and study recordings after galantamine administration (300 min) were evaluated using a running spectral analysis. Results were expressed as dominant frequency of gastric slow waves and power analysis (areas of amplitudes). Altogether, 3780 one-minute EGG recordings were evaluated. In Group A, power was steady from basal values for 180 min, then gradually decreased till 270 min (p = 0.007). In Group B, there was a rapid gradual fall from basal values to those after 120 min (p = 0.007) till 300 min (p ˂ 0.001). In conclusion, galantamine alone revealed an unfavourable effect on porcine myoelectric activity assessed by gastric power. It can be a plausible explanation of galantamine-associated dyspepsia in humans. DSS caused further profound decrease of EGG power. That may indicate that underlying inflammatory, ischaemic or NSAIDs-induced condition of the intestine in humans can have aggravated the effect of galantamine on gastric myoelectric activity.}, }
@article {pmid34206776, year = {2021}, author = {Benito-Cuesta, I and Ordoñez-Gutierrez, L and Wandosell, F}, title = {Trehalose Reduces the Secreted Beta-Amyloid Levels in Primary Neurons Independently of Autophagy Induction.}, journal = {Metabolites}, volume = {11}, number = {7}, pages = {}, pmid = {34206776}, issn = {2218-1989}, 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 Neurodegenerativas/ ; }, abstract = {The disaccharide trehalose was described as possessing relevant neuroprotective properties as an mTORC1-independent inducer of autophagy, with the ability to protect cellular membranes and denaturation, resulting from desiccation, and preventing the cellular accumulation of protein aggregates. These properties make trehalose an interesting therapeutic candidate against proteinopathies such as Alzheimer's disease (AD), which is characterized by deposits of aggregated amyloid-beta (Aβ) and hyperphosphorylated tau. In this study, we observed that trehalose was able to induce autophagy in neurons only in the short-term, whereas long-term treatment with trehalose provoked a relevant anti-amyloidogenic effect in neurons from an AD mouse model that was not mediated by autophagy. Trehalose treatment reduced secreted Aβ levels in a manner unrelated to its intracellular accumulation or its elimination through endocytosis or enzymatic degradation. Moreover, the levels of Aβ precursor protein (APP) and beta-secretase (BACE1) remained unaltered, as well as the proper acidic condition of the endo-lysosome system. Instead, our results support that the neuroprotective effect of trehalose was mediated by a reduced colocalization of APP and BACE1 in the cell, and, therefore, a lower amyloidogenic processing of APP. This observation illustrates that the determination of the mechanism, or mechanisms, that associate APP and BACE is a relevant therapeutic target to investigate.}, }
@article {pmid34206456, year = {2021}, author = {Milán-Tomás, Á and Fernández-Matarrubia, M and Rodríguez-Oroz, MC}, title = {Lewy Body Dementias: A Coin with Two Sides?.}, journal = {Behavioral sciences (Basel, Switzerland)}, volume = {11}, number = {7}, pages = {}, pmid = {34206456}, issn = {2076-328X}, abstract = {Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on α-synuclein markers.}, }
@article {pmid34203763, year = {2021}, author = {Forés-Martos, J and Boullosa, C and Rodrigo-Domínguez, D and Sánchez-Valle, J and Suay-García, B and Climent, J and Falcó, A and Valencia, A and Puig-Butillé, JA and Puig, S and Tabarés-Seisdedos, R}, title = {Transcriptomic and Genetic Associations between Alzheimer's Disease, Parkinson's Disease, and Cancer.}, journal = {Cancers}, volume = {13}, number = {12}, pages = {}, pmid = {34203763}, issn = {2072-6694}, support = {PROMETEOII/2015/021//Generalitat Valenciana/ ; PI17/00719//ISCIII-FEDER/ ; }, abstract = {Alzheimer's (AD) and Parkinson's diseases (PD) are the two most prevalent neurodegenerative disorders in human populations. Epidemiological studies have shown that patients suffering from either condition present a reduced overall risk of cancer than controls (i.e., inverse comorbidity), suggesting that neurodegeneration provides a protective effect against cancer. Reduced risks of several site-specific tumors, including colorectal, lung, and prostate cancers, have also been observed in AD and PD. By contrast, an increased risk of melanoma has been described in PD patients (i.e., direct comorbidity). Therefore, a fundamental question to address is whether these associations are due to shared genetic and molecular factors or are explained by other phenomena, such as flaws in epidemiological studies, exposure to shared risk factors, or the effect of medications. To this end, we first evaluated the transcriptomes of AD and PD post-mortem brain tissues derived from the hippocampus and the substantia nigra and analyzed their similarities to those of a large panel of 22 site-specific cancers, which were obtained through differential gene expression meta-analyses of array-based studies available in public repositories. Genes and pathways that were deregulated in both disorders in each analyzed pair were examined. Second, we assessed potential genetic links between AD, PD, and the selected cancers by establishing interactome-based overlaps of genes previously linked to each disorder. Then, their genetic correlations were computed using cross-trait LD score regression and GWAS summary statistics data. Finally, the potential role of medications in the reported comorbidities was assessed by comparing disease-specific differential gene expression profiles to an extensive collection of differential gene expression signatures generated by exposing cell lines to drugs indicated for AD, PD, and cancer treatment (LINCS L1000). We identified significant inverse associations of transcriptomic deregulation between AD hippocampal tissues and breast, lung, liver, and prostate cancers, and between PD substantia nigra tissues and breast, lung, and prostate cancers. Moreover, significant direct (same direction) associations of deregulation were observed between AD and PD and brain and thyroid cancers, as well as between PD and kidney cancer. Several biological processes, including the immune system, oxidative phosphorylation, PI3K/AKT/mTOR signaling, and the cell cycle, were found to be deregulated in both cancer and neurodegenerative disorders. Significant genetic correlations were found between PD and melanoma and prostate cancers. Several drugs indicated for the treatment of neurodegenerative disorders and cancer, such as galantamine, selegiline, exemestane, and estradiol, were identified as potential modulators of the comorbidities observed between neurodegeneration and cancer.}, }
@article {pmid34191107, year = {2021}, author = {Farhat, A and Panchaud, A and Al-Hajje, A and Lang, PO and Csajka, C}, title = {Ability to detect potentially inappropriate prescribing in older patients: comparative analysis between PIM-Check and STOPP/STARTv2.}, journal = {European journal of clinical pharmacology}, volume = {77}, number = {11}, pages = {1747-1756}, pmid = {34191107}, issn = {1432-1041}, mesh = {Aged ; Aged, 80 and over ; Comorbidity ; Female ; Geriatric Assessment/*methods ; Hospitals, University ; Humans ; Inappropriate Prescribing/*statistics &amp; numerical data ; Male ; Polypharmacy ; Potentially Inappropriate Medication List/*statistics &amp; numerical data ; Reproducibility of Results ; Retrospective Studies ; Sociodemographic Factors ; Switzerland ; }, abstract = {PURPOSE: Potentially inappropriate prescribing (PIP) is a source of preventable adverse drug events. The objective of this study was a comparative analysis (quantitative and qualitative) between two tools used to detect PIP, PIM-Check and STOPP/START.<br><br>METHODS: First, a qualitative analysis (QAC) was conducted to evaluate the concordance between the criteria, which constitute PIM-Check and the gold standard STOPP/START. Second, a retrospective comparative and observational study was performed on the list of treatment at the admission of 50 older patients hospitalized in an acute geriatric ward of a university hospital in Switzerland in 2016 using both tools.<br><br>RESULTS: The QAC has shown that 50% (57 criteria) of STOPP/START criteria are fully or partially concordant with those of PIM-Check. The retrospective study was performed on 50 patients aged 87 years, suffering from 5 co-morbidities (min-max 1-11) and treated by of 8 drugs (min-max 2-16), as medians. The prevalence of the detected PIP was 80% by PIM-Check and 90% by STOPP/START. Medication review shows that 4.2 PIP per patient were detected by PIM-Check and 3.5 PIP by STOPP/START among which 1.9 PIP was commonly detected by both tools, as means. PIM-Check detected more PIP related to cardiology, angiology, nephrology, and endocrinology in older patients but missed the PIP related to geriatric syndromes (e.g., fall, dementia, Alzheimer) detected by STOPP/START.<br><br>CONCLUSIONS: By using PIM-Check in geriatric settings, some PIP will not be detected. It is considered as a limitation for this tool in this frail population but brings a certain complementarity in other areas of therapy not covered by STOPP/START.}, }
@article {pmid34183022, year = {2021}, author = {Qiao, O and Zhang, X and Zhang, Y and Ji, H and Li, Z and Han, X and Wang, W and Li, X and Wang, J and Liu, C and Gao, W}, title = {Cerebralcare Granule® enhances memantine hydrochloride efficacy in APP/PS1 mice by ameliorating amyloid pathology and cognitive functions.}, journal = {Chinese medicine}, volume = {16}, number = {1}, pages = {47}, pmid = {34183022}, issn = {1749-8546}, support = {NO. 18ZXXYSY00080//the Science and Technology project of Tianjin/ ; No. 81673535//National Natural Science Foundation of China/ ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Current drugs can only relieve symptoms, but cannot really cure AD. Cerebralcare Granule® (CG) is a Traditional Chinese medicine (TCM) containing a variety of biologically active compounds. In our previous studies, CG has shown a beneficial effect against memory impairment in mice caused by D-galactose. However, whether CG can be used as a complementary medicine for the treatment of AD remains unexplored. Here, we use a combination of CG and memantine hydrochloride (Mm) to treat Alzheimer-like pathology and investigate the effects and mechanisms in vivo.<br><br>METHODS: The histology of brain was examined with Hematoxylin-eosin (HE) staining, Golgi staining and Thioflavin S staining. ELISA was applied to assess the expression levels or activities of CAT, SOD, GSH-Px, MDA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL) in serum, as well as the levels of IL-6, IL-1β, and TNF-α in the mice brain. Western blotting was used to assess the expression of β-secretase (BACE1), amyloid precursor protein (APP), APPβ, APPα, synaptophysin (SYN), growth-associated protein 43 (GAP43), and postsynaptic density 95 (PSD95).<br><br>RESULTS: In the present study, the combination group (CG + Mm) significantly attenuated Alzheimer-like behavior without adverse effects in APP/PS1 mice, indicating its high degree of safety and efficacy after long-term treatment. CG + Mm reduced AD pathological biomarker Aβ plaque accumulation by inhibiting BACE1 and APP expression (P < 0.05 or P < 0.001). Besides, the combination group markedly inhibited the levels of IL-1β, IL-6, and TNF-α in hippocampus (P < 0.001), as well as activities of SOD, CAT, and GSH-Px in serum (P < 0.001). By contrast, the combination group improved synaptic plasticity by enhancing SYN, PSD95, and GAP43 expression.<br><br>CONCLUSIONS: Taken together, these data supported the notion that CG combined with Mm might ameliorate the cognitive impairment through multiple pathways, suggesting that CG could play a role as complementary medicine to increase anti-AD effect of chemical drugs by reducing Aβ deposition, neuroinflammation, oxidative damage, and improving synaptic plasticity.}, }
@article {pmid34182090, year = {2021}, author = {Abdelmeguid, NE and Khalil, MIM and Elhabet, R and Sultan, AS and Salam, SA}, title = {Combination of docosahexaenoic acid and Ginko biloba extract improves cognitive function and hippocampal tissue damages in a mouse model of Alzheimer's disease.}, journal = {Journal of chemical neuroanatomy}, volume = {116}, number = {}, pages = {101995}, doi = {10.1016/j.jchemneu.2021.101995}, pmid = {34182090}, issn = {1873-6300}, mesh = {Aluminum Chloride/toxicity ; Alzheimer Disease/chemically induced/*drug therapy/pathology ; Animals ; Cognition/*drug effects/physiology ; *Disease Models, Animal ; Docosahexaenoic Acids/*administration &amp; dosage ; Drug Therapy, Combination ; Ginkgo biloba ; Hippocampus/*drug effects/pathology ; Male ; Maze Learning/drug effects/physiology ; Mice ; Neuroprotective Agents/administration &amp; dosage ; Plant Extracts/*administration &amp; dosage ; }, abstract = {Alzheimer's disease (AD) is one of the most common neurodegenerative diseases characterized by a progressive loss of memory and other cognitive functions among elder people. Nowadays, natural antioxidants have been used to recover the quality of life for those with AD. In this study, we investigated, for the first time, the combined effect of docosahexaenoic acid (DHA) and Ginkgo bilobastandardized extract (EGb761) on AD mice. AD was induced in adult male albino mice with AlCl3 (20 mg/kg b.w, i.g.) and D-galactose (D-gal; 120 mg/kg, i.p.) for 90 days. 30 days after induction, mice were treated with DHA (200 mg/kg b.w., i.g.) and EGb761 (200 mg/kg b.w., i.g.) for two months. Our data revealed that the dual treatment of DHA and EGb761 significantly improved cognitive memory and spatial learning abilities in AD-induced mice. The drug treatments preserved the hippocampal CA3 architecture and restored neuronal ultrastructural alterations. Expression of protein phosphatase 2A (PP2A), the most implicated protein phosphatase in AD neurodegeneration, was highly upregulated in the CA3 hippocampus of AD mice treated with DHA and EGb761. Intriguingly, TNF-α expression was significantly reduced in the same group. In conclusion, our findings proved that the combined effect of DHA and EGb761 tended to be potent against the neurodegenerative effect of AlCl3 and D-gal. The applied treatment enhanced neuronal survival and cognitive functions via upregulation of PP2A and restoration of TNF-α expression.}, }
@article {pmid34170456, year = {2021}, author = {Mandour, DA and Bendary, MA and Alsemeh, AE}, title = {Histological and imunohistochemical alterations of hippocampus and prefrontal cortex in a rat model of Alzheimer like-disease with a preferential role of the flavonoid "hesperidin".}, journal = {Journal of molecular histology}, volume = {52}, number = {5}, pages = {1043-1065}, pmid = {34170456}, issn = {1567-2387}, mesh = {Alzheimer Disease/*pathology ; Animals ; Behavior, Animal ; Body Weight ; Disease Models, Animal ; Glial Fibrillary Acidic Protein/metabolism ; Glutathione/metabolism ; Hesperidin/*pharmacology ; Hippocampus/*pathology ; Immunohistochemistry ; Male ; Malondialdehyde/metabolism ; Organ Size ; Phosphorylation ; Prefrontal Cortex/*pathology ; Pyramidal Cells/metabolism/pathology ; Rats, Sprague-Dawley ; Synaptophysin/metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a chronic age-related neurodegenerative disease characterized by degeneration of the central cholinergic neurons, inflammation and oxidative stress in the basal forebrain, prefrontal cortex and hippocampus. Hesperidin (Hesp) is one of the flavonoids havinganti-inflammatory and anti-oxidative properties in some neurodegerative brain lesions. To investigate the possible neuroprotective role of Hespin an AD-like rat model induced experimentally by Scopolamine (Scop). Forty adult male Sprague Dawley rats were randomly allocated into four groups. Group I-(Control), group II-(Hesp) (supplemented orally with 100 mg/kg Hesp for 28 days), group III-(AD) (injected i.p with 1 mg/kg Scop for 9 days) and group IV-(Hesp/AD). At the end of the experiment, behavioral (Y-maze test) and biochemical analysis were carried out along with histological, immunohistochemical and morphometric studies of the hippocampus and prefrontal cortex. AD rats displayed memory impairment in the behavioural paradigm with a concomitant increase of serum TNF-α and IL-1β, while IL-10 decreased significantly. Also, there was a rise of amyloid beta-42 (Aβ-42), acetylcholinesterase (AChE) activity and malondialdehyde (MDA) together with a decrease of reduced glutathione (GSH) in hippocampal and prefrontal homogenate. In addition, sections of the hippocampus and prefrontal cortex revealed obvious histopathological changes, overexpression of p-Tau protein and glial fibrillary acidic protein (GFAP) with a decrease in the expression of synaptophysin (SYN). Contradictorily, pre-treatment with Hesp offset the spatial memory deficits, redox imbalance, Aβ-42 and AChE over activity as well as preserved the histological architecture and attenuated the raised p-Tau protein and GFAP while upregulated SYN immuoreactivity of AD rats. Collectively, our results highlight the potential mitigating role of Hesp in AD-like state in rats and this may presumably raise the possibility of its future implementation as a prophylactic remedy against AD in humans.}, }
@article {pmid34169425, year = {2021}, author = {Zhang, Q and Wang, J and Zhu, L and Jiang, SJ and Liu, J and Wang, LX and Qin, XH}, title = {Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats.}, journal = {Current medical science}, volume = {41}, number = {3}, pages = {548-554}, pmid = {34169425}, issn = {2523-899X}, mesh = {Alzheimer Disease/*drug therapy/etiology/genetics/pathology ; Amyloid beta-Peptides ; Animals ; Brain/drug effects/pathology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Humans ; Hyperhomocysteinemia/complications/*drug therapy/genetics/pathology ; Memory Disorders/*drug therapy/etiology/genetics/pathology ; Neurons/drug effects/pathology ; Neuroprotective Agents/pharmacology ; Phosphorylation/drug effects ; Pyrazines/*pharmacology ; Rats ; Rats, Sprague-Dawley ; }, abstract = {Ligustrazine, an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort, has been clinically applied to treat the cerebrovascular diseases. Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer's disease (AD). Memory deficits can be caused by Hhcy via pathologies of AD-like tau and amyloid-β (Aβ) in the hippocampus. Here, we investigated whether homocysteine (Hcy) can induce AD-like pathologies and the effects of ligustrazine on these pathologies. The Hcy rat model was constructed by 14-day Hcy injection via vena caudalis, and rats were treated with daily intragastric administration of ligustrazine at the same time. We found that the pathologies of tau and Aβ were induced by Hcy in the hippocampus, while the Hcy-induced tau hyperphosphorylation and Aβ accumulation could be markedly attenuated by simultaneous ligustrazine treatment. Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced AD-like pathologies.}, }
@article {pmid34160408, year = {2021}, author = {Lee, S and Kwon, DH and Kim, JY and Kim, Y and Cho, SH and Jung, IC}, title = {Efficacy of Yukmijihwang-tang on symptoms of Alzheimer disease: A protocol for systematic review and meta-analysis.}, journal = {Medicine}, volume = {100}, number = {25}, pages = {e26363}, pmid = {34160408}, issn = {1536-5964}, support = {KSN2021240//Korea Institute of Oriental Medicine/ ; HB16C0044//Ministry of Health and Welfare/ ; }, mesh = {Activities of Daily Living ; Alzheimer Disease/complications/diagnosis/*drug therapy ; Cognition/*drug effects ; Drugs, Chinese Herbal/*administration &amp; dosage/adverse effects ; Humans ; Meta-Analysis as Topic ; Neuropsychological Tests ; Systematic Reviews as Topic ; Treatment Outcome ; }, abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia, which may lead to severe memory loss and other cognitive disorders. Yukmijihwang-tang (YMJ), a type of Korean traditional herbal medicine, has been shown to be effective against neurodegenerative diseases. Although a meta-analysis on the efficacy of YMJ on AD exists, the study had some limitations, and there have been several newly published studies assessing the effect of YMJ. Therefore, the purpose of this study is to evaluate the efficacy and safety of YMJ as a treatment for AD through a meta-analysis.<br><br>METHODS: A systematic search of the following electronic databases will be conducted to identify eligible studies: MEDLINE (PubMed), Elsevier (EMBASE), The Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Korean Medical Database (KMBASE), Oriental Medicine Advanced Searching Integrated System (OASIS), Korean Traditional Knowledge Portal, Citation Information by NII (CiNii), China National Knowledge Infrastructure (CNKI). All randomized controlled trials assessing the efficacy and safety of YMJ on the symptoms of AD will be included. Two independent reviewers will perform article retrieval, deduplication, data screening, data extraction, quality evaluation, and data analyses using RevMan version 5.4. The Cochrane risk of bias tool will be used to assess the quality of the trials.<br><br>RESULTS: This study will provide synthesis of the cognitive function measured with neuropsychological tests, behavioral and psychological symptoms of dementia (BPSD), and activities of daily living (ADL) measured using validated scales. The clinical effective rate and adverse events will also be analyzed to assess the efficacy and safety of YMJ for treating AD.<br><br>CONCLUSION: This systematic review will provide evidence for the efficacy and safety of YMJ in AD.<br><br>ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data will not be included in this study. The study findings will be disseminated through conference presentations.}, }
@article {pmid34158563, year = {2021}, author = {Puris, E and Kouřil, Š and Najdekr, L and Loppi, S and Korhonen, P and Kanninen, KM and Malm, T and Koistinaho, J and Friedecký, D and Gynther, M}, title = {Metabolomic and lipidomic changes triggered by lipopolysaccharide-induced systemic inflammation in transgenic APdE9 mice.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {13076}, pmid = {34158563}, issn = {2045-2322}, mesh = {Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/genetics/*immunology/metabolism ; Animals ; Brain/*metabolism ; Disease Models, Animal ; Female ; Hippocampus/metabolism ; Inflammation/*metabolism ; Lipidomics/methods ; Male ; Metabolome ; Metabolomics/methods ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Presenilin-1/metabolism ; }, abstract = {Peripheral infections followed by systemic inflammation may contribute to the onset of Alzheimer`s disease (AD) and accelerate the disease progression later in life. Yet, the impact of systemic inflammation on the plasma and brain tissue metabolome and lipidome in AD has not been investigated. In this study, targeted metabolomic and untargeted lipidomic profiling experiments were performed on the plasma, cortices, and hippocampi of wild-type (WT) mice and transgenic APdE9 mice after chronic lipopolysaccharide (LPS) treatment, as well as saline-treated APdE9 mice. The lipidome and the metabolome of these mice were compared to saline-treated WT animals. In the brain tissue of all three models, the lipidome was more influenced than the metabolome. The LPS-treated APdE9 mice had the highest number of changes in brain metabolic pathways with significant alterations in levels of lysine, myo-inositol, spermine, phosphocreatine, acylcarnitines and diacylglycerols, which were not observed in the saline-treated APdE9 mice. In the WT mice, the effect of the LPS administration on metabolome and lipidome was negligible. The study provided exciting information about the biochemical perturbations due to LPS-induced inflammation in the transgenic AD model, which can significantly enhance our understanding of the role of systemic inflammation in AD pathogenesis.}, }
@article {pmid34149418, year = {2021}, author = {Saleem, U and Hira, S and Anwar, F and Shah, MA and Bashir, S and Baty, RS and Badr, RH and Blundell, R and Batiha, GE and Ahmad, B}, title = {Pharmacological Screening of Viola odorata L. for Memory-Enhancing Effect via Modulation of Oxidative Stress and Inflammatory Biomarkers.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {664832}, pmid = {34149418}, issn = {1663-9812}, abstract = {Purpose: Alzheimer disease (AD) is a progressive neurodegenerative disorder that is caused by neuroinflammation and oxidative stress. The present study aimed to characterize and then investigate the memory-enhancing potential of Viola odorata methanolic extract in lipopolysaccharide (LPS)-treated mice. Methods: V. odorata characterization was done by using the GCMS technique. Neuroinflammation was induced by the intracerebroventricular administration of LPS at a dose of 12 µg. Animals were divided randomly into six groups (n = 10). Group I was normal control, which was given vehicle. Group II was disease control, which received LPS (12 µg) via the intracerebroventricular route. Group III was standard, which was administered with donepezil (3 µg) orally for 21 days. Groups IV-VI were the treatment groups, which were administered with the extract at 100, 200, and 400 mg/kg dose levels orally respectively for 21 days. Groups III-VI received LPS (12 µg) on the first day along with their treatments. During the treatment, the animals were assessed for memory retention by employing different behavioral paradigms namely elevated plus maze, passive avoidance, foot shock and open field. Various mediators [endogenous antioxidants, neurotransmitters, and acetylcholinesterase (AChE)] involved in the pathogenesis of AD were quantified by using the UV spectrophotometric method. Results: Extract-treated groups showed a remarkable improvement in cognitive impairment in all behavioral paradigms. Oxidative stress biomarkers, that is, superoxide dismutase, catalase, and glutathione were raised dose-dependently in the treatment groups with a dose-dependent decrease in the malonaldehyde and AChE levels in the brains of the treated animals. The treatment groups showed decreased levels of inflammatory biomarkers, that is, tumor necrosis factor-alpha, nuclear factor kappa light-chain enhancer of activated β-cells, and cyclo-oxygenase, which supports the therapeutic effectiveness of the treatment. Conclusion: Based on behavioral, oxidative stress biomarker, and neuroinflammatory data, it is concluded that V. odorata possesses memory-enhancing activity and may prove a beneficial role in the management of AD.}, }
@article {pmid34147904, year = {2021}, author = {Gao, Y and Almalki, WH and Afzal, O and Panda, SK and Kazmi, I and Alrobaian, M and Katouah, HA and Altamimi, ASA and Al-Abbasi, FA and Alshehri, S and Soni, K and Ibrahim, IAA and Rahman, M and Beg, S}, title = {Systematic development of lectin conjugated microspheres for nose-to-brain delivery of rivastigmine for the treatment of Alzheimer's disease.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {141}, number = {}, pages = {111829}, doi = {10.1016/j.biopha.2021.111829}, pmid = {34147904}, issn = {1950-6007}, mesh = {Adhesiveness ; Administration, Intranasal ; Alzheimer Disease/*drug therapy ; Animals ; Brain/metabolism ; Cellulose/analogs &amp; derivatives ; Chitosan ; Cholinesterase Inhibitors/*administration &amp; dosage/pharmacokinetics/*therapeutic use ; Drug Compounding ; Drug Delivery Systems ; Drug Liberation ; Goats ; In Vitro Techniques ; Lectins/*chemistry ; Microspheres ; Nasal Mucosa/metabolism ; Particle Size ; Rivastigmine/*administration &amp; dosage/pharmacokinetics/*therapeutic use ; }, abstract = {The current study focuses on development of nasal mucoadhesive microspheres for nose-to-brain delivery of rivastigmine for Alzheimer treatment. A systematic development was employed for optimization of the formulation and process parameters influential on the quality attributes of the microspheres. The risk assessment study revealed major influence of the polymer concentration (ethylcellulose: chitosan), the concentration of surfactant solution (polyvinyl alcohol), and stirring speed as the critical factors for optimization of the microspheres. These factors were systematically optimized using Box-Behnken design and microspheres were evaluated for the particle size, entrapment efficiency, and in vitro drug release as the response variables. The optimized microspheres containing 4.4% wt/vol polymers, 1% wt/vol surfactant, and stirring speed at 1500 rpm showed particle size of 19.9 µm, entrapment efficiency of 77.8%, and drug release parameters as T80% of 7.3 h. The surface modification of microspheres was performed with lectin by carbodiimide activation reaction and confirmed by difference in surface charge before and after chemical functionalization by zeta potential measurement which was found to be - 25.7 mV and 20.5 mV, respectively. Ex vivo study for bioadhesion strength evaluation on goat nasal mucosa indicated a significant difference (p < 0.001) between the plain (29%) and lectin functionalized microspheres (64%). In vivo behavioral and biochemical studies in the rats treated with lectin functionalized microspheres showed markedly better memory-retention vis-à-vis test and pure drug solution treated rats (p < 0.001). In a nutshell, the present studies showed successful development of nasal microspheres for enhanced brain delivery of rivastigmine for Alzheimer's treatment.}, }
@article {pmid34144624, year = {2021}, author = {Brandt, MD}, title = {[Insomnia in the context of neurological diseases].}, journal = {Fortschritte der Neurologie-Psychiatrie}, volume = {89}, number = {6}, pages = {314-328}, doi = {10.1055/a-1309-0793}, pmid = {34144624}, issn = {1439-3522}, mesh = {Humans ; *Nervous System Diseases/complications/epidemiology/therapy ; Quality of Life ; *Restless Legs Syndrome ; *Sleep Initiation and Maintenance Disorders/complications/epidemiology/therapy ; *Sleep Wake Disorders/epidemiology/therapy ; }, abstract = {This article provides an overview of the prevalence, cause and treatment of insomnia in common neurological diseases (restless legs syndrome, stroke, multiple sclerosis, Parkinson´s disease and Alzheimer´s disease) with an additional focus on the bidirectional relationship between sleep and neurological disorders.Insomnia is prevalent, but frequently unrecognized in the context of neurological diseases. Although it is widely known that sleep has a relevant impact on quality of life in general and cerebral function in particular, sleep disorders receive little attention in the prevention and treatment of neurological diseases.}, }
@article {pmid34144146, year = {2021}, author = {Yang, EJ and Kim, H and Choi, Y and Kim, HJ and Kim, JH and Yoon, J and Seo, YS and Kim, HS}, title = {Modulation of Neuroinflammation by Low-Dose Radiation Therapy in an Animal Model of Alzheimer's Disease.}, journal = {International journal of radiation oncology, biology, physics}, volume = {111}, number = {3}, pages = {658-670}, doi = {10.1016/j.ijrobp.2021.06.012}, pmid = {34144146}, issn = {1879-355X}, mesh = {*Alzheimer Disease/radiotherapy ; Amyloid beta-Peptides ; Animals ; *Cognitive Dysfunction ; Cytokines ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Neuroinflammatory Diseases ; }, abstract = {PURPOSE: Recently, several studies have reported that low-dose radiation therapy (RT) suppresses the release of proinflammatory cytokines in inflammatory-degenerative disorders, including Alzheimer disease (AD). AD is the most common cause of dementia, and neuroinflammation is one of the major contributing factors in AD pathogenesis. Therefore, low-dose RT may be used clinically for treating AD. However, the appropriate doses, effects, and underlying mechanisms of RT in AD have not been determined. In this study, we aimed to determine the appropriate RT dose and schedule for AD treatment and to investigate the therapeutic effects and mechanisms of low-dose RT in AD.<br><br>METHODS AND MATERIALS: We first determined the proper dose and schedule for RT in late-stage AD using 8- to 9-month-old 5x Familial AD (5xFAD) mice, a well-known animal model of AD, by comparing the effects of a low total dose with low dose per fraction (LD-LDRT, 5 × 0.6 Gy) with those of a low moderate total dose with conventional dose per fraction (LMD-CDRT, 5 × 2 Gy).<br><br>RESULTS: LD-LDRT and LMD-CDRT were found to reduce the levels of the proinflammatory cytokines CD54, IL-3, CXCL9/10, and CCL2/4 in the hippocampus of 5xFAD mice. Furthermore, increased microgliosis assessed using Iba-1 and CD68 dual immunostaining was significantly reduced by LD-LDRT and LMD-CDRT in the hippocampus of 5xFAD mice. Moreover, LD-LDRT and LMD-CDRT decreased the amyloid plaque burden in the hippocampus of 5xFAD mice and attenuated their cognitive impairment; these effects persisted for 4 to 5 weeks.<br><br>CONCLUSIONS: The present study showed that LD-LDRT alleviates cognitive impairments and prevents the accumulation of amyloid plaques by regulating neuroinflammation in the late stage of AD in 5xFAD mice, with an efficacy equivalent to that of LMD-CDRT. Furthermore, the findings suggest that compared with LMD-CDRT, LD-LDRT may facilitate accessible and convenient treatment in clinical trials.}, }
@article {pmid34140407, year = {2021}, author = {Doyle, JJ and Maios, C and Vrancx, C and Duhaime, S and Chitramuthu, B and Bennett, HPJ and Bateman, A and Parker, JA}, title = {Chemical and genetic rescue of in vivo progranulin-deficient lysosomal and autophagic defects.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {118}, number = {25}, pages = {}, pmid = {34140407}, issn = {1091-6490}, support = {P40 OD010440/OD/NIH HHS/United States ; }, mesh = {Acetophenones/pharmacology ; Animals ; Autophagy/*genetics ; Benzopyrans/pharmacology ; Biosynthetic Pathways ; Caenorhabditis elegans/cytology/*genetics ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Drug Evaluation, Preclinical ; Frontotemporal Dementia/genetics/pathology ; Lysosomes/*genetics ; Mutation/genetics ; Phenotype ; Progranulins/genetics/*metabolism ; Rivastigmine/pharmacology ; Small Molecule Libraries/pharmacology ; Sphingolipids/metabolism ; }, abstract = {In 2006, GRN mutations were first linked to frontotemporal dementia (FTD), the leading cause of non-Alzheimer dementias. While much research has been dedicated to understanding the genetic causes of the disease, our understanding of the mechanistic impacts of GRN deficiency has only recently begun to take shape. With no known cure or treatment available for GRN-related FTD, there is a growing need to rapidly advance genetic and/or small-molecule therapeutics for this disease. This issue is complicated by the fact that, while lysosomal dysfunction seems to be a key driver of pathology, the mechanisms linking a loss of GRN to a pathogenic state remain unclear. In our attempt to address these key issues, we have turned to the nematode, Caenorhabditis elegans, to model, study, and find potential therapies for GRN-deficient FTD. First, we show that the loss of the nematode GRN ortholog, pgrn-1, results in several behavioral and molecular defects, including lysosomal dysfunction and defects in autophagic flux. Our investigations implicate the sphingolipid metabolic pathway in the regulation of many of the in vivo defects associated with pgrn-1 loss. Finally, we utilized these nematodes as an in vivo tool for high-throughput drug screening and identified two small molecules with potential therapeutic applications against GRN/pgrn-1 deficiency. These compounds reverse the biochemical, cellular, and functional phenotypes of GRN deficiency. Together, our results open avenues for mechanistic and therapeutic research into the outcomes of GRN-related neurodegeneration, both genetic and molecular.}, }
@article {pmid34138642, year = {2021}, author = {Alexander, GC and Karlawish, J}, title = {The Problem of Aducanumab for the Treatment of Alzheimer Disease.}, journal = {Annals of internal medicine}, volume = {174}, number = {9}, pages = {1303-1304}, doi = {10.7326/M21-2603}, pmid = {34138642}, issn = {1539-3704}, mesh = {Alzheimer Disease/*drug therapy ; Antibodies, Monoclonal, Humanized/*therapeutic use ; *Drug Approval ; Humans ; United States ; United States Food and Drug Administration ; }, }
@article {pmid34133789, year = {2022}, author = {Pei, X and Hu, F and Luo, F and Huang, X and Li, X and Xing, S and Long, D}, title = {The neuroprotective effects of alpha-lipoic acid on an experimental model of Alzheimer's disease in PC12 cells.}, journal = {Journal of applied toxicology : JAT}, volume = {42}, number = {2}, pages = {285-294}, doi = {10.1002/jat.4213}, pmid = {34133789}, issn = {1099-1263}, mesh = {Alzheimer Disease/*drug therapy ; Amyloid beta-Peptides/*adverse effects ; Animals ; Disease Models, Animal ; Neuroprotective Agents/*pharmacology ; PC12 Cells ; Rats ; Thioctic Acid/*pharmacology ; }, abstract = {With the growth of the aging population, the prevalence of Alzheimer's disease (AD) has increased and influenced the work and daily life of AD patients, imposing a heavy burden on society and the patients' families. AD is a progressive disease with a long duration, and the pathogenesis is very complicated. Here, we found that alpha-lipoic acid (LA), an endogenous, naturally synthesized compound, could attenuate amyloid beta fragment (Aβ25-35)-induced PC12 cell toxicity. Aβ25-35 treatment largely decreased the viability of PC12 cells, increased reactive oxygen species (ROS) levels, and increased the percentage of apoptotic cells, which were accompanied by changes in the expression of the apoptosis-related genes. Further, the Wnt pathway was inactivated, and the expression of Wnt pathway-related proteins such as Frizzled2, GSK3β, and phosphorylated GSK3β were dysregulated after Aβ25-35 treatment. LA efficiently attenuated Aβ25-35 -induced PC12 cell apoptosis and downregulated the phosphorylation-mediated degradation of β-catenin as well as GSK3β. Our results demonstrate that LA rescues Aβ25-35 -induced neurocytotoxicity through the Wnt-β-catenin pathway.}, }
@article {pmid34133088, year = {2021}, author = {Burke, AD and Apostolova, L}, title = {Treatment Challenges and the Hope of Emerging Therapies in Early-Stage Alzheimer Disease.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {4}, pages = {}, doi = {10.4088/JCP.BG20044AH4C}, pmid = {34133088}, issn = {1555-2101}, abstract = {Alzheimer disease (AD), the most common cause of dementia, is a degenerative brain disease with no cure. In the United States alone, an estimated 5.8 million people are living with AD. More than half of individuals living with AD and other dementias are not getting an accurate diagnosis and, when they do receive one, clinicians are not effectively communicating with patients and care partners regarding the illness and next steps. Additionally, prompt treatment initiation does not occur in a substantial number of newly diagnosed patients. This Academic Highlights addresses best practices for identifying patients with early-stage AD, discussing treatment goals and challenges with patients who have AD and their care partners, employing current medications approved by the U.S. Food and Drug Administration to slow symptom progression, and staying informed about emerging therapies that offer new hope for disease modification.}, }
@article {pmid34129637, year = {2021}, author = {Triunfol, M and Gouveia, FC}, title = {What's not in the news headlines or titles of Alzheimer disease articles? #InMice.}, journal = {PLoS biology}, volume = {19}, number = {6}, pages = {e3001260}, pmid = {34129637}, issn = {1545-7885}, mesh = {Alzheimer Disease/*pathology ; Animals ; Humans ; Mice, Transgenic ; Newspapers as Topic ; Publications ; Social Media ; }, abstract = {There is increasing scrutiny around how science is communicated to the public. For instance, a Twitter account @justsaysinmice (with 70.4K followers in January 2021) was created to call attention to news headlines that omit that mice, not humans, are the ones for whom the study findings apply. This is the case of many headlines reporting on Alzheimer disease (AD) research. AD is characterized by a degeneration of the human brain, loss of cognition, and behavioral changes, for which no treatment is available. Around 200 rodent models have been developed to study AD, even though AD is an exclusively human condition that does not occur naturally in other species and appears impervious to reproduction in artificial animal models, an information not always disclosed. It is not known what prompts writers of news stories to either omit or acknowledge, in the story's headlines, that the study was done in mice and not in humans. Here, we raised the hypothesis that how science is reported by scientists plays a role on the news reporting. To test this hypothesis, we investigated whether an association exists between articles' titles and news' headlines regarding the omission, or not, of mice. To this end, we analyzed a sample of 623 open-access scientific papers indexed in PubMed in 2018 and 2019 that used mice either as models or as the biological source for experimental studies in AD research. We found a significant association (p < 0.01) between articles' titles and news stories' headlines, revealing that when authors omit the species in the paper's title, writers of news stories tend to follow suit. We also found that papers not mentioning mice in their titles are more newsworthy and significantly more tweeted than papers that do. Our study shows that science reporting may affect media reporting and asks for changes in the way we report about findings obtained with animal models used to study human diseases.}, }
@article {pmid34119804, year = {2021}, author = {Montazeri, K and Farhadi, M and Fekrazad, R and Akbarnejad, Z and Chaibakhsh, S and Mahmoudian, S}, title = {Transcranial photobiomodulation in the management of brain disorders.}, journal = {Journal of photochemistry and photobiology. B, Biology}, volume = {221}, number = {}, pages = {112207}, doi = {10.1016/j.jphotobiol.2021.112207}, pmid = {34119804}, issn = {1873-2682}, mesh = {Alzheimer Disease/radiotherapy ; Animals ; Brain Diseases/*radiotherapy ; Brain Injuries, Traumatic/radiotherapy ; Disease Models, Animal ; Humans ; *Low-Level Light Therapy ; Parkinson Disease/radiotherapy ; Randomized Controlled Trials as Topic ; }, abstract = {Transcranial photobiomodulation (tPBM) is the process of delivering light photons through the skull to benefit from its modifying effect. Brain disorders are important health problems. The aim of this review was to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Parkinson, and Alzheimer's disease as the common brain disorders. Four online databases, including Cochrane, Pub Med, Embase, and Google scholar were searched according to the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines. 4728 articles were obtained in the initial search. Only those articles that were published until September 2020 and designed as randomized clinical trials (RCTs) or animal-controlled studies were included. 6 RCTs, 2 related supplementary articles, and 38 controlled animal studies met the inclusion criteria of this study. No RCTs were performed in the fields of Alzheimer's and Parkinson's diseases. The human RCTs and animal studies reported no adverse events resulted from the use of tPBM. Useful parameters of tPBM were identified according to the controlled animal studies. Since the investigated RCTs had no homogenous results, making an evidence-based decision for definite therapeutic application of tPBM is still unattainable. Altogether, these data support the need for large confirmatory well-designed RCTs for using tPBM as a novel, safe, and easy-to-administer treatment of brain disorders.<br><br>EVIDENCE BEFORE THIS STUDY: High prevalence and complications of brain disorders and also side effects of neuropsychiatric medications have encouraged researchers to find alternative therapeutic techniques which tPBM can be one of them. In present review we tried to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Alzheimer, and Parkinson's disease as common brain disorders. Four online databases, including "Cochrane", "Pub Med", "Embase", and "Google scholar" were searched. Only those articles that were published until September 2020 and designed as RCTs or animal-controlled studies were included. Search keywords were the followings: transcranial photobiomodulation" OR "transcranial low-level laser therapy" AND "stroke" OR "traumatic brain injury" OR "Alzheimer" OR "Parkinson". Several studies have confirmed effectiveness of tPBM in treatment of different brain disorders but the level of evidence of its effectiveness remain to be determined.<br><br>ADDED VALUE OF THIS STUDY: In this study we systematically reviewed human RCTs to determine the existing evidence of tPBM effectiveness in management of four mentioned brain disorders. Since the outcomes of the reviewed RCTs were not homogeneous, further well-designed RCTs are required to decide more definitively on the evidence of this noninvasive and probably safe therapeutic intervention. We hypothesized that non-homogeneous outcomes could be due to inefficiency of PBM parameters. Controlled animal studies have the advantage of using objective tests to evaluate the results and compare them with the control group. We determined useful tPBM parameters based on these studies.<br><br>This research is part of our main project of tinnitus treatment using photobiomodulation (PBM). Evidence of central nervous system involvement in tinnitus led us to believe that treatment protocol of tinnitus should also include transcranial PBM. The determined useful parameters can be helpful in designing more efficient tPBM protocols in the management of brain disorders and tinnitus as a common debilitating symptom that can be associated with these disorders.}, }
@article {pmid34116955, year = {2021}, author = {Kim, JI and Zhu, D and Barry, E and Kovac, E and Aboumohamed, A and Agalliu, I and Sankin, A}, title = {Intravesical Bacillus Calmette-Guérin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non-muscle-invasive Bladder Cancer.}, journal = {Clinical genitourinary cancer}, volume = {19}, number = {6}, pages = {e409-e416}, doi = {10.1016/j.clgc.2021.05.001}, pmid = {34116955}, issn = {1938-0682}, mesh = {Adjuvants, Immunologic ; Administration, Intravesical ; *Alzheimer Disease/epidemiology ; BCG Vaccine/therapeutic use ; Female ; Humans ; Male ; Neoplasm Invasiveness ; Neoplasm Recurrence, Local/drug therapy ; Retrospective Studies ; *Urinary Bladder Neoplasms/drug therapy/epidemiology ; }, abstract = {BACKGROUND: The immune system plays an important role in the pathogenesis of Alzheimer disease (AD), but it remains unclear whether bacillus Calmette-Guérin (BCG) may affect the risk of AD or not.<br><br>METHODS: Using retrospective chart review, we collected data regarding demographics, comorbidities, cancer diagnosis, BCG treatment, and subsequent diagnosis of AD or other dementia in a racially/ethnically diverse cohort of patients with non-muscle-invasive bladder cancer (NIMBC) receiving treatment between 1984 and 2020 in the Bronx, New York. We used Cox proportional hazard models to examine association between BCG treatment and risk of incident AD or other dementia, adjusting for age, gender, race/ethnicity, and major comorbidities.<br><br>RESULTS: In our cohort of 1290 patients with NMIBC, a total of 99 (7.7%) patients developed AD or other dementia during follow-up. Patients who received BCG treatment (25%) had a 60% lowered incidence of AD or other dementia (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.80) in comparison to those who did not receive BCG. There was also suggestive evidence that the reduction in risk of AD or other dementia associated with BCG treatment was stronger in men (adjusted HR, 0.34; 95% CI, 0.15-0.81) but not in women (adjusted HR, 0.75; 95% CI 0.25-2.24). When we stratified the patients who received BCG by type of treatments, patients who received both induction and maintenance rounds of BCG had a further lowered incidence of AD or other dementia (HR, 0.23; 95% CI, 0.06-0.96) than patients who did not receive BCG.<br><br>CONCLUSIONS: To our knowledge, our study is one of the first to suggest that BCG treatment is associated with a reduced risk of developing AD or other dementia in a multiethnic population, independent of significant comorbidities. Larger cohort studies are needed to corroborate our findings.}, }
@article {pmid34111056, year = {2021}, author = {Diez-Sepulveda, JC and Uribe-Buritica, FL and Angel-Isaza, AM and Bustamante-Cristancho, LA and Mejia-Herrera, F and Watts-Pajaro, FA and Rojas-Martinez, MF}, title = {An 80-Year-Old Woman with Alzheimer Disease and Accidental Poisoning with Pyrethroid Pesticide Successfully Treated with Intravenous Lipid Emulsion.}, journal = {The American journal of case reports}, volume = {22}, number = {}, pages = {e928420}, pmid = {34111056}, issn = {1941-5923}, mesh = {Aged ; Aged, 80 and over ; *Alzheimer Disease/drug therapy ; *Drug Overdose/drug therapy ; Fat Emulsions, Intravenous/therapeutic use ; Female ; Humans ; *Pesticides ; *Pyrethrins/therapeutic use ; }, abstract = {BACKGROUND Pesticides are commonly used in the agricultural industry. Overdose can be lethal due to its effects generating closure of the voltage-gated sodium channels in the axonal membranes. Most case reports of toxicity refer to skin exposure and there are very few that refer to effects due to its oral intake. CASE REPORT We report the case of an elderly woman with Alzheimer disease who accidentally swallowed 50 g of Lambda Cyhalothrin (GOLPE 5 M E®), a pyrethroid of medium toxicity containing a cyano group. It severely harmed the woman's health, causing severe central nervous system depression and refractory vasodilated shock requiring the use of vasopressors. Its management was challenging, requiring orotracheal intubation, vasopressors, and admission to the Intensive Care Unit (ICU). The emergency care team decided to use intravenous lipid emulsion, which clearly helped with the recovery and successful discharge of the patient. CONCLUSIONS The use of intravenous lipid emulsion for the treatment of pyrethroid poisoning can lead to successful outcomes, as described in this case report.}, }
@article {pmid34106590, year = {2021}, author = {Lee, JY and Kim, JY and Lee, JY and Jung, JH and Jung, IC}, title = {Efficacy of Jihwangeumja (Dihuang Yinzi) on cognitive function and activities of daily living in patients with Alzheimer disease: A protocol for a systematic review and meta-analysis.}, journal = {Medicine}, volume = {100}, number = {19}, pages = {e25592}, pmid = {34106590}, issn = {1536-5964}, support = {HB16C0044//Ministry of Health and Welfare/ ; }, mesh = {Activities of Daily Living ; Alzheimer Disease/*drug therapy/*psychology ; Cognition ; Drugs, Chinese Herbal/*therapeutic use ; Humans ; }, abstract = {BACKGROUND: This systematic review protocol describes the methods proposed to evaluate the efficacy and safety of Jihwangeumja in patients with Alzheimer disease.<br><br>METHODS: The following databases, PubMed, EMBASE, CENTRAL, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, National Digital Science Library, Korean Information Service System, and Korean Medical Database will be searched for relevant publications without language or publication status restrictions. Search terms will be based on "Alzheimer" for participants and "Jihwangeumja" or "Dihuang Yinzi" for interventions. Two researchers will independently extract the study data from the included studies and only randomized controlled trials will be included. The risk of bias will also be assessed independently by 2 researchers using the Cochrane risk of bias tool. We will use RevMan software random-effects and fixed-effect models for the assessment of heterogeneity and data synthesis. Any changes in the plan for documenting significant protocol amendments will require the researchers to have a revision agreement and register the international prospective register of systematic review modification.<br><br>RESULTS: The treatment effect and safety will be measured by meta-analysis and the quality of the included studies will be reviewed.<br><br>CONCLUSION: This systematic review will provide evidence regarding the efficacy and safety of Jihwangeumja.<br><br>ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data will not be included in this paper. The study findings will be disseminated through conference presentations.<br><br>OSF REGISTRATION: DOI: 10.17605/OSF.IO/HXA58.}, }
@article {pmid34103899, year = {2021}, author = {Weng, G and Zhou, B and Liu, T and Huang, Z and Huang, S}, title = {Tetramethylpyrazine Improves Cognitive Function of Alzheimer's Disease Mice by Regulating SSTR4 Ubiquitination.}, journal = {Drug design, development and therapy}, volume = {15}, number = {}, pages = {2385-2399}, pmid = {34103899}, issn = {1177-8881}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Animals ; Cognition/drug effects ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pyrazines/*pharmacology ; Rats ; Receptors, Somatostatin/*antagonists &amp; inhibitors/genetics/metabolism ; Tumor Cells, Cultured ; Ubiquitination/drug effects ; }, abstract = {PURPOSE: Many researches have investigated the functions of tetramethylpyrazine (TMP) in Alzheimer's disease (AD). This study aimed to discuss the underlying mechanism of TMP in AD mice.<br><br>METHODS: TMP (200 mg/kg) was administered to 6-month-old APP/PS1 transgenic mice, and behavioral changes and hippocampal nerve injury in AD mice were detected. Apoptosis and autophagy-related protein levels were detected. Changes in gene expression before and after TMP treatment were compared using transcriptome sequencing. The effects of Cullin 4B (CUL4B) overexpression and somatostatin receptor 4 (SSTR4) silencing on AD symptoms and SSTR4 ubiquitination in APP/PS1 mice were observed. SH-SY5Y and PC12 cells were treated with 25 μmol/L Aβ25-35 and TMP to observe cell viability, apoptosis, and autophagy. Cell viability and apoptosis were measured again after treatment with proteasome inhibitor MG132 or lysosomal inhibitor 3-mA.<br><br>RESULTS: TMP treatment improved the behavioral cognition of APP/PS1 mice and improved the neuronal apoptosis and damage in brain tissue. CUL4B was significantly upregulated in APP/PS1 mouse brain tissue, and SSRT4 protein was downregulated, and the levels of CUL4B and SSRT4 were negatively correlated. TMP treatment downregulated CUL4B, inhibited SSRT4 ubiquitination and upregulated SSRT4 protein level in APP/PS1 mouse brain tissue, while CUL4B overexpression or SSRT4 silencing reversed the effect of TMP. TMP and MG132 improved the decreased activity, increased apoptosis and increased SSRT4 protein in SH-SY5Y and PC12 cells treated with Aβ25-35, but not 3-mA. CUL4B overexpression promoted the ubiquitination of SSTR4 in cells, which partially reversed the effect of TMP.<br><br>CONCLUSION: TMP could improve the cognitive ability of AD mice by inhibiting CUL4B expression and the ubiquitination degradation of SSTR, and alleviating neuronal apoptosis and injury. This study may offer a new therapeutic option for AD treatment.}, }
@article {pmid34099509, year = {2021}, author = {Kikuchi, K and Tatebe, T and Sudo, Y and Yokoyama, M and Kidana, K and Chiu, YW and Takatori, S and Arita, M and Hori, Y and Tomita, T}, title = {GPR120 signaling controls amyloid-β degrading activity of matrix metalloproteinases.}, journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience}, volume = {}, number = {}, pages = {}, pmid = {34099509}, issn = {1529-2401}, support = {P50 AG016574/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; }, abstract = {Alzheimer disease (AD) is characterized by the extensive deposition of amyloid-β peptide (Aβ) in the brain. Brain Aβ level is regulated by a balance between Aβ production and clearance. The clearance rate of Aβ is decreased in the brains of sporadic AD patients, indicating that the dysregulation of Aβ clearance mechanisms affects the pathological process of AD. Astrocytes are among the most abundant cells in the brain and are implicated in the clearance of brain Aβ via their regulation of the blood-brain barrier, glymphatic system, and proteolytic degradation. The cellular morphology and activity of astrocytes are modulated by several molecules, including ω3 polyunsaturated fatty acids, such as docosahexaenoic acid, which is one of the most abundant lipids in the brain, via the G protein-coupled receptor GPR120/FFAR4. In this study, we analyzed the role of GPR120 signaling in the Aβ-degrading activity of astrocytes. Treatment with the selective antagonist upregulated the matrix metalloproteinase (MMP) inhibitor-sensitive Aβ-degrading activity in primary astrocytes. Moreover, the inhibition of GPR120 signaling increased the levels of Mmp2 and Mmp14 mRNAs, and decreased the expression levels of tissue inhibitor of metalloproteinases 3 (Timp3) and Timp4, suggesting that GPR120 negatively regulates the astrocyte-derived MMP network. Finally, the intracerebral injection of GPR120 specific antagonist substantially decreased the levels of Tris-buffered saline-soluble Aβ in male AD model mice, and this effect was canceled by the coinjection of an MMP inhibitor. These data indicate that astrocytic GPR120 signaling negatively regulates the Aβ degrading activity of MMPs.SIGNIFICANT STATEMENTThe level of amyloid β (Aβ) in the brain is a crucial determinant of the development of Alzheimer disease. Here we found that astrocytes, which are the most abundant cell type in the central nervous system, harbors degrading activity against amyloid β, which is regulated by GPR120 signaling. GPR120 is involved in the inflammatory response and obesity in peripheral organs. However, the pathophysiological role of GPR120 in Alzheimer disease remains unknown. We found that selective inhibition of GPR120 signaling in astrocytes increased the Aβ-degrading activity of matrix metalloproteases. Our results suggest that GPR120 in astrocytes is a novel therapeutic target for the development of anti-Aβ therapeutics.}, }
@article {pmid34093032, year = {2021}, author = {Svob Strac, D and Konjevod, M and Sagud, M and Nikolac Perkovic, M and Nedic Erjavec, G and Vuic, B and Simic, G and Vukic, V and Mimica, N and Pivac, N}, title = {Personalizing the Care and Treatment of Alzheimer's Disease: An Overview.}, journal = {Pharmacogenomics and personalized medicine}, volume = {14}, number = {}, pages = {631-653}, pmid = {34093032}, issn = {1178-7066}, abstract = {Alzheimer's disease (AD) is a progressive, complex, and multifactorial neurodegenerative disorder, still without effective and stable therapeutic strategies. Currently, available medications for AD are based on symptomatic therapy, which include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Additionally, medications such as antipsychotic drugs, antidepressants, sedative, and hypnotic agents, and mood stabilizers are used for the management of behavioral and psychological symptoms of dementia (BPSD). Clinical research has been extensively investigated treatments focusing on the hallmark pathology of AD, including the amyloid deposition, tau hyperphosphorylation, neuroinflammation, and vascular changes; however, so far without success, as all new potential drugs failed to show significant clinical benefit. The underlying heterogeneous etiology and diverse symptoms of AD suggest that a precision medicine strategy is required, which would take into account the complex genetic, epigenetic, and environmental landscape of each AD patient. The article provides a comprehensive overview of the literature on AD, the current and potential therapy of both cognitive symptoms as well as BPSD, with a special focus on gut microbiota and epigenetic modifications as new emerging drug targets. Their specific patterns could represent the basis for novel individually tailored approaches aimed to optimize precision medicine strategies for AD prevention and treatment. However, the successful application of precision medicine to AD demands a further extensive research of underlying pathological processes, as well as clinical and biological complexity of this multifactorial neurodegenerative disorder.}, }
@article {pmid34088880, year = {2021}, author = {Grill, JD and Karlawish, J}, title = {Implications of FDA Approval of a First Disease-Modifying Therapy for a Neurodegenerative Disease on the Design of Subsequent Clinical Trials.}, journal = {Neurology}, volume = {97}, number = {10}, pages = {496-500}, pmid = {34088880}, issn = {1526-632X}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; U24 AG057437/AG/NIA NIH HHS/United States ; U54 AG063546/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; UL1 TR001414/TR/NCATS NIH HHS/United States ; }, mesh = {Clinical Trials as Topic/*ethics ; Drug Approval ; Humans ; Neurodegenerative Diseases/*drug therapy ; Placebos ; Research Design ; United States ; United States Food and Drug Administration ; }, abstract = {The goal of clinical research is to improve clinical practice. In progressive neurodegenerative conditions without any disease-slowing therapies, this will result in eventual approval of a first disease-modifying treatment. Clinical trials will still be needed to discover treatments that are more effective, safer, or more convenient. This will generate controversies over how to design these trials; specifically, controversies about the use of a placebo control. We consider ethical guidance for these studies with attention to 3 designs: placebo-controlled trials in the absence of the new drug, placebo-controlled trials with the approved drug as background therapy, and trials with the new drug as an active control. To understand the practical implications of these designs, we examine experiences in drug development in multiple sclerosis. We conclude by contemplating the future of clinical trials in Alzheimer disease.}, }
@article {pmid34088777, year = {2022}, author = {Meier, SR and Sehlin, D and Roshanbin, S and Falk, VL and Saito, T and Saido, TC and Neumann, U and Rokka, J and Eriksson, J and Syvänen, S}, title = {11C-PiB and 124I-Antibody PET Provide Differing Estimates of Brain Amyloid-β After Therapeutic Intervention.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {63}, number = {2}, pages = {302-309}, pmid = {34088777}, issn = {1535-5667}, abstract = {PET imaging of amyloid-β (Aβ) has become an important component of Alzheimer disease diagnosis. 11C-Pittsburgh compound B (11C-PiB) and analogs bind to fibrillar Aβ. However, levels of nonfibrillar, soluble, aggregates of Aβ appear more dynamic during disease progression and more affected by Aβ-reducing treatments. The aim of this study was to compare an antibody-based PET ligand targeting nonfibrillar Aβ with 11C-PiB after β-secretase (BACE-1) inhibition in 2 Alzheimer disease mouse models at an advanced stage of Aβ pathology. Methods: Transgenic ArcSwe mice (16 mo old) were treated with the BACE-1 inhibitor NB-360 for 2 mo, whereas another group was kept as controls. A third group was analyzed at the age of 16 mo as a baseline. Mice were PET-scanned with 11C-PiB to measure Aβ plaque load followed by a scan with the bispecific radioligand 124I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Aβ. The same study design was then applied to another mouse model, AppNL-G-F In this case, NB-360 treatment was initiated at the age of 8 mo and animals were scanned with 11C-PiB-PET and 125I-RmAb158-scFv8D3 SPECT. Brain tissue was isolated after scanning, and Aβ levels were assessed. Results: 124I-RmAb158-scFv8D3 concentrations measured with PET in hippocampus and thalamus of NB-360-treated ArcSwe mice were similar to those observed in baseline animals and significantly lower than concentrations observed in same-age untreated controls. Reduced 125I-RmAb158-scFv8D3 retention was also observed with SPECT in hippocampus, cortex, and cerebellum of NB-360-treated AppNL-G-F mice. Radioligand in vivo concentrations corresponded to postmortem brain tissue analysis of soluble Aβ aggregates. For both models, mice treated with NB-360 did not display a reduced 11C-PiB signal compared with untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11C-PiB signal than the baseline groups. Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aβ levels after anti-Aβ therapy in ArcSwe and AppNL-G-F mice with pronounced Aβ pathology. In contrast, the decreased Aβ levels could not be quantified with 11C-PiB PET, suggesting that these ligands detect different pools of Aβ.}, }
@article {pmid34080526, year = {2021}, author = {Manandhar, S and Priya, K and Mehta, CH and Nayak, UY and Kabekkodu, SP and Pai, KSR}, title = {Repositioning of antidiabetic drugs for Alzheimer's disease: possibility of Wnt signaling modulation by targeting LRP6 an in silico based study.}, journal = {Journal of biomolecular structure &amp; dynamics}, volume = {}, number = {}, pages = {1-15}, doi = {10.1080/07391102.2021.1930583}, pmid = {34080526}, issn = {1538-0254}, abstract = {Alzheimer disease (AD) is the most common, irreversible and progressive form of dementia for which the exact pathology and cause are still not clear. At present, we are only confined to symptomatic treatment, and the lack of disease-modifying therapeutics is worrisome. Alteration of Wnt signaling has been linked to metabolic diseases as well as AD. The crosstalk between Canonical Wnt signaling and insulin signaling pathway has been widely studied and accepted from several clinical and preclinical studies that have proven the beneficial effect of antidiabetic medications in the case of memory and cognition loss. This structure-based in silico study was focused on exploring the link between the currently available FDA approved antidiabetic drugs and the Wnt signaling pathway. The library of antidiabetics was obtained from drug bank and was screened for their binding affinity with protein (PDB ID: 3S2K) LRP6, a coreceptor of the Wnt signaling pathway using GLIDE module of Schrodinger. The top molecules, with higher docking score, binding energy and stable interactions, were subjected to energy-based calculation using MMGBSA, followed by a molecular dynamics-based simulation study. Drugs of class α-glucosidase inhibitors and peroxisome proliferator-activated receptors (PPARs) agonists were found to have a strong affinity towards LRP6 proteins, highlighting the possibility of the modulation of Wnt signaling by antidiabetics as one of the possible mechanisms for use in AD. However, further experimental based in vitro and in vivo studies are warranted for verification and support.Communicated by Ramaswamy H. Sarma.}, }
@article {pmid34080437, year = {2021}, author = {Lu, L and Dai, WZ and Zhu, XC and Ma, T}, title = {Analysis of Serum miRNAs in Alzheimer's Disease.}, journal = {American journal of Alzheimer's disease and other dementias}, volume = {36}, number = {}, pages = {15333175211021712}, doi = {10.1177/15333175211021712}, pmid = {34080437}, issn = {1938-2731}, mesh = {*Alzheimer Disease/genetics ; Gene Expression Profiling ; Gene Regulatory Networks ; Humans ; *MicroRNAs/blood ; Signal Transduction ; }, abstract = {This paper was aimed to analyze the microRNA (miRNA) signatures in Alzheimer disease (AD) and find the significant expressions of miRNAs, their target genes, the functional enrichment analysis of the confirmed genes, and potential drug treatment. The miRNA expression information of the gene expression profile data was downloaded from the Gene Expression Omnibus database. The total data sample size is 1309, including 1021 AD samples and 288 normal samples. A total of 21 differentially expressed miRNAs were obtained, of which 16 (hsa-miR-6761-3p, hsa-miR-6747-3p, hsa-miR-6875-3p, hsa-miR-6754-3p, hsa-miR-6736-3p, hsa-miR-6762-3p, hsa-miR-6787-3p, hsa-miR-208a-5p, hsa-miR-6740-3p, hsa-miR-6778-3p, hsa-miR-595, hsa-miR-6753-3p, hsa-miR-4747-3p, hsa-miR-3646, hsa-miR-6716-3p and hsa-miR-4435) were up-regulated and 5 (hsa-miR-125a-3p, hsa-miR-22-3p, hsa-miR-24-3p, hsa-miR-6131 and hsa-miR-125b-1-3p) were down-regulated in AD. A total of 6 miRNAs (hsa-miR-595, hsa-miR-3646, hsa-miR-4435 hsa-miR-125a-3p, hsa-miR-22-3p and hsa-miR-24-3p) and 78 miRNA-disease-related gene sub-networks were predicted, and 116 ceRNA regulatory relationship pairs, and the ceRNA regulatory network were obtained. The results of enrichment analysis suggested that the main target pathways of several miRNAs differentially expressed in AD were mitogen-activated protein kinase signal pathway. According to the prediction results of Drug-Gene Interaction database 2.0, we obtained 53 pairs of drug-gene interaction, including 7 genes (PTGS2, EGFR, CALM1, PDE4D, FGFR2, HMGCR, cdk6) and 53 drugs. We hope our results are helpful to find a viable way to prevent, delay the onset, diagnose, and treat AD.}, }
@article {pmid34079697, year = {2021}, author = {Guo, XY and Chang, Y and Kim, Y and Rhee, HY and Cho, AR and Park, S and Ryu, CW and San Lee, J and Lee, KM and Shin, W and Park, KC and Kim, EJ and Jahng, GH}, title = {Development and evaluation of a T1 standard brain template for Alzheimer disease.}, journal = {Quantitative imaging in medicine and surgery}, volume = {11}, number = {6}, pages = {2224-2244}, pmid = {34079697}, issn = {2223-4292}, abstract = {BACKGROUND: Patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) have high variability in brain tissue loss, making it difficult to use a disease-specific standard brain template. The objective of this study was to develop an AD-specific three-dimensional (3D) T1 brain tissue template and to evaluate the characteristics of the populations used to form the template.<br><br>METHODS: We obtained 3D T1-weighted images from 294 individuals, including 101 AD, 96 amnestic MCI, and 97 cognitively normal (CN) elderly individuals, and segmented them into different brain tissues to generate AD-specific brain tissue templates. Demographic data and clinical outcome scores were compared between the three groups. Voxel-based analyses and regions-of-interest-based analyses were performed to compare gray matter volume (GMV) and white matter volume (WMV) between the three participant groups and to evaluate the relationship of GMV and WMV loss with age, years of education, and Mini-Mental State Examination (MMSE) scores.<br><br>RESULTS: We created high-resolution AD-specific tissue probability maps (TPMs). In the AD and MCI groups, losses of both GMV and WMV were found with respect to the CN group in the hippocampus (F >44.60, P<0.001). GMV was lower with increasing age in all individuals in the left (r=-0.621, P<0.001) and right (r=-0.632, P<0.001) hippocampi. In the left hippocampus, GMV was positively correlated with years of education in the CN groups (r=0.345, P<0.001) but not in the MCI (r=0.223, P=0.0293) or AD (r=-0.021, P=0.835) groups. WMV of the corpus callosum was not significantly correlated with years of education in any of the three subject groups (r=0.035 and P=0.549 for left, r=0.013 and P=0.821 for right). In all individuals, GMV of the hippocampus was significantly correlated with MMSE scores (left, r=0.710 and P<0.001; right, r=0.680 and P<0.001), while WMV of the corpus callosum showed a weak correlation (left, r=0.142 and P=0.015; right, r=0.123 and P=0.035).<br><br>CONCLUSIONS: A 3D, T1 brain tissue template was created using imaging data from CN, MCI, and AD participants considering the participants' age, sex, and years of education. Our disease-specific template can help evaluate brains to promote early diagnosis of MCI individuals and aid treatment of MCI and AD individuals.}, }
@article {pmid34057082, year = {2021}, author = {Wei, W and Liu, Y and Dai, CL and Baazaoui, N and Tung, YC and Liu, F and Iqbal, K}, title = {Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {82}, number = {2}, pages = {631-646}, pmid = {34057082}, issn = {1875-8908}, mesh = {Adamantane/*analogs &amp; derivatives/pharmacology ; *Alzheimer Disease/genetics/prevention &amp; control/psychology ; Animals ; Cognition/drug effects ; *Cognitive Dysfunction/diagnosis/etiology/prevention &amp; control ; Disease Models, Animal ; Early Medical Intervention/methods ; Maze Learning ; Mice ; Mice, Transgenic ; Nerve Growth Factors/pharmacology ; *Neuronal Plasticity/drug effects/physiology ; Oligopeptides/*pharmacology ; Postpartum Period ; Signal Transduction/drug effects ; Treatment Outcome ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction.<br><br>OBJECTIVE: To explore strategies for early intervention to prevent Alzheimer's disease.<br><br>METHODS: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated.<br><br>RESULTS: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice.<br><br>CONCLUSION: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.}, }
@article {pmid34052296, year = {2021}, author = {Abd El-Fatah, IM and Abdelrazek, HMA and Ibrahim, SM and Abdallah, DM and El-Abhar, HS}, title = {Dimethyl fumarate abridged tauo-/amyloidopathy in a D-Galactose/ovariectomy-induced Alzheimer's-like disease: Modulation of AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, adiponectin/Adipo1R, and NF-κB/IL-1β/ROS trajectories.}, journal = {Neurochemistry international}, volume = {148}, number = {}, pages = {105082}, doi = {10.1016/j.neuint.2021.105082}, pmid = {34052296}, issn = {1872-9754}, mesh = {Adiponectin/genetics ; Alzheimer Disease/chemically induced/*drug therapy ; Amyloidosis/chemically induced/*drug therapy/psychology ; Animals ; Behavior, Animal/drug effects ; Brain-Derived Neurotrophic Factor/drug effects/genetics ; Cyclic AMP Response Element-Binding Protein/drug effects/genetics ; Dimethyl Fumarate/*pharmacology ; Female ; Galactose ; Glycogen Synthase Kinase 3 beta/drug effects/genetics ; Interleukin-1beta/drug effects/genetics ; MAP Kinase Signaling System/drug effects ; NF-kappa B/drug effects ; Neuroprotective Agents/*pharmacology ; Oncogene Protein v-akt/drug effects/genetics ; *Ovariectomy ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; Signal Transduction/*drug effects/*genetics ; Tauopathies/chemically induced/*drug therapy/psychology ; }, abstract = {Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aβ42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1β, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3β, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.}, }
@article {pmid34044035, year = {2021}, author = {Souders, CL and Rushin, A and Sanchez, CL and Toth, D and Adamovsky, O and Martyniuk, CJ}, title = {Mitochondrial and transcriptome responses in rat dopaminergic neuronal cells following exposure to the insecticide fipronil.}, journal = {Neurotoxicology}, volume = {85}, number = {}, pages = {173-185}, doi = {10.1016/j.neuro.2021.05.011}, pmid = {34044035}, issn = {1872-9711}, mesh = {Animals ; Cell Line, Transformed ; Cell Survival/drug effects/physiology ; Dopaminergic Neurons/*drug effects/metabolism ; Dose-Response Relationship, Drug ; Insecticides/*toxicity ; Membrane Potential, Mitochondrial/*drug effects/*physiology ; Mitochondria/*drug effects/metabolism ; Pyrazoles/*toxicity ; Rats ; Transcriptome/*drug effects/physiology ; }, abstract = {The phenylpyrazole fipronil is an insecticide that inhibits γ -amino-butyric acid (GABA) ionotropic receptors in the central nervous system. Experimental evidence suggests that fipronil acts as a neurotoxin and it is implicated in neurodegenerative diseases; however, the mechanisms of neurotoxicity are not fully elucidated. The objective of this study was to quantify mechanisms of fipronil-induced neurotoxicity in dopamine cells. Rat primary immortalized mesencephalic dopaminergic cells (N27) were treated with fipronil (0.25 up to 500 μM depending on the assay). We measured endpoints related to mitochondrial bioenergetics, mitophagy, mitochondrial membrane potential, and ATP production in addition to discerning transcriptome responses to the pesticide. Fipronil reduced cell viability at 500 μM after 24 h exposure and caspase 3/7 activity was significant increased after 6 and 12 h by 250 and 500 μM fipronil. Subsequent endpoints were thus assessed at concentrations that were below cytotoxicity. We measured oxidative respiration of N27 cells following a 24 h exposure to one dose of either 0.25, 2.5, 25, or 50 μM fipronil. Oxygen consumption rates (OCR) were not different between vehicle-control and 0.25 or 2.5 μM fipronil treatments, but there was a ∼40-60 % reduction in basal respiration, as well as reduced oligomycin-induced ATP production at 50 μM. The reduction in OCR is hypothesized to be related to lower mitochondrial mass due to mitophagy. Mitochondrial membrane potential was also sensitive to fipronil, and it was compromised at concentrations of 2.5 μM and above. To further elucidate the mechanisms linked to neurotoxicity, we conducted transcriptomics in dopamine cells following treatment with 25 μM fipronil. Fipronil suppressed transcriptional networks associated with mitochondria (damage, depolarization, permeability, and fission), consistent with its effects on mitochondrial membrane potential. Altered gene networks also included those related to Alzheimer disease, inflammatory disease, nerve fiber degeneration, and neurofibrillary tangles. This study clarifies molecular targets of fipronil-induced neurotoxicity and supports, through multiple lines of evidence, that fipronil acts as a mitochondrial toxicant in dopamine cells. This is relevant to neurodegenerative diseases like Parkinson's disease as exposure to fipronil is associated with the progressive loss of nigrostriatal dopaminergic neurons in rodents.}, }
@article {pmid34036518, year = {2021}, author = {Elfouly, A and Awny, M and Ibrahim, MK and Aboelsaad, M and Tian, J and Sayed, M}, title = {Effects of Long-Acting Testosterone Undecanoate on Behavioral Parameters and Na + , K+-ATPase mRNA Expression in Mice with Alzheimer`s Disease.}, journal = {Neurochemical research}, volume = {46}, number = {9}, pages = {2238-2248}, pmid = {34036518}, issn = {1573-6903}, mesh = {Aluminum Chloride ; Alzheimer Disease/chemically induced/*drug therapy/metabolism ; Animals ; Anxiety/chemically induced/drug therapy/metabolism ; Depression/chemically induced/drug therapy/metabolism ; Galactose ; Gene Expression/drug effects ; Hippocampus/drug effects/metabolism ; Male ; Mice ; Morris Water Maze Test/drug effects ; Neuroprotective Agents/*therapeutic use ; Open Field Test/drug effects ; RNA, Messenger/*metabolism ; Sodium-Potassium-Exchanging ATPase/genetics/*metabolism ; Spatial Memory/drug effects ; Testosterone/*analogs &amp; derivatives/therapeutic use ; }, abstract = {Previous studies have shown that testosterone attenuates stress-induced mood dysfunction and memory deterioration. However, the exact mechanism is still unknown. This study was conducted to investigate the role of long-term testosterone undecanoate on the behavioral responses in AD induced by AlCl3 + D-galactose administration and the possible alteration of the gene expression level of the Na/K ATPase pump. Adult male mice received AlCl3 in drinking water (10 mg/kg/day) and (D-gal 200 mg/kg/day), subcutaneously for 90 consecutive days, then received a single intramuscular (I.M) injection of castor oil (vehicle) on day 91, while treated groups received a single I.M injection of either low (100 mg/kg/45 days) or high dose (500 mg/kg/45 days) respectively of long-acting testosterone undecanoate on day 91. The time spent in the interaction zone during the open field test, preference index to novel objects in the novel object recognition test, spontaneous alternation percentage (SAP) in Y-maze test, and escape latency time in the Morris water maze test were used to measure the locomotor activity, long-term memory, and spatial memory in mice, respectively. The results showed that testosterone undecanoate treatment improved locomotor activity, improved preference to novel objects, improved spatial memory, and reversed anxiety and depression induced by AlCl3 + D-galactose administration in male mice, suggesting the enhancement of behavioral and memory functions brought by testosterone treatment. Moreover, testosterone undecanoate treatment did alter gene expression levels of Na/K ATPase isoforms in the brain hippocampus. In most cases, altered gene expression was significant and correlated with the observed behavioral changes. Taken together, our findings provide new insight into the effects of long-acting testosterone undecanoate administration on locomotor activity, long-term memory, anxiety, and spatial memory in male mice with Alzheimer's disease.}, }
@article {pmid34033708, year = {2021}, author = {Burke, AD}, title = {Can Emerging Therapies Resolve Unmet Needs With Current Treatment in Early-Stage Alzheimer Disease?.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {3}, pages = {}, doi = {10.4088/JCP.BG20044WC3C}, pmid = {34033708}, issn = {1555-2101}, abstract = {While no current medications for Alzheimer disease (AD) can modify the disease, the agents do slow symptom progression. The earlier the medications are started for patients diagnosed with AD, the greater the potential benefit. Clinical trials are in progress on drugs with a variety of mechanisms that may modulate the disease course: neuronal protection; protein synthesis or aggregation inhibition; immunologic priming with antibodies; vaccines; and secretase inhibition. Early diagnosis, whether in the primary care setting or the specialty setting, continues to be critical to give patients their best chance at managing their illness. Although current treatments cannot give patients back what they have already lost, in the near future, drugs may be able to slow or even halt their cognitive and functional decline if clinicians identify AD early enough in the disease process.}, }
@article {pmid34032549, year = {2021}, author = {Kandil, LS and Farid, RM and ElGamal, SS and Hanafy, AS}, title = {Intranasal galantamine/chitosan complex nanoparticles elicit neuroprotection potentials in rat brains via antioxidant effect.}, journal = {Drug development and industrial pharmacy}, volume = {47}, number = {5}, pages = {735-740}, doi = {10.1080/03639045.2021.1934861}, pmid = {34032549}, issn = {1520-5762}, mesh = {Administration, Intranasal ; Animals ; Antioxidants ; *Chitosan ; Galantamine ; Male ; *Nanoparticles ; Neuroprotection ; Oxidative Stress ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Alzheimer's disease is a common cause of dementia in the elderly. Galantamine hydrobromide (GH) is an anti-Alzheimer cholinesterase inhibitor that has an intrinsic antioxidant effect. In a previous study, GH was complexed with chitosan to prepare intranasal GH/chitosan complex nanoparticles (CX-NP2). The nanoparticles were located in rat brains 1 h after nasal administration and showed pharmacological superiority to GH nasal solution without showing histopathological toxicity.<br><br>OBJECTIVE: This study aimed to investigate whether the long-term administration of CX-NP2 leads to biochemical toxicity in rat brains compared to GH nasal solution.<br><br>METHODS: CX-NP2 dispersion and GH solution were administrated intranasally to male Wistar rats for 30 days (3 mg/kg/day). Malondialdehyde (MDA), lipid peroxidation marker, glutathione (GSH), superoxide dismutase (SOD) activity and tumor necrosis factor-α (TNF-α) were assessed in the brain extracts in all groups.<br><br>RESULTS: There was statistically insignificant difference between the CX-NP2 and GH nasal solution treated groups in all biochemical toxicity parameters assessed. Interestingly, MDA and TNF-α levels in the CX-NP2-treated group significantly decreased compared to the control group. Also, GSH level and SOD activity were significantly enhanced in CX-NP2 treated group compared to the control group.<br><br>CONCLUSIONS: CX-NP2 did not induce a statistically significant oxidative stress or neuroinflammation in rat brains after 30-day treatment, they rather elicited neuroprotective potentials.HighlightsIntranasal GH/chitosan complex nanoparticles (CX-NP2) show promising potential as a brain targeting carrier.Compared to GH nasal solution, nasal CX-NP2 formulation did not exert oxidative stress nor neuroinflammation when administered for 30 days.}, }
@article {pmid34025423, year = {2021}, author = {Gáspár, A and Hutka, B and Ernyey, AJ and Tajti, BT and Varga, BT and Zádori, ZS and Gyertyán, I}, title = {Intracerebroventricularly Injected Streptozotocin Exerts Subtle Effects on the Cognitive Performance of Long-Evans Rats.}, journal = {Frontiers in pharmacology}, volume = {12}, number = {}, pages = {662173}, pmid = {34025423}, issn = {1663-9812}, abstract = {Intracerebroventricularly injected streptozotocin (STZ)-induced learning impairment has been an increasingly used rat model of Alzheimer disease. The evoked pathological changes involve many symptoms of the human disease (cognitive decline, increase in β-amyloid and phospho-tau level, amyloid plaque-like deposits). However, the model has predominantly been used with Wistar rats in the literature. The objective of the current study was to transfer it to Long-Evans rats with the ulterior aim to integrate it in a complex cognitive test battery where we use this strain because of its superior cognitive capabilities. We performed two experiments (EXP1, EXP2) with three months old male animals. At EXP1, rats were treated with 2 × 1.5 mg/kg STZ (based on the literature) or citrate buffer vehicle injected bilaterally into the lateral ventricles on days 1 and 3. At EXP2 animals were treated with 3 × 1.5 mg/kg STZ or citrate buffer vehicle injected in the same way as in EXP1 at days 1, 3, and 5. Learning and memory capabilities of the rats were then tested in the following paradigms: five choice serial reaction time test (daily training, started from week 2 or 8 post surgery in Exp1 or Exp2, respectively, and lasting until the end of the experiment); novel object recognition (NOR) test (at week 8 or 14), passive avoidance (at week 11 or 6) and Morris water-maze (at week 14 or 6). 15 or 14 weeks after the STZ treatment animals were sacrificed and brain phospho-tau/tau protein ratio and β -amyloid level were determined by western blot technique. In EXP1 we could not find any significant difference between the treated and the control groups in any of the assays. In EXP2 we found significant impairment in the NOR test and elevated β-amyloid level in the STZ treated group in addition to slower learning of the five-choice paradigm and a trend for increased phospho-tau/tau ratio. Altogether our findings suggest that the Long-Evans strain may be less sensitive to the STZ treatment than the Wistar rats and higher doses may be needed to trigger pathological changes in these animals. The results also highlight the importance of strain diversity in modelling human diseases.}, }
@article {pmid34024838, year = {2021}, author = {Alves, SS and Silva-Junior, RMPD and Servilha-Menezes, G and Homolak, J and Šalković-Petrišić, M and Garcia-Cairasco, N}, title = {Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {82}, number = {1}, pages = {71-105}, doi = {10.3233/JAD-210234}, pmid = {34024838}, issn = {1875-8908}, mesh = {Alzheimer Disease/drug therapy/*genetics/*metabolism ; Amyloid/genetics/metabolism ; Biomarkers ; *Brain/drug effects/metabolism ; Drug Discovery ; Humans ; Insulin Resistance/*physiology ; *Models, Biological ; tau Proteins/genetics/metabolism ; }, abstract = {Almost 115 years ago, Alois Alzheimer described Alzheimer's disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses.}, }
@article {pmid34024231, year = {2021}, author = {Bailus, BJ and Scheeler, SM and Simons, J and Sanchez, MA and Tshilenge, KT and Creus-Muncunill, J and Naphade, S and Lopez-Ramirez, A and Zhang, N and Lakshika Madushani, K and Moroz, S and Loureiro, A and Schreiber, KH and Hausch, F and Kennedy, BK and Ehrlich, ME and Ellerby, LM}, title = {Modulating FKBP5/FKBP51 and autophagy lowers HTT (huntingtin) levels.}, journal = {Autophagy}, volume = {17}, number = {12}, pages = {4119-4140}, pmid = {34024231}, issn = {1554-8635}, support = {R01 NS094422/NS/NINDS NIH HHS/United States ; R01 NS100529/NS/NINDS NIH HHS/United States ; T32 AG000266/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Autophagy/physiology ; Huntingtin Protein/genetics/metabolism ; *Huntington Disease/metabolism ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Mice ; Neurons/metabolism ; Tacrolimus Binding Proteins/metabolism/pharmacology ; }, abstract = {Current disease-modifying therapies for Huntington disease (HD) focus on lowering mutant HTT (huntingtin; mHTT) levels, and the immunosuppressant drug rapamycin is an intriguing therapeutic for aging and neurological disorders. Rapamycin interacts with FKBP1A/FKBP12 and FKBP5/FKBP51, inhibiting the MTORC1 complex and increasing cellular clearance mechanisms. Whether the levels of FKBP (FK506 binding protein) family members are altered in HD models and if these proteins are potential therapeutic targets for HD have not been investigated. Here, we found levels of FKBP5 are significantly reduced in HD R6/2 and zQ175 mouse models and human HD isogenic neural stem cells and medium spiny neurons derived from induced pluripotent stem cells. Moreover, FKBP5 interacts and colocalizes with HTT in the striatum and cortex of zQ175 mice and controls. Importantly, when we decreased FKBP5 levels or activity by genetic or pharmacological approaches, we observed reduced levels of mHTT in our isogenic human HD stem cell model. Decreasing FKBP5 levels by siRNA or pharmacological inhibition increased LC3-II levels and macroautophagic/autophagic flux, suggesting autophagic cellular clearance mechanisms are responsible for mHTT lowering. Unlike rapamycin, the effect of pharmacological inhibition with SAFit2, an inhibitor of FKBP5, is MTOR independent. Further, in vivo treatment for 2 weeks with SAFit2, results in reduced HTT levels in both HD R6/2 and zQ175 mouse models. Our studies establish FKBP5 as a protein involved in the pathogenesis of HD and identify FKBP5 as a potential therapeutic target for HD.Abbreviations : ACTB/β-actin: actin beta; AD: Alzheimer disease; BafA1: bafilomycin A1; BCA: bicinchoninic acid; BBB: blood brain barrier; BSA: bovine serum albumin; CoIP: co-immunoprecipitation; DMSO: dimethyl sulfoxide; DTT: dithiothreitol; FKBPs: FK506 binding proteins; HD: Huntington disease; HTT: huntingtin; iPSC: induced pluripotent stem cells; MAP1LC3/LC3:microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MES: 2-ethanesulfonic acid; MOPS: 3-(N-morphorlino)propanesulfonic acid); MSN: medium spiny neurons; mHTT: mutant huntingtin; MTOR: mechanistic target of rapamycin kinase; NSC: neural stem cells; ON: overnight; PD: Parkinson disease; PPIase: peptidyl-prolyl cis/trans-isomerases; polyQ: polyglutamine; PPP1R1B/DARPP-32: protein phosphatase 1 regulatory inhibitor subunit 1B; PTSD: post-traumatic stress disorder; RT: room temperature; SQSTM1/p62: sequestosome 1; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TBST:Tris-buffered saline, 0.1% Tween 20; TUBA: tubulin; ULK1: unc-51 like autophagy activating kinase 1; VCL: vinculin; WT: littermate controls.}, }
@article {pmid34023120, year = {2021}, author = {Richards, K and Britt, KC and Cuellar, N and Wang, Y and Morrison, J}, title = {Clinical Decision-Making: Restless Legs Syndrome and Dementia in Older Adults.}, journal = {The Nursing clinics of North America}, volume = {56}, number = {2}, pages = {265-274}, doi = {10.1016/j.cnur.2021.02.005}, pmid = {34023120}, issn = {1558-1357}, mesh = {Aged ; Aged, 80 and over ; *Decision Making ; Dementia/*complications/epidemiology/psychology ; Female ; Humans ; Male ; Restless Legs Syndrome/epidemiology/*etiology/psychology ; Sleep Wake Disorders/epidemiology/etiology/psychology ; Surveys and Questionnaires ; }, abstract = {Restless legs syndrome (RLS), one of the more prevalent sleep disturbances among older adults, impacts quality of life. Patients with dementia are at high risk for developing RLS and may be unable to describe their symptoms. Often underdiagnosed, RLS can contribute to discomfort, pain, nighttime agitation, disturbed sleep, and falls. Clinical assessment is crucial and should include a thorough evaluation with input from the patient and family, deprescribing medication if possible, and consideration of common sleep-disturbing factors. Evidence-based treatment in this population is limited; overall focus should center on relieving discomfort while identifying and treating bothersome sleep symptoms.}, }
@article {pmid34018966, year = {2021}, author = {McMurray, J and Levy, A and Holyoke, P}, title = {Psychometric Evaluation and Workflow Integration Study of a Tablet-Based Tool to Detect Mild Cognitive Impairment in Older Adults: Protocol for a Mixed Methods Study.}, journal = {JMIR research protocols}, volume = {10}, number = {5}, pages = {e25520}, pmid = {34018966}, issn = {1929-0748}, abstract = {BACKGROUND: With the rapid aging of the global population, experts anticipate a surge in the prevalence of mild cognitive impairment (MCI) and dementia worldwide. It is argued that developing more sensitive, easy to administer, and valid MCI screening tools for use in primary care settings may initiate timely clinical and personal care planning and treatment, enabling early access to programs and services. Including functional competence measures in screening tests makes them more ecologically valid and may help to identify cognitive deficits at an earlier stage.<br><br>OBJECTIVE: We aim to conduct a preliminary evaluative study comparing the sensitivity, specificity, and reliability of the BrainFx Screen (referred to as SCREEN hereafter), a novel digital tool designed to assess functional competence and detect early signs of cognitive impairment, with the Quick Mild Cognitive Impairment, a validated and highly sensitive tool that detects MCI in the older adult population. We will also investigate the perceived usefulness and integration of the SCREEN into primary care practice to identify demonstrable impacts on clinical workflow and health care providers' (HCP) perceptions of its success as a screening tool. Patients' perceptions of completing the SCREEN and its impact on their quality of life will also be explored.<br><br>METHODS: This study has a concurrent, mixed methods, prospective, and quasi-experimental design. Participants will be recruited from 5 primary care family health teams (FHTs; defined by multidisciplinary practice and capitated funding) across southwestern Ontario, Canada. Participants will include HCPs, patients, care partners, and FHT administrative executives. Patients 55 years and older with no history of diagnoses for MCI, dementia, or Alzheimer disease rostered in one of the FHTs participating in the study will be eligible to participate. Their care partners will help triangulate the qualitative data collected from patients. Participating FHTs will identify an occupational therapist from their site to participate in the study; this HCP will both administer the research protocol and participate in semistructured in-depth interviews and questionnaires. Principal component analysis will be conducted on the SCREEN data to understand the test components better. Tests comparing sensitivity, specificity, and test-retest reliability will assess the validity of SCREEN as a screening tool for MCI.<br><br>RESULTS: This paper describes the study protocol and its activities to date. Data collection was halted early because of COVID-19 restrictions on research activity, and data analysis is currently in progress.<br><br>CONCLUSIONS: At the end of the project, we anticipate having an initial comparative evaluation of the SCREEN as a tool for early detection of MCI in primary care older adult patient populations. Resource constraints on this research study limit our ability to conduct a randomized controlled trial; however, the results will assist developers of the SCREEN in determining whether rigorous controlled testing is warranted.<br><br>DERR1-10.2196/25520.}, }
@article {pmid34004093, year = {2021}, author = {Goldfarb, D}, title = {Advances in Diagnosis of Alzheimer Disease and Emerging Treatment Targets.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {3}, pages = {}, doi = {10.4088/JCP.LI19012AS1C}, pmid = {34004093}, issn = {1555-2101}, abstract = {Until recently, the diagnosis of Alzheimer disease (AD) could not be truly made until an autopsy was done. Patients' diagnosis relied on clinicians' skills to recognize signs and symptoms of AD, and the diagnosis was often incorrect. The rate of misdiagnosis was higher in earlier disease stages when symptoms are milder. Researchers have made great strides over the past 2 decades in identifying diagnostic biomarkers and treatment targets. Can AD now be diagnosed before patients show symptoms? What do potential treatments look like? This CME presentation highlights exciting developments.}, }
@article {pmid34004089, year = {2021}, author = {Burke, AD and Apostolova, L}, title = {Talking With Patients and Care Partners About Treatment Goals and Challenges in Early-Stage Alzheimer Disease.}, journal = {The Journal of clinical psychiatry}, volume = {82}, number = {3}, pages = {}, doi = {10.4088/JCP.BG20044WC2C}, pmid = {34004089}, issn = {1555-2101}, abstract = {Alzheimer disease (AD) requires timely diagnosis and treatment initiation as early as possible to delay further loss of functioning. Clinicians must attempt to answer patients' and care partners' questions about treatment goals and expected challenges. In this webcast, Drs Burke and Apostolova address topics critical to the care of patients with early-stage AD. They highlight barriers to diagnosis, describe genetic risk factors, and emphasize the role of neuropsychologic testing. Drs Burke and Apostolova agree that, although current medications slow symptom progression associated with AD, emerging therapies offer hope for disease modification. These experts also talk about important conversations to have with patients and their care partners, such as about diet, exercise, driving, and plans for the later stage of illness.}, }
@article {pmid33991495, year = {2021}, author = {Ahmadi, N and Hosseini, MJ and Rostamizadeh, K and Anoush, M}, title = {Investigation of therapeutic effect of curcumin α and β glucoside anomers against Alzheimer's disease by the nose to brain drug delivery.}, journal = {Brain research}, volume = {1766}, number = {}, pages = {147517}, doi = {10.1016/j.brainres.2021.147517}, pmid = {33991495}, issn = {1872-6240}, mesh = {Administration, Intranasal ; Alzheimer Disease/*drug therapy/metabolism ; Animals ; Brain/*drug effects/metabolism ; Curcumin/*administration &amp; dosage/chemical synthesis ; Drug Combinations ; Drug Delivery Systems/*methods ; Glucosides/*administration &amp; dosage/chemical synthesis ; Male ; Maze Learning/drug effects/physiology ; Rats ; Rats, Wistar ; }, abstract = {Alzheimer's disease (AD) is one of the greatest geriatric medicinal challenges of our century and is the main disease leading to dementia. Despite extensive scientific research advances, available disease-modifying treatment strategies remained limited; thus, increasing demand for new drugs. In recent years, medicinal plants attracted attention due to their potential role in dementia. In the present study, α and β anomers of curcumin glucosides (CGs) were synthesized and evaluated for Alzheimer's treatment. CGs were synthesized by fusion reaction as a novel and easy method with more advantages (high yield, short reaction time, and low chemicals), and the products were characterized using HNMR. Wistar male rats were used to administer different treatments. They divided into control, sham, Alzheimer, and test groups (Alzheimer + α anomer and Alzheimer + β anomer). Animals received normal saline, Scopolamine (1 mg/kg), high dose anomers, scopolamine, and two doses (12.5 and 25 mg/kg) of anomers, respectively, for 10 days. Then the Morris Water Maze (MWM) test was performed on all animals. Finally, the animals' brains were extracted and homogenized for glutathione, acetylcholine esterase activity, protein carbonyl, and lipid peroxide level detection. The escape latency and the distance towards the hidden platform in Morris water maze in the Alzheimer group were significantly higher than both the control and test groups. Besides, there were no significant differences between sham and control groups in all tests. Both anomers led to a significant increase in glutathione, and acetylcholine levels while they caused a decrease in lipid peroxidation and protein carbonyl levels in brain tissue. It seems that intranasal administration of both anomers positively influenced maze learning in scopolamine receiving subjects. Although both anomers resulted in similar biochemistry tests, a higher dose of β anomer indicated better results than α anomer not only in behavioral tests but also in biochemical tests.}, }
@article {pmid33977953, year = {2021}, author = {Li, J and Wang, T and Liu, P and Yang, F and Wang, X and Zheng, W and Sun, W}, title = {Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD.}, journal = {Food &amp; function}, volume = {12}, number = {9}, pages = {3898-3918}, doi = {10.1039/d0fo02736g}, pmid = {33977953}, issn = {2042-650X}, mesh = {Animals ; Antioxidant Response Elements ; Diet, High-Fat/*adverse effects ; Hep G2 Cells ; Hepatocytes/*drug effects/metabolism ; Hesperidin/*pharmacology ; Humans ; Interleukin-6/metabolism ; Lipid Metabolism/drug effects ; Liver/drug effects/*metabolism/pathology ; Liver Cirrhosis/pathology ; Male ; NF-E2-Related Factor 2/metabolism ; Non-alcoholic Fatty Liver Disease/etiology/*metabolism/pathology ; Oleic Acid/pharmacology ; Oxidative Stress/*drug effects ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Rats, Wistar ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Transcription Factor RelA/metabolism ; Transcriptional Activation ; Tumor Necrosis Factor-alpha/metabolism ; }, abstract = {Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Dietary supplementation has become a promising strategy for managing NAFLD. Hesperetin, a citrus flavonoid, is mainly found in citrus fruits (oranges, grapefruit, and lemons) and possesses multiple pharmacological properties, including anti-cancer, anti-Alzheimer and anti-diabetic effects. However, the anti-NAFLD effect and mechanisms of hesperetin remain unclear. In this study, we investigated the therapeutic effect of hesperetin against NAFLD and the underlying mechanism in vitro and in vivo. In oleic acid (OA)-induced HepG2 cells, hesperetin upregulated antioxidant levels (SOD/GPx/GR/GCLC/HO-1) by triggering the PI3 K/AKT-Nrf2 pathway, alleviating OA-induced reactive oxygen species (ROS) overproduction and hepatotoxicity. Furthermore, hesperetin suppressed NF-κB activation and reduced inflammatory cytokine secretion (TNF-α and IL-6). More importantly, we revealed that this anti-inflammatory effect is attributed to reduced ROS overproduction by the Nrf2 pathway, as pre-treatment with Nrf2 siRNA or an inhibitor of superoxide dismutase (SOD) or/and glutathione peroxidase (GPx) abolished hesperetin-induced NF-κB inactivation and reductions in inflammatory cytokine secretion. In a rat model of high-fat diet (HFD)-induced NAFLD, we confirmed that hesperetin relieved hepatic steatosis, oxidative stress, inflammatory cell infiltration and fibrosis. Moreover, hesperetin activated the PI3 K/AKT-Nrf2 pathway in the liver, increasing antioxidant expression and inhibiting NF-κB activation and inflammatory cytokine secretion. In summary, our results demonstrate that hesperetin ameliorates hepatic oxidative stress through the PI3 K/AKT-Nrf2 pathway and that this antioxidative effect further suppresses NF-κB-mediated inflammation during NAFLD progression. Thus, our study suggests that hesperetin may be an effective dietary supplement for improving NAFLD by suppressing hepatic oxidative stress and inflammation.}, }
@article {pmid33977683, year = {2021}, author = {Samandari-Bahraseman, MR and Elyasi, L}, title = {Apelin-13 protects human neuroblastoma SH-SY5Y cells against amyloid-beta induced neurotoxicity: Involvement of anti oxidant and anti apoptotic properties.}, journal = {Journal of basic and clinical physiology and pharmacology}, volume = {}, number = {}, pages = {}, doi = {10.1515/jbcpp-2020-0294}, pmid = {33977683}, issn = {2191-0286}, abstract = {OBJECTIVES: We investigated the effect of apelin-13 on the cellular model of AD, amyloid-β (Aβ) treated SH-SY5Y cells in rats.<br><br>METHODS: The SH-SY5Y cells were pretreated with different doses of apelin-13 (1, 2.5, 5, and 10 μg/mL), half an hour before adding 50% Aβ treatment. After 24 h, cells were evaluated for survival, oxidative stress, mitochondrial calcium release, caspase-3, and cytochrome c levels, compared to control group (beta-actin). Statistical analysis was performed by SPSS 16.<br><br>RESULTS: Apelin-13 at the dose of 2.5 μg/mL protected against IC50 Aβ (p<0.001). Apelin-13 at doses of 1, 2.5, and 5 μg/mL showed protective effects against the reactive oxygen species (ROS) produced by Aβ (p<0.001). Apelin-13 at doses of 2.5 and 5 μg/mL reduced calcium release, caspase-3, and cytochrome c (all p<0.001).<br><br>CONCLUSIONS: Apelin-13 prevented apoptosis, oxidative stress, and mitochondrial toxicity and can be a suitable option for treatment of AD. The appropriate treatment strategy for humans has to be investigated in future studies.}, }
@article {pmid33970919, year = {2021}, author = {Stojanovic, F and Taktek, M and Khieu, NH and Huang, J and Jiang, S and Rennie, K and Chakravarthy, B and Costain, WJ and Cuperlovic-Culf, M}, title = {NMR analysis of the correlation of metabolic changes in blood and cerebrospinal fluid in Alzheimer model male and female mice.}, journal = {PloS one}, volume = {16}, number = {5}, pages = {e0250568}, pmid = {33970919}, issn = {1932-6203}, mesh = {Alzheimer Disease/blood/cerebrospinal fluid/*pathology ; Amyloid beta-Protein Precursor/*genetics ; Animals ; Biomarkers/blood/cerebrospinal fluid ; Cerebrospinal Fluid/*metabolism ; Disease Models, Animal ; Female ; Magnetic Resonance Spectroscopy/*methods ; Male ; *Metabolome ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Presenilin-1/*genetics ; Serum/*metabolism ; }, abstract = {The development of effective therapies as well as early, molecular diagnosis of Alzheimer's disease is impeded by the lack of understanding of the underlying pathological mechanisms. Metabolomics studies of body fluids as well as brain tissues have shown major changes in metabolic profiles of Alzheimer's patients. However, with analysis performed at the late stages of the disease it is not possible to distinguish causes and consequence. The mouse model APP/PS1 expresses a mutant amyloid precursor protein resulting in early Amyloid β (Aβ) accumulation as well as many resulting physiological changes including changes in metabolic profile and metabolism. Analysis of metabolic profile of cerebrospinal fluid (CSF) and blood of APP/PS1 mouse model can provide information about metabolic changes in these body fluids caused by Aβ accumulation. Using our novel method for analysis of correlation and mathematical ranking of significant correlations between metabolites in CSF and blood, we have explored changes in metabolite correlation and connectedness in APP/PS1 and wild type mice. Metabolites concentration and correlation changes in CSF, blood and across the blood brain barrier determined in this work are affected by the production of amyloid plaque. Metabolite changes observed in the APP/PS1 mouse model are the response to the mutation causing plaque formation, not the cause for the plaque suggesting that they are less relevant in the context of early treatment and prevention then the metabolic changes observed only in humans.}, }
@article {pmid33968600, year = {2021}, author = {Gürdere, MB and Budak, Y and Kocyigit, UM and Taslimi, P and Tüzün, B and Ceylan, M}, title = {ADME properties, bioactivity and molecular docking studies of 4-amino-chalcone derivatives: new analogues for the treatment of Alzheimer, glaucoma and epileptic diseases.}, journal = {In silico pharmacology}, volume = {9}, number = {1}, pages = {34}, pmid = {33968600}, issn = {2193-9616}, abstract = {In this study, in vitro inhibition effects of (E)-1-(4-aminophenyl)-3-(aryl) prop-2-en-1-one (4-amino-chalcones) derivatives (3a-o) on acetylcholinesterase (AChE) enzyme and human erythrocyte carbonic anhydrase I and II isoenzymes (hCA I- II) were investigated. And also, the biological activities of 4-amino-chalcone derivatives against enzymes which names are acetylcholinesterase (PDB ID: 1OCE), human Carbonic Anhydrase I (PDB ID: 2CAB), human carbonic anhydrase II (PDB ID: 3DC3), were compared. After the results obtained, ADME/T analysis was performed in order to use 4-amino-chalcone derivatives as a drug in the future. Effective inhibitors of carbonic anhydrase I and II isozymes (hCAI and II) and acetylcholinesterase (AChE) enzymes with Ki values in the range of 2.55 ± 0.35-11.75 ± 3.57 nM for hCA I, 4.31 ± 0.78-17.55 ± 5.86 nM for hCA II and 96.01 ± 25.34-1411.41 ± 32.88 nM for AChE, respectively, were the 4-amino-chalcone derivatives (3a-o) molecules.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00094-x.}, }
@article {pmid33964436, year = {2021}, author = {Huang, Y and Huang, W and Yang, G and Wang, R and Ma, L}, title = {Design and synthesis of novel diosgenin-triazole hybrids targeting inflammation as potential neuroprotective agents.}, journal = {Bioorganic &amp; medicinal chemistry letters}, volume = {43}, number = {}, pages = {128092}, doi = {10.1016/j.bmcl.2021.128092}, pmid = {33964436}, issn = {1464-3405}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Animals ; Cell Line ; Diosgenin/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; *Drug Design ; Inflammation/*drug therapy/metabolism ; Lipopolysaccharides/antagonists &amp; inhibitors/pharmacology ; Molecular Conformation ; Neuroprotective Agents/chemical synthesis/chemistry/*pharmacology ; Nitric Oxide/antagonists &amp; inhibitors/biosynthesis ; Rats ; Structure-Activity Relationship ; Triazoles/chemistry/*pharmacology ; }, abstract = {Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase as the global population ages. Recent studies provide increasing evidence that inflammation plays a key role in the pathogenesis and progression of AD. Diosgenin, an active ingredient in Dioscorea nipponica Makino, is a promising bioactive lead compound in the treatment of Alzheimer's disease, which exhibited anti-inflammatory activity. To search for more efficient anti-Alzheimer agents, a series of novel diosgenin-triazolyl hybrids were designed, synthesized, and their neuroprotective effects against oxygen-glucose deprivation-induced neurotoxicity and LPS-induced NO production were evaluated. Most of these new hybrids displayed better activities than DIO. In particular, the promising compound L6 not only demonstrated an excellent neuroprotective effect but also showed the best anti-inflammatory activity. The structure-activity relationship study illustrated that the introduction of benzyl or phenyl triazole did improve the activity, and the introduction of benzyl triazole was better than that of phenyl triazole. The results we obtained showed that the diosgenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates, and compound L6 has the potential to be an important lead compound for further research.}, }
@article {pmid33962665, year = {2021}, author = {Berres, M and Monsch, AU and Spiegel, R}, title = {Using historical data to facilitate clinical prevention trials in Alzheimer disease? An analysis of longitudinal MCI (mild cognitive impairment) data sets.}, journal = {Alzheimer's research &amp; therapy}, volume = {13}, number = {1}, pages = {97}, pmid = {33962665}, issn = {1758-9193}, mesh = {*Alzheimer Disease/drug therapy ; *Cognitive Dysfunction ; Cohort Studies ; Disease Progression ; Germany ; Humans ; Neuropsychological Tests ; Placebos ; Randomized Controlled Trials as Topic ; Switzerland ; }, abstract = {BACKGROUND: The Placebo Group Simulation Approach (PGSA) aims at partially replacing randomized placebo-controlled trials (RPCTs), making use of data from historical control groups in order to decrease the needed number of study participants exposed to lengthy placebo treatment. PGSA algorithms to create virtual control groups were originally derived from mild cognitive impairment (MCI) data of the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. To produce more generalizable algorithms, we aimed to compile five different MCI databases in a heuristic manner to create a "standard control algorithm" for use in future clinical trials.<br><br>METHODS: We compared data from two North American cohort studies (n=395 and 4328, respectively), one company-sponsored international clinical drug trial (n=831) and two convenience patient samples, one from Germany (n=726), and one from Switzerland (n=1558).<br><br>RESULTS: Despite differences between the five MCI samples regarding inclusion and exclusion criteria, their baseline demographic and cognitive performance data varied less than expected. However, the five samples differed markedly with regard to their subsequent cognitive performance and clinical development: (1) MCI patients from the drug trial did not deteriorate on verbal fluency over 3 years, whereas patients in the other samples did; (2) relatively few patients from the drug trial progressed from MCI to dementia (about 10% after 4 years), in contrast to the other four samples with progression rates over 30%.<br><br>CONCLUSION: Conventional MCI criteria were insufficient to allow for the creation of well-defined and internationally comparable samples of MCI patients. More recently published criteria for MCI or "MCI due to AD" are unlikely to remedy this situation. The Alzheimer scientific community needs to agree on a standard set of neuropsychological tests including appropriate selection criteria to make MCI a scientifically more useful concept. Patient data from different sources would then be comparable, and the scientific merits of algorithm-based study designs such as the PGSA could be properly assessed.}, }
@article {pmid33957376, year = {2021}, author = {Şeker, M and Özbek, Y and Yener, G and Özerdem, MS}, title = {Complexity of EEG Dynamics for Early Diagnosis of Alzheimer's Disease Using Permutation Entropy Neuromarker.}, journal = {Computer methods and programs in biomedicine}, volume = {206}, number = {}, pages = {106116}, doi = {10.1016/j.cmpb.2021.106116}, pmid = {33957376}, issn = {1872-7565}, mesh = {*Alzheimer Disease/diagnosis ; *Cognitive Dysfunction/diagnosis ; Early Diagnosis ; Electroencephalography ; Entropy ; Humans ; }, abstract = {BACKGROUND AND OBJECTIVE: Electroencephalogram (EEG) is one of the most demanded screening tools that investigates the effects of Alzheimer's Disease (AD) on human brain. Identification of AD in early stage gives rise to efficient treatment in dementia. Mild Cognitive Impairment (MCI) is considered as a conversion stage. Reducing EEG complexity can be used as a marker to detect AD. The aim of this study is to develop a 3-way diagnostic classification using EEG complexity in the detection of MCI/AD in clinical practice. This study also investigates the effects of different eyes states, i.e. eyes-open, eyes-closed on classification performance.<br><br>METHODS: EEG recordings from 85 AD, 85 MCI subjects, and 85 Healthy Controls with eyes-open and eyes- closed are analyzed. Permutation Entropy (PE) values are computed from frontal, central, parietal, temporal, and occipital regions for each EEG epoch. Distribution of PE values are visualized to observe discrimination of MCI/AD with HC. Visual investigations are combined with statistical analysis using ANOVA to determine whether groups are significant or not. Multinomial Logistic Regression model is applied to feature sets in order to classify participants individually.<br><br>RESULTS: Distribution of measured PE shows that EEG complexity is lower in AD and higher in HC group. MCI group is observed as an intermediate form due to heterogeneous values. Results from 3-way classification indicate that F1-scores and rates of sensitivity and specificity achieve the highest overall discrimination rates reaching up to 100% for at TP8 for eyes-closed condition; and C3, C4, T8, O2 electrodes for eyes-open condition. Classification of HC from both patient groups is achieved best. Eyes-open state increases discrimination of MCI and AD.<br><br>CONCLUSIONS: This nonlinear EEG methodology study contributes to literature with high discrimination rates for identification of AD. PE is recommended as a practical diagnostic neuro-marker for AD studies. Resting state EEG at eyes-open condition can be more advantageous over eyes-closed EEG recordings for diagnosis of AD.}, }
@article {pmid33953832, year = {2021}, author = {Ikram, M and Jo, MG and Park, TJ and Kim, MW and Khan, I and Jo, MH and Kim, MO}, title = {Oral Administration of Gintonin Protects the Brains of Mice against Aβ-Induced Alzheimer Disease Pathology: Antioxidant and Anti-Inflammatory Effects.}, journal = {Oxidative medicine and cellular longevity}, volume = {2021}, number = {}, pages = {6635552}, pmid = {33953832}, issn = {1942-0994}, mesh = {Administration, Oral ; Alzheimer Disease/*drug therapy/*prevention &amp; control ; Animals ; Anti-Inflammatory Agents/pharmacology/*therapeutic use ; Antioxidants/pharmacology/*therapeutic use ; Disease Models, Animal ; Glycoproteins/*therapeutic use ; Male ; Mice ; Oxidative Stress/*drug effects ; Plant Extracts/pharmacology/*therapeutic use ; }, abstract = {The study was aimed at analyzing the protective effects of gintonin in an amyloid beta- (Aβ-) induced Alzheimer's disease (AD) mouse model. For the development of the Aβ-induced AD mouse model, the amyloid-β (Aβ 1-42) peptide was stereotaxically injected into the brains of mice. Subsequently, gintonin was administered at a dose of 100 mg/kg/day/per oral (p.o) for four weeks daily, and its effects were evaluated by using western blotting, fluorescence analysis of brain sections, biochemical tests, and memory-related behavioral evaluations. To elucidate the effects of gintonin at the mechanistic level, the activation of endogenous antioxidant mechanisms, as well as the activation of astrocytes, microglia, and proinflammatory mediators such as nuclear factor erythroid 2-related factor 2 (NRF-2) and heme oxygenase-1 (HO-1), was evaluated. In addition, microglial cells (BV-2 cells) were used to analyze the effects of gintonin on microglial activation and signaling mechanisms. Collectively, the results suggested that gintonin reduced elevated oxidative stress by improving the expression of NRF-2 and HO-1 and thereby reducing the generation of reactive oxygen species (ROS) and lipid peroxidation (LPO). Moreover, gintonin significantly suppressed activated microglial cells and inflammatory mediators in the brains of Aβ-injected mice. Our findings also indicated improved synaptic and memory functions in the brains of Aβ-injected mice after treatment with gintonin. These results suggest that gintonin may be effective for relieving AD symptoms by regulating oxidative stress and inflammatory processes in a mouse model of AD. Collectively, the findings of this preclinical study highlight and endorse the potential, multitargeted protective effects of gintonin against AD-associated oxidative damage, neuroinflammation, cognitive impairment, and neurodegeneration.}, }
@article {pmid33952652, year = {2021}, author = {Ballarini, T and Melo van Lent, D and Brunner, J and Schröder, A and Wolfsgruber, S and Altenstein, S and Brosseron, F and Buerger, K and Dechent, P and Dobisch, L and Duzel, E and Ertl-Wagner, B and Fliessbach, K and Freiesleben, SD and Frommann, I and Glanz, W and Hauser, D and Haynes, JD and Heneka, MT and Janowitz, D and Kilimann, I and Laske, C and Maier, F and Metzger, CD and Munk, M and Perneczky, R and Peters, O and Priller, J and Ramirez, A and Rauchmann, B and Roy, N and Scheffler, K and Schneider, A and Spottke, A and Spruth, EJ and Teipel, SJ and Vukovich, R and Wiltfang, J and Jessen, F and Wagner, M and , }, title = {Mediterranean Diet, Alzheimer Disease Biomarkers and Brain Atrophy in Old Age.}, journal = {Neurology}, volume = {}, number = {}, pages = {}, pmid = {33952652}, issn = {1526-632X}, abstract = {OBJECTIVE: To determine if following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer's disease (AD), we analyzed cross-sectional data from the German Longitudinal Cognitive Impairment and Dementia Study METHOD: The sample (n=512, mean age: 69.5±5.9 years) included 169 cognitively normal participants and subjects at higher AD risk (53 AD relatives, 209 SCD and 81 MCI). We defined MeDi adherence based on the Food Frequency Questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI and cognitive performance with an extensive neuropsychological battery. AD-related biomarkers (Aβ42/40 ratio, pTau181) in cerebrospinal fluid were assessed in n=226 individuals. We analyzed the associations between MeDi and the outcomes with linear regression models controlling for several covariates. Additionally, we applied hypothesis-driven mediation and moderation analysis.<br><br>RESULTS: Higher MeDi adherence related to larger mediotemporal gray matter volume (p<0.05 FWE corrected), better memory (β±SE = 0.03 ± 0.02; p=0.038), and less amyloid (Aβ42/40 ratio, β±SE = 0.003 ± 0.001; p=0.008) and pTau181 pathology (β±SE = -1.96±0.68; p=0.004). Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations between Aβ42/40 ratio, pTau181 and mediotemporal atrophy. Results were consistent correcting for ApoE-ε4 status.<br><br>CONCLUSION: Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. Importantly, they suggest that these associations might be explained by a decrease of amyloidosis and tau-pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications.}, }
@article {pmid33946559, year = {2021}, author = {Ahmad, SS and Khan, MB and Ahmad, K and Lim, JH and Shaikh, S and Lee, EJ and Choi, I}, title = {Biocomputational Screening of Natural Compounds against Acetylcholinesterase.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {9}, pages = {}, pmid = {33946559}, issn = {1420-3049}, support = {2020R1A6A1A03044512//National Research Foundation of Korea/ ; NRF-2021R1A2C2004177//National Research Foundation of Korea/ ; NRF-2019R1C1C1006542//National Research Foundation of Korea/ ; }, mesh = {Acetylcholinesterase/*chemistry ; Alzheimer Disease/drug therapy ; Binding Sites ; Biological Products/*chemistry/pharmacology ; Cholinesterase Inhibitors/*chemistry/pharmacology ; Computational Biology/*methods ; Databases, Pharmaceutical ; Humans ; *Molecular Docking Simulation ; *Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; }, abstract = {Alzheimer's disease (AD) is the most common form of dementia and is characterized by irreversible and progressive neurodegeneration. Cholinergic dysfunction has been reported in AD, and several cholinesterase inhibitors, including natural compounds and synthetic analogs, have been developed to treat the disease. However, there is currently no treatment for AD, as most drug-like compounds have failed in clinical trials.&amp;nbsp;Acetylcholinesterase (AChE) is the target of most drugs used commercially to treat AD. This work focused on screening natural compounds obtained from the ZINC database (224, 205 compounds) against AChE to identify those possibly capable of enabling the management of AD. Indirubin and dehydroevodiamine were the best potential AChE inhibitors with free binding energies of -10.03 and -9.00 kcal/mol, respectively. The key residue (His447) of the active site of AChE was found to participate in complex interactions with these two molecules. Six H-bonds were involved in the 'indirubin-AChE' interaction and three H-bonds in the 'dehydroevodiamine-AChE' interaction. These compounds were predicted to cross the blood-brain barrier (BBB) and to exhibit high levels of intestinal absorption. Furthermore, 'indirubin-AChE' and 'dehydroevodiamine-AChE' complexes were found to be stable, as determined by root mean square deviation (RMSD) during a 50 ns molecular dynamics simulation study. Based on the free binding energies and stabilities obtained by simulation studies, we recommend that experimental studies be undertaken on indirubin and dehydroevodiamine with a view towards their potential use as treatments for AD.}, }
@article {pmid33935095, year = {2021}, author = {Somaa, F}, title = {A Review of the Application of Hyperbaric Oxygen Therapy in Alzheimer's Disease.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {81}, number = {4}, pages = {1361-1367}, doi = {10.3233/JAD-210157}, pmid = {33935095}, issn = {1875-8908}, mesh = {Alzheimer Disease/*therapy ; Animals ; Humans ; Hyperbaric Oxygenation/*methods ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; }, abstract = {Alzheimer's disease (AD) is considered as the most common cause of dementia in elderly population. While the exact mechanism of AD has not been discovered, hyperbolic oxygen therapy (HBOT) has been proven to be effective in the treatment of this degenerative disease. The objectives of this article are to review the literature available on molecular and physiological mechanisms underlying HBOT and its efficacy in treating AD and to review the effectiveness of HBOT as an alternate treatment intervention in both human and animal models. 391 full text articles were included in the review after literature search between 1980-2021 from two online data base (ScienceDirect and PubMed). The following key words were used: 'hyperbaric oxygen therapy' and 'Alzheimer disease.' Based on the outcomes of clinical and experimental studies, this review advocates the use of HBOT for the treatment of AD. This review explores future directions and recommends further research into a treatment protocol that will maintain long-term cognitive health of AD patients.}, }
@article {pmid33933071, year = {2021}, author = {Balmik, AA and Sonawane, SK and Chinnathambi, S}, title = {The extracellular HDAC6 ZnF UBP domain modulates the actin network and post-translational modifications of Tau.}, journal = {Cell communication and signaling : CCS}, volume = {19}, number = {1}, pages = {49}, pmid = {33933071}, issn = {1478-811X}, support = {MLP029526//Council of Scientific and Industrial Research, India/ ; BT/PR/19562/MED/122/13/2016//Department of Biotechnology from Neuroscience Task Force (Medical Biotechnology-Human Development &amp; Disease Biology (DBT-HDDB)/ ; }, mesh = {Actins/*metabolism ; Animals ; Apolipoproteins E/metabolism ; Apoptosis ; Cell Line ; Cell Nucleus/metabolism ; Down-Regulation ; Extracellular Space/*enzymology ; Glycogen Synthase Kinase 3 beta/metabolism ; Histone Deacetylase 6/*chemistry/*metabolism ; Humans ; Mice ; Microtubule-Organizing Center/metabolism ; Models, Biological ; Neurons/metabolism ; Phosphorylation ; Podosomes/metabolism ; Protein Domains ; *Protein Processing, Post-Translational ; Tubulin/metabolism ; *Zinc Fingers ; tau Proteins/*metabolism ; }, abstract = {BACKGROUND: Microtubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein.<br><br>METHODS: Here, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization.<br><br>RESULTS: HDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3β increases without any change in total GSK-3β level.<br><br>CONCLUSIONS: HDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases. Video abstract.}, }
@article {pmid33920326, year = {2021}, author = {Cruz-Vicente, P and Passarinha, LA and Silvestre, S and Gallardo, E}, title = {Recent Developments in New Therapeutic Agents against Alzheimer and Parkinson Diseases: In-Silico Approaches.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {8}, pages = {}, pmid = {33920326}, issn = {1420-3049}, support = {Centro-01-0145-FEDER-000019-C4-Centro de Competências em Cloud Computing//European Regional Development Fund through the "Programa Operacional Regional do Centro (Centro 2020)-Sistema de Apoio à Investigação Científica e Tecnológica-Programas Integrados de IC&amp;DT (Covilhã)/ ; UIDB/00709/2020//Fundação para a Ciência e a Tecnologia/ ; UIDP/04378/2020//Fundação para a Ciência e a Tecnologia/ ; UIDB/04378/2020//Fundação para a Ciência e a Tecnologia/ ; SFRH/BSAB/150376/2019//Fundação para a Ciência e a Tecnologia/ ; }, mesh = {Acetylcholinesterase/genetics/metabolism ; Alzheimer Disease/*drug therapy/genetics/metabolism/pathology ; Amyloid Precursor Protein Secretases/antagonists &amp; inhibitors/genetics/metabolism ; Antiparkinson Agents/chemical synthesis/*therapeutic use ; Aspartic Acid Endopeptidases/antagonists &amp; inhibitors/genetics/metabolism ; Catechol O-Methyltransferase/genetics/metabolism ; Cholinesterase Inhibitors/chemical synthesis/*therapeutic use ; Clinical Trials as Topic ; Computer Simulation ; Dopamine Agents/chemical synthesis/*therapeutic use ; Drug Design ; Excitatory Amino Acid Antagonists/chemical synthesis/*therapeutic use ; GPI-Linked Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Gene Expression Regulation ; Humans ; Neuroprotective Agents/chemical synthesis/*therapeutic use ; Parkinson Disease/*drug therapy/genetics/metabolism/pathology ; Receptors, N-Methyl-D-Aspartate/antagonists &amp; inhibitors/genetics/metabolism ; Sirtuins/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {Neurodegenerative diseases (ND), including Alzheimer's (AD) and Parkinson's Disease (PD), are becoming increasingly more common and are recognized as a social problem in modern societies. These disorders are characterized by a progressive neurodegeneration and are considered one of the main causes of disability and mortality worldwide. Currently, there is no existing cure for AD nor PD and the clinically used drugs aim only at symptomatic relief, and are not capable of stopping neurodegeneration. Over the last years, several drug candidates reached clinical trials phases, but they were suspended, mainly because of the unsatisfactory pharmacological benefits. Recently, the number of compounds developed using in silico approaches has been increasing at a promising rate, mainly evaluating the affinity for several macromolecular targets and applying filters to exclude compounds with potentially unfavorable pharmacokinetics. Thus, in this review, an overview of the current therapeutics in use for these two ND, the main targets in drug development, and the primary studies published in the last five years that used in silico approaches to design novel drug candidates for AD and PD treatment will be presented. In addition, future perspectives for the treatment of these ND will also be briefly discussed.}, }
@article {pmid33920113, year = {2021}, author = {Whitmore, CA and Boules, MI and Behof, WJ and Haynes, JR and Koktysh, D and Rosenberg, AJ and Tantawy, MN and Pham, W}, title = {Design, Synthesis, and Validation of a Novel [11C]Promethazine PET Probe for Imaging Abeta Using Autoradiography.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {8}, pages = {}, pmid = {33920113}, issn = {1420-3049}, support = {R01 AG061138/AG/NIA NIH HHS/United States ; AG061138/NH/NIH HHS/United States ; }, mesh = {Alzheimer Disease/*diagnosis/diagnostic imaging/pathology ; Animals ; Autoradiography ; Brain/*diagnostic imaging/drug effects ; Humans ; Mice ; Plaque, Amyloid/diagnosis/diagnostic imaging/pathology ; Positron-Emission Tomography ; Promethazine/chemical synthesis/chemistry/*pharmacology ; Radiochemistry ; Radiopharmaceuticals/chemical synthesis/chemistry/*pharmacology ; }, abstract = {Promethazine, an antihistamine drug used in the clinical treatment of nausea, has been demonstrated the ability to bind Abeta in a transgenic mouse model of Alzheimer's disease. However, so far, all of the studies were performed in vitro using extracted tissues. In this work, we report the design and synthesis of a novel [11C]promethazine PET radioligand for future in vivo studies. The [11C]promethazine was isolated by RP-HPLC with radiochemical purity >95% and molar activity of 48 TBq/mmol. The specificity of the probe was demonstrated using human hippocampal tissues via autoradiography.}, }
@article {pmid33916300, year = {2021}, author = {Senol Deniz, FS and Eren, G and Orhan, IE and Sener, B and Ozgen, U and Aldaba, R and Calis, I}, title = {Outlining In Vitro and In Silico Cholinesterase Inhibitory Activity of Twenty-Four Natural Products of Various Chemical Classes: Smilagenin, Kokusaginine, and Methyl Rosmarinate as Emboldening Inhibitors.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {7}, pages = {}, pmid = {33916300}, issn = {1420-3049}, support = {2021//Türkiye Bilimler Akademisi/ ; }, mesh = {Binding Sites ; Biological Products/*chemistry/isolation &amp; purification/*pharmacology ; Cholinesterase Inhibitors/*chemistry/isolation &amp; purification/*pharmacology ; Furans/chemistry/pharmacology ; Inhibitory Concentration 50 ; Molecular Conformation ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Quinolines/chemistry/pharmacology ; Spirostans/chemistry/pharmacology ; Structure-Activity Relationship ; }, abstract = {Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer's disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC50 = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC50 = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC50 values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.}, }
@article {pmid33911901, year = {2021}, author = {Pisa, F and Reinold, J and Lavikainen, P and Koponen, M and Taipale, H and Tanskanen, A and Tiihonen, J and Hartikainen, S and Tolppanen, AM}, title = {Hip Fracture Risk in Antiepileptic Drug Initiators and Non-Initiators with Alzheimer's Disease.}, journal = {Clinical epidemiology}, volume = {13}, number = {}, pages = {295-307}, pmid = {33911901}, issn = {1179-1349}, abstract = {OBJECTIVE: To determine the risk of hip fracture in persons with Alzheimer´s disease (AD) who initiated antiepileptic drugs (AEDs).<br><br>METHODS: In the Medication use and AD (MEDALZ) cohort of 70,719 Finnish community dwellers with clinically verified incident AD diagnosis in 2005-2011, we identified all incident users of AEDs using national Prescription register. AEDs were classified as older (valproate, carbamazepine, clonazepam, phenytoin, levetiracetam, primidone) or newer (pregabalin, gabapentin, oxcarbazepine, lamotrigine, topiramate). We matched each user to 2 non-users. Incident hip fractures until 2015 were identified from the Care register for health care. We calculated inverse probability of treatment weighted hazard ratios (HR), with 95% confidence intervals, using Cox regression.<br><br>RESULTS: Altogether 5522 incident users were identified and matched to 11,044 non-users (in both groups, women: 65%; median age: 81 years). Altogether 53.3% of users initiated with newer AEDs (pregabalin 79.8%, gabapentin 10.2%) while 46.7% initiated with older AEDs (valproate 67.6%, carbamazepine 13.0%). Age- and sex-adjusted IR of hip fracture per 100 person-years was 1.8 (95% CI 1.6-1.9) in non-users and 2.0 (95% CI 1.8-2.2) in users. Increased risk of hip fracture was observed in users (HR 1.17, 95% CI 1.05-1.30) compared with non-users. The risk was higher for short duration of use (<14 weeks, HR 3.64, 95% CI 2.90-4.58) than for medium duration (14 to <64 weeks, HR 1.74, 95% CI 1.48-2.05) or ≥64 weeks' use (HR 1.23, 95% CI 1.08-1.40), compared to non-users with same follow-up time. Older AEDs had HR of 1.46 (1.03-2.08) compared with newer AEDs.<br><br>CONCLUSION: Our results imply that AED use is associated with an increased risk of hip fracture in people with AD. These findings prompt careful consideration before prescribing AEDs to persons with AD. Persons with AD treated with antiepileptics should be carefully monitored due to their increased risk of falling and fractures.}, }
@article {pmid33884656, year = {2022}, author = {Zou, H and Zhou, N and Huang, Y and Luo, A and Sun, J}, title = {Phenotypes, roles, and modulation of regulatory lymphocytes in periodontitis and its associated systemic diseases.}, journal = {Journal of leukocyte biology}, volume = {111}, number = {2}, pages = {451-467}, doi = {10.1002/JLB.3VMR0321-027RRR}, pmid = {33884656}, issn = {1938-3673}, mesh = {Animals ; B-Lymphocytes, Regulatory/*immunology ; Humans ; Metabolic Diseases/immunology/*pathology ; Periodontitis/immunology/*pathology ; Phenotype ; T-Lymphocytes, Regulatory/*immunology ; }, abstract = {Periodontitis is a common chronic inflammatory disease that can result in tooth loss and poses a risk to systemic health. Lymphocytes play important roles in periodontitis through multiple mechanisms. Regulatory lymphocytes including regulatory B cells (Bregs) and T cells (Tregs) are the main immunosuppressive cells that maintain immune homeostasis, and are critical to our understanding of the pathogenesis of periodontitis and the development of effective treatments. In this review, we discuss the phenotypes, roles, and modulating strategies of regulatory lymphocytes including Bregs and Tregs in periodontitis and frequently cooccurring inflammatory diseases such as rheumatoid arthritis, Alzheimer disease, diabetes mellitus, and stroke. The current evidence suggests that restoring immune balance through therapeutic targeting of regulatory lymphocytes is a promising strategy for the treatment of periodontitis and other systemic inflammatory diseases.}, }
@article {pmid33883015, year = {2021}, author = {Marchi, LZ and Ferreira, RGD and de Lima, GNS and da Silva, JAS and da Cruz, DMC and Fernandez-Calvo, B and Andrade, SMMDS}, title = {Multisite transcranial direct current stimulation associated with cognitive training in episodic memory and executive functions in individuals with Alzheimer's disease: a case report.}, journal = {Journal of medical case reports}, volume = {15}, number = {1}, pages = {185}, pmid = {33883015}, issn = {1752-1947}, mesh = {Aged, 80 and over ; Alzheimer Disease/*therapy ; Brazil ; Cognition/*physiology ; Executive Function ; Female ; Humans ; Memory/*physiology ; *Memory, Episodic ; *Transcranial Direct Current Stimulation ; Treatment Outcome ; }, abstract = {BACKGROUND: Dementia is among the most common chronic noncommunicable neurodegenerative diseases. In the long term, it causes disability and loss of autonomy and independence. It is estimated that there are 35.6 million people with Alzheimer's disease worldwide. Several clinical aspects of this disease have been widely studied, but the main focus of study has been memory loss, which is one of the first symptoms. The present study proposes an innovative intervention that combines cognitive training and multisite transcranial direct current stimulation, which interferes with other clinical aspects of the subject.<br><br>CASE PRESENTATION: In this study, we present two subjects diagnosed with mild Alzheimer's disease. Subject 1 is an 82-year-old Brazilian Latin American woman with a high school education who was diagnosed with Alzheimer's disease 8 years ago and uses an Exelon patch. Subject 2 is an 88-year-old Brazilian Latin American woman with an incomplete primary education who was diagnosed with Alzheimer's disease 1 year ago and received medical orientation to temporarily discontinue medications for Alzheimer's disease. Both participants were subjected to intermittent cognitive training sessions and concomitant transcranial stimulation in three weekly 30-minute sessions in which a brain area was stimulated every 10 minutes for a total of 24 sessions, with a 2-month follow-up. Transcranial stimulation was applied to six different regions of the cortex: the dorsolateral prefrontal cortex bilaterally, the somatosensory association cortex bilaterally and Broca's and Wernicke's areas. Comparing the results of tests performed before and after the treatment period, a 1-point improvement was observed for both subjects on the Word Recall task of the Alzheimer Disease Assessment Scale, which evaluates symptoms related to the decline of episodic memory. Improvement in the executive functions domain was also observed through the results of the Stroop test, Victoria version.<br><br>CONCLUSIONS: The results from the two presented cases show that multisite transcranial stimulation associated with cognitive training is an effective adjuvant method for the treatment of patients diagnosed with mild Alzheimer's disease. Its effects can benefit patients' daily routines by reducing cognitive deficits by keeping intact areas active and/or compensating for lost functions. Trial registration NCT02772185. Registered 13 May 2016, http://www.clinicaltrials.gov/ct2/show/NCT02772185 . Retrospectively registered.}, }
@article {pmid33881530, year = {2021}, author = {Lin, CH and Chen, PK and Wang, SH and Lane, HY}, title = {Effect of Sodium Benzoate on Cognitive Function Among Patients With Behavioral and Psychological Symptoms of Dementia: Secondary Analysis of a Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {4}, number = {4}, pages = {e216156}, pmid = {33881530}, issn = {2574-3805}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*drug therapy ; Cognition/*drug effects ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Male ; Sex Factors ; Sodium Benzoate/*administration &amp; dosage ; }, abstract = {Importance: Female gender is a major risk factor for dementia; however, gender has not yet been adequately addressed by clinical trials. A recent study demonstrated that sodium benzoate, a D-amino acid oxidase inhibitor, improved cognitive function in early-phase Alzheimer disease.<br><br>Objective: To examine the potential gender difference in the effects of benzoate treatment on the behavioral and psychological symptoms of dementia (BPSD).<br><br>This post hoc secondary analysis used data from a randomized, double-masked, placebo-controlled trial conducted in 3 major medical centers in Taiwan and enrolled 97 patients with BPSD. Data were analyzed between February 2014 and November 2017.<br><br>Interventions: Six weeks of treatment of 250 to 1500 mg/d of sodium benzoate or placebo.<br><br>Main Outcomes and Measures: The primary outcome measures were Alzheimer disease assessment scale-cognitive subscale (ADAS-cog) and Behavioral Pathology in Alzheimer Disease Rating Scale (BEHAVE-AD) scores.<br><br>Results: Among 97 total participants (62 [64%] women; mean [SD] age, 75.4 [7.7] years), 49 patients (30 women and 19 men) were randomized to sodium benzoate, and 48 (32 women and 16 men) were randomized to placebo. Among 62 women, 6-week benzoate treatment significantly surpassed placebo in the effects on ADAS-cog performance (mean [SD] difference in score between baseline and end point, -3.1 [6.4] points vs 0 [4.5] points; Cohen d = 0.56; P = .04) but not BEHAVE-AD performance. In contrast, among 35 men, the 2 treatment groups did not differ significantly in both ADAS-cog and BEHAVE-AD scores. Compared with placebo, benzoate treatment also increased estradiol to follicle-stimulating hormone ratios among women (mean [SD] difference between baseline and end point, 0 [0.2] vs -0.1 [0.3]; P = .03).<br><br>Conclusions and Relevance: These findings suggest that benzoate treatment may improve cognitive function in women with later-phase dementia. In the future, longer dose-finding trials are warranted to further clarify the efficacy of benzoate for later-phase dementia and investigate the role of sex hormones and other factors in the pathogenesis of dementia.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT02103673.}, }
@article {pmid33872681, year = {2021}, author = {El Gaamouch, F and Liu, K and Lin, HY and Wu, C and Wang, J}, title = {Development of grape polyphenols as multi-targeting strategies for Alzheimer's disease.}, journal = {Neurochemistry international}, volume = {147}, number = {}, pages = {105046}, pmid = {33872681}, issn = {1872-9754}, support = {P50 AT008661/AT/NCCIH NIH HHS/United States ; R03 AG070506/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*drug therapy ; Animals ; Anti-Inflammatory Agents/*therapeutic use ; Antioxidants/*therapeutic use ; Humans ; Neuroprotective Agents/therapeutic use ; Plaque, Amyloid/drug therapy ; Polyphenols/*pharmacology ; }, abstract = {Alzheimer's disease (AD) is by far the most prevalent neurodegenerative disease of aging and is a major burden for patients, caregivers, and the overall health care system. The complexity of AD pathophysiology and the lack of deep understanding of disease mechanisms impeded the development of AD therapy. Currently approved treatments for AD only modestly improve cognitive function but do not modify disease course. The lack of pharmacological approaches has led to the consideration of alternative strategies to prevent or to slow down the progression of AD. There has been a growing interest in the scientific community regarding the impact of diet and nutrition on AD. Grape derived nutraceuticals and phytochemical compounds have demonstrated anti-amyloidogenic, antioxidative, anti-inflammatory and neurotrophic properties and present as potential novel strategies for AD treatment. In this review, we summarize promising grape derived polyphenols that have been shown to modulate AD pathophysiology including amyloid plaques and neurofibrillary tangles formation, AD-induced oxidative stress, neuroinflammation and synaptic dysfunction.}, }
@article {pmid33860663, year = {2021}, author = {K C, S and Kakoty, V and Krishna, KV and Dubey, SK and Chitkara, D and Taliyan, R}, title = {Neuroprotective Efficacy of Co-Encapsulated Rosiglitazone and Vorinostat Nanoparticle on Streptozotocin Induced Mice Model of Alzheimer Disease.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {9}, pages = {1528-1541}, doi = {10.1021/acschemneuro.1c00022}, pmid = {33860663}, issn = {1948-7193}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Mice ; *Nanoparticles ; PPAR gamma ; Rosiglitazone/pharmacology ; Streptozocin ; *Thiazolidinediones/pharmacology ; Vorinostat/pharmacology ; }, abstract = {Anomalies in brain insulin signaling have been demonstrated to be involved in the pathology of Alzheimer disease (AD). In this context, the neuroprotective efficacy of an insulin sensitizer, rosiglitazone, has been confirmed in our previous study. In the present study, we hypothesize that a combination of an epigenetic modulator, vorinostat, along with rosiglitazone can impart improved gene expression of neurotrophic factors and attenuate biochemical and cellular alteration associated with AD mainly by loading these drugs in a surface modified nanocarrier system for enhanced bioavailability and enhanced therapeutic efficacy. Hence, in this study, rosiglitazone and vorinostat were loaded onto a poloxamer stabilized polymeric nanocarrier system and administered to mice in the intracerebroventricular streptozotocin (3 mg/kg) induced model of AD. Treatment with the free drug combination (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) for 3 weeks attenuated the behavioral, biochemical, and cellular alterations as compared to either treatment alone (rosiglitazone 10 mg/kg, vorinostat 50 mg/kg). Further, the coencapsulated nanoformulation (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) exerted better neuroprotective efficacy than the free drug combination as evidenced by improved behavioral outcome, reduced oxidative stress, and elevated levels of neurotrophic factors. In conclusion, the synergistic neuroprotective efficacy of rosiglitazone and vorinostat has been increased through the poloxamer stabilized polymeric nanocarrier system.}, }
@article {pmid33850616, year = {2020}, author = {Zeinivand, M and Nahavandi, A and Baluchnejadmojarad, T and Roghani, M and Golab, F}, title = {Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation.}, journal = {Basic and clinical neuroscience}, volume = {11}, number = {6}, pages = {795-804}, pmid = {33850616}, issn = {2008-126X}, abstract = {INTRODUCTION: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models.<br><br>METHODS: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200-250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6.<br><br>RESULTS: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline.<br><br>CONCLUSION: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes.}, }
@article {pmid33847926, year = {2021}, author = {Grunenwald, A and Roumenina, LT}, title = {The Benefits of Complement Measurements for the Clinical Practice.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2227}, number = {}, pages = {1-20}, pmid = {33847926}, issn = {1940-6029}, mesh = {Alzheimer Disease/diagnosis/immunology/metabolism ; Atypical Hemolytic Uremic Syndrome/diagnosis/immunology/metabolism ; Autoimmune Diseases/diagnosis/immunology/metabolism ; Complement Activation/physiology ; Complement System Proteins/*analysis/metabolism ; Diagnostic Tests, Routine/*methods ; Drug Development ; Graft Rejection/diagnosis/immunology/metabolism ; Humans ; Kidney Diseases/diagnosis/immunology/metabolism ; Macular Degeneration/diagnosis/immunology/metabolism ; Neoplasms/diagnosis/immunology/metabolism ; *Practice Patterns, Physicians' ; }, abstract = {The complement cascade is an evolutionary ancient innate immune defense system, playing a major role in the defense against infections. Its function in maintaining host homeostasis on activated cells has been emphasized by the crucial role of its overactivation in ever growing number of diseases, such as atypical hemolytic uremic syndrome (aHUS), autoimmune diseases as systemic lupus erythematosus (SLE), C3 glomerulopathies (C3GN), age-related macular degeneration (AMD), graft rejection, Alzheimer disease, and cancer, to name just a few. The last decade of research on complement has extended its implication in many pathological processes, offering new insights to potential therapeutic targets and asserting the necessity of reliable, sensitive, specific, accurate, and reproducible biomarkers to decipher complement role in pathology. We need to evaluate accurately which pathway or role should be targeted pharmacologically, and optimize treatment efficacy versus toxicity. This chapter is an introduction to the role of complement in human diseases and the use of complement-related biomarkers in the clinical practice. It is a part of a book intending to give reliable and standardized methods to evaluate complement according to nowadays needs and knowledge.}, }
@article {pmid33845375, year = {2021}, author = {Saviano, A and Casillo, GM and Raucci, F and Pernice, A and Santarcangelo, C and Piccolo, M and Ferraro, MG and Ciccone, M and Sgherbini, A and Pedretti, N and Bonvicini, D and Irace, C and Daglia, M and Mascolo, N and Maione, F}, title = {Supplementation with ribonucleotide-based ingredient (Ribodiet®) lessens oxidative stress, brain inflammation, and amyloid pathology in a murine model of Alzheimer.}, journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie}, volume = {139}, number = {}, pages = {111579}, doi = {10.1016/j.biopha.2021.111579}, pmid = {33845375}, issn = {1950-6007}, mesh = {Alzheimer Disease/*prevention &amp; control/psychology ; Amyloid beta-Peptides ; Animals ; Behavior, Animal/drug effects ; Biomarkers ; Cerebral Amyloid Angiopathy/*prevention &amp; control/psychology ; Diet ; *Dietary Supplements ; Encephalitis/*prevention &amp; control/psychology ; Gliosis/prevention &amp; control ; Injections, Intraventricular ; Male ; Mice ; Nonheme Iron Proteins/metabolism ; Oxidative Stress/*drug effects ; Peptide Fragments ; Psychomotor Performance/drug effects ; Ribonucleotides/pharmacology/*therapeutic use ; }, abstract = {Alzheimer's disease (AD) is the most common type of dementia worldwide, characterized by the deposition of neurofibrillary tangles and amyloid-β (Aβ) peptides in the brain. Additionally, increasing evidence demonstrates that a neuroinflammatory state and oxidative stress, iron-dependent, play a crucial role in the onset and disease progression. Besides conventional therapies, the use of natural-based products represents a future medical option for AD treatment and/or prevention. We, therefore, evaluated the effects of a ribonucleotides-based ingredient (Ribodiet®) in a non-genetic mouse model of AD. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aβ1-42 peptide (3 µg/3 μl) and after with Ribodiet® (0.1-10 mg/mouse) orally (p.o.) 3 times weekly for 21 days following the induction of experimental AD. The mnemonic and cognitive decline was then evaluated, and, successively, we have assessed ex vivo the modulation of different cyto-chemokines on mice brain homogenates. Finally, the level of GFAP, S100β, and iron-related metabolic proteins were monitored as markers of reactive gliosis, neuro-inflammation, and oxidative stress. Results indicate that Ribodiet® lessens oxidative stress, brain inflammation, and amyloid pathology via modulation of iron-related metabolic proteins paving the way for its rationale use for the treatment of AD and other age-related diseases.}, }
@article {pmid33842683, year = {2021}, author = {Müller, P and Vellage, AK and Schmicker, M and Menze, I and Grothe, MJ and Teipel, SJ and Müller, NG}, title = {Structural MRI of the basal forebrain as predictor of cognitive response to galantamine in healthy older adults-A randomized controlled double-blinded crossover study.}, journal = {Alzheimer's &amp; dementia (New York, N. Y.)}, volume = {7}, number = {1}, pages = {e12153}, pmid = {33842683}, issn = {2352-8737}, abstract = {INTRODUCTION: Cholinesterase inhibitors can enhance cognitive functions in healthy elderly and delay cognitive decline in patients with Alzheimer`s disease (AD). However, not everyone benefits from this treatment (non-responders). Current studies show clinical meaningful improvements only in one third of AD patients treated with cholinesterase inhibitors.<br><br>METHODS: Here we investigate structural magnetic resonance imaging of the basal forebrain cholinergic system volume (BFvol) as a potential predictor of cognitive response to a single dose of galantamine in healthy adults (n = 18; 59 to 75 years).<br><br>RESULTS: We observed that the cognitive response to galantamine, more specifically the attention-dependent filtering performance in a delayed match-to-sample working memory task, correlated with BFvol: Only participants with high BFvol showed a significant positive effect of galantamine on the ability to filter out distracting information during the working memory encoding process.<br><br>DISCUSSION: Future studies need to assess whether BFvol may serve as a predictor of the galantamine response in AD patients, too.}, }
@article {pmid33841127, year = {2021}, author = {Duong, MT and Nasrallah, IM and Wolk, DA and Chang, CCY and Chang, TY}, title = {Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {647990}, pmid = {33841127}, issn = {1663-4365}, support = {P30 AG010124/AG/NIA NIH HHS/United States ; R01 AG037609/AG/NIA NIH HHS/United States ; R01 AG063544/AG/NIA NIH HHS/United States ; R21 AG056281/AG/NIA NIH HHS/United States ; }, abstract = {Vascular contributions to cognitive impairment and dementia (VCID) are a common cause of cognitive decline, yet limited therapies exist. This cerebrovascular disease results in neurodegeneration via acute, chronic, local, and systemic mechanisms. The etiology of VCID is complex, with a significant impact from atherosclerosis. Risk factors including hypercholesterolemia and hypertension promote intracranial atherosclerotic disease and carotid artery stenosis (CAS), which disrupt cerebral blood flow and trigger ischemic strokes and VCID. Apolipoprotein E (APOE) is a cholesterol and phospholipid carrier present in plasma and various tissues. APOE is implicated in dyslipidemia and Alzheimer disease (AD); however, its connection with VCID is less understood. Few experimental models for VCID exist, so much of the present information has been drawn from clinical studies. Here, we review the literature with a focus on the clinical aspects of atherosclerotic cerebrovascular disease and build a working model for the pathogenesis of VCID. We describe potential intermediate steps in this model, linking cholesterol, atherosclerosis, and APOE with VCID. APOE4 is a minor isoform of APOE that promotes lipid dyshomeostasis in astrocytes and microglia, leading to chronic neuroinflammation. APOE4 disturbs lipid homeostasis in macrophages and smooth muscle cells, thus exacerbating systemic inflammation and promoting atherosclerotic plaque formation. Additionally, APOE4 may contribute to stromal activation of endothelial cells and pericytes that disturb the blood-brain barrier (BBB). These and other risk factors together lead to chronic inflammation, atherosclerosis, VCID, and neurodegeneration. Finally, we discuss potential cholesterol metabolism based approaches for future VCID treatment.}, }
@article {pmid33841007, year = {2021}, author = {Choi, SH and Lee, NE and Cho, HJ and Lee, RM and Rhim, H and Kim, HC and Han, M and Lee, EH and Park, J and Nah, SY}, title = {Gintonin facilitates brain delivery of donepezil, a therapeutic drug for Alzheimer disease, through lysophosphatidic acid 1/3 and vascular endothelial growth factor receptors.}, journal = {Journal of ginseng research}, volume = {45}, number = {2}, pages = {264-272}, pmid = {33841007}, issn = {1226-8453}, abstract = {BACKGROUND: Gintonin is a ginseng-derived exogenous G-protein-coupled lysophosphatidic acid (LPA) receptor ligand, which exhibits in vitro and in vivo functions against Alzheimer disease (AD) through lysophosphatidic acid 1/3 receptors. A recent study demonstrated that systemic treatment with gintonin enhances paracellular permeability of the blood-brain barrier (BBB) through the LPA1/3 receptor. However, little is known about whether gintonin can enhance brain delivery of donepezil (DPZ) (Aricept), which is a representative cognition-improving drug used in AD clinics. In the present study, we examined whether systemic administration of gintonin can stimulate brain delivery of DPZ.<br><br>METHODS: We administered gintonin and DPZ alone or coadministered gintonin with DPZ intravenously or orally to rats. Then we collected the cerebral spinal fluid (CSF) and serum and determined the DPZ concentration through liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis.<br><br>RESULTS: Intravenous, but not oral, coadministration of gintonin with DPZ increased the CSF concentration of DPZ in a concentration- and time-dependent manner. Gintonin-mediated enhancement of brain delivery of DPZ was blocked by Ki16425, a LPA1/3 receptor antagonist. Coadministration of vascular endothelial growth factor (VEGF) + gintonin with DPZ similarly increased CSF DPZ concentration. However, gintonin-mediated enhancement of brain delivery of DPZ was blocked by axitinip, a VEGF receptor antagonist. Mannitol, a BBB disrupting agent that increases the BBB permeability, enhanced gintonin-mediated enhancement of brain delivery of DPZ.<br><br>CONCLUSIONS: We found that intravenous, but not oral, coadministration of gintonin facilitates brain delivery of DPZ from plasma via LPA1/3 and VEGF receptors. Gintonin is a potential candidate as a ginseng-derived novel agent for the brain delivery of DPZ for treatment of patients with AD.}, }
@article {pmid33838585, year = {2021}, author = {Pasieka, A and Panek, D and Jończyk, J and Godyń, J and Szałaj, N and Latacz, G and Tabor, J and Mezeiova, E and Chantegreil, F and Dias, J and Knez, D and Lu, J and Pi, R and Korabecny, J and Brazzolotto, X and Gobec, S and Höfner, G and Wanner, K and Więckowska, A and Malawska, B}, title = {Discovery of multifunctional anti-Alzheimer's agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters.}, journal = {European journal of medicinal chemistry}, volume = {218}, number = {}, pages = {113397}, doi = {10.1016/j.ejmech.2021.113397}, pmid = {33838585}, issn = {1768-3254}, mesh = {Alzheimer Disease/*drug therapy/metabolism ; Butyrylcholinesterase/*metabolism ; Cholinesterase Inhibitors/chemical synthesis/chemistry/*pharmacology ; Dose-Response Relationship, Drug ; *Drug Discovery ; GABA Plasma Membrane Transport Proteins/*metabolism ; Humans ; Molecular Structure ; Neuroprotective Agents/chemical synthesis/chemistry/*pharmacology ; Structure-Activity Relationship ; }, abstract = {Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50 = 2.86 μM; eqBuChE IC50 = 60 nM; hBuChE IC50 = 20 nM; hBACE1 IC50 = 5.9 μM; inhibition of Aβ aggregation = 57.9% at 10 μM; mGAT1 IC50 = 10.96 μM; and mGAT2 IC50 = 19.05 μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50 = 5.01 μM and IC50 = 2.95 μM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.}, }
@article {pmid33836798, year = {2021}, author = {Leinenga, G and Koh, WK and Götz, J}, title = {A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease.}, journal = {Alzheimer's research &amp; therapy}, volume = {13}, number = {1}, pages = {76}, pmid = {33836798}, issn = {1758-9193}, mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/metabolism ; Animals ; Antibodies, Monoclonal, Humanized ; Brain/diagnostic imaging/metabolism ; Disease Models, Animal ; Mice ; Mice, Transgenic ; *Plaque, Amyloid/drug therapy ; }, abstract = {BACKGROUND: Aducanumab is an anti-amyloid-β (Aβ) antibody that achieved reduced amyloid pathology in Alzheimer's disease (AD) trials; however, it is controversial whether it also improved cognition, which has been suggested would require a sufficiently high cumulative dose of the antibody in the brain. Therapeutic ultrasound, in contrast, has only begun to be investigated in human AD clinical trials. We have previously shown that scanning ultrasound in combination with intravenously injected microbubbles (SUS), which temporarily and safely opens the blood-brain barrier (BBB), removes amyloid and restores cognition in APP23 mice. However, there has been no direct testing of how the effects of SUS compare to immunotherapy or whether a combination therapy is more effective.<br><br>METHODS: In a study comprising four treatment arms, we tested the efficacy of an Aducanumab analog, Adu, both in comparison to SUS, and as a combination therapy, in APP23 mice (aged 13-22 months), using sham as a control. The active place avoidance (APA) test was used to test spatial memory, and histology and ELISA were used to measure amyloid. Brain antibody levels were also determined.<br><br>RESULTS: We found that both Adu and SUS reduced the total plaque area in the hippocampus with no additive effect observed with the combination treatment (SUS + Adu). Whereas in the cortex where there was a trend towards reducing the total plaque area from either Adu or SUS, only the combination treatment yielded a statistically significant decrease in total plaque area compared to sham. Only the SUS and SUS + Adu groups included animals that had their plaque load reduced to below 1% from above 10%. There was a robust improvement in spatial memory for the SUS + Adu group only, and in this group the level of Adu, when measured 3 days post-treatment, was 5-fold higher compared to those mice that received Adu on its own. Together, these findings suggest that SUS should be considered as a treatment option for AD. Alternatively, a combination trial using Aducanumab together with ultrasound to increase brain levels of the antibody may be warranted.}, }
@article {pmid33818056, year = {2021}, author = {Pan, Y and Zhang, Y and Liu, N and Lu, W and Yang, J and Li, Y and Liu, Z and Wei, Y and Lou, Y and Kong, J}, title = {Vitamin D Attenuates Alzheimer-like Pathology Induced by Okadaic Acid.}, journal = {ACS chemical neuroscience}, volume = {12}, number = {8}, pages = {1343-1350}, doi = {10.1021/acschemneuro.0c00812}, pmid = {33818056}, issn = {1948-7193}, mesh = {Aged ; *Alzheimer Disease/chemically induced/drug therapy ; *Cognitive Dysfunction/chemically induced/drug therapy ; Humans ; Okadaic Acid/toxicity ; Phosphorylation ; Vitamin D ; tau Proteins/metabolism ; }, abstract = {Many elderly individuals suffer from Alzheimer's disease (AD), which causes a growing concern. We investigated the mechanism underlying the effects of vitamin D (VD) as a prophylactic treatment. A mouse model of okadaic-acid-induced AD-like pathology was used in vivo and in vitro. Morris water maze and field trials were used to assess cognitive function. The expression levels of VDR, MTHFR, LCMT-1, PP2A, p-TAU (Thr396), and T-TAU and the methylation level of PP2A were measured by Western blotting, and a reversal of the increase in the levels of these proteins in an AD cell model was observed. We used MTHFR-knockdown SH-SY5Y cells to further test the effects of VD, treated these cells with cycloheximide and MG132, and used RT-PCR to explore the mechanism underlying MTHFR targeting. We found that the effects of VD on AD were impaired by MTHFR knockdown through a pretranscriptional mechanism. In addition, VD attenuated AD-induced cognitive impairment and significantly suppressed the expression of TAU. Our findings indicated that VD treatment alleviated TAU accumulation and rescued methylated PP2A by increasing the expression of LCMT-1 and MTHFR.}, }
@article {pmid33816762, year = {2021}, author = {Forcano, L and Fauria, K and Soldevila-Domenech, N and Minguillón, C and Lorenzo, T and Cuenca-Royo, A and Menezes-Cabral, S and Pizarro, N and Boronat, A and Molinuevo, JL and de la Torre, R and , }, title = {Prevention of cognitive decline in subjective cognitive decline APOE ε4 carriers after EGCG and a multimodal intervention (PENSA): Study design.}, journal = {Alzheimer's &amp; dementia (New York, N. Y.)}, volume = {7}, number = {1}, pages = {e12155}, pmid = {33816762}, issn = {2352-8737}, abstract = {INTRODUCTION: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials.<br><br>METHODS: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium.<br><br>DISCUSSION: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions.}, }
@article {pmid33809771, year = {2021}, author = {Queda, F and Calò, S and Gwizdala, K and Magalhães, JD and Cardoso, SM and Chaves, S and Piemontese, L and Santos, MA}, title = {Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {6}, pages = {}, pmid = {33809771}, issn = {1420-3049}, mesh = {Acetylcholinesterase/metabolism ; Alzheimer Disease/*drug therapy/metabolism ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Cholinesterase Inhibitors/pharmacology ; Donepezil/*pharmacology ; Humans ; Ligands ; Piperazines/pharmacology ; Piperidines/pharmacology ; Structure-Activity Relationship ; Sulfonamides/*pharmacology ; }, abstract = {Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.}, }
@article {pmid33801961, year = {2021}, author = {Jain, AP and Sathe, G}, title = {Proteomics Landscape of Alzheimer's Disease.}, journal = {Proteomes}, volume = {9}, number = {1}, pages = {}, pmid = {33801961}, issn = {2227-7382}, abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia, and the numbers of AD patients are expected to increase as human life expectancy improves. Deposition of β-amyloid protein (Aβ) in the extracellular matrix and intracellular neurofibrillary tangles are molecular hallmarks of the disease. Since the precise pathophysiology of AD has not been elucidated yet, effective treatment is not available. Thus, understanding the disease pathology, as well as identification and development of valid biomarkers, is imperative for early diagnosis as well as for monitoring disease progression and therapeutic responses. Keeping this goal in mind several studies using quantitative proteomics platform have been carried out on both clinical specimens including the brain, cerebrospinal fluid (CSF), plasma and on animal models of AD. In this review, we summarize the mass spectrometry (MS)-based proteomics studies on AD and discuss the discovery as well as validation stages in brief to identify candidate biomarkers.}, }
@article {pmid33800891, year = {2021}, author = {Bivona, G and Lo Sasso, B and Gambino, CM and Giglio, RV and Scazzone, C and Agnello, L and Ciaccio, M}, title = {The Role of Vitamin D as a Biomarker in Alzheimer's Disease.}, journal = {Brain sciences}, volume = {11}, number = {3}, pages = {}, pmid = {33800891}, issn = {2076-3425}, abstract = {Vitamin D and cognition is a popular association, which led to a remarkable body of literature data in the past 50 years. The brain can synthesize, catabolize, and receive Vitamin D, which has been proved to regulate many cellular processes in neurons and microglia. Vitamin D helps synaptic plasticity and neurotransmission in dopaminergic neural circuits and exerts anti-inflammatory and neuroprotective activities within the brain by reducing the synthesis of pro-inflammatory cytokines and the oxidative stress load. Further, Vitamin D action in the brain has been related to the clearance of amyloid plaques, which represent a feature of Alzheimer Disease (AD), by the immune cell. Based on these considerations, many studies have investigated the role of circulating Vitamin D levels in patients affected by a cognitive decline to assess Vitamin D's eventual role as a biomarker or a risk factor in AD. An association between low Vitamin D levels and the onset and progression of AD has been reported, and some interventional studies to evaluate the role of Vitamin D in preventing AD onset have been performed. However, many pitfalls affected the studies available, including substantial discrepancies in the methods used and the lack of standardized data. Despite many studies, it remains unclear whether Vitamin D can have a role in cognitive decline and AD. This narrative review aims to answer two key questions: whether Vitamin D can be used as a reliable tool for diagnosing, predicting prognosis and response to treatment in AD patients, and whether it is a modifiable risk factor for preventing AD onset.}, }
@article {pmid33798905, year = {2021}, author = {de Souza, IFF and Dos Santos, TQ and Placido, RV and Mangerona, BA and Carvalho, FC and Boralli, VB and Ruela, ALM and Pereira, GR}, title = {The liquid crystalline phase behaviour of a nasal formulation modifies the brain disposition of donepezil in rats in the treatment of Alzheimer's disease.}, journal = {Colloids and surfaces. B, Biointerfaces}, volume = {203}, number = {}, pages = {111721}, doi = {10.1016/j.colsurfb.2021.111721}, pmid = {33798905}, issn = {1873-4367}, mesh = {*Alzheimer Disease/drug therapy ; Animals ; Brain ; Donepezil ; Liposomes ; Rats ; Rats, Wistar ; }, abstract = {Although nanoparticles, polymeric micelles, liposomes, nanoemulsions, and microemulsions were extensively evaluated as formulations for nasal administration of drugs, lyotropic liquid crystal (LLC) mesophases have been few studied. The phase transition from a low-viscosity microemulsion to a more viscous LLC may improve the mucoadhesion of the formulation. Donepezil is a drug administered orally in the treatment of Alzheimer's disease, and with gastrointestinal side effects that are typical of acetylcholinesterase inhibitors. Based on this, donepezil administration by nasal pathway using a mucoadhesive LLC may be a feasible alternative. A colloidal formulation was selected from a ternary diagram, combining CETETH-10, oleic acid, and water (40:45:15, w/w). Donepezil was incorporated into the formulation, and the characterisation included in vitro studies, such as mucoadhesion and drug release. Pharmacokinetics in Wistar rats included evaluations by the nasal pathway with donepezil incorporated into microemulsion. A phase transition from an isotropic to an anisotropic system was observed after the swelling of the microemulsion with artificial nasal fluid (12-20 %). The release of donepezil in vitro occurred in a sustained manner. Significant levels of donepezil were achieved in the brain after nasal administration of the microemulsion, as a promising strategy for the treatment of Alzheimer's disease.}, }
@article {pmid33796018, year = {2021}, author = {Südkamp, N and Shchyglo, O and Manahan-Vaughan, D}, title = {Absence of Pannexin 1 Stabilizes Hippocampal Excitability After Intracerebral Treatment With Aβ (1-42) and Prevents LTP Deficits in Middle-Aged Mice.}, journal = {Frontiers in aging neuroscience}, volume = {13}, number = {}, pages = {591735}, pmid = {33796018}, issn = {1663-4365}, abstract = {Beta-amyloid protein [Aβ(1-42)] plays an important role in the disease progress and pathophysiology of Alzheimer's disease (AD). Membrane properties and neuronal excitability are altered in the hippocampus of transgenic AD mouse models that overexpress amyloid precursor protein. Although gap junction hemichannels have been implicated in the early pathogenesis of AD, to what extent Pannexin channels contribute to Aβ(1-42)-mediated brain changes is not yet known. In this study we, therefore, investigated the involvement of Pannexin1 (Panx1) channels in Aβ-mediated changes of neuronal membrane properties and long-term potentiation (LTP) in an animal model of AD. We conducted whole-cell patch-clamp recordings in CA1 pyramidal neurons 1 week after intracerebroventricular treatments of adult wildtype (wt) and Panx1 knockout (Panx1-ko) mice with either oligomeric Aβ(1-42), or control peptide. Panx1-ko hippocampi treated with control peptide exhibited increased neuronal excitability compared to wt. In addition, action potential (AP) firing frequency was higher in control Panx1-ko slices compared to wt. Aβ-treatment reduced AP firing frequency in both cohorts. But in Aβ-treated wt mice, spike frequency adaptation was significantly enhanced, when compared to control wt and to Aβ-treated Panx1-ko mice. Assessment of hippocampal LTP revealed deficits in Aβ-treated wt compared to control wt. By contrast, Panx1-ko exhibited LTP that was equivalent to LTP in control ko hippocampi. Taken together, our data show that in the absence of Pannexin1, hippocampi are more resistant to the debilitating effects of oligomeric Aβ. Both Aβ-mediated impairments in spike frequency adaptation and in LTP that occur in wt animals, are ameliorated in Panx1-ko mice. These results suggest that Panx1 contributes to early changes in hippocampal neuronal and synaptic function that are triggered by oligomeric Aβ.}, }
@article {pmid33790404, year = {2021}, author = {Nakamura, Y and Yamamoto, T and Xu, X and Kobayashi, S and Tanaka, S and Tamitani, M and Saito, T and Saido, TC and Yano, M}, title = {Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease.}, journal = {Scientific reports}, volume = {11}, number = {1}, pages = {7289}, pmid = {33790404}, issn = {2045-2322}, mesh = {Alzheimer Disease/genetics/*metabolism/pathology ; Amino Acid Substitution ; Amyloid beta-Protein Precursor/genetics ; Animals ; Calcium/metabolism ; Calmodulin/genetics/*metabolism ; Cells, Cultured ; Dantrolene/pharmacology ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/metabolism ; Protein Binding ; Ryanodine Receptor Calcium Release Channel/*metabolism ; tau Proteins/metabolism ; }, abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from AppNL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.}, }
@article {pmid33771384, year = {2021}, author = {Zhao, J and Li, T and Wang, J}, title = {Association between psoriasis and dementia: A systematic review.}, journal = {Neurologia (Barcelona, Spain)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.nrl.2020.12.007}, pmid = {33771384}, issn = {2173-5808}, abstract = {INTRODUCTION: Risk factors for dementia include genetic factors, aging, environmental factors, certain diseases, and unhealthy lifestyle; most types of dementia share a common chronic systemic inflammatory phenotype. Psoriasis is also considered to be a chronic systemic inflammatory disease. It has been suggested that psoriasis may also contribute to the risk of dementia. The aim of this study was to systematically review the literature on the association between psoriasis and dementia.<br><br>DEVELOPMENT: Articles were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the PubMed and Web of Science databases to identify articles published in peer-reviewed journals and studying the association between psoriasis and dementia. Studies meeting the inclusion criteria were reviewed. We used the Newcastle-Ottawa Scale to assess the quality of each study. After applying the inclusion and exclusion criteria, we included 8 studies for review, 3 of which were found to present a higher risk of bias. Six of the 8 studies supported the hypothesis that prior diagnosis of psoriasis increases the risk of dementia; one study including only a few cases reported that psoriasis decreased the risk of dementia, and one study including relatively young patients found no significant association between psoriasis and the risk of dementia.<br><br>CONCLUSION: Most studies included in this review supported the hypothesis that psoriasis constitutes a risk factor for dementia. However, well-designed stratified cohort studies assessing both psoriasis severity and treatment status are still required to determine the real effect of psoriasis on the risk of dementia and its subtypes.}, }
@article {pmid33762220, year = {2021}, author = {Benussi, A and Cantoni, V and Cotelli, MS and Cotelli, M and Brattini, C and Datta, A and Thomas, C and Santarnecchi, E and Pascual-Leone, A and Borroni, B}, title = {Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study.}, journal = {Brain stimulation}, volume = {14}, number = {3}, pages = {531-540}, doi = {10.1016/j.brs.2021.03.007}, pmid = {33762220}, issn = {1876-4754}, mesh = {*Alzheimer Disease/therapy ; Humans ; *Memory, Episodic ; Pilot Projects ; *Transcranial Direct Current Stimulation ; Transcranial Magnetic Stimulation ; }, abstract = {OBJECTIVE: To assess whether exposure to non-invasive brain stimulation with transcranial alternating current stimulation at γ frequency (γ-tACS) applied over Pz (an area overlying the medial parietal cortex and the precuneus) can improve memory and modulate cholinergic transmission in mild cognitive impairment due to Alzheimer's disease (MCI-AD).<br><br>METHODS: In this randomized, double-blind, sham controlled, crossover pilot study, participants were assigned to a single 60 min treatment with exposure to γ-tACS over Pz or sham tACS. Each subject underwent a clinical evaluation including assessment of episodic memory pre- and post-γ-tACS or sham stimulation. Indirect measures of cholinergic transmission evaluated using transcranial magnetic stimulation (TMS) pre- and post-γ-tACS or sham tACS were evaluated.<br><br>RESULTS: Twenty MCI-AD participants completed the study. No tACS-related side effects were observed, and the intervention was well tolerated in all participants. We observed a significant improvement at the Rey auditory verbal learning (RAVL) test total recall (5.7 [95% CI, 4.0 to 7.4], p < 0.001) and long delayed recall scores (1.3 [95% CI, 0.4 to 2.1], p = 0.007) after γ-tACS but not after sham tACS. Face-name associations scores improved during γ-tACS (4.3 [95% CI, 2.8 to 5.8], p < 0.001) but not after sham tACS. Short latency afferent inhibition, an indirect measure of cholinergic transmission evaluated with TMS, increased only after γ-tACS (0.31 [95% CI, 0.24 to 0.38], p < 0.001) but not after sham tACS.<br><br>CONCLUSIONS: exposure to γ-tACS over Pz showed a significant improvement of memory performances, along with restoration of intracortical connectivity measures of cholinergic neurotransmission, compared to sham tACS.}, }
@article {pmid33754647, year = {2021}, author = {Köylü, A and Altunkaynak, BZ and Delibaş, B}, title = {Effects of tacrolimus on c-fos in hippocampus and memory performances in streptozotocin model of Alzheimer’s disease of rats.}, journal = {Turkish journal of medical sciences}, volume = {51}, number = {4}, pages = {2159-2166}, doi = {10.3906/sag-2008-291}, pmid = {33754647}, issn = {1303-6165}, mesh = {Alzheimer Disease/*drug therapy ; Animals ; Calcineurin ; Calcineurin Inhibitors/*pharmacology ; Disease Models, Animal ; Genes, fos/*drug effects ; Hippocampus/*drug effects ; Immunosuppressive Agents/*pharmacology ; Male ; Maze Learning ; Rats ; Rats, Wistar ; Streptozocin/*toxicity ; Tacrolimus/*pharmacology ; }, abstract = {Background/aim: Calcineurin, an inhibitor of calcium dependent phosphatase is highly presented in a brain of an Alzheimer’s disease. Aging brain gets more sensitive to hyperactivation of calcineurin, and this event causes tau neurofibrillary plaque accumulation, which is one of the outcomes of this disease. The regions of hippocampus are much effected from the results of this process. Our hypothesis is that a calcineurin inhibitor, tacrolimus, could prevent the accumulation and the decrease of the neuronal cells. Therefore, this immunosuppressive drug could be a candidate for an early treatment of Alzheimer disease.<br><br>Materials and methods: Fifteen male Wistar albino rats were divided to three groups; control, Alzheimer, and Alzheimer+Tacrolimus. The Alzheimer group received an injection of streptozotocin intracerebroventricularly for the purpose of modelling the disease via generating free radicals leading a cognitive impairment. Alzheimer+Tacrolimus group first received an oral drug, a calcineurin inhibitor for 10 days afterwards prepared for the model as same as the Alzheimer group received. Finally, all groups performed the Morris water maze test for four days then sacrificed. For the aim of counting neurons in the hippocampus stereological methods, as well as for an evaluation of cellular response to stress in dentate gyrus, a c-Fos immunohistochemistry was performed.<br><br>Results: According to the probe trial of Morris water maze test, the latency time was dramatically higher at both Alzheimer and Alzheimer+Tacrolimus group (p < 0.01). We confirmed these results with our stereology data. The results from stereology technique indicate that there was a neuronal decrease at the hippocampus regions in Alzheimer and Alzheimer+Tacrolimus group. Our outcomes from immunohistochemical data showed a significant increase in the number of c-Fos-positive cells in Alzheimer group when comparing with Alzheimer+Tacrolimus group (p < 0.001).<br><br>Conclusion: There was none preventive effect for neuronal loss in the hippocampus under the effect of tacrolimus drug according to stereological results. However, tacrolimus administration may have reduced cellular stress and cell damage.}, }
@article {pmid33749645, year = {2021}, author = {Miranda, A and Montiel, E and Ulrich, H and Paz, C}, title = {Selective Secretase Targeting for Alzheimer's Disease Therapy.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {81}, number = {1}, pages = {1-17}, doi = {10.3233/JAD-201027}, pmid = {33749645}, issn = {1875-8908}, mesh = {Alzheimer Disease/*drug therapy ; Amyloid Precursor Protein Secretases/*antagonists &amp; inhibitors/*metabolism ; Animals ; Humans ; Neuroprotective Agents/*therapeutic use ; }, abstract = {Alzheimer's disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979 Verubecestat, LY2886721, Lanabecestat, LY2811376 and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase activity enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.}, }
@article {pmid33748669, year = {2021}, author = {Van Dyk, K and Zhou, X and Small, BJ and Ahn, J and Zhai, W and Ahles, T and Graham, D and Jacobsen, PB and Jim, H and McDonald, BC and Nudelman Holohan, K and Patel, SK and Rebeck, GW and Root, JC and Saykin, AJ and Cohen, HJ and Mandelblatt, JS and Carroll, JE}, title = {Protective Effects of APOE ε2 Genotype on Cognition in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study.}, journal = {JNCI cancer spectrum}, volume = {5}, number = {2}, pages = {}, pmid = {33748669}, issn = {2515-5091}, support = {P30 AG010133/AG/NIA NIH HHS/United States ; U24 NS095871/NS/NINDS NIH HHS/United States ; R01 LM011360/LM/NLM NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA082709/CA/NCI NIH HHS/United States ; R01 CA129769/CA/NCI NIH HHS/United States ; R01 CA237535/CA/NCI NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; R01 CA172119/CA/NCI NIH HHS/United States ; R01 CA244673/CA/NCI NIH HHS/United States ; K08 CA241337/CA/NCI NIH HHS/United States ; U01 AG057195/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; R01 AG019771/AG/NIA NIH HHS/United States ; R01 AG068193/AG/NIA NIH HHS/United States ; R01 AG067258/AG/NIA NIH HHS/United States ; R35 CA197289/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Apolipoprotein E2/*genetics ; Apolipoprotein E4/genetics ; Attention/physiology ; Breast Neoplasms/*genetics ; *Cancer Survivors ; Case-Control Studies ; Cognition/*physiology ; Cognitive Dysfunction/*genetics ; Executive Function/physiology ; Female ; *Genotype ; Humans ; Learning/physiology ; Memory/physiology ; Middle Aged ; Neuropsychological Tests ; Polymorphism, Genetic ; }, abstract = {Background: Cancer-related cognitive decline (CRCD) has been linked to apolipoprotein E (APOE) gene ε4 polymorphisms. APOE ε4 polymorphisms are also the strongest genetic risk for late-onset Alzheimer disease (AD), whereas ε2 polymorphisms protect against AD. However, the effects of ε2 polymorphisms on CRCD have not been evaluated.<br><br>Methods: We evaluated nonmetastatic breast cancer survivors (n = 427) and matched noncancer controls (n = 407) ages 60-98 years assessed presystemic therapy from August 2010 to December 2017 with annual follow-up to 24 months. Neuropsychological assessment measured attention, processing speed, executive function, and learning and memory. Linear mixed-effects models tested the effects of having an ε2 allele (vs none) on longitudinal cognitive domain z scores by treatment group (chemotherapy with or without hormonal therapy, hormonal therapy, and control) controlling for covariates; participants with ε2/ε4 genotype were excluded. Sensitivity analyses examined effects of other covariates and any ε4 positivity.<br><br>Results: There was an interaction with genotype for attention, processing speed, and executive functioning domain scores (Beta = 0.32, 95% confidence interval = 0.00 to 0.65); the chemotherapy group with an ε2 allele had higher scores at baseline and maintained higher scores over time compared with those without an ε2 allele, and this protective effect was not seen for other groups. There was no effect of ε2 on learning and memory domain scores.<br><br>Conclusions: APOE ε2 polymorphisms may protect against CRCD in older breast cancer survivors receiving chemotherapy. With replication, this information could be useful for survivorship care and informing future studies of possible links to AD and defining mechanisms of protection.}, }
@article {pmid33734170, year = {2021}, author = {Haeckert, J and Brendel, M and Beyer, L and Barthel, H and Sabri, O and Hasan, A and Perneczky, R}, title = {Effective Valproic Acid Treatment in a Patient With Delusional Parasitosis Due to Corticobasal Syndrome and Alzheimer Disease.}, journal = {Journal of clinical psychopharmacology}, volume = {41}, number = {3}, pages = {335-337}, doi = {10.1097/JCP.0000000000001378}, pmid = {33734170}, issn = {1533-712X}, mesh = {Aged ; Alzheimer Disease/complications ; Delusional Parasitosis/*drug therapy/etiology ; Female ; GABA Agents/*administration &amp; dosage ; Humans ; Syndrome ; Treatment Outcome ; Valproic Acid/*administration &amp; dosage ; }, }
@article {pmid33716981, year = {2021}, author = {Duez, H and Pourcet, B}, title = {Nuclear Receptors in the Control of the NLRP3 Inflammasome Pathway.}, journal = {Frontiers in endocrinology}, volume = {12}, number = {}, pages = {630536}, pmid = {33716981}, issn = {1664-2392}, mesh = {Animals ; Humans ; Inflammasomes/*metabolism ; Inflammation/*metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism ; Receptors, Cytoplasmic and Nuclear/*metabolism ; Signal Transduction/physiology ; }, abstract = {The innate immune system is the first line of defense specialized in the clearing of invaders whether foreign elements like microbes or self-elements that accumulate abnormally including cellular debris. Inflammasomes are master regulators of the innate immune system, especially in macrophages, and are key sensors involved in maintaining cellular health in response to cytolytic pathogens or stress signals. Inflammasomes are cytoplasmic complexes typically composed of a sensor molecule such as NOD-Like Receptors (NLRs), an adaptor protein including ASC and an effector protein such as caspase 1. Upon stimulation, inflammasome complex components associate to promote the cleavage of the pro-caspase 1 into active caspase-1 and the subsequent activation of pro-inflammatory cytokines including IL-18 and IL-1β. Deficiency or overactivation of such important sensors leads to critical diseases including Alzheimer diseases, chronic inflammatory diseases, cancers, acute liver diseases, and cardiometabolic diseases. Inflammasomes are tightly controlled by a two-step activation regulatory process consisting in a priming step, which activates the transcription of inflammasome components, and an activation step which leads to the inflammasome complex formation and the subsequent cleavage of pro-IL1 cytokines. Apart from the NF-κB pathway, nuclear receptors have recently been proposed as additional regulators of this pathway. This review will discuss the role of nuclear receptors in the control of the NLRP3 inflammasome and the putative beneficial effect of new modulators of inflammasomes in the treatment of inflammatory diseases including colitis, fulminant hepatitis, cardiac ischemia-reperfusion and brain diseases.}, }
@article {pmid33715884, year = {2021}, author = {Zhan-Qiang, H and Hai-Hua, Q and Chi, Z and Miao, W and Cui, Z and Zi-Yin, L and Jing, H and Yi-Wei, W}, title = {miR-146a aggravates cognitive impairment and Alzheimer disease-like pathology by triggering oxidative stress through MAPK signaling.}, journal = {Neurologia (Barcelona, Spain)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.nrl.2020.12.006}, pmid = {33715884}, issn = {2173-5808}, abstract = {INTRODUCTION: Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ)1-42.<br><br>METHODS: To create a model of AD, SH-SY5Y cells were treated with Aβ1-42 and mice received intracerebroventricular injections of Aβ1-42. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations.<br><br>RESULTS: Aβ1-42-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ1-42, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway.<br><br>CONCLUSIONS: Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.}, }
@article {pmid33715084, year = {2021}, author = {Shamsipour, S and Sharifi, G and Taghian, F}, title = {An 8-Week Administration of Bifidobacterium bifidum and Lactobacillus plantarum Combined with Exercise Training Alleviates Neurotoxicity of Aβ and Spatial Learning via Acetylcholine in Alzheimer Rat Model.}, journal = {Journal of molecular neuroscience : MN}, volume = {71}, number = {7}, pages = {1495-1505}, pmid = {33715084}, issn = {1559-1166}, mesh = {Acetylcholine/*biosynthesis ; Alzheimer Disease/metabolism/*therapy ; Amyloid beta-Peptides/toxicity ; Animals ; *Bifidobacterium bifidum ; Cell Survival ; Disease Models, Animal ; Hippocampus/metabolism ; *Lactobacillus plantarum ; Male ; Memory Disorders/metabolism/*therapy ; Morris Water Maze Test ; Peptide Fragments/toxicity ; *Physical Conditioning, Animal ; Plaque, Amyloid ; *Probiotics ; RNA, Messenger/biosynthesis ; Random Allocation ; Rats ; Rats, Wistar ; *Spatial Learning ; Vascular Endothelial Growth Factor A/biosynthesis/genetics ; }, abstract = {This study aimed to determine the effects of 8 weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training on neurotoxicity of Aβ, spatial learning, acetylcholine (ACH), and vascular endothelial growth factor (VEGF) in Alzheimer rats. Twenty-five Wistar rats were randomly divided into 5 groups (n = 5 in each): (1) healthy control (control), (2) Alzheimer disease (AD), (3) AD with treadmill exercise (AD + Exe), (4) AD with probiotic (combined administration of Bifidobacterium bifidum and Lactobacillus plantarum) treatment (AD + Pro), and (5) AD with treadmill exercise and probiotic treatment (AD + Exe + Pro). AD was induced by intra-cerebroventricular injection of Aβ1-42 peptide. Then, the training groups exercised on treadmill for 8 weeks, 5 days per weeks. The rats were treated daily with probiotic supplements via gavage for 8 weeks. The Morris water maze (MWM) test was administered to measure spatial learning. Then, the animals were sacrificed and Vegf and ACH were analyzed using the qPCR and immunohistochemistry (IHC) methods, respectively. Results showed that the β-amyloid plaques were significantly increased in the brains of the AD group compared with the control group (p < 0.001). The combined use of probiotics and exercise training significantly increased the time spent in the target quadrant after removing the platform, compared with the AD group in the Morris water maze test (p < 0.001). Crystal violet analysis showed that sole (p < 0.01) and combined exercise training and probiotic supplementation (p < 0.001) significantly reduced the number of dead cells in the brains of rats compared with the AD group. AD significantly decreased Vegf mRNA and ACH in the CA1 area of the hippocampus (p < 0.001). However, mono and combined therapy (exercise and probiotics) significantly increased ACH in the rats' brain compared with the AD group. Overall, 8 weeks of an administration of Bifidobacterium bifidum and Lactobacillus plantarum combined with exercise training can improve spatial learning impairment in the AD rats. Exercise and probiotics seem to offer potential benefits to AD patients by upregulating ACH.}, }
@article {pmid33708071, year = {2021}, author = {Sharma, S and Tiarks, G and Haight, J and Bassuk, AG}, title = {Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy.}, journal = {Frontiers in molecular neuroscience}, volume = {14}, number = {}, pages = {612073}, pmid = {33708071}, issn = {1662-5099}, abstract = {Traumatic brain injury (TBI) is a leading cause of death in young adults and a risk factor for acquired epilepsy. Severe TBI, after a period of time, causes numerous neuropsychiatric and neurodegenerative problems with varying comorbidities; and brain homeostasis may never be restored. As a consequence of disrupted equilibrium, neuropathological changes such as circuit remodeling, reorganization of neural networks, changes in structural and functional plasticity, predisposition to synchronized activity, and post-translational modification of synaptic proteins may begin to dominate the brain. These pathological changes, over the course of time, contribute to conditions like Alzheimer disease, dementia, anxiety disorders, and post-traumatic epilepsy (PTE). PTE is one of the most common, devastating complications of TBI; and of those affected by a severe TBI, more than 50% develop PTE. The etiopathology and mechanisms of PTE are either unknown or poorly understood, which makes treatment challenging. Although anti-epileptic drugs (AEDs) are used as preventive strategies to manage TBI, control acute seizures and prevent development of PTE, their efficacy in PTE remains controversial. In this review, we discuss novel mechanisms and risk factors underlying PTE. We also discuss dysfunctions of neurovascular unit, cell-specific neuroinflammatory mediators and immune response factors that are vital for epileptogenesis after TBI. Finally, we describe current and novel treatments and management strategies for preventing PTE.}, }
@article {pmid33704916, year = {2021}, author = {Bigarré, IM and Trombetta, BA and Guo, YJ and Arnold, SE and Carlyle, BC}, title = {IGF2R circular RNA hsa_circ_0131235 expression in the middle temporal cortex is associated with AD pathology.}, journal = {Brain and behavior}, volume = {11}, number = {4}, pages = {e02048}, pmid = {33704916}, issn = {2162-3279}, mesh = {*Alzheimer Disease/genetics ; Cohort Studies ; Humans ; *RNA, Circular ; Real-Time Polymerase Chain Reaction ; Temporal Lobe ; }, abstract = {OBJECTIVE: To identify circular RNAs as candidates for differential expression in the middle temporal (MT) cortex in a well-characterized cohort with contrasting Alzheimer disease (AD) pathology and cognition. Top screen candidates were assessed for proof of circularity and then quantified by qPCR in a larger number of samples.<br><br>METHODS: An initial RNA sequencing screen was performed on n = 20 frozen human tissue samples. Filters were applied to select candidate circular RNAs for further investigation. Frozen human tissue samples were selected for global AD pathology burden and global cognition scores (n = 100). Linear and divergent primers were used to assess circularity using RNaseR digestion. RT-qPCR was performed to quantify relative hsa_circ_0131235 abundance.<br><br>RESULTS: Eleven circular RNAs were selected for further investigation. Four candidates produced circular RNA primers with appropriate efficiencies for qPCR. RNaseR treatment and analysis by both basic PCR and qPCR confirmed hsa_circ_0131235 circularity. There was a significant main effect of AD pathology on hsa_circ_0131235 expression.<br><br>CONCLUSIONS: Elevated hsa_circ_0131235 expression in the MT cortex was significantly associated with AD pathology.}, }
@article {pmid33693397, year = {2020}, author = {Raket, LL}, title = {Statistical Disease Progression Modeling in Alzheimer Disease.}, journal = {Frontiers in big data}, volume = {3}, number = {}, pages = {24}, pmid = {33693397}, issn = {2624-909X}, support = {U01 AG024904/AG/NIA NIH HHS/United States ; }, abstract = {Background: The characterizing symptom of Alzheimer disease (AD) is cognitive deterioration. While much recent work has focused on defining AD as a biological construct, most patients are still diagnosed, staged, and treated based on their cognitive symptoms. But the cognitive capability of a patient at any time throughout this deterioration reflects not only the disease state, but also the effect of the cognitive decline on the patient's pre-disease cognitive capability. Patients with high pre-disease cognitive capabilities tend to score better on cognitive tests that are sensitive early in disease relative to patients with low pre-disease cognitive capabilities at a similar disease stage. Thus, a single assessment with a cognitive test is often not adequate for determining the stage of an AD patient. Repeated evaluation of patients' cognition over time may improve the ability to stage AD patients, and such longitudinal assessments in combinations with biomarker assessments can help elucidate the time dynamics of biomarkers. In turn, this can potentially lead to identification of markers that are predictive of disease stage and future cognitive decline, possibly before any cognitive deficit is measurable. Methods and Findings: This article presents a class of statistical disease progression models and applies them to longitudinal cognitive scores. These non-linear mixed-effects disease progression models explicitly model disease stage, baseline cognition, and the patients' individual changes in cognitive ability as latent variables. Maximum-likelihood estimation in these models induces a data-driven criterion for separating disease progression and baseline cognition. Applied to data from the Alzheimer's Disease Neuroimaging Initiative, the model estimated a timeline of cognitive decline that spans ~15 years from the earliest subjective cognitive deficits to severe AD dementia. Subsequent analyses demonstrated how direct modeling of latent factors that modify the observed data patterns provides a scaffold for understanding disease progression, biomarkers, and treatment effects along the continuous time progression of disease. Conclusions: The presented framework enables direct interpretations of factors that modify cognitive decline. The results give new insights to the value of biomarkers for staging patients and suggest alternative explanations for previous findings related to accelerated cognitive decline among highly educated patients and patients on symptomatic treatments.}, }
@article {pmid33691319, year = {2021}, author = {Piao, Z and Song, L and Yao, L and Zhang, L and Lu, Y}, title = {Schisandrin Restores the Amyloid β-Induced Impairments on Mitochondrial Function, Energy Metabolism, Biogenesis, and Dynamics in Rat Primary Hippocampal Neurons.}, journal = {Pharmacology}, volume = {106}, number = {5-6}, pages = {254-264}, doi = {10.1159/000507818}, pmid = {33691319}, issn = {1423-0313}, mesh = {Alzheimer Disease/drug therapy ; Amyloid beta-Peptides/toxicity ; Animals ; Animals, Newborn ; Cyclooctanes/*pharmacology ; Cytochromes c/antagonists &amp; inhibitors ; Energy Metabolism/*drug effects ; Hippocampus/*cytology/*drug effects ; Lignans/*pharmacology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria/*drug effects ; Mitochondrial Dynamics/drug effects ; Models, Biological ; Neurons/*drug effects ; Neuroprotective Agents/*pharmacology ; Organelle Biogenesis ; Peptide Fragments/toxicity ; Polycyclic Compounds/*pharmacology ; Primary Cell Culture ; Rats, Sprague-Dawley ; }, abstract = {INTRODUCTION: Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer's disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders.<br><br>OBJECTIVE: Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons.<br><br>METHODS: In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1-42 (Aβ1-42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1-42 oligomer-treated neurons.<br><br>RESULTS AND CONCLUSIONS: Our findings indicated that schisandrin significantly alleviated the Aβ1-42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.}, }
@article {pmid33688938, year = {2021}, author = {Stroup, TS and Olfson, M and Huang, C and Wall, MM and Goldberg, T and Devanand, DP and Gerhard, T}, title = {Age-Specific Prevalence and Incidence of Dementia Diagnoses Among Older US Adults With Schizophrenia.}, journal = {JAMA psychiatry}, volume = {78}, number = {6}, pages = {632-641}, doi = {10.1001/jamapsychiatry.2021.0042}, pmid = {33688938}, issn = {2168-6238}, support = {P50 MH115843/MH/NIMH NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Comorbidity ; Dementia/*epidemiology ; Female ; Humans ; Incidence ; Male ; Medicare ; Prevalence ; Retrospective Studies ; Schizophrenia/*epidemiology ; United States/epidemiology ; }, abstract = {Importance: People with schizophrenia are at high risk of receiving a diagnosis of dementia. Understanding the magnitude and timing of this increased risk has important implications for practice and policy.<br><br>Objective: To estimate the age-specific incidence and prevalence of dementia diagnoses among older US adults with schizophrenia and in a comparison group without serious mental illness (SMI).<br><br>This retrospective cohort study used a 50% random national sample of Medicare beneficiaries 66 years or older with fee-for-service plans and Part D prescription drug coverage from January 1, 2007, to December 31, 2017. The cohort with schizophrenia included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and at least 2 outpatient claims or at least 1 inpatient claim for schizophrenia during the qualifying years. The comparison group included adults with at least 12 months of continuous enrollment in fee-for-service Medicare and Part D and without a diagnosis of schizophrenia, bipolar disorder, or recurrent major depressive disorder during the qualifying year. Data were analyzed from January 1 to July 31, 2020.<br><br>Main Outcomes and Measures: Dementia was defined using the Centers for Medicare &amp; Medicaid Services Chronic Conditions Warehouse diagnosis codes for Alzheimer disease and related disorders or senile dementia. Incident diagnoses were defined by at least 12 consecutive eligible months without a qualifying code before meeting dementia criteria.<br><br>Results: The study population of 8 011 773 adults 66 years or older (63.4% women; mean [SD] age, 74.0 [8.2] years) included 74 170 individuals with a diagnosis of schizophrenia (56.6% women) and 7 937 603 without an SMI diagnosis (63.5% women) who contributed 336 814 and 55 499 543 person-years of follow-up, respectively. At 66 years of age, the prevalence of diagnosed dementia was 27.9% (17 640 of 63 287) among individuals with schizophrenia compared with 1.3% (31 295 of 2 389 512) in the group without SMI. By 80 years of age, the prevalence of dementia diagnoses was 70.2% (2011 of 2866) in the group with schizophrenia and 11.3% (242 094 of 2 134 602) in the group without SMI. The annual incidence of dementia diagnoses per 1000 person-years at 66 years of age was 52.5 (95% CI, 50.1-54.9) among individuals with schizophrenia and 4.5 (95% CI, 4.4-4.6) among individuals without SMI and increased to 216.2 (95% CI, 179.9-252.6) and 32.3 (95% CI, 32.0-32.6), respectively, by 80 years of age.<br><br>Conclusions and Relevance: In this cohort study, compared with older adults without SMI, those with schizophrenia had increased risk of receiving a diagnosis of dementia across a wide age range, possibly because of cognitive and functional deterioration related to schizophrenia or factors contributing to other types of dementia. High rates of dementia among adults with schizophrenia have implications for the course of illness, treatment, and service use.}, }
@article {pmid33687445, year = {2021}, author = {Shaw, C and Hayes-Larson, E and Glymour, MM and Dufouil, C and Hohman, TJ and Whitmer, RA and Kobayashi, LC and Brookmeyer, R and Mayeda, ER}, title = {Evaluation of Selective Survival and Sex/Gender Differences in Dementia Incidence Using a Simulation Model.}, journal = {JAMA network open}, volume = {4}, number = {3}, pages = {e211001}, pmid = {33687445}, issn = {2574-3805}, support = {R21 AG059941/AG/NIA NIH HHS/United States ; R00 AG053410/AG/NIA NIH HHS/United States ; R01 AG059716/AG/NIA NIH HHS/United States ; R21 AG055361/AG/NIA NIH HHS/United States ; RF1 AG050782/AG/NIA NIH HHS/United States ; R01 AG069128/AG/NIA NIH HHS/United States ; P2C HD041022/HD/NICHD NIH HHS/United States ; K01 AG049164/AG/NIA NIH HHS/United States ; R13 AG064971/AG/NIA NIH HHS/United States ; }, mesh = {Age Distribution ; Aged ; Aged, 80 and over ; Dementia/*epidemiology ; Female ; Humans ; Incidence ; Male ; Middle Aged ; *Models, Theoretical ; Risk Factors ; Sex Distribution ; Survival Rate ; }, abstract = {Importance: Dementia research is susceptible to bias arising from selective survival, a process that results in individuals with certain characteristics disproportionately surviving to old age. Spurious associations between risk factors and dementia may be induced when factors associated with longer survival also influence dementia incidence.<br><br>Objective: To assess the role of selective survival in explaining reported sex/gender differences in dementia incidence.<br><br>This decision analytical model used a simulated cohort of US participants aged 50 years and without dementia at baseline followed up for incident dementia through age 95 years. Selective survival was induced by a selection characteristic (eg, childhood social disadvantage or Alzheimer genetic risk) that influenced both mortality and dementia incidence at varying magnitudes. Data analysis was performed from April 2018 to May 2020.<br><br>Exposure: Sex/gender, conceptualized as the combination of biological sex and social consequences of gender.<br><br>Main Outcomes and Measures: Dementia incidence rate ratios (IRRs) for women compared with men. In all simulations, it was assumed that there would be no true effect of sex/gender on dementia incidence; all observed sex/gender differences were due to selective survival.<br><br>Results: At baseline, the simulation included 100 000 participants aged 50 years (51 000 [51%] women, mirroring the 1919-1921 US birth cohort of non-Latino White individuals at age 50 years); distributions of the selection characteristic were standard normal (mean [SD], 0.0 [1.0]). Observed sex/gender differences in dementia incidence in individuals aged 85 years or older ranged from insignificant (IRR, 1.00; 95% CI, 0.91-1.11) to consistent with sex/gender differences (20% higher risk for women [IRR, 1.20; 95% CI, 1.08-1.32]) reported in an extant study. Simulations in which bias was large enough to explain prior findings required moderate to large differential effects of selective survival (eg, hazard ratio for selection characteristic on mortality at least 2.0 among men, no effect among women).<br><br>Conclusions and Relevance: These results suggest that selective survival may contribute to observed sex/gender differences in dementia incidence but do not preclude potential contributions of sex/gender-specific mechanisms. Further research on plausibility of selection characteristics with outcomes of the magnitude required for selective survival to explain sex/gender differences in dementia incidence and sex/gender-specific mechanisms represent an opportunity to understand prevention and treatment of dementia.}, }
@article {pmid33685483, year = {2021}, author = {Roca-Agujetas, V and Barbero-Camps, E and de Dios, C and Podlesniy, P and Abadin, X and Morales, A and Marí, M and Trullàs, R and Colell, A}, title = {Cholesterol alters mitophagy by impairing optineurin recruitment and lysosomal clearance in Alzheimer's disease.}, journal = {Molecular neurodegeneration}, volume = {16}, number = {1}, pages = {15}, pmid = {33685483}, issn = {1750-1326}, mesh = {Alzheimer Disease/*metabolism ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/*metabolism ; Animals ; Autophagy/*physiology ; Cholesterol/metabolism ; Lysosomes/*metabolism ; Mice, Transgenic ; Mitochondria/metabolism ; Neurons/metabolism ; Ubiquitin-Protein Ligases ; }, abstract = {BACKGROUND: Emerging evidence indicates that impaired mitophagy-mediated clearance of defective mitochondria is a critical event in Alzheimer's disease (AD) pathogenesis. Amyloid-beta (Aβ) metabolism and the microtubule-associated protein tau have been reported to regulate key components of the mitophagy machinery. However, the mechanisms that lead to mitophagy dysfunction in AD are not fully deciphered. We have previously shown that intraneuronal cholesterol accumulation can disrupt the autophagy flux, resulting in low Aβ clearance. In this study, we examine the impact of neuronal cholesterol changes on mitochondrial removal by autophagy.<br><br>METHODS: Regulation of PINK1-parkin-mediated mitophagy was investigated in conditions of acute (in vitro) and chronic (in vivo) high cholesterol loading using cholesterol-enriched SH-SY5Y cells, cultured primary neurons from transgenic mice overexpressing active SREBF2 (sterol regulatory element binding factor 2), and mice of increasing age that express the amyloid precursor protein with the familial Alzheimer Swedish mutation (Mo/HuAPP695swe) and mutant presenilin 1 (PS1-dE9) together with active SREBF2.<br><br>RESULTS: In cholesterol-enriched SH-SY5Y cells and cultured primary neurons, high intracellular cholesterol levels stimulated mitochondrial PINK1 accumulation and mitophagosomes formation triggered by Aβ while impairing lysosomal-mediated clearance. Antioxidant recovery of cholesterol-induced mitochondrial glutathione (GSH) depletion prevented mitophagosomes formation indicating mitochondrial ROS involvement. Interestingly, when brain cholesterol accumulated chronically in aged APP-PSEN1-SREBF2 mice the mitophagy flux was affected at the early steps of the pathway, with defective recruitment of the key autophagy receptor optineurin (OPTN). Sustained cholesterol-induced alterations in APP-PSEN1-SREBF2 mice promoted an age-dependent accumulation of OPTN into HDAC6-positive aggresomes, which disappeared after in vivo treatment with GSH ethyl ester (GSHee). The analyses in post-mortem brain tissues from individuals with AD confirmed these findings, showing OPTN in aggresome-like structures that correlated with high mitochondrial cholesterol levels in late AD stages.<br><br>CONCLUSIONS: Our data demonstrate that accumulation of intracellular cholesterol reduces the clearance of defective mitochondria and suggest recovery of the cholesterol homeostasis and the mitochondrial scavenging of ROS as potential therapeutic targets for AD.}, }
@article {pmid33683313, year = {2021}, author = {Nasrallah, IM and Gaussoin, SA and Pomponio, R and Dolui, S and Erus, G and Wright, CB and Launer, LJ and Detre, JA and Wolk, DA and Davatzikos, C and Williamson, JD and Pajewski, NM and Bryan, RN and , }, title = {Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease: Secondary Analysis of the SPRINT MIND Randomized Trial.}, journal = {JAMA neurology}, volume = {78}, number = {5}, pages = {568-577}, doi = {10.1001/jamaneurol.2021.0178}, pmid = {33683313}, issn = {2168-6157}, support = {HHSN271201300284P/DA/NIDA NIH HHS/United States ; RF1 AG054409/AG/NIA NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; R01 HL141846/HL/NHLBI NIH HHS/United States ; S10 OD023495/OD/NIH HHS/United States ; }, mesh = {Aged ; Alzheimer Disease/drug therapy/*pathology/*physiopathology ; Antihypertensive Agents/therapeutic use ; Biomarkers/analysis ; Blood Pressure/drug effects/*physiology ; Brain/drug effects/pathology/physiopathology ; Cognitive Dysfunction/complications/drug therapy/*pathology ; Female ; Humans ; Hypertension/drug therapy ; *Magnetic Resonance Imaging/methods ; Male ; Middle Aged ; Risk Factors ; }, abstract = {Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control.<br><br>Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers.<br><br>This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020.<br><br>Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317).<br><br>Main Outcomes and Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle.<br><br>Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy.<br><br>Conclusions and Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment.<br><br>Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.}, }
@article {pmid33674360, year = {2021}, author = {Friedman, LG and McKeehan, N and Hara, Y and Cummings, JL and Matthews, DC and Zhu, J and Mohs, RC and Wang, D and Hendrix, SB and Quintana, M and Schneider, LS and Grundman, M and Dickson, SP and Feldman, HH and Jaeger, J and Finger, EC and Ryan, JM and Niehoff, D and Dickinson, SL and Markowitz, JT and Owen, M and Travaglia, A and Fillit, HM}, title = {Value-Generating Exploratory Trials in Neurodegenerative Dementias.}, journal = {Neurology}, volume = {96}, number = {20}, pages = {944-954}, pmid = {33674360}, issn = {1526-632X}, support = {P20 AG068053/AG/NIA NIH HHS/United States ; P20 GM109025/GM/NIGMS NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; }, mesh = {Alzheimer Disease/*drug therapy ; Clinical Trials as Topic/*methods ; Clinical Trials, Phase I as Topic ; Clinical Trials, Phase II as Topic ; Dementia/drug therapy ; Drug Development/*methods ; Frontotemporal Dementia/*drug therapy ; Humans ; Neurodegenerative Diseases/drug therapy ; Outcome Assessment, Health Care ; Proof of Concept Study ; Research Design ; Treatment Failure ; Treatment Outcome ; }, abstract = {Drug development for Alzheimer disease and other neurodegenerative dementias, including frontotemporal dementia, has experienced a long history of phase 2 and phase 3 clinical trials that failed to show efficacy of investigational drugs. Despite differences in clinical and behavioral characteristics, these disorders have shared pathologies and face common challenges in designing early-phase trials that are predictive of late-stage success. Here, we discuss exploratory clinical trials in neurodegenerative dementias. These are generally phase 1b or phase 2a trials that are designed to assess pharmacologic effects and rely on biomarker outcomes, with shorter treatment durations and fewer patients than traditional phase 2 studies. Exploratory trials can establish go/no-go decision points, support proof of concept and dose selection, and terminate drugs that fail to show target engagement with suitable exposure and acceptable safety profiles. Early failure saves valuable resources including opportunity costs. This is especially important for programs in academia and small biotechnology companies but may be applied to high-risk projects in large pharmaceutical companies to achieve proof of concept more rapidly at lower costs than traditional approaches. Exploratory studies in a staged clinical development program may provide promising data to warrant the substantial resources needed to advance compounds through late-stage development. To optimize the design and application of exploratory trials, the Alzheimer's Drug Discovery Foundation and the Association for Frontotemporal Degeneration convened an advisory panel to provide recommendations on outcome measures and statistical considerations for these types of studies and study designs that can improve efficiency in clinical development.}, }
@article {pmid33665436, year = {2021}, author = {Elmorsy, E and Elsharkawy, E and Alhumaydhi, FA and Salama, M}, title = {The protective effect of Indian Catechu methanolic extract against aluminum chloride-induced neurotoxicity, A rodent model of Alzheimer's disease.}, journal = {Heliyon}, volume = {7}, number = {2}, pages = {e06269}, pmid = {33665436}, issn = {2405-8440}, abstract = {Alzheimer's disease (AD) is the commonest neurodegenerative disorder with a wide array of manifestations, courses, and contributing causes. Despite being clinically characterized a long time ago; no treatment has been developed that could improve the pathology or slow down the disease manifestation- so far. Indian Catechu methanolic extract (ICME) has proved to have multiple beneficial effects that support its use in several disorders- especially those with complex etiology. In the present study, we evaluated the neuroprotective effect of ICME in a rat model of AD using Aluminum Chloride (AlCl3). The results showed that ICME could have a positive impact on the course of AD through its anticholinesterase effect and significant antioxidant effect which was reflected on the animals both on behavioral tests as well as hallmark pathological findings.}, }
@article {pmid33657269, year = {2021}, author = {Schnier, C and Janbek, J and Williams, L and Wilkinson, T and Laursen, TM and Waldemar, G and Richter, H and Kostev, K and Lathe, R and G Haas, J}, title = {Antiherpetic medication and incident dementia: Observational cohort studies in four countries.}, journal = {European journal of neurology}, volume = {28}, number = {6}, pages = {1840-1848}, doi = {10.1111/ene.14795}, pmid = {33657269}, issn = {1468-1331}, support = {MR/P011349/1/MRC_/Medical Research Council/United Kingdom ; }, mesh = {Cohort Studies ; *Dementia/epidemiology ; *Herpesviridae Infections ; Humans ; Incidence ; Registries ; Risk Factors ; }, abstract = {BACKGROUND AND PURPOSE: Several epidemiological studies from Taiwan, all using the same data resource, found significant associations between herpes virus infection, antiherpetic medication, and subsequent dementia. We conducted a multicenter observational cohort study using health registry data from Wales, Germany, Scotland, and Denmark to investigate potential associations between antiherpetic medication and incident dementia, and also to comprehensively investigate such associations broken down according to medication type and dose, type of herpes virus, and dementia subtype.<br><br>METHODS: A total of 2.5 million individuals aged 65 years or more were followed up using linked electronic health records in four national observational cohort studies. Exposure and outcome were classified using coded data from primary and secondary care. Data were analyzed using survival analysis with time-dependent covariates.<br><br>RESULTS: Results were heterogeneous, with a tendency toward decreased dementia risk in individuals exposed to antiherpetic medication. Associations were not affected by treatment number, herpes subtype, dementia subtype, or specific medication. In one cohort, individuals diagnosed with herpes but not exposed to antiherpetic medication were at higher dementia risk.<br><br>CONCLUSIONS: Short-term antiherpetic medication is not markedly associated with incident dementia. Because neither dementia subtype nor herpes subtype modified the association, the small but significant decrease in dementia incidence with antiherpetic administration may reflect confounding and misclassification.}, }
@article {pmid33653273, year = {2021}, author = {Guzmán-Ruiz, MA and Herrera-González, A and Jiménez, A and Candelas-Juárez, A and Quiroga-Lozano, C and Castillo-Díaz, C and Orta-Salazar, E and Organista-Juárez, D and Díaz-Cintra, S and Guevara-Guzmán, R}, title = {Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid β1-42 rat model.}, journal = {BMC neuroscience}, volume = {22}, number = {1}, pages = {14}, pmid = {33653273}, issn = {1471-2202}, mesh = {Adiponectin/*pharmacology ; *Alzheimer Disease ; Amyloid beta-Peptides/toxicity ; Animals ; Brain/*drug effects ; Disease Models, Animal ; Injections, Intraventricular ; Male ; Neuroprotective Agents/*pharmacology ; *Olfaction Disorders/etiology ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive impairment that eventually develops into dementia. Amyloid-beta (Aβ) accumulation is a widely described hallmark in AD, and has been reported to cause olfactory dysfunction, a condition considered an early marker of the disease associated with injuries in the olfactory bulb (OB), the hippocampus (HIPP) and other odor-related cortexes. Adiponectin (APN) is an adipokine with neuroprotective effects. Studies have demonstrated that APN administration decreases Aβ neurotoxicity and Tau hyperphosphorylation in the HIPP, reducing cognitive impairment. However, there are no studies regarding the neuroprotective effects of APN in the olfactory dysfunction observed in the Aβ rat model. The aim of the present study is to determine whether the intracerebroventricular (i.c.v) administration of APN prevents the early olfactory dysfunction in an i.c.v Amyloid-beta1-42 (Aβ1-42) rat model. Hence, we evaluated olfactory function by using a battery of olfactory tests aimed to assess olfactory memory, discrimination and detection in the Aβ rat model treated with APN. In addition, we determined the number of cells expressing the neuronal nuclei (NeuN), as well as the number of microglial cells by using the ionized calcium-binding adapter molecule 1 (Iba-1) marker in the OB and, CA1, CA3, hilus and dentate gyrus (DG) in the HIPP. Finally, we determined Arginase-1 expression in both nuclei through Western blot.<br><br>RESULTS: We observed that the i.c.v injection of Aβ decreased olfactory function, which was prevented by the i.c.v administration of APN. In accordance with the olfactory impairment observed in i.c.v Aβ-treated rats, we observed a decrease in NeuN expressing cells in the glomerular layer of the OB, which was also prevented with the i.c.v APN. Furthermore, we observed an increase of Iba-1 cells in CA1, and DG in the HIPP of the Aβ rats, which was prevented by the APN treatment.<br><br>CONCLUSION: The present study describes the olfactory impairment of Aβ treated rats and evidences the protective role that APN plays in the brain, by preventing the olfactory impairment induced by Aβ1-42. These results may lead to APN-based pharmacological therapies aimed to ameliorate AD neurotoxic effects.}, }
@article {pmid33652938, year = {2021}, author = {Librizzi, D and Cabanel, N and Zavorotnyy, M and Riehl, E and Kircher, T and Luster, M and Hooshyar Yousefi, B}, title = {Clinical Relevance of [18F]Florbetaben and [18F]FDG PET/CT Imaging on the Management of Patients with Dementia.}, journal = {Molecules (Basel, Switzerland)}, volume = {26}, number = {5}, pages = {}, pmid = {33652938}, issn = {1420-3049}, mesh = {Aged ; Aged, 80 and over ; Alzheimer Disease/*diagnostic imaging/genetics/physiopathology ; Amyloid beta-Peptides/genetics/isolation &amp; purification ; Brain/diagnostic imaging/physiopathology ; Cognitive Dysfunction/diagnosis/*diagnostic imaging/physiopathology ; Dementia/diagnosis/*diagnostic imaging/physiopathology ; Female ; Fluorodeoxyglucose F18/*administration &amp; dosage ; Humans ; Male ; Middle Aged ; Positron Emission Tomography Computed Tomography/methods ; tau Proteins/genetics/isolation &amp; purification ; }, abstract = {PET of β-Amyloid plaques (Aβ) using [18F]florbetaben ([18F]FBB) and [18F]fluorodeoxyglucose ([18F]FDG) increasingly aid clinicians in early diagnosis of dementia, including Alzheimer's disease (AD), frontotemporal disease, dementia with Lewy bodies, and vascular dementia. The aim of this retrospective analysis was to evaluate clinical relevance of [18F]FBB, [18F]FDG PET and complimentary CSF measurements in patients with suspected dementia. In this study, 40 patients with clinically suspected or history of dementia underwent (1) measurement of Aβ peptides, total tau, and p-tau protein levels in the cerebrospinal fluid (CSF) compared with healthy controls (HC); (2) clinical and neuropsychological assessment, which included Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery (CERAD-NAB); (3) [18F]FBB and [18F]FDG PET imaging within an average of 3 weeks. The subjects were within 15 days stratified using PET, CSF measurements as HC, mild cognitive impaired (MCI) and dementia including Alzheimer´s disease. The predictive dementia-related cognitive decline values were supporting the measurements. PET images were evaluated visually and quantitatively using standard uptake value ratios (SUVR). Twenty-one (52.5%) subjects were amyloid-positive (Aβ+), with a median neocortical SUVR of 1.80 for AD versus 1.20 relative to the respective 19 (47.5 %) amyloid-negative (Aβ-) subjects. Moreover, the [18F]FDG and [18F]FBB confirmed within a sub-group of 10 patients a good complimentary role by correlation between amyloid pathology and brain glucose metabolism in 8 out of 10 subjects. The results suggest the clinical relevance for [18F]FBB combined with [18F]FDG PET retention and CFS measurements serving the management of our patients with dementia. Therefore, [18F]FBB combined with [18F]FDG PET is a helpful tool for differential diagnosis, and supports the patients' management as well as treatment.}, }
@article {pmid33646990, year = {2021}, author = {Reiss, AB and Montufar, N and DeLeon, J and Pinkhasov, A and Gomolin, IH and Glass, AD and Arain, HA and Stecker, MM}, title = {Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans.}, journal = {The neurologist}, volume = {26}, number = {2}, pages = {52-61}, doi = {10.1097/NRL.0000000000000320}, pmid = {33646990}, issn = {2331-2637}, mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; Animals ; Biomarkers ; Humans ; Mice ; }, abstract = {BACKGROUND: The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-β and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered.<br><br>REVIEW SUMMARY: In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway.<br><br>CONCLUSION: Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.}, }
@article {pmid33637039, year = {2021}, author = {Watt, JA and Veroniki, AA and Tricco, AC and Straus, SE}, title = {Using a distribution-based approach and systematic review methods to derive minimum clinically important differences.}, journal = {BMC medical research methodology}, volume = {21}, number = {1}, pages = {41}, pmid = {33637039}, issn = {1471-2288}, mesh = {*Alzheimer Disease/diagnosis/drug therapy ; Humans ; *Minimal Clinically Important Difference ; Outcome Assessment, Health Care ; Research Design ; Surveys and Questionnaires ; Systematic Reviews as Topic ; }, abstract = {BACKGROUND: Clinical interpretation of changes measured on a scale is dependent on knowing the minimum clinically important difference (MCID) for that scale: the threshold above which clinicians, patients, and researchers perceive an outcome difference. Until now, approaches to determining MCIDs were based upon individual studies or surveys of experts. However, the comparison of meta-analytic treatment effects to a MCID derived from a distribution of standard deviations (SDs) associated with all trial-specific outcomes in a meta-analysis could improve our clinical understanding of meta-analytic treatment effects.<br><br>METHODS: We approximated MCIDs using a distribution-based approach that pooled SDs associated with baseline mean or mean change values for two scales (i.e. Mini-Mental State Exam [MMSE] and Alzheimer Disease Assessment Scale - Cognitive Subscale [ADAS-Cog]), as reported in parallel randomized trials (RCTs) that were included in a systematic review of cognitive enhancing medications for dementia (i.e. cholinesterase inhibitors and memantine). We excluded RCTs that did not report baseline or mean change SD values. We derived MCIDs at 0.4 and 0.5 SDs of the pooled SD and compared our derived MCIDs to previously published MCIDs for the MMSE and ADAS-Cog.<br><br>RESULTS: We showed that MCIDs derived from a distribution-based approach approximated published MCIDs for the MMSE and ADAS-Cog. For the MMSE (51 RCTs, 12,449 patients), we derived a MCID of 1.6 at 0.4 SDs and 2 at 0.5 SDs using baseline SDs and we derived a MCID of 1.4 at 0.4 SDs and 1.8 at 0.5 SDs using mean change SDs. For the ADAS-Cog (37 RCTs, 10,006 patients), we derived a MCID of 4 at 0.4 SDs and 5 at 0.5 SDs using baseline SDs and we derived a MCID of 2.6 at 0.4 SDs and 3.2 at 0.5 SDs using mean change SDs.<br><br>CONCLUSION: A distribution-based approach using data included in a systematic review approximated known MCIDs. Our approach performed better when we derived MCIDs from baseline as opposed to mean change SDs. This approach could facilitate clinical interpretation of outcome measures reported in RCTs and systematic reviews of interventions. Future research should focus on the generalizability of this method to other clinical scenarios.}, }
@article {pmid33634105, year = {2020}, author = {Chen, C and Liu, P and Wang, J and Yu, H and Zhang, Z and Liu, J and Chen, X and Zhu, F and Yang, X}, title = {Dauricine Attenuates Spatial Memory Impairment and Alzheimer-Like Pathologies by Enhancing Mitochondrial Function in a Mouse Model of Alzheimer's Disease.}, journal = {Frontiers in cell and developmental biology}, volume = {8}, number = {}, pages = {624339}, pmid = {33634105}, issn = {2296-634X}, abstract = {Alzheimer's disease (AD) is characterized by extracellular amyloid plaques composed of β-amyloid (Aβ) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. No effective therapy is available for this disease. In this study, we investigated the potential therapeutic effects of dauricine (DAU), a benzyl tetrahydroisoquinoline alkaloid, on AD, and found that DAU administration significantly improved cognitive impairments in 3xTg-AD mice by decreasing Aβ plaques and hyperphosphorylated tau and increasing the hippocampal ATP level. Proteomic and western blot analyses revealed that DAU treatment mainly modified the expression of proteins involved in mitochondrial energy metabolism, such as Aco2, Ndufs1, Cox5a, and SDHB, and that of synapse-related proteins such as Syn1 and Syn2. Pathway analysis revealed that DAU modulated the tricarboxylic acid cycle, synaptic vesicle cycle, glycolysis, and gluconeogenesis in 3xTg-AD mice. Our study suggests that DAU may be a potential drug for the treatment of AD.}, }
@article {pmid33629902, year = {2021}, author = {Yamazaki, K and Yoshimura, A and Miyahara, S and Sugi, S and Itono, M and Kondo, M and Tsuji, N and Shimizu, M and Fukushima, R and Kishimoto, M}, title = {Evaluation of cerebral blood flow in the hippocampus, thalamus, and basal ganglia and the volume of the hippocampus in dogs before and during treatment with prednisolone.}, journal = {American journal of veterinary research}, volume = {82}, number = {3}, pages = {230-236}, doi = {10.2460/ajvr.82.3.230}, pmid = {33629902}, issn = {1943-5681}, mesh = {Animals ; Basal Ganglia/diagnostic imaging ; Brain ; *Cerebrovascular Circulation ; Dogs ; Hippocampus/diagnostic imaging ; *Prednisolone ; Thalamus/diagnostic imaging ; }, abstract = {OBJECTIVE: To examine whether glucocorticoid (GC) administration alters hippocampal cerebral blood flow (CBF) or volume in dogs.<br><br>ANIMALS: 6 clinically normal adult Beagles.<br><br>PROCEDURES: Each dog underwent CT and MRI to measure the CBF in the hippocampus, basal ganglia, thalamus, and cerebral cortex and the volume of the hippocampus in each hemisphere of the brain before (day 0) and during (days 7 and 21) a 21-day treatment with prednisolone (1.0 mg/kg, PO, q 24 h) and famotidine (0.5 mg/kg, PO, q 12 h). Results for hippocampal volume, anesthesia-related variables, and semiquantitative measurements of CBF (hemisphere-specific ratios of the CBF in the hippocampus, basal ganglia, and thalamus relative to the CBF in the ipsilateral cerebral cortex and the left cerebral cortex CBF-to-right cerebral cortex CBF ratio) were compared across assessment time points (days 0, 7, and 21).<br><br>RESULTS: The ratios of CBF in the right hippocampus and right thalamus to that in the right cerebral cortex on day 21 were significantly lower than those on day 0. No meaningful differences were detected in results for the hippocampal volume in either hemisphere or for the anesthesia-related variables across the 3 time points.<br><br>Results indicated that GC administration reduced CBF in the hippocampus and thalamus in dogs of the present study, similar to that which occurs in humans. Research on GC-related brain alteration in dogs could potentially contribute to advancements in understanding Alzheimer disease in humans and neurodegenerative conditions in dogs.}, }
@article {pmid33627920, year = {2020}, author = {Feng, X and Li, T and Song, X and Zhu, H}, title = {Bayesian Scalar on Image Regression With Nonignorable Nonresponse.}, journal = {Journal of the American Statistical Association}, volume = {115}, number = {532}, pages = {1574-1597}, pmid = {33627920}, issn = {0162-1459}, support = {R01 MH086633/MH/NIMH NIH HHS/United States ; R01 MH116527/MH/NIMH NIH HHS/United States ; }, abstract = {Medical imaging has become an increasingly important tool in screening, diagnosis, prognosis, and treatment of various diseases given its information visualization and quantitative assessment. The aim of this article is to develop a Bayesian scalar-on-image regression model to integrate high-dimensional imaging data and clinical data to predict cognitive, behavioral, or emotional outcomes, while allowing for nonignorable missing outcomes. Such a nonignorable nonresponse consideration is motivated by examining the association between baseline characteristics and cognitive abilities for 802 Alzheimer patients enrolled in the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI1), for which data are partially missing. Ignoring such missing data may distort the accuracy of statistical inference and provoke misleading results. To address this issue, we propose an imaging exponential tilting model to delineate the data missing mechanism and incorporate an instrumental variable to facilitate model identifiability followed by a Bayesian framework with Markov chain Monte Carlo algorithms to conduct statistical inference. This approach is validated in simulation studies where both the finite sample performance and asymptotic properties are evaluated and compared with the model with fully observed data and that with a misspecified ignorable missing mechanism. Our proposed methods are finally carried out on the ADNI1 dataset, which turns out to capture both of those clinical risk factors and imaging regions consistent with the existing literature that exhibits clinical significance. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.}, }
@article {pmid33618651, year = {2021}, author = {Mooko, T and Bala, A and Tripathy, S and Kumar, CS and Mahadevappa, CP and Chaudhary, SK and Matsabisa, MG}, title = {Cannabis Sativa L. Flower and Bud Extracts inhibited In vitro Cholinesterases and b-Secretase Enzymes Activities: Possible Mechanisms of Cannabis use in Alzheimer Disease.}, journal = {Endocrine, metabolic &amp; immune disorders drug targets}, volume = {}, number = {}, pages = {}, doi = {10.2174/1871530321666210222124349}, pmid = {33618651}, issn = {2212-3873}, abstract = {BACKGROUND: There are anecdotal claims on the use of Cannabis sativa L. in the treatment of Alzheimer's disease, but there is lack of scientific data to support the efficacy and safety of Cannabis sativa L. for Alzheimer's disease.<br><br>AIM: The aim of the study was to evaluate the effect of aerial parts of Cannabis sativa L. on the cholinesterases and β-secretase enzyme activity as one of the possible mechanisms of Alzheimer's disease.<br><br>METHODS: The phytochemical and heavy metal contents were analysed. The extracts were screened for acetylcholinesterase, butyrylcholinesterase and β-secretase activity. Cytotoxicity of extracts was performed in normal vero and pre-adipocytes cell lines. The extracts were characterized using high performance thin layer chromatography and high-performance liquid chromatography for their chemical fingerprints. Alkaloids, flavonoids and glycosides were present amongst the tested phytochemicals. Cannabidiol concentrations were comparatively high in the hexane and dichloromethane than in dichloromethane: methanol (1:1) and methanol extracts.<br><br>RESULTS: Hexane and dichloromethane extracts showed a better inhibitory potential towards cholinesterase activity, while water, hexane, dichloromethane: methanol (1:1) and methanol showed an inhibitory potential towards β-secretase enzyme activity. All extracts showed no cytotoxic effect on pre-adipocytes and vero cells after 24- and 48-hours of exposure.<br><br>CONCLUSION: Therefore, this may explain the mechanism through which AD symptoms may be treated and managed by Cannabis sativa L. extracts.}, }
@article {pmid33613890, year = {2020}, author = {Fahanik-Babaei, J and Baluchnejadmojarad, T and Roghani, M}, title = {Differential Effect of Amyloid Beta1-40 on Short-term and Long-term Plasticity in Dentate Gyrus of a Rat Model of Alzheimer Disease.}, journal = {Basic and clinical neuroscience}, volume = {11}, number = {4}, pages = {517-524}, pmid = {33613890}, issn = {2008-126X}, abstract = {INTRODUCTION: Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aβ1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD.<br><br>METHODS: The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aβ-lesioned groups. For modeling AD, aggregated Aβ1-40 (10 μg/2 μl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway.<br><br>RESULTS: No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aβ-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters.<br><br>CONCLUSION: Findings of this study clearly demonstrated that microinjection of Aβ1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.}, }
@article {pmid33613888, year = {2020}, author = {Fahimi Truski, F and Ghotbeddin, Z and Tabandeh, MR and Pourmahdi Borujeni, M}, title = {Crocin Treatment after Maternal Hypoxia Attenuates Spatial Memory Impairment and Expression of BACE1 and HIF-1α in Rat Offspring Brain.}, journal = {Basic and clinical neuroscience}, volume = {11}, number = {4}, pages = {499-506}, pmid = {33613888}, issn = {2008-126X}, abstract = {INTRODUCTION: Hypoxia via expression of Hypoxia-Inducible Factor-1 (HIF-1) is an important and effective factor in the onset and progression of memory disorders, such as Alzheimer Disease (AD). The activity of β-secretase (BACE1) is increased in hypoxia conditions. BACE1 triggers a cascade of pathological events resulting in AD. Crocin acts as a memoryimproving agent but its molecular mechanism is not well-known. Therefore, in this study, the effect of crocin on spatial memory, HIF-1α, and BACE1 gene expression was investigated in rat offspring under maternal hypoxia.<br><br>METHODS: Female pregnant rats on the 20th day of pregnancy were divided into 4 groups, including sham, crocin-treated, hypoxia, and hypoxia group treated with crocin. In the hypoxia groups, pregnant rats were exposed to 7% oxygen and 93% nitrogen intensity for 3 h. In the crocin-treated group, crocin (30 mg/kg) was injected at P14-28 (i.p). At the end, Morris water maze was used to assess spatial memory and real-time polymerase chain reaction was performed to measure the expression of BACE1 and HIF-1α genes in the brain of offspring.<br><br>RESULTS: Maternal hypoxia impaired memory compared with the sham group. However, crocin treatment improved cognitive behavior. HIF-1α and BACE1 expressions were upregulated in the brain of offspring in the hypoxia group. Crocin treatment could attenuate the expression of both genes.<br><br>CONCLUSION: According to our results, down-regulation of HIF-1α and BACE1 gene expressions in the brain of rat offspring after crocin treatment can be suggested as a molecular mechanism for crocin to improve spatial memory.}, }
@article {pmid33611334, year = {2021}, author = {Liu, MN and Liou, YJ and Wang, WC and Su, KC and Yeh, HL and Lau, CI and Hu, LY and Tsai, SJ and Chen, HY}, title = {Group Music Intervention Using Percussion Instruments to Reduce Anxiety Among Elderly Male Veterans with Alzheimer Disease.}, journal = {Medical science monitor : international medical journal of experimental and clinical research}, volume = {27}, number = {}, pages = {e928714}, pmid = {33611334}, issn = {1643-3750}, mesh = {Age Factors ; Aged ; Aged, 80 and over ; Alzheimer Disease/psychology/*therapy ; Anxiety/psychology/*therapy ; Anxiety Disorders/psychology/therapy ; Humans ; Male ; Music Therapy/*methods ; Taiwan ; Veterans/*psychology ; }, abstract = {BACKGROUND This study aimed to assess the impact of a group music intervention on anxiety and depression of elderly male veterans with dementia. MATERIAL AND METHODS In total, 50 elderly men with Alzheimer disease were randomly divided into intervention and control groups. Patients in the intervention group attended a 60-minute group music session that used percussion instruments with familiar music in the morning once a week for 12 weeks, whereas those in the control group received a rest and reading session at the same intervals and under the same conditions. The Hamilton Anxiety Rating Scale and Geriatric Depression Scale were used to assess anxiety and depression at baseline, week 6, and week 12. The Primary Measures of Music Audiation (PMMA) was used to assess musical aptitude at the baseline. RESULTS A significant reduction in the anxiety level following the 12-week music sessions was observed in the intervention group (P<.001), but there was no significant change in the control group. However, the change in depressive symptoms between the 2 groups was nonsignificant. In the intervention group, when stratifying patients based on music aptitude determined through PMMA assessment, patients with high PMMA scores had significantly reduced anxiety symptoms over time compared with those with low scores. CONCLUSIONS For elderly male veterans with dementia, participating in a group music intervention reduced anxiety symptoms. In patients with high musical aptitude, the treatment effects on anxiety reduction were satisfactory. Measures of music aptitude may provide valuable information regarding patients' response to music intervention.}, }
@article {pmid33602092, year = {2020}, author = {Vasconcelos-Filho, FSL and da Rocha-E-Silva, RC and Martins, JER and Godinho, WDN and da Costa, VV and Ribeiro, JKC and da Silva, CA and Ceccatto, VM and Soares, PM and Evangelista, JSAM}, title = {Neuroprotector Effect of Daily 8-Minutes of High-Intensity Interval Training in Rat Aβ1-42 Alzheimer Disease Model.}, journal = {Current Alzheimer research}, volume = {17}, number = {14}, pages = {1320-1333}, doi = {10.2174/1567205018666210218161856}, pmid = {33602092}, issn = {1875-5828}, mesh = {Alzheimer Disease/*metabolism ; Amyloid beta-Peptides/*metabolism ; Animals ; *High-Intensity Interval Training ; *Hippocampus ; Learning ; Male ; Memory/physiology ; *Neuroprotection ; Peptide Fragments/*metabolism ; *Physical Conditioning, Animal ; Rats ; Rats, Wistar ; }, abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common and irreversible neurodegenerative disorder, and amyloid peptide plays a central role in its pathogenesis. Physical training contributes as a beneficial adaptation to AD. However, these effects may be underestimated because much of the literature used fixed training prescription variables (intensity and volume) throughout the protocol. Moreover, researchers poorly understand whether chronic high-intensity interval training (HIIT) exerts similar effects on the brain tissue of individuals with AD.<br><br>OBJECTIVE: This study evaluated the effect of 8 minutes of HIIT with incremental overload in an AD model.<br><br>METHODS: Forty male Wistar rats were divided into four groups: an untrained Sham group, Sham trained group, Aβ1-42 (Alzheimer's) untrained group, and Aβ1-42 (Alzheimer's) trained group (n=10 rats per group). Animals underwent stereotactic surgery and received a hippocampal injection of Aβ1-42 or a saline solution. Seven days after surgery, two weeks of treadmill adaptation followed by a maximal running test (MRT) was performed. Then, animals were subjected to eight weeks of HIIT. Rats were sacrificed 24 h after the behavioral tests (open field and Morris water maze), hippocampal tissue was extracted to analyze the redox balance and BDNF/TrkB pathway, and neuritic plaques (NP) were detected by evaluating silver impregnation.<br><br>RESULTS: The AD trained group presented a physical capacity amelioration every two weeks and locomotor, learning, and memory improvements (p<0.05). These effects were accompanied by increased CAT and SOD levels, followed by decreased lipid peroxidation (p<0.05). Furthermore, increased activation of the BDNF/TrkB (p<0.05) pathway and decreased NP was observed.<br><br>CONCLUSION: Based on these results, MRT was essential for an excellent chronic training protocol prescription and overload adjustment. Therefore, 8 minutes of HIIT daily for 8 weeks may reduce behavioral deficits by promoting a positive redox balance and increased activity of the BDNF/TrkB pathway that may contribute to NP attenuation.}, }
@article {pmid33602090, year = {2020}, author = {Siafaka, PI and Mutlu, G and Okur, NÜ}, title = {Alzheimer's Disease and its Related Dementia Types: A Review on Their Management Via Nanotechnology Based Therapeutic Strategies.}, journal = {Current Alzheimer research}, volume = {17}, number = {14}, pages = {1239-1261}, doi = {10.2174/1567205018666210218160812}, pmid = {33602090}, issn = {1875-5828}, mesh = {Alzheimer Disease/*drug therapy ; Blood-Brain Barrier ; Brain/physiopathology ; Dementia, Vascular/drug therapy ; Drug Administration Routes ; *Drug Delivery Systems ; Humans ; Lipids ; *Nanoparticles ; *Nanotechnology ; }, abstract = {BACKGROUND: Dementia and its related types such as Alzheimer's disease, vascular dementia and mixed dementia belong to brain associated diseases, resulting in long-term progressive memory loss. These diseases are so severe that can affect a person's daily routine. Up to date, treatment of dementia is still an unmet challenge due to their complex pathophysiology and unavailable efficient pharmacological approaches. The use of nanotechnology based pharmaceutical products could possibly improve the management of dementia given that nanocarriers could more efficiently deliver drugs to the brain.<br><br>OBJECTIVE: The objective of this study is to provide the current nanotechnology based drug delivery systems for the treatment of various dementia types. In addition, the current diagnosis biomarkers for the mentioned dementia types along with their available pharmacological treatment are being discussed.<br><br>METHODS: An extensive review of the current nanosystems such as brain drug delivery systems against Alzheimer's disease, vascular dementia and mixed dementia was performed. Moreover, nanotheranostics as possible imaging markers for such dementias were also reported.<br><br>RESULTS: The field of nanotechnology is quite advantageous for targeting dementia given that nanoscale drug delivery systems easily penetrate the blood brain barrier and circulate in the body for prolonged time. These nanoformulations consist of polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, microemulsions, nanoemulsions, and liquid crystals. The delivery of the nanotherapeutics can be achieved via various administration routes such as transdermal, injectable, oral, and more importantly, through the intranasal route. Nonetheless, the nanocarriers are mostly limited to Alzheimer's disease targeting; thus, nanocarriers for other types of dementia should be developed.<br><br>CONCLUSION: To conclude, understanding the mechanism of neurodegeneration and reviewing the current drug delivery systems for Alzheimer's disease and other dementia types are significant for medical and pharmaceutical society to produce efficient therapeutic choices and novel strategies based on multifunctional and biocompatible nanocarriers, which can deliver the drug sufficiently into the brain.}, }
@article {pmid33586916, year = {2021}, author = {Ghotbeddin, Z and Tabandeh, MR and Pourmahdi Borujeni, M and Fahimi Truski, F and Zalaki Ghorbani Pour, MR and Tabrizian, L}, title = {Crocin mitigated cognitive impairment and brain molecular alterations induced by different intensities of prenatal hypoxia in neonatal rats.}, journal = {Brain and behavior}, volume = {11}, number = {4}, pages = {e02078}, pmid = {33586916}, issn = {2162-3279}, mesh = {*Amyloid Precursor Protein Secretases ; Animals ; Animals, Newborn ; Aspartic Acid Endopeptidases/genetics ; Brain ; Carotenoids ; *Cognitive Dysfunction/drug therapy ; Female ; Hypoxia/drug therapy ; Pregnancy ; Rats ; }, abstract = {INTRODUCTION: Brain hypoxia has important role to the onset and progression of sporadic form of Alzheimer disease via expression of hypoxia-inducible factor-1 (HIF-1). Crocin by anti-amyloidogenic property inhibits β-amyloid formation. However, the molecular mechanism associated with anti-amyloidogenic activity of crocin is unknown. So, the present study was designed to investigate the effect of crocin on cognitive behavior and expression of HIF-1α and β-secretase (BACE1) genes in the brain of neonate rats following different intensities of hypoxia during pregnancy.<br><br>MATERIAL AND METHODS: Pregnant female rats were divided into six groups including sham, control crocin treated (CC), hypoxia with three different intensities (H1-H3), and most intense of hypoxic group treated with crocin (H3C) (30 mg/kg; i.p) at P14. Hypoxia induced on the 20th day of pregnancy. Animals in sham and CC were put in hypoxia chamber at the same time of hypoxia group without any hypoxia induction. Morris water maze (MWM) and qRT-PCR were used to evaluate the cognitive behavior and mRNA levels of BACE1 and HIF-1α genes in the brain tissues.<br><br>RESULTS: Animal under 7% O2 + 93% N2 condition for 3 hr showed the highest cognitive behavior impairment and upregulated HIF-1α and BACE1 mRNA in brains of offspring (p < .001). Crocin treatment improved memory impairment and attenuated the gene expression of HIF-1α and BACE1 in the brains of neonate rat.<br><br>CONCLUSIONS: It was concluded that crocin has beneficial effects on the brain of neonate rats under gestational hypoxia by improvement of memory impairment and molecular alteration related to hypoxia.}, }
@article {pmid33579844, year = {2021}, author = {Yu, E and Liao, Z and Fan, W and Hu, W and Tian, G and Chen, K and Chen, S and Hua, H and Zheng, H and Fang, X and Li, G and Xie, J and Wu, S}, title = {The Economic Burden of Alzheimer's Disease in Zhejiang Province.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {80}, number = {2}, pages = {539-553}, doi = {10.3233/JAD-201285}, pmid = {33579844}, issn = {1875-8908}, mesh = {Age Factors ; Aged ; Aged, 80 and over ; Alzheimer Disease/*economics ; China ; Comorbidity ; *Cost of Illness ; Educational Status ; Employment ; Female ; Health Care Costs ; Humans ; Male ; Marital Status ; Mental Status and Dementia Tests ; Middle Aged ; Socioeconomic Factors ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: The World Alzheimer Report has described and predicted the economic burden of Alzheimer's disease (AD) patients in detail for four consecutive years. There was a large-scale national survey in China launched by Professor Jianping Jia in 2015, but it did not adequately represent the average economic burden of AD patients in Zhejiang Province.<br><br>OBJECTIVE: To investigate the economic burden and main factors influencing Alzheimer's disease (AD) in Zhejiang Province.<br><br>METHODS: We recruited 830 patients from 10 cities in Zhejiang Province, evaluated their per capita and total cost related to AD treatment and care in 2017, and analyzed the main factors affecting economic burden from the perspective of demographic characteristics and disease severity.<br><br>RESULTS: In 2017, per capita cost of AD was 114,343.7 yuan, while the total cost was 27.53 billion yuan, accounting for 0.77% of Zhejiang Province's GDP (5176.8 billion yuan). Total cost, direct medical cost, and indirect cost have different correlations with age, education level, type of work, marital status, comorbidity, and disease severity.<br><br>CONCLUSION: The economic burden of AD in Zhejiang Province is heavy, similar to the national burden, and interventions based on demographic characteristics and disease severity can help reduce it.}, }
@article {pmid33577362, year = {2021}, author = {Ratto, F and Franchini, F and Musicco, M and Caruso, G and Di Santo, SG}, title = {A narrative review on the potential of tomato and lycopene for the prevention of Alzheimer's disease and other dementias.}, journal = {Critical reviews in food science and nutrition}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/10408398.2021.1880363}, pmid = {33577362}, issn = {1549-7852}, abstract = {Oxidative stress is a major factor in aging and is implicated in the pathogenesis of tumors, diabetes mellitus, cardiovascular and neurodegenerative diseases, including Alzheimer Disease (AD). Bioactive constituents of tomato as polyphenols and carotenoids, among which lycopene (LYC) are effective in reducing markers of oxidative stress, and appear to have a protective modulator role on the pathogenetic mechanisms, cognitive symptoms and behavioral manifestations of these diseases in cell cultures and animal models. Epidemiological evidence indicates a consistent association between the intake of tomatoes and reduced cardiovascular and neoplastic risk. LYC deficiency is common in elders and AD patients and it is strongly predictive of mortality and poor cardiovascular (CV) outcomes. Dietary intake of tomatoes seems to be more effective than tomato/LYC supplementation. Limited evidence from human intervention trials suggests that increasing tomato intake, besides improving CV markers, enhances cognitive performances. In this narrative review, we analyze the existing evidence on the beneficial effects of tomatoes on AD-related processes or risk factors. Results support the development of promising nutritional strategies to increase the levels of tomato consumption for the prevention or treatment of AD and other dementias. Extensive well-structured research, however, is mandatory to confirm the neuroprotective effects of tomato/LYC in humans.}, }
@article {pmid33573114, year = {2021}, author = {Garad, M and Edelmann, E and Leßmann, V}, title = {Impairment of Spike-Timing-Dependent Plasticity at Schaffer Collateral-CA1 Synapses in Adult APP/PS1 Mice Depends on Proximity of Aβ Plaques.}, journal = {International journal of molecular sciences}, volume = {22}, number = {3}, pages = {}, pmid = {33573114}, issn = {1422-0067}, support = {Project No. 643417, jointly supported by BMBF and Horizon 2020//EU Joint Programme - Neurodegenerative Disease Research/ ; }, mesh = {Alzheimer Disease/drug therapy/genetics/*pathology/physiopathology ; Amyloid beta-Peptides/genetics/metabolism ; Amyloid beta-Protein Precursor/genetics ; Animals ; CA1 Region, Hippocampal/cytology/*pathology/physiopathology ; Disease Models, Animal ; Fingolimod Hydrochloride/administration &amp; dosage ; Humans ; Long-Term Potentiation/drug effects/*physiology ; Male ; Mice ; Mice, Transgenic ; Mutation ; Patch-Clamp Techniques ; Plaque, Amyloid/drug therapy/genetics/*pathology/physiopathology ; Presenilin-1/genetics ; Pyramidal Cells/drug effects/pathology/physiology ; Synapses/drug effects/*pathology/physiology ; }, abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-β (Aβ) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aβ plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aβ plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aβ plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aβ plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.}, }
@article {pmid33570733, year = {2021}, author = {Saleem, U and Akhtar, R and Anwar, F and Shah, MA and Chaudary, Z and Ayaz, M and Ahmad, B}, title = {Neuroprotective potential of Malva neglecta is mediated via down-regulation of cholinesterase and modulation of oxidative stress markers.}, journal = {Metabolic brain disease}, volume = {36}, number = {5}, pages = {889-900}, pmid = {33570733}, issn = {1573-7365}, mesh = {Alzheimer Disease/drug therapy/*metabolism ; Animals ; Cholinesterases/*metabolism ; Cognition/drug effects ; Down-Regulation/drug effects ; Female ; Glutathione/metabolism ; Male ; Malva ; Maze Learning/drug effects ; Neuroprotective Agents/*pharmacology/therapeutic use ; Oxidative Stress/*drug effects/physiology ; Plant Extracts/*pharmacology/therapeutic use ; Ra