@article {pmid34329683,
year = {2021},
author = {Sato, K and Watamura, N and Fujioka, R and Mihira, N and Sekiguchi, M and Nagata, K and Ohshima, T and Saito, T and Saido, TC and Sasaguri, H},
title = {A 3rd generation mouse model of Alzheimer's disease shows early and increased cored plaque pathology composed of wild-type human amyloid β peptide.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {101004},
doi = {10.1016/j.jbc.2021.101004},
pmid = {34329683},
issn = {1083-351X},
abstract = {We previously developed single App knock-in mouse models of Alzheimer's disease (AD) harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice, respectively). These models showed Aβ pathology, neuroinflammation, and cognitive impairment in an age-dependent manner. The former model exhibits extensive pathology as early as 6 months, but is unsuitable for investigating Aβ metabolism and clearance because the Arctic mutation renders Aβ resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aβ antibodies. The latter model may take as long as 18 months for the pathology to become prominent, which leaves an unfulfilled need for an Alzheimer's disease animal model that is both swift to show pathology and useful for antibody therapy. We thus utilized mutant Psen1 knock-in mice into which a pathogenic mutation (P117L) had been introduced to generate a new model that exhibits early deposition of wild-type human Aβ by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new 3rd generation mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice, and will help accelerate the development of disease-modifying therapies to treat preclinical AD.},
}

@article {pmid34328428,
year = {2021},
author = {O'Loughlin, P and Pavithra, P and Regan, J and Bennett, M and Knight, R and Lenaert, B and Marquez, M and Taddeo, M and Griffith, J and Shapiro, R and Farina, F},
title = {A Randomized Controlled Trial Investigating the Feasibility of a Low-Intensity Psychological Intervention for Fear of Memory Loss and Quality of Life in Older Adults: Protocol for the Reducing Fear and Avoidance of Memory Loss (REFRAME) Study.},
journal = {JMIR research protocols},
volume = {10},
number = {7},
pages = {e30514},
doi = {10.2196/30514},
pmid = {34328428},
issn = {1929-0748},
abstract = {BACKGROUND: Dementia is the most feared disease associated with aging. Prolonged fears about memory loss and dementia can have harmful consequences even in the absence of cognitive decline. Fear of dementia is associated with poorer health outcomes and psychological well-being and increased memory failures in older adults.

OBJECTIVE: We will conduct a randomized controlled trial to determine the feasibility of a tailored, web-based mindfulness program to reduce fear of memory loss and increase quality of life in older adults experiencing heightened fear.

METHODS: Eighty participants will be recruited and divided into 2 groups (40 in each group). One group will receive psychoeducation plus mindfulness training. A second group will receive psychoeducation, mindfulness training, and additional modules targeting maladaptive behavioral avoidance (ie, social and cognitive withdrawal).

RESULTS: Our recent etiological model posits that maladaptive behavioral avoidance strategies critically underlie psychosocial dysfunction associated with fear of memory loss. Thus, we predict better outcomes in the second group, including reduced fear of memory loss (primary outcome), Alzheimer disease, anxiety, and subjective memory failures, and increased quality of life (secondary outcomes). Outcome measures will be applied at 5 time points (before, baseline, interim, and after the intervention, and at 3-month follow-up). Data will be analyzed using mixed models and correlations.

CONCLUSIONS: Results from this study will contribute to the current literature on dementia-related fear and improve our understanding of how to effectively address and reduce these fears.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04821960; https://clinicaltrials.gov/ct2/show/NCT04821960.

PRR1-10.2196/30514.},
}

@article {pmid34324551,
year = {2021},
author = {Pérez-Arancibia, R and Ordoñez, JL and Rivas, A and Pihán, P and Sagredo, A and Ahumada, U and Barriga, A and Seguel, I and Cárdenas, C and Vidal, RL and Hetz, C and Delporte, C},
title = {A phenolic-rich extract from Ugni molinae berries reduces abnormal protein aggregation in a cellular model of Huntington's disease.},
journal = {PloS one},
volume = {16},
number = {7},
pages = {e0254834},
doi = {10.1371/journal.pone.0254834},
pmid = {34324551},
issn = {1932-6203},
abstract = {Accumulation of misfolded proteins in the brain is a common hallmark of most age-related neurodegenerative diseases. Previous studies from our group identified the presence of anti-inflammatory and antioxidant compounds in leaves derived from the Chilean berry Ugni molinae (murtilla), in addition to show a potent anti-aggregation activity in models of Alzheimer´s disease. However, possible beneficial effects of berry extracts of murtilla was not investigated. Here we evaluated the efficacy of fruit extracts from different genotypes of Chilean-native U. molinae on reducing protein aggregation using cellular models of Huntington´s disease and assess the correlation with their chemical composition. Berry extraction was performed by exhaustive maceration with increasing-polarity solvents. An unbiased automatic microscopy platform was used for cytotoxicity and protein aggregation studies in HEK293 cells using polyglutamine-EGFP fusion proteins, followed by secondary validation using biochemical assays. Phenolic-rich extracts from murtilla berries of the 19-1 genotype (ETE 19-1) significantly reduced polyglutamine peptide aggregation levels, correlating with the modulation in the expression levels of autophagy-related proteins. Using LC-MS and molecular network analysis we correlated the presence of flavonoids, phenolic acids, and ellagitannins with the protective effects of ETE 19-1 effects on protein aggregation. Overall, our results indicate the presence of bioactive components in ethanolic extracts from U. molinae berries that reduce the load of protein aggregates in living cells.},
}

@article {pmid34322508,
year = {2021},
author = {Sukkar, SG and Muscaritoli, M},
title = {A Clinical Perspective of Low Carbohydrate Ketogenic Diets: A Narrative Review.},
journal = {Frontiers in nutrition},
volume = {8},
number = {},
pages = {642628},
doi = {10.3389/fnut.2021.642628},
pmid = {34322508},
issn = {2296-861X},
abstract = {Low carbohydrates diets (LCDs), which provide 20-120 g of carbohydrates per day, have long been used as therapeutic options in the treatment of severe obesity, type 2 diabetes mellitus and other morbid conditions, with good results in terms of weight loss and control of the main metabolic parameters, at least in the short and medium term. According to the caloric content and the macronutrient composition, we can classify LCDs in hypocaloric, normoproteic diets [such as the Very Low-Calorie Ketogenic Diet (VLCKD) or the protein-sparing modified fasting (PSMF)], hypocaloric, hyperproteic and hyperlipidic diets (e.g., Atkins, Paleo diets…) and normocaloric, normo-/hyperproteic diets (eucaloric KD), the latter mainly used in patients with brain tumors (gliomas) and refractory epilepsy. In addition to LCD diets, another interesting dietary approach which gained attention in the last few decades is fasting and its beneficial effects in terms of modulation of metabolic pathways, cellular processes and hormonal secretions. Due to the impossibility of using fasting regimens for long periods of time, several alternative strategies have been proposed that can mimic the effects, including calorie restriction, intermittent or alternating fasting, and the so-called fasting mimicking diets (FMDs). Recent preclinical studies have shown positive effects of FMDs in various experimental models of tumors, diabetes, Alzheimer Disease, and other morbid conditions, but to date, the scientific evidence in humans is limited to some opens studies and case reports. The purpose of our narrative review is to offer an overview of the characteristics of the main dietary regimens applied in the treatment of different clinical conditions as well as of the scientific evidence that justifies their use, focusing on low and zero-carb diets and on the different types of fasting.},
}

@article {pmid34321636,
year = {2021},
author = {Wood, H},
title = {Astrocytic IL-3 could help microglia protect against Alzheimer disease.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34321636},
issn = {1759-4766},
}

@article {pmid34320558,
year = {2021},
author = {Chauhan, AV and Guralnik, J and dosReis, S and Sorkin, JD and Badjatia, N and Albrecht, JS},
title = {Repetitive Traumatic Brain Injury Among Older Adults.},
journal = {The Journal of head trauma rehabilitation},
volume = {},
number = {},
pages = {},
doi = {10.1097/HTR.0000000000000719},
pmid = {34320558},
issn = {1550-509X},
abstract = {OBJECTIVE: To determine the incidence of and assess risk factors for repetitive traumatic brain injury (TBI) among older adults in the United States.

DESIGN: Retrospective cohort study.

SETTING: Administrative claims data obtained from the Centers for Medicare & Medicaid Services' Chronic Conditions Data Warehouse.

PARTICIPANTS: Individuals 65 years or older and diagnosed with TBI between July 2008 and September 2012 drawn from a 5% random sample of US Medicare beneficiaries.

MAIN MEASURES: Repetitive TBI was identified as a second TBI occurring at least 90 days after the first occurrence of TBI following an 18-month TBI-free period. We identified factors associated with repetitive TBI using a log-binomial model.

RESULTS: A total of 38 064 older Medicare beneficiaries experienced a TBI. Of these, 4562 (12%) beneficiaries sustained at least one subsequent TBI over up to 5 years of follow-up. The unadjusted incidence rate of repetitive TBI was 3022 (95% CI, 2935-3111) per 100 000 person-years. Epilepsy was the strongest predictor of repetitive TBI (relative risk [RR] = 1.44; 95% CI, 1.25-1.56), followed by Alzheimer disease and related dementias (RR = 1.32; 95% CI 1.20-1.45), and depression (RR = 1.30; 95% CI, 1.21-1.38).

CONCLUSIONS: Injury prevention and fall-reduction interventions could be targeted to identify groups of older adults at an increased risk of repetitive head injury. Future work should focus on injury-reduction initiatives to reduce the risk of repetitive TBI as well as assessment of outcomes related to repetitive TBI.},
}

@article {pmid34319442,
year = {2021},
author = {Chen, CD and Joseph-Mathurin, N and Sinha, N and Zhou, A and Li, Y and Friedrichsen, K and McCullough, A and Franklin, EE and Hornbeck, R and Gordon, B and Sharma, V and Cruchaga, C and Goate, A and Karch, C and McDade, E and Xiong, C and Bateman, RJ and Ghetti, B and Ringman, JM and Chhatwal, J and Masters, CL and McLean, C and Lashley, T and Su, Y and Koeppe, R and Jack, C and Klunk, WE and Morris, JC and Perrin, RJ and Cairns, NJ and Benzinger, TLS},
title = {Comparing amyloid-β plaque burden with antemortem PiB PET in autosomal dominant and late-onset Alzheimer disease.},
journal = {Acta neuropathologica},
volume = {},
number = {},
pages = {},
pmid = {34319442},
issn = {1432-0533},
support = {P30AG066444, P01AG026276, P01AG03991, UF1AG032438, U19 AG032438, U19 AG024904/NH/NIH HHS/United States ; U19AG032438/NH/NIH HHS/United States ; P30NS098577/NH/NIH HHS/United States ; K01AG053474/NH/NIH HHS/United States ; DGE-1745038//National Science Foundation/ ; AARFD-20-681815/ALZ/Alzheimer's Association/United States ; },
abstract = {Pittsburgh compound B (PiB) radiotracer for positron emission tomography (PET) imaging can bind to different types of amyloid-β plaques and blood vessels (cerebral amyloid angiopathy). However, the relative contributions of different plaque subtypes (diffuse versus cored/compact) to in vivo PiB PET signal on a region-by-region basis are incompletely understood. Of particular interest is whether the same staging schemes for summarizing amyloid-β burden are appropriate for both late-onset and autosomal dominant forms of Alzheimer disease (LOAD and ADAD). Here, we compared antemortem PiB PET with follow-up postmortem estimation of amyloid-β burden using stereologic methods to estimate the relative area fraction of diffuse and cored/compact amyloid-β plaques across 16 brain regions in 15 individuals with ADAD and 14 individuals with LOAD. In ADAD, we found that PiB PET correlated with diffuse plaques in the frontal, parietal, temporal, and striatal regions commonly used to summarize amyloid-β burden in PiB PET, and correlated with both diffuse and cored/compact plaques in the occipital lobe and parahippocampal gyrus. In LOAD, we found that PiB PET correlated with both diffuse and cored/compact plaques in the anterior cingulate, frontal lobe (middle frontal gyrus), and parietal lobe, and showed additional correlations with diffuse plaque in the amygdala and occipital lobe, and with cored/compact plaque in the temporal lobe. Thus, commonly used PiB PET summary regions predominantly reflect diffuse plaque burden in ADAD and a mixture of diffuse and cored/compact plaque burden in LOAD. In direct comparisons of ADAD and LOAD, postmortem stereology identified much greater mean amyloid-β plaque burdens in ADAD versus LOAD across almost all brain regions studied. However, standard PiB PET did not recapitulate these stereologic findings, likely due to non-trivial amyloid-β plaque burdens in ADAD within the cerebellum and brainstem-commonly used reference regions in PiB PET. Our findings suggest that PiB PET summary regions correlate with amyloid-β plaque burden in both ADAD and LOAD; however, they might not be reliable in direct comparisons of regional amyloid-β plaque burden between the two forms of AD.},
}

@article {pmid34315132,
year = {2021},
author = {Zeng, P and Fang, M and Zhao, H and Guo, J},
title = {A network pharmacology approach to uncover the key ingredients in Ginkgo Folium and their anti-Alzheimer's disease mechanisms.},
journal = {Aging},
volume = {13},
number = {undefined},
pages = {},
doi = {10.18632/aging.203348},
pmid = {34315132},
issn = {1945-4589},
abstract = {This study aimed to identify potential anti-Alzheimer's disease (AD) targets and action mechanisms of Ginkgo Folium (GF) through a network pharmacology approach. Eighty-four potential targets of 10 active anti-AD ingredients of GF were identified, among which genkwanin (GK) had the greatest number of AD-related targets. KEGG pathway enrichment analysis showed that the most significantly enriched signaling pathway of GF against AD was Alzheimer disease (hsa05010). More importantly, 29 of the 84 targets were significantly correlated with tau, Aβ or both Aβ and tau pathology. In addition, GO analysis suggested that the main biological processes of GF in AD treatment were the regulation of chemical synaptic transmission (GO:0007268), neuron death (GO:0070997), amyloid-beta metabolic process (GO:0050435), etc. We further investigated the anti-AD effects of GK using N2A-APP cells (a classical cellular model of AD). Treatment N2A-APP cells with 100 μM GK for 48 h affected core targets related to tau pathology (such as CDK5 and GSK3β). In conclusion, these findings indicate that GF exerts its therapeutic effects on AD by acting directly on multiple pathological processes of AD.},
}

@article {pmid34314956,
year = {2021},
author = {Voronkov, M and Ataiants, J and Cocchiaro, B and Stock, JB and Lankenau, SE},
title = {A vicious cycle of neuropathological, cognitive and behavioural sequelae of repeated opioid overdose.},
journal = {The International journal on drug policy},
volume = {97},
number = {},
pages = {103362},
doi = {10.1016/j.drugpo.2021.103362},
pmid = {34314956},
issn = {1873-4758},
abstract = {In the midst of an escalating U.S. opioid crisis, the immediate focus of public health interventions is on fatal overdose prevention. Few studies, however, have sought to examine the long-term health consequences of exposure to repeated nonfatal opioid overdose. We reviewed recent literature to examine three corresponding downstream health outcomes of repeated overdose: a) neurodegenerative processes; b) cognition and memory; and c) overdose risk behaviours. We found a remarkable congruency among available biochemical and cognitive data on how nonfatal overdose precipitates various pathological feedforward and feedback loops that affect people who use opioids for years to come. We found however that downstream behavioural implications of neurodegenerative and cognitive sequelae are less studied despite being most proximal to an overdose. Findings point to a vicious cycle of nonfatal overdose leading to neurodegeneration - closely resembling Alzheimer Disease - that results in cognitive decline that in turn leads to potentially reduced adherence to safe drug use behaviours. The collected evidence not only brings into the focus the long-term health consequences of nonfatal overdose from the perspectives of biology, neuroscience, and public health, but also creates new cross-disciplinary context and awareness in the research and public health community that should benefit people at risk.},
}

@article {pmid34314593,
year = {2021},
author = {Heinken, A and Basile, A and Hertel, J and Thinnes, C and Thiele, I},
title = {Genome-Scale Metabolic Modeling of the Human Microbiome in the Era of Personalized Medicine.},
journal = {Annual review of microbiology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-micro-060221-012134},
pmid = {34314593},
issn = {1545-3251},
abstract = {The human microbiome plays an important role in human health and disease. Meta-omics analyses provide indispensable data for linking changes in microbiome composition and function to disease etiology. Yet, the lack of a mechanistic understanding of, e.g., microbiome-metabolome links hampers the translation of these findings into effective, novel therapeutics. Here, we propose metabolic modeling of microbial communities through constraint-based reconstruction and analysis (COBRA) as a complementary approach to meta-omics analyses. First, we highlight the importance of microbial metabolism in cardiometabolic diseases, inflammatory bowel disease, colorectal cancer, Alzheimer disease, and Parkinson disease. Next, we demonstrate that microbial community modeling can stratify patients and controls, mechanistically link microbes with fecal metabolites altered in disease, and identify host pathways affected by the microbiome. Finally, we outline our vision for COBRA modeling combined with meta-omics analyses and multivariate statistical analyses to inform and guide clinical trials, yield testable hypotheses, and ultimately propose novel dietary and therapeutic interventions. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.},
}

@article {pmid34313551,
year = {2021},
author = {Tong, BC and Wu, AJ and Huang, AS and Dong, R and Malampati, S and Iyaswamy, A and Krishnamoorthi, S and Sreenivasmurthy, SG and Zhu, Z and Su, C and Liu, J and Song, J and Lu, JH and Tan, J and Pan, W and Li, M and Cheung, KH},
title = {Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/15548627.2021.1945220},
pmid = {34313551},
issn = {1554-8635},
abstract = {ABBREVIATIONS: Aβ: β-amyloid; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ALP: autophagy-lysosomal pathway; APP: amyloid beta precursor protein; ATP6V1B1/V-ATPase V1b1: ATPase H+ transporting V1 subunit B1; AVs: autophagy vacuoles; BAF: bafilomycin A1; CFC: contextual/cued fear conditioning assay; CHX: Ca2+/H+ exchanger; CTF-β: carboxy-terminal fragment derived from β-secretase; CTSD: cathepsin D; fAD: familial Alzheimer disease; GFAP: glial fibrillary acidic protein; LAMP1: lysosomal associated membrane protein 1; LTP: long-term potentiation; MCOLN1/TRPML1: mucolipin 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPT: microtubule associated protein tau; MWM: Morris water maze; NFT: neurofibrillary tangles; PFC: prefrontal cortex; PSEN1: presenilin 1; SQSTM1/p62: sequestosome 1; TBS: theta burst stimulation; TEM: transmission electronic microscopy; TPCN2/TPC2: two pore segment channel 2; WT: wild-type; V-ATPase: vacuolar type H+-ATPase.},
}

@article {pmid34313331,
year = {2021},
author = {Arevalo-Rodriguez, I and Smailagic, N and Roqué-Figuls, M and Ciapponi, A and Sanchez-Perez, E and Giannakou, A and Pedraza, OL and Bonfill Cosp, X and Cullum, S},
title = {Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI).},
journal = {The Cochrane database of systematic reviews},
volume = {7},
number = {},
pages = {CD010783},
pmid = {34313331},
issn = {1469-493X},
abstract = {BACKGROUND: Dementia is a progressive global cognitive impairment syndrome. In 2010, more than 35 million people worldwide were estimated to be living with dementia. Some people with mild cognitive impairment (MCI) will progress to dementia but others remain stable or recover full function. There is great interest in finding good predictors of dementia in people with MCI. The Mini-Mental State Examination (MMSE) is the best-known and the most often used short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings.

OBJECTIVES: To determine the accuracy of the Mini Mental State Examination for the early detection of dementia in people with mild cognitive impairment SEARCH METHODS: We searched ALOIS (Cochrane Dementia and Cognitive Improvement Specialized Register of diagnostic and intervention studies (inception to May 2014); MEDLINE (OvidSP) (1946 to May 2014); EMBASE (OvidSP) (1980 to May 2014); BIOSIS (Web of Science) (inception to May 2014); Web of Science Core Collection, including the Conference Proceedings Citation Index (ISI Web of Science) (inception to May 2014); PsycINFO (OvidSP) (inception to May 2014), and LILACS (BIREME) (1982 to May 2014). We also searched specialized sources of diagnostic test accuracy studies and reviews, most recently in May 2014: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). No language or date restrictions were applied to the electronic searches and methodological filters were not used as a method to restrict the search overall so as to maximize sensitivity. We also checked reference lists of relevant studies and reviews, tracked citations in Scopus and Science Citation Index, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on MMSE for dementia diagnosis to try to locate possibly relevant but unpublished data.

SELECTION CRITERIA: We considered longitudinal studies in which results of the MMSE administered to MCI participants at baseline were obtained and the reference standard was obtained by follow-up over time. We included participants recruited and clinically classified as individuals with MCI under Petersen and revised Petersen criteria, Matthews criteria, or a Clinical Dementia Rating = 0.5. We used acceptable and commonly used reference standards for dementia in general, Alzheimer's dementia, Lewy body dementia, vascular dementia and frontotemporal dementia.

DATA COLLECTION AND ANALYSIS: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create two by two tables for dementia in general and other dementias. Two authors independently performed quality assessment using the QUADAS-2 tool. Due to high heterogeneity and scarcity of data, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic curve.

MAIN RESULTS: In this review, we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of the MMSE in conversion from MCI to all-cause dementia and eight studies assessed this test in conversion from MCI to Alzheimer´s disease dementia. Only one study provided information about the MMSE and conversion from MCI to vascular dementia. For conversion from MCI to dementia in general, the accuracy of baseline MMSE scores ranged from sensitivities of 23% to 76% and specificities from 40% to 94%. In relationship to conversion from MCI to Alzheimer's disease dementia, the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%. Only one study provided information about conversion from MCI to vascular dementia, presenting a sensitivity of 36% and a specificity of 80% with an incidence of vascular dementia of 6.2%. Although we had planned to explore possible sources of heterogeneity, this was not undertaken due to the scarcity of studies included in our analysis.

AUTHORS' CONCLUSIONS: Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia.},
}

@article {pmid34312362,
year = {2021},
author = {Lv, S and Zhou, X and Li, Y and Zhang, S and Wang, Y and Jia, S and Niu, X and Wang, L and Peng, D},
title = {The Association Between Plasma α-Synuclein (α-syn) Protein, Urinary Alzheimer-Associated Neuronal Thread Protein (AD7c-NTP), and Apolipoprotein Epsilon 4 (ApoE ε4) Alleles and Cognitive Decline in 60 Patients with Alzheimer's Disease Compared with 28 Age-Matched Normal Individuals.},
journal = {Medical science monitor : international medical journal of experimental and clinical research},
volume = {27},
number = {},
pages = {e932998},
doi = {10.12659/MSM.932998},
pmid = {34312362},
issn = {1643-3750},
abstract = {BACKGROUND Accumulating evidence has shown that alpha-synuclein (alpha-syn) pathology is involved in the pathophysiology of Alzheimer's disease (AD). This study aimed to investigate the association between the levels of plasma alpha-syn protein, urinary Alzheimer-associated neuronal thread protein (AD7c-NTP), apolipoprotein epsilon 4 (ApoE ε4) alleles and cognitive decline in 60 AD patients compared with 28 age-matched normal controls (NCs) at a single center. MATERIAL AND METHODS All participants underwent alpha-syn, apolipoprotein E (ApoE), AD7c-NTP, cholesterol (CHO), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TGs) analyses, neuropsychological scale assessments and neuroimaging analysis. Moreover, urine and peripheral blood samples were collected from all participants. The levels of plasma alpha-syn and AD7c-NTP were assayed using an enzyme-linked immunosorbent assay (ELISA) kit. Other test results were obtained from China-Japan Friendship Hospital. RESULTS We found that plasma alpha-syn levels were significantly different between AD patients and NCs (p=0.045). alpha-Syn levels were also associated with AD7c-NTP (r=0.231, p=0.03) but not ApoE e4 (Z=-0.147, p=0.883) levels. Neither a-syn [CHO (p=0.432), HDL (p=0.484), LDL (p=0.733) or TGs (p=0.253)] nor AD7c-NTP [CHO (p=0.867), HDL (p=0.13), LDL (p=0.57) or TGs (p=0.678)] had a relationship with lipids. CONCLUSIONS This study showed that the levels of plasma alpha-syn protein and urinary AD7c-NTP were significantly increased in AD patients compared with NCs, but not with ApoE alleles or serum lipid levels.},
}

@article {pmid34311759,
year = {2021},
author = {Sarahian, N and Sarvazad, H and Sajadi, E and Rahnejat, N and Eskandari Roozbahani, N},
title = {Investigation of common risk factors between polycystic ovary syndrome and Alzheimer's disease: a narrative review.},
journal = {Reproductive health},
volume = {18},
number = {1},
pages = {156},
pmid = {34311759},
issn = {1742-4755},
mesh = {*Alzheimer Disease/epidemiology/etiology ; *Anovulation ; Female ; Humans ; *Hyperandrogenism ; *Insulin Resistance ; *Polycystic Ovary Syndrome/complications ; Risk Factors ; },
abstract = {BACKGROUND: The most common endocrine and metabolic disorders in premenopausal women is polycystic ovary syndrome (PCOS), characterized by hyperandrogenism, chronic anovulation, and/or ultrasound evidence of small ovarian cysts. Obesity and insulin resistance are also the main factors influencing the clinical manifestations of this syndrome. Alzheimer's disease (AD) is the most typical progressive neurodegenerative disorder of the brain, and recent studies suggest a relationship between endocrinal dysregulation and neuronal loss during AD pathology.

AIM: This study aimed to evaluate the common risk factors for Alzheimer's and PCOS based on previous studies. Knowing the common risk factors and eliminating them may prevent neurodegenerative Alzheimer's disease in the future.

METHOD: In this narrative review, international databases, including Google Scholar, Scopus, PubMed, and the Web of Science, were searched to retrieve the relevant studies. The relevant studies' summaries were categorized to discuss the possible pathways that may explain the association between Alzheimer's and PCOS signs/symptoms and complications.

RESULTS: According to our research, the factors involved in Alzheimer's and PCOS disorders may share some common risk factors. In patients with PCOS, increased LH to FSH ratio, decreased vitamin D, insulin resistance, and obesity are some of the most important factors that may increase the risk of Alzheimer's disease.},
}

*Alzheimer Disease/epidemiology/etiology
*Anovulation
Female
Humans
*Hyperandrogenism
*Insulin Resistance
*Polycystic Ovary Syndrome/complications
Risk Factors

@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 & 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.

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.

CONCLUSIONS: Collectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.},
}

@article {pmid34310820,
year = {2021},
author = {Foxe, D and Irish, M and D'Mello, M and Barhon, L and Burrell, JR and Kessels, RPC and Piguet, O},
title = {The Box Task: A novel tool to differentiate the primary progressive aphasias.},
journal = {European journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1111/ene.15035},
pmid = {34310820},
issn = {1468-1331},
abstract = {OBJECTIVE: Differentiating the primary progressive aphasia (PPA) variants in clinical settings remains complex and challenging, especially for the logopenic (lv-PPA) and non-fluent variants (nfv-PPA). Recent studies suggest that visuospatial memory is more compromised in lv-PPA than in nfv-PPA and is relatively spared in the semantic variant (sv-PPA). Accordingly, assessment of visuospatial memory performance may assist in the differential diagnosis of PPA variants. Here, we investigated the utility of a novel computerised visuospatial working memory test-the Box Task-to differentiate the three PPA variants and typical Alzheimer's disease (AD).

METHODS: Eighteen lv-PPA, 14 nfv-PPA, 23 sv-PPA, 33 AD patients, and 32 healthy controls matched for age and education were recruited. All participants completed the computerised Box Task and WMS-III Spatial Span as measures of visuospatial working memory.

RESULTS: The lv-PPA group made significantly more Box Task between-search errors than nfv-PPA, sv-PPA and control groups. The AD group, however, displayed the greatest impairments on this measure relative to the PPA variants. Logistic regression analyses in lv-PPA and nfv-PPA demonstrated that the combination of Box Task between-search error variables (i.e., 4- and 6-box levels) could correctly classify 72% of lv-PPA patients and nearly 79% of nfv-PPA patients. Area under the receiver operator characteristics curve (AUC) analyses revealed the Box Task was more sensitive than Spatial Span at differentiating lv-PPA from nfv-PPA.

CONCLUSIONS: Our findings suggest that a simple, computerised measure of visuospatial working memory-the Box Task-shows potential diagnostic utility in differentiating lv-PPA from the other PPA variants.},
}

@article {pmid34310441,
year = {2021},
author = {Bastin, C and Bahri, MA and Giacomelli, F and Miévis, F and Lemaire, C and Degueldre, C and Balteau, E and Guillaume, B and Salmon, E},
title = {Familiarity in Mild Cognitive Impairment as a Function of Patients' Clinical Outcome 4 Years Later.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000466},
pmid = {34310441},
issn = {1546-4156},
abstract = {OBJECTIVES: The current study addresses the nature of memory difficulties in amnestic mild cognitive impairment (aMCI). Whereas recollection is consistently found to be impaired in aMCI, the results on familiarity are divergent. One potential factor that could explain this divergence in findings relates to the heterogeneity of aMCI patients, so that only those aMCI patients who develop Alzheimer disease (AD) may present with impaired familiarity. The present study aimed at testing this hypothesis.

METHODS: A group of 45 aMCI patients and a group of 26 healthy older adults performed a verbal recognition memory test with the Remember/Know paradigm to assess recollection and familiarity processes. All participants were followed for 4 years with clinical and neuropsychological testing. At the end of follow-up, 22 aMCI patients progressed to AD and 23 aMCI patients remained stable. Initial memory performance was compared between the 3 groups.

RESULTS: Whereas recollection was severely diminished in all aMCI patients, familiarity accuracy (and consequently global recognition accuracy) was found to be impaired only in aMCI patients who subsequently developed AD.

CONCLUSION: These findings suggest that the enrichment of the aMCI population with predementia stage patients may modulate the likelihood to observe familiarity deficits, and impaired global recognition accuracy may accompany incipient AD.},
}

@article {pmid34309632,
year = {2021},
author = {Mielke, MM and Frank, RD and Dage, JL and Jeromin, A and Ashton, NJ and Blennow, K and Karikari, TK and Vanmechelen, E and Zetterberg, H and Algeciras-Schimnich, A and Knopman, DS and Lowe, V and Bu, G and Vemuri, P and Graff-Radford, J and Jack, CR and Petersen, RC},
title = {Comparison of Plasma Phosphorylated Tau Species With Amyloid and Tau Positron Emission Tomography, Neurodegeneration, Vascular Pathology, and Cognitive Outcomes.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2293},
pmid = {34309632},
issn = {2168-6157},
abstract = {Importance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed.

Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes.

This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible.

Main Outcomes And Measures: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition.

Results: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity.

Conclusions and Relevance: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.},
}

@article {pmid34309066,
year = {2021},
author = {Montal, V and Barroeta, I and Bejanin, A and Pegueroles, J and Carmona-Iragui, M and Altuna, M and Benejam, B and Videla, L and Fernández, S and Padilla, C and Aranha, M and Iulita, F and Vidal-Piñeiro, D and Alcolea, D and Blesa, R and Lleó, A and Fortea, J and , },
title = {Metabolite signature of Alzheimer's disease in adults with Down syndrome.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.26178},
pmid = {34309066},
issn = {1531-8249},
abstract = {OBJECTIVE: To examine the Alzheimer's Disease metabolite signature through magnetic resonance spectroscopy in adults with Down syndrome and its relation with Alzheimer's Disease biomarkers and cortical thickness.

METHODS: We included 118 adults with Down syndrome from the Down Alzheimer Barcelona Imaging Initiative and 71 euploid healthy controls from the Sant Pau Initiative on Neurodegeneration cohort. We measured the levels of myo-inositol (a marker of neuroinflammation) and N-acetyl-aspartate (a marker of neuronal integrity) in the precuneus using magnetic resonance spectroscopy. We investigated the changes with age and along the disease continuum (asymptomatic, prodromal Alzheimer's Disease, and Alzheimer's Disease dementia stages). We assessed the relationship between these metabolites and Aβ42 /Aβ40 ratio, phosphorylated tau-181, NfL, and YKL-40 Cerebrospinal fluid levels as well as amyloid positron emission tomography uptake using Spearman correlations controlling for multiple comparisons. Finally, we computed the relationship between cortical thickness and metabolite levels using Freesurfer.

RESULTS: Asymptomatic adults with Down syndrome had a 27.5% increase in the levels of myo-inositol, but equal levels of N-acetyl-aspartate compared to euploid healthy controls. With disease progression, myo-inositol levels increased while N-acetyl-aspartate levels decreased in symptomatic stages of the disease. Myo-inositol was associated with amyloid, tau, and neurodegeneration markers, mainly at symptomatic stages of the disease, whereas N-acetyl-aspartate was related to neurodegeneration biomarkers in symptomatic stages. Both metabolites were significantly associated with cortical thinning, mainly in symptomatic participants.

INTERPRETATION: Magnetic resonance spectroscopy detects Alzheimer's disease related inflammation and neurodegeneration, and could be a good noninvasive disease-stage biomarker in Down syndrome. This article is protected by copyright. All rights reserved.},
}

@article {pmid34303202,
year = {2021},
author = {Koga, S and Cheshire, WP and Tipton, PW and Driver-Dunckley, ED and Wszolek, ZK and Uitti, RJ and Graff-Radford, NR and van Gerpen, JA and Dickson, DW},
title = {Clinical features of autopsy-confirmed multiple system atrophy in the Mayo Clinic Florida brain bank.},
journal = {Parkinsonism & related disorders},
volume = {89},
number = {},
pages = {155-161},
doi = {10.1016/j.parkreldis.2021.07.007},
pmid = {34303202},
issn = {1873-5126},
abstract = {BACKGROUND: Multiple system atrophy (MSA) presents with various combinations of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Although clinical diagnostic criteria have been widely used, the sensitivity and specificity are suboptimal. This study aims to provide evidence supporting the revision of the current diagnostic criteria for MSA.

METHODS: Medical records of 171 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank were reviewed with regard to their clinical features and diagnoses. Pathologic features, including concomitant pathologies (i.e., Alzheimer-related and Lewy-related pathologies), were also assessed.

RESULTS: The cohort included 133 MSA-parkinsonian type, 36 MSA-cerebellar type, and 2 unclassified MSA patients who did not show significant motor symptoms. Twenty-three patients (13%) were not clinically diagnosed with MSA, but instead with progressive supranuclear palsy, Parkinson's disease (PD), PD with dementia (PDD), or dementia with Lewy bodies (DLB). Three patients with PDD and DLB also had concomitant Lewy body pathology. Six patients had late-onset MSA, with an age of onset greater than 75 years. Erectile dysfunction was frequent in male patients (60/63; 95%) in all age ranges. REM sleep behavior disorder (RBD) was present in 82 patients (48%) and was the initial symptom in 13 patients. Cognitive impairment was present in 60 patients (35%), but was an initial symptom in only two patients.

CONCLUSIONS: Our findings support the conclusion that late-onset presentation should not exclude MSA. The findings of this large autopsy-based cohort provides valuable insights for improving clinical criteria for MSA.},
}

@article {pmid34302786,
year = {2021},
author = {Fagan, AM and Henson, RL and Li, Y and Boerwinkle, AH and Xiong, C and Bateman, RJ and Goate, A and Ances, BM and Doran, E and Christian, BT and Lai, F and Rosas, HD and Schupf, N and Krinsky-McHale, S and Silverman, W and Lee, JH and Klunk, WE and Handen, BL and Allegri, RF and Chhatwal, JP and Day, GS and Graff-Radford, NR and Jucker, M and Levin, J and Martins, RN and Masters, CL and Mori, H and Mummery, CJ and Niimi, Y and Ringman, JM and Salloway, S and Schofield, PR and Shoji, M and Lott, IT and , and , },
title = {Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study.},
journal = {The Lancet. Neurology},
volume = {20},
number = {8},
pages = {615-626},
doi = {10.1016/S1474-4422(21)00139-3},
pmid = {34302786},
issn = {1474-4465},
abstract = {BACKGROUND: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer's disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer's disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer's disease.

METHODS: We did a cross-sectional study using data from adults enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer's disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer's disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer's disease mutations, and non-carrier siblings (aged 30-61 years) were analysed for markers of amyloid β (Aβ1-40, Aβ1-42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups.

FINDINGS: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30-61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer's disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer's disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer's disease mutations, including reductions (all p<0·0080) in Aβ1-42 to Aβ1-40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p<0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p<0·0008) in Down syndrome and potential elevations in CSF tau (p<0·010) and NfL (p<0·0001) in the asymptomatic stage (ie, no dementia symptoms).

FUNDING: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development.},
}

@article {pmid34302466,
year = {2021},
author = {Paumier, A and Boisseau, S and Jacquier-Sarlin, M and Pernet-Gallay, K and Buisson, A and Albrieux, M},
title = {Astrocyte-neuron interplay is critical for Alzheimer's disease pathogenesis and is rescued by TRPA1 channel blockade.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awab281},
pmid = {34302466},
issn = {1460-2156},
abstract = {The sequence of cellular dysfunctions in preclinical Alzheimer's disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer's disease in both humans and mouse models. The most common hypothesis describes amyloid β accumulation as the triggering factor of the disease but the effects of this accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection against Alzheimer's disease progression provided by early chronic pharmacological inhibition of TRPA1 channel. A specific inhibitor of TRPA1 channel (HC030031) was administered intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer's disease. Short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade were characterized on Alzheimer's disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels. Our results revealed that the first observable disruptions in the Alzheimer's disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction and preserves structural synaptic integrity. These protective effects preserved spatial working-memory in this Alzheimer's disease mouse model. The toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer's disease progression. TRPA1 blockade prevents irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.},
}

@article {pmid34301823,
year = {2021},
author = {Papke, RL and Horenstein, NA},
title = {Therapeutic Targeting of α7 Nicotinic Acetylcholine Receptors.},
journal = {Pharmacological reviews},
volume = {73},
number = {3},
pages = {1118-1149},
doi = {10.1124/pharmrev.120.000097},
pmid = {34301823},
issn = {1521-0081},
abstract = {The α7-type nicotinic acetylcholine receptor is one of the most unique and interesting of all the members of the cys-loop superfamily of ligand-gated ion channels. Since it was first identified initially as a binding site for α-bungarotoxin in mammalian brain and later as a functional homomeric receptor with relatively high calcium permeability, it has been pursued as a potential therapeutic target for numerous indications, from Alzheimer disease to asthma. In this review, we discuss the history and state of the art for targeting α7 receptors, beginning with subtype-selective agonists and the basic pharmacophore for the selective activation of α7 receptors. A key feature of α7 receptors is their rapid desensitization by standard "orthosteric" agonist, and we discuss insights into the conformational landscape of α7 receptors that has been gained by the development of ligands binding to allosteric sites. Some of these sites are targeted by positive allosteric modulators that have a wide range of effects on the activation profile of the receptors. Other sites are targeted by direct allosteric agonist or antagonists. We include a perspective on the potential importance of α7 receptors for metabotropic as well as ionotropic signaling. We outline the challenges that exist for future development of drugs to target this important receptor and approaches that may be considered to address those challenges. SIGNIFICANCE STATEMENT: The α7-type nicotinic acetylcholine receptor (nAChR) is acknowledged as a potentially important therapeutic target with functional properties associated with both ionotropic and metabotropic signaling. The functional properties of α7 nAChR can be regulated in diverse ways with the variety of orthosteric and allosteric ligands described in this review.},
}

@article {pmid34301434,
year = {2021},
author = {Zhang, WT and Zhang, GX and Gao, SS},
title = {The potential diagnostic accuracy of circulating microRNAs for Alzheimer's disease: A meta-analysis.},
journal = {Neurologia (Barcelona, Spain)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.nrl.2021.06.001},
pmid = {34301434},
issn = {1578-1968},
abstract = {BACKGROUND & OBJECTIVE: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease that seriously affects cognitive ability and has become a key public health problem. Many studies have identified the possibility of peripheral blood microRNA as effective non-invasive biomarkers for AD diagnosis, but the results are inconsistent. Therefore, we carried out this meta-analysis to evaluate the diagnostic accuracy of circulating microRNAs in the diagnosis of AD patients.

METHODS: We performed a systematic literature search of the following databases: PubMed, EMBASE, Web of Science, Cochrane Library, Wanfang database and China National Knowledge Infrastructure, updated to March 15, 2021. A random effects model was used to pool the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and area under the curve. Meta-regression and subgroup analysis were performed to explore the sources of heterogeneity, and Deeks' funnel plot was used to assess whether there was publication bias.

RESULTS: 62 studies from 18 articles were included in this meta-analysis. The pooled sensitivity was 0.82 (95% CI: 0.78-0.85), specificity was 0.80 (95% CI: 0.76-0.83), PLR was 4. 1 (95% CI: 3.4-4.9), NLR was 0.23 (95% CI: 0.19-0.28), DOR was 18 (95% CI: 13-25) and AUC was 0.88 (95% CI: 0.84-0.90). Subgroup analysis shows that the microRNA clusters of plasma type performed a better diagnostic accuracy of AD patients. In addition, publication bias was not found.

CONCLUSIONS: Circulating microRNAs can be used as a promising non-invasive biomarker in AD diagnosis.},
}

@article {pmid34301296,
year = {2021},
author = {Claes, C and Danhash, EP and Hasselmann, J and Chadarevian, JP and Shabestari, SK and England, WE and Lim, TE and Hidalgo, JLS and Spitale, RC and Davtyan, H and Blurton-Jones, M},
title = {Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {16},
number = {1},
pages = {50},
pmid = {34301296},
issn = {1750-1326},
support = {A2020451F//BrightFocus Foundation/ ; AG048099/NH/NIH HHS/United States ; AG056303/NH/NIH HHS/United States ; AG061895/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer's disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown.

METHODS: To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed.

RESULTS: Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE.

CONCLUSIONS: Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.},
}

@article {pmid34300282,
year = {2021},
author = {Lai, F and Mercaldo, N and Wang, CM and Hersch, GG and Rosas, HD},
title = {Association between Inflammatory Conditions and Alzheimer's Disease Age of Onset in Down Syndrome.},
journal = {Journal of clinical medicine},
volume = {10},
number = {14},
pages = {},
doi = {10.3390/jcm10143116},
pmid = {34300282},
issn = {2077-0383},
support = {U01-AG051412/NH/NIH HHS/United States ; },
abstract = {Adults with Down syndrome (DS) have an exceptionally high prevalence of Alzheimer disease (AD), with an earlier age of onset compared with the neurotypical population. In addition to beta amyloid, immunological processes involved in neuroinflammation and in peripheral inflammatory/autoimmune conditions are thought to play important roles in the pathophysiology of AD. Individuals with DS also have a high prevalence of autoimmune/inflammatory conditions which may contribute to an increased risk of early AD onset, but this has not been studied. Given the wide range in the age of AD onset in those with DS, we sought to evaluate the relationship between the presence of inflammatory conditions and the age of AD onset. We performed a retrospective study on 339 adults with DS, 125 who were cognitively stable (CS) and 214 with a diagnosis of AD. Data were available for six autoimmune conditions (alopecia, celiac disease, hypothyroidism, psoriasis, diabetes and vitamin B12 deficiency) and for one inflammatory condition, gout. Gout was associated with a significant delay in the age of AD onset by more than 2.5 years. Our data suggests that inflammatory conditions may play a role in the age of AD onset in DS. Further studies are warranted.},
}

@article {pmid34299650,
year = {2021},
author = {Naldi, M and Brusotti, G and Massolini, G and Andrisano, V and Temporini, C and Bartolini, M},
title = {Bio-Guided Fractionation of Stem Bark Extracts from Phyllanthus muellarianus: Identification of Phytocomponents with Anti-Cholinesterase Activity.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {14},
pages = {},
doi = {10.3390/molecules26144376},
pmid = {34299650},
issn = {1420-3049},
support = {no code//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; },
abstract = {A combination of flash chromatography, solid phase extraction, high-performance liquid chromatography, and in vitro bioassays was used to isolate phytocomponents endowed with anticholinesterase activity in extract from Phyllanthus muellarianus. Phytocomponents responsible for the anti-cholinesterase activity of subfractions PMF1 and PMF4 were identified and re-assayed to confirm their activity. Magnoflorine was identified as an active phytocomponent from PMF1 while nitidine was isolated from PMF4. Magnoflorine was shown to be a selective inhibitor of human butyrylcholinesterase-hBChE (IC50 = 131 ± 9 μM and IC50 = 1120 ± 83 μM, for hBuChE and human acetylcholinesterase-hAChE, respectively), while nitidine showed comparable inhibitory potencies against both enzymes (IC50 = 6.68 ± 0.13 μM and IC50 = 5.31 ± 0.50 μM, for hBChE and hAChE, respectively). When compared with the commercial anti-Alzheimer drug galanthamine, nitidine was as potent as galanthamine against hAChE and one order of magnitude more potent against hBuChE. Furthermore, nitidine also showed significant, although weak, antiaggregating activity towards amyloid-β self-aggregation.},
}

@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 = {},
doi = {10.3390/molecules26144301},
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/ ; },
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},
doi = {10.1001/jamanetworkopen.2021.17573},
pmid = {34297074},
issn = {2574-3805},
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.

Objective: To evaluate the associations between daytime and nighttime sleep duration with regional Aβ pathology in older cognitively unimpaired adults.

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.

Exposures: Self-reported daytime and nighttime sleep duration.

Main Outcomes and Measures: Regional Aβ pathology, measured by florbetapir PET standardized uptake value ratio.

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.

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 {pmid34296549,
year = {2021},
author = {Kim, YJ and Kim, HR and Jung, YH and Park, YH and Seo, SW},
title = {Effects of Electrical Automatic Massage on Cognition and Sleep Quality in Alzheimer's Disease Spectrum Patients: A Randomized Controlled Trial.},
journal = {Yonsei medical journal},
volume = {62},
number = {8},
pages = {717-725},
doi = {10.3349/ymj.2021.62.8.717},
pmid = {34296549},
issn = {1976-2437},
support = {//Bodyfriend/Korea ; },
mesh = {*Alzheimer Disease/therapy ; Anxiety/therapy ; Cognition ; Humans ; Massage ; Sleep ; },
abstract = {PURPOSE: Muscle relaxation following electrical automatic massage (EAM) has been found to reduce fatigue, depression, stress, anxiety, and pain in individuals with various conditions. However, the effects of EAM have not been extensively explored in patients with Alzheimer's disease (AD).

MATERIALS AND METHODS: Here, we conducted a randomized controlled study to evaluate the effects of EAM on the cognitive and non-cognitive functions of patients with AD spectrum disorders.

RESULTS: We found that EAM attenuated changes in attention-associated cognitive scores and subjective sleep quality relative to those in controls.

CONCLUSION: While further studies in a clinical setting are needed to support our findings, these encouraging results suggest that EAM may be an alternative therapy for the management of associated symptoms in AD (ClinicalTrials.gov ID: NCT03507192, 24/04/2018).},
}

*Alzheimer Disease/therapy
Anxiety/therapy
Cognition
Humans
Massage
Sleep

@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.

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.

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.

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},
doi = {10.9758/cpn.2021.19.3.423},
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 {pmid34292159,
year = {2021},
author = {Sato, K and Niimi, Y and Ihara, R and Suzuki, K and Toda, T and Iwata, A and Iwatsubo, T},
title = {Efficacy and Cost-effectiveness of Promotion Methods to Recruit Participants to an Online Screening Registry for Alzheimer Disease Prevention Trials: Observational Study.},
journal = {Journal of medical Internet research},
volume = {23},
number = {7},
pages = {e26284},
doi = {10.2196/26284},
pmid = {34292159},
issn = {1438-8871},
abstract = {BACKGROUND: Web-based screening may be suitable for identifying individuals with presymptomatic latent diseases for recruitment to clinical studies, as such people do not often visit hospitals in the presymptomatic stage. The promotion of such online screening studies is critical to their success, although it remains uncertain how the effectiveness of such promotion can differ, depending on the different promotion methods, domains of interest, or countries of implementation.

OBJECTIVE: The Japanese Trial-Ready Cohort (J-TRC) web study is our ongoing online screening registry to identify individuals with presymptomatic Alzheimer disease (AD), aimed at facilitating the clinical trials for AD prevention. Within the first 9 months of its 2019 launch, the J-TRC web study recruited thousands of online participants via multiple methods of promotion, including press releases, newspaper advertisements, web advertisements, or direct email invitations. Here, we aimed to quantitatively evaluate efficacy and cost-effectiveness of each of these multimodal promotion methods.

METHODS: We applied the vector-autoregression model to assess the degree of contribution of each type of promotion to the following target metrics: number of daily visitors to the J-TRC website, number of daily registrants to the J-TRC web study, daily rate of registration among visitors, daily rate of eligible participants among registrants, and median age of daily registrants. The average cost-effectiveness for each promotion method was also calculated using the total cost and the coefficients in the vector-autoregression model.

RESULTS: During the first 9 months of the reviewed period from October 31, 2019 to June 17, 2020, there were 48,334 website visitors and 4429 registrations (9.16% of 48,334 visitors), of which 3081 (69.56%) were eligible registrations. Initial press release reports and newspaper advertisements had a marked effect on increasing the number of daily visitors and daily registrants. Web advertisements significantly contributed to the increase in daily visitors (P<.001) but not to the daily registrants, and it also lowered the rate of registrations and the median age of daily registrants. Website visitors from the direct email invitation sent to other cognitive registries seem to have registered with the highest reliability. The calculated average cost-effectiveness for the initial press release was US $24.60 per visitor and US $96.10 per registrant, while the calculated average cost-effectiveness for the newspaper advertisements was US $28.60 per visitor and US $227.90 per registrant.

CONCLUSIONS: Our multivariate time-series analysis showed that each promotion method had different features in their effect of recruiting participants to the J-TRC web study. Under the advertisement condition settings thus far, newspaper advertisements and initial press releases were the most effective promotion methods, with fair cost-effectiveness that was equivalent to earlier online studies. These results can provide important suggestions for future promotions for the recruitment of presymptomatic participants to AD clinical trials in Japan.},
}

@article {pmid34291435,
year = {2021},
author = {Xu, X and Sun, Y and Cen, X and Shan, B and Zhao, Q and Xie, T and Wang, Z and Hou, T and Xue, Y and Zhang, M and Peng, D and Sun, Q and Yi, C and Najafov, A and Xia, H},
title = {Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model.},
journal = {Protein & cell},
volume = {},
number = {},
pages = {},
pmid = {34291435},
issn = {1674-8018},
abstract = {Chaperone-mediated autophagy (CMA) is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases. However, the mechanisms that regulate CMA are not fully understood. Here, using unbiased drug screening approaches, we discover Metformin, a drug that is commonly the first medication prescribed for type 2 diabetes, can induce CMA. We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA, Hsc70, and its activation. Notably, we find that amyloid-beta precursor protein (APP) is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner. The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity. Importantly, we find that in the APP/PS1 mouse model of Alzheimer's disease (AD), activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβ plaque levels and reverses the molecular and behavioral AD phenotypes. Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases, such as AD, where such therapeutic intervention could be beneficial.},
}

@article {pmid34291080,
year = {2021},
author = {Kretzschmar, GC and Alencar, NM and da Silva, SSL and Sulzbach, CD and Meissner, CG and Petzl-Erler, ML and Souza, RLR and Boldt, ABW},
title = {GWAS-Top Polymorphisms Associated With Late-Onset Alzheimer Disease in Brazil: Pointing Out Possible New Culprits Among Non-Coding RNAs.},
journal = {Frontiers in molecular biosciences},
volume = {8},
number = {},
pages = {632314},
doi = {10.3389/fmolb.2021.632314},
pmid = {34291080},
issn = {2296-889X},
abstract = {Several genome-wide association studies (GWAS) have been carried out with late-onset Alzheimer's disease (LOAD), mainly in European and Asian populations. Different polymorphisms were associated, but several of them without a functional explanation. GWAS are fundamental for identifying loci associated with diseases, although they often do not point to causal polymorphisms. In this sense, functional investigations are a fundamental tool for discovering causality, although the failure of this validation does not necessarily indicate a non-causality. Furthermore, the allele frequency of associated genetic variants may vary widely between populations, requiring replication of these associations in other ethnicities. In this sense, our study sought to replicate in 150 AD patients and 114 elderly controls from the South Brazilian population 18 single-nucleotide polymorphisms (SNPs) associated with AD in European GWAS, with further functional investigation using bioinformatic tools for the associated SNPs. Of the 18 SNPs investigated, only four were associated in our population: rs769449 (APOE), rs10838725 (CELF1), rs6733839, and rs744373 (BIN1-CYP27C1). We identified 54 variants in linkage disequilibrium (LD) with the associated SNPs, most of which act as expression or splicing quantitative trait loci (eQTLs/sQTLs) in genes previously associated with AD or with a possible functional role in the disease, such as CELF1, MADD, MYBPC3, NR1H3, NUP160, SPI1, and TOMM40. Interestingly, eight of these variants are located within long non-coding RNA (lncRNA) genes that have not been previously investigated regarding AD. Some of these polymorphisms can result in changes in these lncRNAs' secondary structures, leading to either loss or gain of microRNA (miRNA)-binding sites, deregulating downstream pathways. Our pioneering work not only replicated LOAD association with polymorphisms not yet associated in the Brazilian population but also identified six possible lncRNAs that may interfere in LOAD development. The results lead us to emphasize the importance of functional exploration of associations found in large-scale association studies in different populations to base personalized and inclusive medicine in the future.},
}

@article {pmid34289882,
year = {2021},
author = {McDade, E and Llibre-Guerra, JJ and Holtzman, DM and Morris, JC and Bateman, RJ},
title = {The informed road map to prevention of Alzheimer Disease: A call to arms.},
journal = {Molecular neurodegeneration},
volume = {16},
number = {1},
pages = {49},
pmid = {34289882},
issn = {1750-1326},
support = {U01AG042791/AG/NIA NIH HHS/United States ; R1AG046179/AG/NIA NIH HHS/United States ; R01/R56 AG053267/AG/NIA NIH HHS/United States ; U01AG059798/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward.},
}

@article {pmid34289663,
year = {2021},
author = {Lorenzi, C and Bianchi, N and Pinto, A and Mazzetti, V and Arcuri, C},
title = {The role of periodontal bacteria, Porphyromonas Gingivalis, in Alzheimer's disease pathogenesis and aggravation: a review.},
journal = {Journal of biological regulators and homeostatic agents},
volume = {35},
number = {3 Suppl. 1},
pages = {37-45},
doi = {10.23812/21-3supp1-6},
pmid = {34289663},
issn = {0393-974X},
abstract = {The aim of this study was to establish the role of Porphyromonas gingivalis in Alzheimer's disease. An electronic search of publications was established from three electronic databases: Cochrane, PubMed and Web of Science. The search strategy used a combination of controlled vocabulary and free-text words. Inclusion and exclusion criteria were defined by the authors before the start of the study. The inclusion criteria were: all studies published in English language; in vitro analysis; in vivo on animals and postmortem biopsies on humans; studies analyzing the correlation between periodontal disease and Alzheimer. The search resulted in 262 titles. Only 9 articles were included in the quantitative analysis. An inflammatory status in the oral cavity might be connect to a brain degeneration syndrome such as dementia and AD. However, a strictly connection is still not evincible. More trials are recommended in order to investigate the role of periodontal bacteria and Porphyromonas gingivalis in AD pathogenesis and aggravation.},
}

@article {pmid34287610,
year = {2021},
author = {Rubin, R},
title = {Recently Approved Alzheimer Drug Raises Questions That Might Never Be Answered.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2021.11558},
pmid = {34287610},
issn = {1538-3598},
}

@article {pmid34286787,
year = {2021},
author = {El-Hawary, SS and Sayed, AM and Issa, MY and Ebrahim, HS and Alaaeldin, R and Elrehany, MA and Abd El-Kadder, EM and Abdelmohsen, UR},
title = {Anti-Alzheimer chemical constituents of Morus macroura Miq.: chemical profiling, in silico and in vitro investigations.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d1fo01177d},
pmid = {34286787},
issn = {2042-650X},
abstract = {Herein, we investigated both fruits and leaves of Morus macroura Miq. as a potential source of bioactive compounds against Alzheimer's disease (AD). LC-HRMS-assisted chemical profiling of its extracts showed that they are a rich source of diverse phytochemicals. Among the 29 identified compounds in both the fruit and leaf extracts, moracin D, chrysin, resveratrol, and ferulic acid were predicted to pass the human blood-brain barrier (BBB), and hence, reach their therapeutic targets in the brain. Subsequently, these compounds were subjected to a comprehensive pharmacophore-based screening for their protein targets relevant to AD using two independent software programs (i.e. Swiss Target Prediction and PharmMapper). The results of this initial virtual screening were further refined by a number of docking and molecular dynamic simulation experiments to suggest a number of crucial AD-related proteins (e.g. acetylcholine esterase, β-secretase, and monoamine oxidase) as potential targets for these compounds. Finally, in vitro testing was performed to validate the in silico investigation's results, where chrysin, resveratrol, and ferulic acid were found to inhibit the predicted AD-related enzymes with IC50 values comparable with those of the reference inhibitors. Additionally, they were able to inhibit the aggregation of amyloid-beta, one of the hallmarks in AD pathogenesis, and to exhibit considerable antioxidant capacity. Our results highlighted Morus macroura compounds as future anti-Alzheimer chemical leads.},
}

@article {pmid34285392,
year = {2021},
author = {Yu, M and Sporns, O and Saykin, AJ},
title = {The human connectome in Alzheimer disease - relationship to biomarkers and genetics.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34285392},
issn = {1759-4766},
abstract = {The pathology of Alzheimer disease (AD) damages structural and functional brain networks, resulting in cognitive impairment. The results of recent connectomics studies have now linked changes in structural and functional network organization in AD to the patterns of amyloid-β and tau accumulation and spread, providing insights into the neurobiological mechanisms of the disease. In addition, the detection of gene-related connectome changes might aid in the early diagnosis of AD and facilitate the development of personalized therapeutic strategies that are effective at earlier stages of the disease spectrum. In this article, we review studies of the associations between connectome changes and amyloid-β and tau pathologies as well as molecular genetics in different subtypes and stages of AD. We also highlight the utility of connectome-derived computational models for replicating empirical findings and for tracking and predicting the progression of biomarker-indicated AD pathophysiology.},
}

@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 & dementia (Amsterdam, Netherlands)},
volume = {13},
number = {1},
pages = {e12197},
pmid = {34258377},
issn = {2352-8729},
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.

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.

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.

Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.},
}

@article {pmid34283828,
year = {2021},
author = {Mazzarino, RC and Baresova, V and Zikánová, M and Duval, N and Wilkinson, TG and Patterson, D and Vacano, GN},
title = {Transcriptome and metabolome analysis of crGART, a novel cell model of de novo purine synthesis deficiency: Alterations in CD36 expression and activity.},
journal = {PloS one},
volume = {16},
number = {7},
pages = {e0247227},
doi = {10.1371/journal.pone.0247227},
pmid = {34283828},
issn = {1932-6203},
abstract = {In humans, GART [phosphoribosylglycinamide formyltransferase (EC 2.1.2.2) / phosphoribosylglycinamide synthetase (EC 6.3.4.13) / phosphoribosylaminoimidazole synthetase (EC 6.3.3.1)] is a trifunctional protein which catalyzes the second, third, and fifth reactions of the ten step de novo purine synthesis (DNPS) pathway. The second step of DNPS is conversion of phosphoribosylamine (5-PRA) to glycineamide ribonucleotide (GAR). 5-PRA is extremely unstable under physiological conditions and is unlikely to accumulate in the absence of GART activity. Recently, a HeLa cell line null mutant for GART was constructed via CRISPR-Cas9 mutagenesis. This cell line, crGART, is an important cellular model of DNPS inactivation that does not accumulate DNPS pathway intermediates. In the current study, we characterized the crGART versus HeLa transcriptomes in purine-supplemented and purine-depleted growth conditions. We observed multiple transcriptome changes and discuss pathways and ontologies particularly relevant to Alzheimer disease and Down syndrome. We selected the Cluster of Differentiation (CD36) gene for initial analysis based on its elevated expression in crGART versus HeLa as well as its high basal expression, high log2 value, and minimal P-value.},
}

@article {pmid34283221,
year = {2021},
author = {Shinohara, M and Hirokawa, J and Shimodaira, A and Tashiro, Y and Suzuki, K and Gheni, G and Fukumori, A and Matsubara, T and Morishima, M and Saito, Y and Murayama, S and Sato, N},
title = {ELISA Evaluation of Tau Accumulation in the Brains of Patients with Alzheimer Disease.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab047},
pmid = {34283221},
issn = {1554-6578},
abstract = {Despite the routine use of sandwich enzyme-linked immunosorbent assays (ELISAs) for quantifying tau levels in CSF and plasma, tau accumulations in the brains of patients with Alzheimer disease (AD) have rarely been evaluated by this method. Thus, by introducing several tau ELISAs that target different epitopes, we evaluated accumulated tau levels in postmortem brains depending on disease stage, brain areas, and other AD-related changes. Notably, tau levels in insoluble fraction determined by each ELISAs differ depending on the epitopes of antibodies: non-AD control samples yield relatively high signals when an antibody against the N-terminal region of tau is used. On the other hand, ELISAs combining antibodies against the later-middle to C-terminal regions of tau produced substantially increased signals from AD samples, compared to those from non-AD controls. Such ELISAs better distinguish AD and non-AD controls, and the results are more closely associated with Braak neurofibrillary tangles stage, Aβ accumulation, and glial markers. Moreover, these ELISAs can reflect the pattern of tau spread across brain regions. In conclusion, Tau ELISAs that combine antibodies against the later-middle to C-terminal regions of tau can better reflect neuropathological tau accumulation, which would enable to evaluate tau accumulation in the brain at a biochemical level.},
}

@article {pmid34283217,
year = {2021},
author = {Muccioli, L and Mammana, A and Incensi, A and Baiardi, S and Parchi, P and Liguori, R and Donadio, V},
title = {The In Vivo Diagnosis of Concomitant Alzheimer and Lewy Body Pathology: A Case Report.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab065},
pmid = {34283217},
issn = {1554-6578},
}

@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 = {},
number = {},
pages = {1-7},
doi = {10.1080/01677063.2021.1954641},
pmid = {34282704},
issn = {1563-5260},
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 {pmid34280617,
year = {2021},
author = {Oikawa, N and Fabiano, M and Müller, UC and Walter, J},
title = {Carboxy-terminal fragment of amyloid precursor protein mediates lipid droplet accumulation upon γ-secretase inhibition.},
journal = {Biochemical and biophysical research communications},
volume = {570},
number = {},
pages = {137-142},
doi = {10.1016/j.bbrc.2021.07.021},
pmid = {34280617},
issn = {1090-2104},
abstract = {γ-Secretase is a protease catalysing the proteolysis of type-I membrane proteins usually after precedent ectodomain shedding of the respective protein substrates. Since proteolysis of membrane proteins is involved in fundamental cellular signaling pathways, dysfunction of γ-secretase can have significant impact on cellular metabolism and differentiation. Here, we examined the role of γ-secretase in cellular lipid metabolism using neuronally differentiated human SH-SY5Y cells. The pharmacological inhibition of γ-secretase induced lipid droplet (LD) accumulation. The LD accumulation was significantly attenuated by preventing the accumulation of C-terminal fragment of the amyloid precursor protein (APP-CTF), which is a direct substrate of γ-secretase. Additionally, LD accumulation upon γ-secretase inhibition was not induced in APP-knock out (APP-KO) mouse embryonic fibroblasts (MEFs), suggesting significant involvement of APP-CTF accumulation in LD accumulation upon γ-secretase inhibition. On the other hand, γ-secretase inhibition-dependent cholesterol accumulation was not attenuated by inhibition of APP-CTF accumulation in the differentiated SH-SY5Y cells nor in APP-KO MEFs. These results suggest that γ-secretase inhibition can induce accumulation of LD and cholesterol differentially via APP-CTF accumulation.},
}

@article {pmid34280191,
year = {2021},
author = {Liu, CH and Sung, PS and Li, YR and Huang, WK and Lee, TW and Huang, CC and Lee, TH and Chen, TH and Wei, YC},
title = {Telmisartan use and risk of dementia in type 2 diabetes patients with hypertension: A population-based cohort study.},
journal = {PLoS medicine},
volume = {18},
number = {7},
pages = {e1003707},
doi = {10.1371/journal.pmed.1003707},
pmid = {34280191},
issn = {1549-1676},
abstract = {BACKGROUND: Angiotensin receptor blockers (ARBs) may have protective effects against dementia occurrence in patients with hypertension (HTN). However, whether telmisartan, an ARB with peroxisome proliferator-activated receptor γ (PPAR-γ)-modulating effects, has additional benefits compared to other ARBs remains unclear.

METHODS AND FINDINGS: Between 1997 and 2013, 2,166,944 type 2 diabetes mellitus (T2DM) patients were identified from the National Health Insurance Research Database of Taiwan. Patients with HTN using ARBs were included in the study. Patients with a history of stroke, traumatic brain injury, or dementia were excluded. Finally, 65,511 eligible patients were divided into 2 groups: the telmisartan group and the non-telmisartan ARB group. Propensity score matching (1:4) was used to balance the distribution of baseline characteristics and medications. The primary outcome was the diagnosis of dementia. The secondary outcomes included the diagnosis of Alzheimer disease and occurrence of symptomatic ischemic stroke (IS), any IS, and all-cause mortality. The risks between groups were compared using a Cox proportional hazard model. Statistical significance was set at p < 0.05. There were 2,280 and 9,120 patients in the telmisartan and non-telmisartan ARB groups, respectively. Patients in the telmisartan group had a lower risk of dementia diagnosis (telmisartan versus non-telmisartan ARBs: 2.19% versus 3.20%; HR, 0.72; 95% CI, 0.53 to 0.97; p = 0.030). They also had lower risk of dementia diagnosis with IS as a competing risk (subdistribution HR, 0.70; 95% CI, 0.51 to 0.95; p = 0.022) and with all-cause mortality as a competing risk (subdistribution HR, 0.71; 95% CI, 0.53 to 0.97; p = 0.029). In addition, the telmisartan users had a lower risk of any IS (6.84% versus 8.57%; HR, 0.79; 95% CI, 0.67 to 0.94; p = 0.008) during long-term follow-up. Study limitations included potential residual confounding by indication, interpretation of causal effects in an observational study, and bias caused by using diagnostic and medication codes to represent real clinical data.

CONCLUSIONS: The current study suggests that telmisartan use in hypertensive T2DM patients may be associated with a lower risk of dementia and any IS events in an East-Asian population.},
}

@article {pmid34279572,
year = {2021},
author = {Schulman, KA and Greicius, MD and Richman, B},
title = {Will CMS Find Aducanumab Reasonable and Necessary for Alzheimer Disease After FDA Approval?.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2021.11768},
pmid = {34279572},
issn = {1538-3598},
}

@article {pmid34279198,
year = {2021},
author = {Reinhardt, F and Scarmeas, N and Karan, R and Veldandi, UK and Modali, S and Duvvuri, K and Pathan, RK},
title = {Real-world Utilisation of the Rivastigmine Transdermal Patches Accompanying the use of Risk Minimisation Tools in Patients with Dementia.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/1567205018666210716120540},
pmid = {34279198},
issn = {1875-5828},
abstract = {BACKGROUND: Transdermal patches are convenient to use, especially in patients with Alzheimer's disease (AD)-associated dementia. However, various identified risks of errors in ad- ministering the patches cannot be disregarded. Patient Reminder Cards (PRCs, included a Medica- tion record sheet [MRS]) have been recently introduced as a risk minimisation tool to prevent incor- rect patch use (IU).

OBJECTIVES: This study aimed to assess the effectiveness of PRCs to prevent IU and to investigate the dose titration pattern of rivastigmine patches in a real-world setting.

METHODS: This multinational, observational, 11-month study included patients with AD currently using rivastigmine patches (4.6 mg/day, 9.5 mg/day, 13.3 mg/day) accompanied by a caregiver. Study outcomes were IU, including multiple patch use (MPU), incorrect patch placement, other IUs, perceived usefulness of the PRCs, and titration patterns of the patches.

RESULTS: Of the total 614 patients included, most were aged ≥65 years and had mild-to-moderate AD. Before and during the study, 27.7% and 18.0% of patients reported IU, respectively. Most pa- tients used MRS, and 73.5% rated it 'helpful' and reported lower rates of IU than those who report- ed it 'not helpful' (13.9%-16.5% vs. 20.2%). Overall, 141 patients had dose titrations, with 75.8% being up-titrated from 4.6 mg/day to 9.5 mg/day after a mean duration of 58 days. Safety findings were consistent with the established profile for the rivastigmine patch.

CONCLUSION: PRC was effective as a risk minimisation tool in limiting the inappropriate use of ri- vastigmine patches. The majority of patients requiring dose-change were up-titrated to 9.5 mg/day patches.},
}

@article {pmid34279043,
year = {2021},
author = {Dautricourt, S and de Flores, R and Landeau, B and Poisnel, G and Vanhoutte, M and Delcroix, N and Eustache, F and Vivien, D and de la Sayette, V and Chételat, G},
title = {Longitudinal changes in hippocampal network connectivity in Alzheimer's disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.26168},
pmid = {34279043},
issn = {1531-8249},
abstract = {OBJECTIVE: The hippocampus is connected to two distinct cortical brain networks, the posterior-medial and the anterior-temporal networks, involving different medial temporal lobe (MTL) subregions. The aim of this study was to assess the functional alterations of these two networks, their changes over time and links to cognition in Alzheimer's disease.

METHODS: We assessed MTL connectivity in 53 amyloid-β positive patients with mild cognitive impairment and Alzheimer dementia and 68 healthy elderly controls, using resting-state functional magnetic resonance imaging, cross-sectionally and longitudinally. First, we compared the functional connectivity of the posterior-medial and anterior-temporal networks within the control group to highlight their specificities. Second, we compared the connectivity of these networks between groups, and between baseline and 18-months follow-up in patients. Third, we assessed the association in the connectivity changes between the two networks, and with cognitive performance.

RESULTS: We found decreased connectivity in patients specifically between the hippocampus and the posterior-medial network, together with increased connectivity between several MTL subregions and the anterior-temporal network. Moreover, changes in the posterior-medial and anterior-temporal networks were interrelated such that decrease MTL-posterior-medial connectivity was associated with increased MTL-anterior-temporal connectivity. Finally, both MTL-posterior-medial decrease and MTL-anterior-temporal increase predicted cognitive decline.

INTERPRETATION: Our findings demonstrate that longitudinal connectivity changes in the posterior-medial and anterior-temporal hippocampal networks are linked together and that they both contribute to cognitive decline in Alzheimer's disease. These results shed light on the critical role of the posterior-medial and anterior-temporal networks in Alzheimer's disease pathophysiology and clinical symptoms. This article is protected by copyright. All rights reserved.},
}

@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},
doi = {10.3389/fgene.2021.658323},
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.

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.

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.

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},
doi = {10.3389/fneur.2021.673347},
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 & modelling},
volume = {108},
number = {},
pages = {107983},
doi = {10.1016/j.jmgm.2021.107983},
pmid = {34274727},
issn = {1873-4243},
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 {pmid34274071,
year = {2021},
author = {González-Bautista, E and de Souto Barreto, P and Andrieu, S and Rolland, Y and Vellas, B and , },
title = {Screening for intrinsic capacity impairments as markers of increased risk of frailty and disability in the context of integrated care for older people: Secondary analysis of MAPT.},
journal = {Maturitas},
volume = {150},
number = {},
pages = {1-6},
doi = {10.1016/j.maturitas.2021.05.011},
pmid = {34274071},
issn = {1873-4111},
abstract = {AIM: This longitudinal secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT) aimed to test whether the Integrated Care for Older People (ICOPE) Step 1 screening tool is able to identify people at risk of developing frailty and disability in basic (ADL) and instrumental (IADL) activities of daily living among community-dwelling older adults.

PARTICIPANTS AND SETTING: Seven hundred and fifty-nine (n = 759) non-demented participants of the MAPT aged 70-89 years were assessed in memory clinics in France between 2008 and 2013.

METHODS: We measured six intrinsic capacity (IC) impairments, adapted from the ICOPE screening tool. We used Cox models to estimate the adjusted hazard ratios of incident frailty and IADL/ADL disability. Incident frailty was defined by Fried's phenotype, and incident disability was measured according to Lawton and Katz for IADLs and ADLs.

RESULTS: Limited mobility (HR= 2.97, 95%CI= 1.85-4.76), depressive symptoms (HR= 2.07, 95%CI= 1.03-4.19), and visual impairment (HR= 1.70, 95%CI 1.01-2.86) were associated with a higher incidence of frailty over 5 years. Each additional IC condition demonstrated a positive association with a higher risk of incident frailty, IADL, ADL disability, with risk increased by 47%, 27%, and 23% over 5 years, respectively.

CONCLUSION: Screening for IC impairments identifies older adults at higher risk of incident frailty and incident IADL/ADL disability. It is relevant to screen for these impairments together because the risk of frailty and disability increases with each additional one. ClinicalTrials.gov identifier: NCT00672685.},
}

@article {pmid34274005,
year = {2021},
author = {Prins, S and Zhuparris, A and Hart, EP and Doll, RJ and Groeneveld, GJ},
title = {A cross-sectional study in healthy elderly subjects aimed at development of an algorithm to increase identification of Alzheimer pathology for the purpose of clinical trial participation.},
journal = {Alzheimer's research & therapy},
volume = {13},
number = {1},
pages = {132},
pmid = {34274005},
issn = {1758-9193},
abstract = {BACKGROUND: In the current study, we aimed to develop an algorithm based on biomarkers obtained through non- or minimally invasive procedures to identify healthy elderly subjects who have an increased risk of abnormal cerebrospinal fluid (CSF) amyloid beta42 (Aβ) levels consistent with the presence of Alzheimer's disease (AD) pathology. The use of the algorithm may help to identify subjects with preclinical AD who are eligible for potential participation in trials with disease modifying compounds being developed for AD. Due to this pre-selection, fewer lumbar punctures will be needed, decreasing overall burden for study subjects and costs.

METHODS: Healthy elderly subjects (n = 200; age 65-70 (N = 100) and age > 70 (N = 100)) with an MMSE > 24 were recruited. An automated central nervous system test battery was used for cognitive profiling. CSF Aβ1-42 concentrations, plasma Aβ1-40, Aβ1-42, neurofilament light, and total Tau concentrations were measured. Aβ1-42/1-40 ratio was calculated for plasma. The neuroinflammation biomarker YKL-40 and APOE ε4 status were determined in plasma. Different mathematical models were evaluated on their sensitivity, specificity, and positive predictive value. A logistic regression algorithm described the data best. Data were analyzed using a 5-fold cross validation logistic regression classifier.

RESULTS: Two hundred healthy elderly subjects were enrolled in this study. Data of 154 subjects were used for the per protocol analysis. The average age of the 154 subjects was 72.1 (65-86) years. Twenty-four (27.3%) were Aβ positive for AD (age 65-83). The results of the logistic regression classifier showed that predictive features for Aβ positivity/negativity in CSF consist of sex, 7 CNS tests, and 1 plasma-based assay. The model achieved a sensitivity of 70.82% (± 4.35) and a specificity of 89.25% (± 4.35) with respect to identifying abnormal CSF in healthy elderly subjects. The receiver operating characteristic curve showed an AUC of 65% (± 0.10).

CONCLUSION: This algorithm would allow for a 70% reduction of lumbar punctures needed to identify subjects with abnormal CSF Aβ levels consistent with AD. The use of this algorithm can be expected to lower overall subject burden and costs of identifying subjects with preclinical AD and therefore of total study costs.

TRIAL REGISTRATION: ISRCTN.org identifier: ISRCTN79036545 (retrospectively registered).},
}

@article {pmid34261788,
year = {2021},
author = {Wilson, RS and Wang, T and Yu, L and Grodstein, F and Bennett, DA and Boyle, PA},
title = {Cognitive Activity and Onset Age of Incident Alzheimer Disease Dementia.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012388},
pmid = {34261788},
issn = {1526-632X},
abstract = {OBJECTIVE: To test the hypothesis that higher level of cognitive activity predicts older age of dementia onset in Alzheimer's disease (AD) dementia.

METHODS: As part of a longitudinal cohort study, 1,903 older persons without dementia at enrollment reported their frequency of participation in cognitively stimulating activities. They had annual clinical evaluations to diagnose dementia and AD, and the deceased underwent neuropathologic examination. In analyses, we assessed the relation of baseline cognitive activity to age at diagnosis of incident AD dementia and to postmortem markers of AD and other dementias.

RESULTS: During a mean of 6.8 years of follow-up, 457 individuals were diagnosed with incident AD at a mean age of 88.6 (SD = 6.4; range: 64.1-106.5). In an extended accelerated failure time model, higher level of baseline cognitive activity (mean 3.2, SD = 0.7) was associated with older age of AD dementia onset (estimate = 0.026; 95% confidence interval: 0.013. 0.039). Low cognitive activity (score = 2.1, 10th percentile) was associated with a mean onset age of 88.6 compared to a mean onset age of 93.6 associated with high cognitive activity (score = 4.0, 90th percentile). Results were comparable in subsequent analyses that adjusted for potentially confounding factors. In 695 participants who died and underwent a neuropathologic examination, cognitive activity was unrelated to postmortem markers of AD and other dementias.

CONCLUSION: A cognitively active lifestyle in old age may delay the onset of dementia in AD by as much as 5 years.},
}

@article {pmid34272490,
year = {2021},
author = {Alić, I and Goh, PA and Murray, A and Portelius, E and Gkanatsiou, E and Gough, G and Mok, KY and Koschut, D and Brunmeir, R and Yeap, YJ and O'Brien, NL and Groet, J and Shao, X and Havlicek, S and Dunn, NR and Kvartsberg, H and Brinkmalm, G and Hithersay, R and Startin, C and Hamburg, S and Phillips, M and Pervushin, K and Turmaine, M and Wallon, D and Rovelet-Lecrux, A and Soininen, H and Volpi, E and Martin, JE and Foo, JN and Becker, DL and Rostagno, A and Ghiso, J and Krsnik, Ž and Šimić, G and Kostović, I and Mitrečić, D and , and Francis, PT and Blennow, K and Strydom, A and Hardy, J and Zetterberg, H and Nižetić, D},
title = {Correction: Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41380-021-01206-x},
pmid = {34272490},
issn = {1476-5578},
}

@article {pmid34270750,
year = {2021},
author = {Nelson, PT},
title = {LATE Neuropathologic Changes with Little or No Alzheimer Disease is Common and is Associated with Cognitive Impairment but Not Frontotemporal Dementia.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlab050},
pmid = {34270750},
issn = {1554-6578},
abstract = {Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) often occur in aged brains that also contain appreciable Alzheimer disease neuropathologic changes (ADNC). Question has arisen as to whether LATE-NC can occur independently of ADNC. We evaluated data from the University of Kentucky Alzheimer's Disease Research Center autopsy cohort (383 included subjects) to address 2 questions: (i) Is LATE-NC seen in the absence of ADNC, outside of persons who had the frontotemporal dementia (FTD) clinical syndrome? and (ii) is LATE-NC associated with cognitive impairment across the full spectrum of ADNC severity? In the present study, the pathologic combination of LATE-NC (Stage >1) and low/no ADNC was common: 8.9% (34/383) of all subjects (including demented and non-demented individuals) showed this combination. There were no FTLD-TDP cases to be included from the community-based cohort. Across a broad range of ADNC severity, the presence of LATE-NC was associated with impaired cognition but was never associated with a FTD clinical syndrome.},
}

@article {pmid34268646,
year = {2021},
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 = {},
number = {},
pages = {},
pmid = {34268646},
issn = {1556-0961},
support = {T32HL007381/HL/NHLBI NIH HHS/United States ; RO1HL133675/NH/NIH HHS/United States ; R01NS10742101/NH/NIH HHS/United States ; },
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.

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.

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.

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 {pmid34267383,
year = {2021},
author = {Karlawish, J and Grill, JD},
title = {The approval of Aduhelm risks eroding public trust in Alzheimer research and the FDA.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34267383},
issn = {1759-4766},
}

@article {pmid34266923,
year = {2021},
author = {Tao, Q and Alvin Ang, TF and Akhter-Khan, SC and Itchapurapu, IS and Killiany, R and Zhang, X and Budson, AE and Turk, KW and Goldstein, L and Mez, J and Alosco, ML and Qiu, WQ and , },
title = {Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous Apolipoprotein E ɛ4 Carriers.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012512},
pmid = {34266923},
issn = {1526-632X},
abstract = {OBJECTIVE: Previous research has shown that elevated blood C-reactive protein (CRP) is associated with increased Alzheimer's disease (AD) risk only in apoliprotein E4 genotype (APOE ε4) allele carriers. The objective of this study was to examine the interactive effects of plasma CRP and apoliprotein E (APOE) genotype on cognition and AD biomarkers.

METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study was analyzed, including APOE genotype; plasma CRP concentrations; diagnostic status (i.e., MCI and dementia due to AD); Mini-Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) Dementia Staging Instrument; cerebral spinal fluid (CSF) concentrations of amyloid-β peptide (Aβ42), total tau (t-Tau) and phosphorylated tau (p-Tau); and amyloid (AV45) PET imaging. Multivariable regression analyses tested the associations between plasma CRP and APOE on cognitive and biomarker outcomes.

RESULTS: Among 566 ADNI participants, 274 (48.4%) had no, 222 (39.2%) had one, and 70 (12.4%) had two APOE ε4 alleles. Only among participants who had two APOE ε4 alleles, elevated CRP was associated with lower MMSE at baseline [β (95%CI): -0.52 (-1.01, -0.12)] and 12-month follow-up [β (95%CI): -1.09 (-1.88, -0.17)] after adjusting for sex, age and education. The interaction of two APOE ε4 alleles and elevated plasma CRP was associated with increased CSF levels of t-Tau (β = +11.21, SE = 3.37, p < 0.001) and p-Tau (β = +2.74, SE = 1.14, p < 0.01). Among those who had no APOE ε4 allele, elevated CRP was associated with decreased CSF t-Tau and p-Tau. These effects were stronger at 12-month follow-up.

CONCLUSIONS: CRP released during peripheral inflammation could be a mediator in APOE ε4 related AD neurodegeneration and serve as a drug target for AD.},
}

@article {pmid34266918,
year = {2021},
author = {Bocancea, DI and Catharina van Loenhoud, A and Groot, C and Barkhof, F and van der Flier, WM and Ossenkoppele, R},
title = {Measuring Resilience and Resistance in Aging and Alzheimer Disease Using Residual Methods: A Systematic Review and Meta-analysis.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012499},
pmid = {34266918},
issn = {1526-632X},
abstract = {OBJECTIVE: There is currently a lack of consensus on how to optimally define and measure resistance and resilience in brain and cognitive aging. Residual methods use residuals from regression analysis to quantify the capacity to avoid (resistance) or cope (resilience) "better or worse than expected" given a certain level of risk or cerebral damage. We reviewed the rapidly growing literature on residual methods in the context of aging and Alzheimer's disease (AD) and performed meta-analyses to investigate associations of residual-method based resilience and resistance measures with longitudinal cognitive and clinical outcomes.

METHODS: A systematic literature search of PubMed and Web-of-Science databases (consulted until March 2020) and subsequent screening led to 54 studies fulfilling eligibility criteria, including 10 studies suitable for the meta-analyses.

RESULTS: We identified articles using residual methods aimed at quantifying resistance (n=33), cognitive resilience (n=23) and brain resilience (n=2). Critical examination of the literature revealed that there is considerable methodological variability in how the residual measures were derived and validated. Despite methodological differences across studies, meta-analytic assessments showed significant associations of levels of resistance (HR[95%CI]=1.12[1.07-1.17], p<0.0001) and levels of resilience (HR[95%CI]=0.46[0.32-0.68], p<0.001) with risk of progression to dementia/AD. Resilience was also associated with rate of cognitive decline (β[95%CI]=0.05[0.01-0.08], p<0.01).

CONCLUSION: This review and meta-analysis supports the usefulness of residual methods as appropriate measures of resilience and resistance, as they capture clinically meaningful information in aging and AD. More rigorous methodological standardization is needed, however, to increase comparability across studies and, ultimately, application in clinical practice.},
}

@article {pmid34266917,
year = {2021},
author = {Grothe, MJ and Moscoso, A and Ashton, NJ and Karikari, TK and Lantero-Rodriguez, J and Snellman, A and Zetterberg, H and Blennow, K and Schöll, M and , },
title = {Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012513},
pmid = {34266917},
issn = {1526-632X},
abstract = {OBJECTIVE: To study cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.

METHODS: We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).

RESULTS: All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.

CONCLUSIONS: Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.},
}

@article {pmid34266916,
year = {2021},
author = {Poggesi, A},
title = {Resilience and Resistance in Aging and Alzheimer Disease: Another Step to Fill the Gap Between Clinicians and Researchers.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012500},
pmid = {34266916},
issn = {1526-632X},
}

@article {pmid34266592,
year = {2021},
author = {Shekari, A and Fahnestock, M},
title = {Cholinergic neurodegeneration in Alzheimer disease mouse models.},
journal = {Handbook of clinical neurology},
volume = {182},
number = {},
pages = {191-209},
doi = {10.1016/B978-0-12-819973-2.00013-7},
pmid = {34266592},
issn = {0072-9752},
abstract = {Cholinergic signaling is critical for cognitive function. The basal forebrain is the major cholinergic output of the central nervous system. Degeneration of basal forebrain cholinergic neurons is a hallmark of Alzheimer's disease (AD). Mouse models are invaluable tools in disease research and have been used to study AD for over 25 years. However, animal models of AD vary greatly with respect to the degree of cholinergic degeneration observed. The following review will outline the most influential animal models of AD with an emphasis on the basal forebrain cholinergic system.},
}

@article {pmid34265833,
year = {2021},
author = {Ren, C and Chen, M and Mu, G and Peng, S and Liu, X and Ou, C},
title = {NLRP3 Inflammasome Mediates Neurodegeneration in Rats With Chronic Neuropathic Pain.},
journal = {Shock (Augusta, Ga.)},
volume = {},
number = {},
pages = {},
doi = {10.1097/SHK.0000000000001832},
pmid = {34265833},
issn = {1540-0514},
abstract = {ABSTRACT: Patients with chronic neuropathic pain (NP) have a significantly increased risk of central nervous degeneration. Trigeminal neuralgia (TN) is a typical NP, and this manifestation is more obvious. In addition to severe pain, patients with TN are often accompanied by cognitive dysfunction and have a higher risk of central nervous system degeneration, but the mechanism is not clear. The NLRP3 inflammasome assembles inside of microglia on activation, which plays an important role in neurodegeneration such as Alzheimer disease. MCC950 is a specific blocker of NLRP3 inflammasome, which can improve the performance of degenerative diseases. Although NLRP3 inflammasome assembles inside of microglia on activation has been shown to be essential for the development and progression of amyloid pathology, its whether it mediates the neurodegeneration caused by NP is currently unclear. By constructing a rat model of chronic TN, we found that as the course of the disease progresses, TN rats have obvious cognitive and memory deficit. In addition, Tau hyperphosphorylation and Aβ expression increase in the cortex and hippocampus of the brain. At the same time, we found that NLRP3 expression increased significantly in model rats. Interestingly, NLRP3 specific blocker MCC950 can alleviate the neurodegeneration of trigeminal neuralgia rats to a certain extent. It is suggested that our NLRP3 inflammasome plays an important role in the neurodegeneration of trigeminal neuralgia rats. And it is related to the activation of central nervous system inflammation.},
}

@article {pmid34263093,
year = {2021},
author = {Lopes de Andrade, V and Marreilha Dos Santos, AP and Aschner, M},
title = {NEUROTOXICITY OF METAL MIXTURES.},
journal = {Advances in neurotoxicology},
volume = {5},
number = {},
pages = {329-364},
doi = {10.1016/bs.ant.2020.12.003},
pmid = {34263093},
issn = {2468-7480},
abstract = {Environmental exposures and/or alterations in the homeostasis of essential transition metals (ETM), such as Fe, Cu, Zn or Mn, are known to contribute to neurodegenerative diseases (ND), such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). Aberrant ETM homeostasis leads to altered distributions, as significant amounts may accumulate in specific brain areas, while causing metal deficiency in others. The disruption of processes reliant on the interplay between these ETM, may lead to loss of metal balance and the ensuing neurotoxicity via shared mechanisms, such as the induction of oxidative stress (OS). Both ETM imbalance and OS may play a role, via complex positive loop processes, in primary neuropathological signatures of AD, such as the accumulation of amyloid plaques and neurofibrillary tangles (NTF), and in PD, α-Syn aggregation and loss of dopamine(DA)rgic neurons. The association between ETM imbalance and ND is rarely approached under the view that metals such as Fe, Cu, Zn and Mn, can act as dangerous endogenous neurotoxic mixtures when their control mechanisms became disrupted. In fact, their presence as mixtures implies intricacies, which should be kept in mind when developing therapies for complex disorders of metal dyshomeostasis, which commonly occur in ND.},
}

@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},
doi = {10.7759/cureus.16188},
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 {pmid34255194,
year = {2021},
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 = {},
number = {},
pages = {},
pmid = {34255194},
issn = {1590-3478},
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.

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.

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.

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 = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2021.4622},
pmid = {34254991},
issn = {2168-6114},
}

@article {pmid34254984,
year = {2021},
author = {Dunn, B and Stein, P and Cavazzoni, P},
title = {Approval of Aducanumab for Alzheimer Disease-the FDA's Perspective.},
journal = {JAMA internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2021.4607},
pmid = {34254984},
issn = {2168-6114},
}

@article {pmid34253141,
year = {2021},
author = {Pritchard, C and Hansen, L and Silk, A and Rosenorn-Lanng, E},
title = {21st Century Early Adult (55-74) Deaths from Brain-Disease-Deaths Compared to All Other Cause Mortality in the Major Western Countries - Exposing a Hidden Epidemic.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/01616412.2021.1943121},
pmid = {34253141},
issn = {1743-1328},
abstract = {OBJECTIVES: To examine early adult deaths (EAD) - people aged 55-74 due to brain disease deaths (BDD) compared to all other causes (AOC) in the 21st century in 21 major Western countries (MWC).

METHOD: EAD are below MWCc average life expectancy. All mortality drawn from the latest WHO data. The three global BDD categories consist of mental and behaviour disorder, nervous diseases and Alzheimer and other dementias. Mortality rates per million are analysed for people 55-74 years and total age-standardised death rates (ASDR). BDD rates between 2000-2015 compared against AOC of deaths for EAD and ASDR. Confidence Intervals determine any significant difference AOC and BDD over the period 2000-15, plus an examination of EAD in six separate global mortality categories.

RESULTS: EAD: The separate BDD categories for EAD significantly positively correlated, validating their combination as BDD. Every country's AOC 55-74 rates fell substantially, but fourteen country's BDD rose substantially (>20%) and all MWC countries BDD rose significantly more than AOC. ASDR: All nations total AOC fell substantially, whereas seventeen BDD rates rose substantially and every country's BDD significantly increased compared to AOC deaths. Six other EAD mortalities, circulatory, cancer, respiratory, compared to BDD produced Odds Ratios ranging from 1:1.54 to 1:2.36 such were the marked differences over the period.

DISCUSSION: Positive news is that AOC are down across all investigated countries in the 21st century. However, the extent of the EAD rises in just 16 years indicates that these BDD conditions are starting earlier suggesting multiple interactive environmental factors impacting upon brain related diseases.},
}

@article {pmid34251402,
year = {2021},
author = {Fernandes, C and Taveira, I and Nzwalo, H},
title = {Mirrored-Self Misidentification in a Patient With Probable Alzheimer Dementia.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2021.2142},
pmid = {34251402},
issn = {2168-6157},
}

@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 = {},
number = {},
pages = {},
doi = {10.1001/jamainternmed.2021.3098},
pmid = {34251396},
issn = {2168-6114},
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.

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.

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.

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.

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.

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.

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.

Trial Registration: ClinicalTrials.gov Identifier: NCT03244917.},
}

@article {pmid34250871,
year = {2021},
author = {Talebi, M and Esmaeeli, H and Talebi, M and Farkhondeh, T and Samarghandian, S},
title = {A Concise Overview of Biosensing Technologies for the Detection of Alzheimer's Disease Biomarkers.},
journal = {Current pharmaceutical biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/2666796702666210709122407},
pmid = {34250871},
issn = {1873-4316},
abstract = {Alzheimer's disease (AD) is a brain-linked pathophysiological condition with neuronal degeneration, cognition dysfunctions, and other debilitations. Due to the growing prevalence of AD, there is a highly commended tendency to accelerate and develop analytical technologies for easy, cost-effective, and sensitive detection of AD biomarkers. In the last decade, remarkable advancements have been achieved on the gate to the progression of biosensors, predominantly optical and electrochemical, to detect AD biomarkers. Biosensors are commanding analytical devices that can conduct biological responses on transducers into measurable signals. These analytical devices can assist the case finding and management of AD. This review focuses on up-to-date developments, contests, and tendencies regarding AD biosensing principally, emphasizing the exclusive possessions of nanomaterials.},
}

@article {pmid34250268,
year = {2021},
author = {Tevik, K and Benth, JŠ and Aarøen, M and Lornstad, MT and Bergh, S and Helvik, AS},
title = {Prevalence and persistent use of analgesic drugs in older adults receiving domiciliary care at baseline-A longitudinal study.},
journal = {Health science reports},
volume = {4},
number = {3},
pages = {e316},
pmid = {34250268},
issn = {2398-8835},
abstract = {Aims: To describe the prevalence and persistence of analgesic drug use (opioids and antipyretics [ie, paracetamol and acetylsalicylic acid]) in participants (≥70 years) with and without dementia receiving domiciliary care in the eastern part of Norway. In addition, to explore factors associated with persistent drug use and examine whether drug use has changed after admission to a nursing home.

Methods: A longitudinal study with 1001 participants (mean [SD] age 83.4 [5.7] years) receiving domiciliary care. Medical information including analgesic drug use was collected at baseline (A1) between August 2008 and December 2010, follow-up assessments after 18 (A2) and 36 months (A3). Analgesic drugs prescribed for regular use were recorded from the participants' medical records. The participants' cognitive and physical health was evaluated at all assessments. Level of care (domiciliary care or nursing home care) was recorded at A2 and A3. Generalized linear mixed models were used to examine the prevalence and persistence of analgesic drug use.

Results: The prevalence of prescribed use of antipyretics and opioids was 13.6% and 9.2%, respectively. Participants with dementia had more frequent use of antipyretics in all assessments and opioids in the last assessment than participants without dementia. Persistent use of both antipyretics and opioids was high between two consecutive assessments, both for participants with and without dementia. Persistent use of analgesics was associated with poorer physical functioning, but not by level of care. Overall, there was no difference between those admitted to a nursing home and those receiving domiciliary care at follow-up, with respect to change in analgesic drug use over time.

Conclusion: The prevalence and persistent use of analgesics were high in older adults receiving domiciliary care at baseline and especially in participants with dementia. A holistic approach and interdisciplinary collaboration are essential to effectively assess and treat pain in older adults.},
}

@article {pmid34249948,
year = {2021},
author = {Zhu, W and Zheng, D and Wang, D and Yang, L and Zhao, C and Huang, X},
title = {Emerging Roles of Ubiquitin-Specific Protease 25 in Diseases.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {698751},
pmid = {34249948},
issn = {2296-634X},
abstract = {The balance of ubiquitination and deubiquitination plays diverse roles in regulating protein stability and cellular homeostasis. Deubiquitinating enzymes catalyze the hydrolysis and removal of ubiquitin chains from target proteins and play critical roles in various disease processes, including cancer, immune responses to viral infections and neurodegeneration. This article aims to summarize roles of the deubiquitinating enzyme ubiquitin-specific protease 25 (USP25) in disease onset and progression. Previous studies have focused on the role of USP25 in antiviral immunity and neurodegenerative diseases. Recently, however, as the structural similarities and differences between USP25 and its homolog USP28 have become clear, mechanisms of action of USP25 in cancer and other diseases have been gradually revealed.},
}

@article {pmid34248607,
year = {2021},
author = {Feringa, FM and van der Kant, R},
title = {Cholesterol and Alzheimer's Disease; From Risk Genes to Pathological Effects.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {690372},
pmid = {34248607},
issn = {1663-4365},
abstract = {While the central nervous system compromises 2% of our body weight, it harbors up to 25% of the body's cholesterol. Cholesterol levels in the brain are tightly regulated for physiological brain function, but mounting evidence indicates that excessive cholesterol accumulates in Alzheimer's disease (AD), where it may drive AD-associated pathological changes. This seems especially relevant for late-onset AD, as several of the major genetic risk factors are functionally associated with cholesterol metabolism. In this review we discuss the different systems that maintain brain cholesterol metabolism in the healthy brain, and how dysregulation of these processes can lead, or contribute to, Alzheimer's disease. We will also discuss how AD-risk genes might impact cholesterol metabolism and downstream AD pathology. Finally, we will address the major outstanding questions in the field and how recent technical advances in CRISPR/Cas9-gene editing and induced pluripotent stem cell (iPSC)-technology can aid to study these problems.},
}

@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 & modelling},
volume = {107},
number = {},
pages = {107981},
doi = {10.1016/j.jmgm.2021.107981},
pmid = {34246109},
issn = {1873-4243},
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},
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 {pmid34245584,
year = {2021},
author = {Boustani, M and Unützer, J and Leykum, LK},
title = {Design, implement, and diffuse scalable and sustainable solutions for dementia care.},
journal = {Journal of the American Geriatrics Society},
volume = {69},
number = {7},
pages = {1755-1762},
doi = {10.1111/jgs.17342},
pmid = {34245584},
issn = {1532-5415},
abstract = {Most innovations developed to reduce the burden of Alzheimer disease and other related dementias (ADRD) are difficult to implement, diffuse, and scale. The consequences of such challenges in design, implementation, and diffusion are suboptimal care and resulting harm for people living with ADRD and their caregivers. National experts identified four factors that contribute to our limited ability to implement and diffuse of evidence-based services and interventions for people living with ADRD: (1) limited market demand for the implementation and diffusion of effective ADRD interventions; (2) insufficient engagement of persons living with ADRD and those caring for them in the development of potential ADRD services and interventions; (3) limited evidence and experience regarding scalability and sustainability of evidence-based ADRD care services; and (4) difficulties in taking innovations that work in one context and successfully implementing them in other contexts. New investments in the science of human-centered design, implementation, and diffusion are crucial for meeting the goals of the National Plan to Address Alzheimer's Disease under the auspices of the National Alzheimer's Project Act.},
}

@article {pmid34245502,
year = {2021},
author = {Berezutsky, MA and Durnova, NA and Sigareva, LE},
title = {[Neurobiological effects of tenuigenin and the opportunity of it's using in the therapy of Alzheimer's and Parkinson's diseases (literature review).].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {34},
number = {2},
pages = {210-216},
pmid = {34245502},
issn = {1561-9125},
mesh = {*Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; *Drugs, Chinese Herbal/pharmacology ; Humans ; *Parkinson Disease/drug therapy ; },
abstract = {The analysis of experimental and partially clinical data about researches of neurobiological effects of tenuigenin - the most important bioactive substance of Polygala tenuifolia Willd. in this review was given. The neuroprotective and neurotrophic action of given substance were described in detail. It was noted, that the capacities of the tenuigenin to decrease the secretion of beta amyloid and to protect of neurons from damage by already made beta ameloids, to inhibit the processes of the tau proteins` hyperphosphorylation and inflammations in microglia, as well as increase the main synaptic transmission can be used by the development of effective therapeutic drugs aimed to reduce the pathogenesis of Alzheimer`s disease. The effects of dopaminergic neurons and mitochondrial membrane potential protection as well as reduction of α-synuclein phosphorylation can influence the processes by Parkinson`s disease. It was concluded, that the tenuigenin deserves further study and possibly will be used as augmentation of Alzheimer`s, Parkinson`s and other neurodegenerative diseases therapy.},
}

*Alzheimer Disease/drug therapy
Amyloid beta-Peptides
*Drugs, Chinese Herbal/pharmacology
Humans
*Parkinson Disease/drug therapy

@article {pmid34245203,
year = {2021},
author = {Sajjad, M and Ramzan, F and Khan, MUG and Rehman, A and Kolivand, M and Fati, SM and Bahaj, SA},
title = {Deep convolutional generative adversarial network for Alzheimer's disease classification using positron emission tomography (PET) and synthetic data augmentation.},
journal = {Microscopy research and technique},
volume = {},
number = {},
pages = {},
doi = {10.1002/jemt.23861},
pmid = {34245203},
issn = {1097-0029},
abstract = {With the evolution of deep learning technologies, computer vision-related tasks achieved tremendous success in the biomedical domain. For supervised deep learning training, we need a large number of labeled datasets. The task of achieving a large number of label dataset is a challenging. The availability of data makes it difficult to achieve and enhance an automated disease diagnosis model's performance. To synthesize data and improve the disease diagnosis model's accuracy, we proposed a novel approach for the generation of images for three different stages of Alzheimer's disease using deep convolutional generative adversarial networks. The proposed model out-perform in synthesis of brain positron emission tomography images for all three stages of Alzheimer disease. The three-stage of Alzheimer's disease is normal control, mild cognitive impairment, and Alzheimer's disease. The model performance is measured using a classification model that achieved an accuracy of 72% against synthetic images. We also experimented with quantitative measures, that is, peak signal-to-noise (PSNR) and structural similarity index measure (SSIM). We achieved average PSNR score values of 82 for AD, 72 for CN, and 73 for MCI and SSIM average score values of 25.6 for AD, 22.6 for CN, and 22.8 for MCI.},
}

@article {pmid34244999,
year = {2021},
author = {Korecka, M and Shaw, LM},
title = {Mass spectrometry-based methods for robust measurement of Alzheimer's Disease biomarkers in biological fluids.},
journal = {Journal of neurochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1111/jnc.15465},
pmid = {34244999},
issn = {1471-4159},
abstract = {Alzheimer's disease (AD) is the most common form of dementia affecting 60-70% of people afflicted with this disease. Accurate antemortem diagnosis is urgently needed for early detection of AD to enable reliable estimation of prognosis, intervention and monitoring of the disease. The National Institute on Aging/Alzheimer's Association sponsored the "Research Framework: towards a biological definition of AD", which recommends using different biomarkers in living persons for a biomarker-based definition of AD regardless of clinical status. Fluid biomarkers represents one of key groups of them. Since cerebrospinal fluid (CSF) is in direct contact with brain and many proteins present in the brain can be detected in CSF, this fluid has been regarded as the best biofluid in which to measure AD biomarkers. Recently technological advancements in protein detection made possible the effective study of plasma AD biomarkers despite their significantly lower concentrations vs to that in CSF. This and other challenges that face plasma based biomarker measurements can be overcome by using mass spectrometry. In this review we discuss AD biomarkers which can be reliably measured in CSF and plasma using targeted mass spectrometry coupled to liquid chromatography (LC/MSMS). We describe progress in LC/MSMS methods development, emphasize the challenges and summarize major findings. We also highlight the role of mass spectrometry and progress made in the process of global standardization of the measurement of Aβ42/Aβ40. Finally, we briefly describe exploratory proteomics which seek to identify new biomarkers that can contribute to detection of co-pathological processes which are common in sporadic AD.},
}

@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 & behavior},
volume = {},
number = {},
pages = {113525},
doi = {10.1016/j.physbeh.2021.113525},
pmid = {34242671},
issn = {1873-507X},
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 {pmid34239130,
year = {2021},
author = {Hampel, H and Cummings, J and Blennow, K and Gao, P and Jack, CR and Vergallo, A},
title = {Developing the ATX(N) classification for use across the Alzheimer disease continuum.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34239130},
issn = {1759-4766},
abstract = {Breakthroughs in the development of highly accurate fluid and neuroimaging biomarkers have catalysed the conceptual transformation of Alzheimer disease (AD) from the traditional clinical symptom-based definition to a clinical-biological construct along a temporal continuum. The AT(N) system is a symptom-agnostic classification scheme that categorizes individuals using biomarkers that chart core AD pathophysiological features, namely the amyloid-β (Aβ) pathway (A), tau-mediated pathophysiology (T) and neurodegeneration (N). This biomarker matrix is now expanding towards an ATX(N) system, where X represents novel candidate biomarkers for additional pathophysiological mechanisms such as neuroimmune dysregulation, synaptic dysfunction and blood-brain barrier alterations. In this Perspective, we describe the conceptual framework and clinical importance of the existing AT(N) system and the evolving ATX(N) system. We provide a state-of-the-art summary of the potential contexts of use of these systems in AD clinical trials and future clinical practice. We also discuss current challenges related to the validation, standardization and qualification process and provide an outlook on the real-world application of the AT(N) system.},
}

@article {pmid34239093,
year = {2021},
author = {Mullard, A},
title = {Alzheimer antibody rush begins, as efficacy concerns remain.},
journal = {Nature reviews. Drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/d41573-021-00122-7},
pmid = {34239093},
issn = {1474-1784},
}

@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},
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).

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.

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).

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 {pmid34238524,
year = {2021},
author = {Mar, J and Arrospide, A and Soto-Gordoa, M and Machón, M and Iruin, Á and Martinez-Lage, P and Gabilondo, A and Moreno-Izco, F and Gabilondo, A and Arriola, L},
title = {Validity of a computerised population registry of dementia based on clinical databases.},
journal = {Neurologia (Barcelona, Spain)},
volume = {36},
number = {6},
pages = {418-425},
doi = {10.1016/j.nrleng.2018.03.005},
pmid = {34238524},
issn = {2173-5808},
abstract = {INTRODUCTION: The handling of information through digital media allows innovative approaches for identifying cases of dementia through computerised searches within the clinical databases that include systems for coding diagnoses. The aim of this study was to analyse the validity of a dementia registry in Gipuzkoa based on the administrative and clinical databases existing in the Basque Health Service.

METHODS: This is a descriptive study based on the evaluation of available data sources. First, through review of medical records, the diagnostic validity was evaluated in two samples of cases identified and not identified as dementia. The sensitivity, specificity and positive and negative predictive value of the diagnosis of dementia were measured. Subsequently, the cases of living dementia in December 31, 2016 were searched in the entire Gipuzkoa population to collect sociodemographic and clinical variables.

RESULTS: The validation samples included 986 cases and 327 no cases. The calculated sensitivity was 80.2% and the specificity was 99.9%. The negative predictive value was 99.4% and positive value was 95.1%. The cases in Gipuzkoa were 10 551, representing 65% of the cases predicted according to the literature. Antipsychotic medication were taken by a 40% and a 25% of the cases were institutionalised.

CONCLUSIONS: A registry of dementias based on clinical and administrative databases is valid and feasible. Its main contribution is to show the dimension of dementia in the health system.},
}

@article {pmid34238366,
year = {2021},
author = {Mensch, M and Dunot, J and Yishan, SM and Harris, SS and Blistein, A and Avdiu, A and Pousinha, PA and Giudici, C and Busche, MA and Jedlicka, P and Willem, M and Marie, H},
title = {Aη-α and Aη-β peptides impair LTP ex vivo within the low nanomolar range and impact neuronal activity in vivo.},
journal = {Alzheimer's research & therapy},
volume = {13},
number = {1},
pages = {125},
pmid = {34238366},
issn = {1758-9193},
support = {ANR-11-LABX-0028-01//Agence Nationale de la Recherche/ ; AAP SM 2018 number 1795//Association France Alzheimer/ ; EXC 2145 SyNergy//Deutsche Forschungsgemeinschaft (DE)/ ; 15038//Alzheimer Forschung Initiative/ ; MR/S017003/1//UKRI Future Leaders Fellowship (UK)/ ; A2019112S//BrightFocus Foundation/ ; ANR-15-IDEX-01//Agence Nationale de la Recherche (ANR)/ ; ANR-19-HBPR-0004-02-MILEDI//Agence Nationale de la Recherche (ANR)/ ; },
abstract = {BACKGROUND: Amyloid precursor protein (APP) processing is central to Alzheimer's disease (AD) etiology. As early cognitive alterations in AD are strongly correlated to abnormal information processing due to increasing synaptic impairment, it is crucial to characterize how peptides generated through APP cleavage modulate synapse function. We previously described a novel APP processing pathway producing η-secretase-derived peptides (Aη) and revealed that Aη-α, the longest form of Aη produced by η-secretase and α-secretase cleavage, impaired hippocampal long-term potentiation (LTP) ex vivo and neuronal activity in vivo.

METHODS: With the intention of going beyond this initial observation, we performed a comprehensive analysis to further characterize the effects of both Aη-α and the shorter Aη-β peptide on hippocampus function using ex vivo field electrophysiology, in vivo multiphoton calcium imaging, and in vivo electrophysiology.

RESULTS: We demonstrate that both synthetic peptides acutely impair LTP at low nanomolar concentrations ex vivo and reveal the N-terminus to be a primary site of activity. We further show that Aη-β, like Aη-α, inhibits neuronal activity in vivo and provide confirmation of LTP impairment by Aη-α in vivo.

CONCLUSIONS: These results provide novel insights into the functional role of the recently discovered η-secretase-derived products and suggest that Aη peptides represent important, pathophysiologically relevant, modulators of hippocampal network activity, with profound implications for APP-targeting therapeutic strategies in AD.},
}

@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 = {},
number = {},
pages = {2698811211030181},
doi = {10.1177/02698811211030181},
pmid = {34238048},
issn = {1461-7285},
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.

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.

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.

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 {pmid34236536,
year = {2021},
author = {Kharrati-Koopaee, H and Ebrahimie, E and Dadpasand, M and Niazi, A and Tian, R and Esmailizadeh, A},
title = {Gene network analysis to determine the effect of hypoxia-associated genes on brain damages and tumorigenesis using an avian model.},
journal = {Journal, genetic engineering & biotechnology},
volume = {19},
number = {1},
pages = {100},
pmid = {34236536},
issn = {2090-5920},
abstract = {BACKGROUND: Hypoxia refers to the condition of low oxygen pressure in the atmosphere and characterization of response to hypoxia as a biological complex puzzle, is challenging. Previously, we carried out a comparative genomic study by whole genome resequencing of highland and lowland Iranian native chickens to identify genomic variants associated with hypoxia conditions. Based on our previous findings, we used chicken as a model and the identified hypoxia-associated genes were converted to human's orthologs genes to construct the informative gene network. The main goal of this study was to visualize the features of diseases due to hypoxia-associated genes by gene network analysis.

RESULTS: It was found that hypoxia-associated genes contained several gene networks of disorders such as Parkinson, Alzheimer, cardiomyopathy, drug toxicity, and cancers. We found that biological pathways are involved in mitochondrion dysfunctions including peroxynitrous acid production denoted in brain injuries. Lewy body and neuromelanin were reported as key symptoms in Parkinson disease. Furthermore, calmodulin, and amyloid precursor protein were detected as leader proteins in Alzheimer's diseases. Dexamethasone was reported as the candidate toxic drug under the hypoxia condition that implicates diabetes, osteoporosis, and neurotoxicity. Our results suggested DNA damages caused by the high doses of UV radiation in high-altitude conditions, were associated with breast cancer, ovarian cancer, and colorectal cancer.

CONCLUSIONS: Our results showed that hypoxia-associated genes were enriched in several gene networks of disorders including Parkinson, Alzheimer, cardiomyopathy, drug toxicity, and different types of cancers. Furthermore, we suggested, UV radiation and low oxygen conditions in high-altitude regions may be responsible for the variety of human diseases.},
}

@article {pmid34233942,
year = {2021},
author = {Salloway, S and Cummings, J},
title = {Aducanumab, Amyloid Lowering, and Slowing of Alzheimer Disease.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012451},
pmid = {34233942},
issn = {1526-632X},
}

@article {pmid34233376,
year = {2021},
author = {Duru Aşiret, G and Kütmeç Yılmaz, C and Sayın Kasar, K},
title = {Investigation of the effects of interventions made according to the Progressively Lowered Stress Threshold Model on the care outcomes of Alzheimer patients and their families: a randomized clinical trial.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/psyg.12734},
pmid = {34233376},
issn = {1479-8301},
support = {2019-020//the Scientific Research Projects Coordination Unit of Aksaray University/ ; },
abstract = {BACKGROUND: One of the non-pharmacological methods used to reduce behavioural problems of Alzheimer's patients and the negative emotions accordingly experienced by caregivers consists of interventions performed according to the Progressively Lowered Stress Threshold (PLST) model.

METHODS: This randomized controlled study aimed to determine the effect of interventions performed according to PLST on the care burden, care satisfaction, and life satisfaction of caregivers of middle and advanced stage Alzheimer's disease patients, and on the neuropsychiatric symptoms and agitation levels of these patients. The research was conducted with a total of 29 caregivers divided into intervention (15) and control (14) groups. Data were collected using an Introductory Information Form, plus the Standardised Mini-Mental State Examination, Neuropsychiatric Inventory, Cohen-Mansfield Agitation Inventory, Carer's Assessment of Satisfaction Index, and Life Satisfaction Scale. Three home visits were made to the caregivers by the researchers in the first, second, and twelfth weeks of the intervention. During the home visits, face-to-face training was given as necessary to the individual caring for problems identified in the nursing care plan according to PLST.

RESULTS: As a result of the PLST training, there was a decrease in the behavioural problems of Alzheimer's patients, along with a decrease in the care burden of the caregivers and an increase in their care satisfaction. When the scale total scores of the individuals in the intervention and control groups were compared, it was found that only caregivers' care satisfaction increased at a statistically significant level (P < 0.05).

CONCLUSION: At the end of the training given according to PLST, it was found that behavioural problems of Alzheimer's patients and the care burden of caregivers had decreased, and the care satisfaction of caregivers increased. It is recommended that Alzheimer's patients and their caregivers be given training and interventions according to PLST.},
}

@article {pmid34232476,
year = {2021},
author = {Levit, A and Gibson, A and Hough, O and Jung, Y and Agca, Y and Agca, C and Hachinski, V and Allman, BL and Whitehead, SN},
title = {Precocious White Matter Inflammation and Behavioural Inflexibility Precede Learning and Memory Impairment in the TgAPP21 Rat Model of Alzheimer Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {34232476},
issn = {1559-1182},
support = {435819//Natural Sciences and Engineering Research Council of Canada/ ; 418489//Natural Sciences and Engineering Research Council/ ; 126127/CAPMC/CIHR/Canada ; 34213//Canadian Foundation for Innovation/ ; },
abstract = {Neuroinflammation and behavioural inflexibility are both common in late adulthood but far more profound in Alzheimer disease (AD). To investigate the relationship between ageing, AD, neuroinflammation, and behavioural flexibility, male wild-type Fischer 344 (Wt) and the transgenic APP21 (TgAPP21) rats were aged to 4, 8, 13, and 22 months and evaluated for neuroinflammation and cognitive impairment. TgAPP21 rats overexpress a pathogenic variant of the human amyloid precursor protein (hAPP; Swedish and Indiana mutations) but do not spontaneously develop overt pathology related to AD. In both genotypes, learning and memory were similarly impaired in older rats. However, at 8 months of age, TgAPP21 rats demonstrated behavioural inflexibility in set shifting, reversal, and the Morris water maze, while Wt rats showed inflexibility at 13 and 22 months of age. This early inflexibility in TgAPP21 rats was accompanied by a precocious increase in microglia activation within the corpus callosum; 8- and 13-month-old TgAPP21 rats had similar levels of microglia activation as 13- and 22-month-old Wt rats, respectively. However, while neuroinflammation within the white matter continued to progress with age, behavioural inflexibility peaked in 8-month-old TgAPP21 rats; in older TgAPP21 rats, memory and learning impairments masked inflexibility. These findings suggest that the behavioural inflexibility and white matter inflammation seen in normal ageing are accelerated in AD and may precede impairments of learning and memory.},
}

@article {pmid34231519,
year = {2021},
author = {Duong, MT and Chen, YJ and Doot, RK and Young, AJ and Lee, H and Cai, J and Pilania, A and Wolk, DA and Nasrallah, IM},
title = {Astrocyte activation imaging with 11C-acetate and amyloid PET in mild cognitive impairment due to Alzheimer pathology.},
journal = {Nuclear medicine communications},
volume = {},
number = {},
pages = {},
doi = {10.1097/MNM.0000000000001460},
pmid = {34231519},
issn = {1473-5628},
abstract = {BACKGROUND: Neuroinflammation is a well-known feature of early Alzheimer disease (AD) yet astrocyte activation has not been extensively evaluated with in vivo imaging in mild cognitive impairment (MCI) due to amyloid plaque pathology. Unlike neurons, astrocytes metabolize acetate, which has potential as a glial biomarker in neurodegeneration in response to AD pathologic features. Since the medial temporal lobe (MTL) is a hotspot for AD neurodegeneration and inflammation, we assessed astrocyte activity in the MTL and compared it to amyloid and cognition.

METHODS: We evaluate spatial patterns of in vivo astrocyte activation and their relationships to amyloid deposition and cognition in a cross-sectional pilot study of six participants with MCI and five cognitively normal participants. We measure 11C-acetate and 18F-florbetaben amyloid standardized uptake values ratios (SUVRs) and kinetic flux compared to the cerebellum on PET, with MRI and neurocognitive testing.

RESULTS: MTL 11C-acetate SUVR was significantly elevated in MCI compared to cognitively normal participants (P = 0.03; Cohen d = 1.76). Moreover, MTL 11C-acetate SUVR displayed significant associations with global and regional amyloid burden in MCI. Greater MTL 11C-acetate retention was significantly related with worse neurocognitive measures including the Montreal Cognitive Assessment (P = 0.001), word list recall memory (P = 0.03), Boston naming test (P = 0.04) and trails B test (P = 0.04).

CONCLUSIONS: While further validation is required, this exploratory pilot study suggests a potential role for 11C-acetate PET as a neuroinflammatory biomarker in MCI and early AD to provide clinical and translational insights into astrocyte activation as a pathological response to amyloid.},
}

@article {pmid34231429,
year = {2020},
author = {Agulló-Cantos, JM and García-Alandete, J and Paredes-Carbonell, JJ},
title = {Activos para la salud en cuidadores familiares de enfermos de Alzheimer: desarrollo de un mapa de activos para la salud.},
journal = {Global health promotion},
volume = {27},
number = {3},
pages = {209-216},
doi = {10.1177/1757975919843076},
pmid = {34231429},
issn = {1757-9767},
abstract = {El Alzheimer es la enfermedad más prevalente en mayores de 65 años, siendo una enfermedad neurodegenerativa progresiva. El cuidado de estas personas enfermas se sustenta, en la mayoría de los casos, desde el núcleo familiar, siendo éste quien sufre las consecuencias del cuidado. Tradicionalmente, el estudio y análisis de las personas cuidadoras se ha realizado desde perspectivas de déficit o negativas. El presente estudio introduce el modelo salutogénico y de activos para la salud, e intenta comprender el valor positivo del cuidado y la superación de las circunstancias adversas, a través de aquellas habilidades o recursos del cuidador o de su entorno que le ayudan a afrontar de forma positiva esta enfermedad.En el estudio participaron cuidadores familiares (n=45) de tres Centros de Estancias Diurnas para enfermos de Alzheimer diferentes, donde fueron entrevistados en grupos (de 5 a 13 participantes por entrevista) y grabados en audio, para su posterior trascripción y análisis de contenido temático.Los resultados muestran que los cuidadores familiares a pesar de vivir bajo una fuente de estrés, también puedn obtener consecuencias positivas de la experiencia del cuidado, siendo capaces de identificar activos para la salud, tanto internos como externos, que les ayudan a mejorar y/o mantener su salud como cuidador.},
}

@article {pmid34229262,
year = {2021},
author = {Bae, JB and Han, JW and Song, J and Lee, K and Kim, TH and Kwak, KP and Kim, BJ and Kim, SG and Kim, JL and Moon, SW and Park, JH and Ryu, SH and Youn, JC and Lee, DY and Lee, DW and Lee, SB and Lee, JJ and Jhoo, JH and Kim, KW},
title = {Hypohomocysteinemia may increases the risk of dementia and Alzheimer's disease: A nationwide population-based prospective cohort study.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {40},
number = {7},
pages = {4579-4584},
doi = {10.1016/j.clnu.2021.05.034},
pmid = {34229262},
issn = {1532-1983},
abstract = {BACKGROUND: Hyperhomocysteinemia has been repeatedly found to increase the risk of dementia. However, the effects of hypohomocysteinemia on the risk of dementia have been barely investigated. If hypohomocysteinemia, like hyperhomocysteinemia, increases the risk of dementia, misuse or overuse of homocysteine-lowing agents such as vitamin supplements may increase the risk of dementia.

AIMS: To investigate whether hypohomocysteinemia, like hyperhomocysteinemia, could increase the risk of dementia and Alzheimer's disease (AD) in a large population-based cohort of older adults.

METHODS: This prospective cohort study followed 2655 randomly sampled, community-dwelling, non-demented individuals aged 60 years or older from 2010 to 2018. We measured baseline serum total homocysteine (tHcy) levels and examined the effect of serum tHcy on the risks of dementia and AD using Cox proportional hazards models.

RESULTS: During the follow-up period (mean = 5.4 years, SD = 0.9), dementia and AD developed in 85 and 64 participants, respectively. Not only the participants with high serum tHcy (≥10.6 μmol/L) but also those with low serum tHcy (≤8.9 μmol/L) were 4-5 times more likely to develop dementia and AD compared to those with serum tHcy levels between 9.0 and 10.5 μmol/L. With the increase in serum tHcy concentration, the use of vitamin supplements decreased, and 41.2% of the participants with low serum tHcy (≤8.9 μmol/L) were taking vitamin supplements.

CONCLUSIONS: Not only hyperhomocysteinemia but also hypohomocysteinemia considerably increased the risk of dementia and AD in older adults. The risk of dementia that results from overuse or misuse of vitamin supplements should be acknowledged and homocysteine-lowering health policies should be tailored to consider dementia risks that are associated with hypohomocysteinemia.},
}

@article {pmid34228639,
year = {2021},
author = {Sáez-Orellana, F and Leroy, T and Ribeiro, F and Kreis, A and Leroy, K and Lalloyer, F and Baugé, E and Staels, B and Duyckaerts, C and Brion, JP and Gailly, P and Octave, JN and Pierrot, N},
title = {Regulation of PPARα by APP in Alzheimer disease impacts the pharmacological modulation of synaptic activity.},
journal = {JCI insight},
volume = {},
number = {},
pages = {},
doi = {10.1172/jci.insight.150099},
pmid = {34228639},
issn = {2379-3708},
abstract = {Among genetic susceptibility loci associated with late-onset Alzheimer disease (LOAD), genetic polymorphisms identified in genes encoding lipid carriers led to the hypothesis that a disruption of lipid metabolism could promote disease progression. We previously reported that amyloid precursor protein (APP) involved in AD physiopathology impairs lipid synthesis needed for cortical networks activity and that activation of peroxisome proliferator-activated receptor α (PPARα), a metabolic regulator involved in lipid metabolism, improves synaptic plasticity in an AD mouse model. These observations led us to investigate a possible correlation between PPARα function and full-length APP expression. Here, we report that PPARα expression and activation are inversely related to APP expression both in LOAD brains and in early-onset AD cases with a duplication of the APP gene, but not in control human brains. Moreover, human APP expression decreased PPARA expression and its related target genes in transgenic mice and in cultured cortical cells, while opposite results were observed in APP silenced cortical networks. In cultured neurons, APP-mediated decrease or increase in synaptic activity was corrected by PPARα specific agonist and antagonist, respectively. APP-mediated control of synaptic activity was abolished following PPARα deficiency, indicating a key function of PPARα in this process.},
}

@article {pmid34228130,
year = {2021},
author = {Manly, JJ and Gilmore-Bykovskyi, A and Deters, KD},
title = {Inclusion of Underrepresented Groups in Preclinical Alzheimer Disease Trials-Opportunities Abound.},
journal = {JAMA network open},
volume = {4},
number = {7},
pages = {e2114606},
doi = {10.1001/jamanetworkopen.2021.14606},
pmid = {34228130},
issn = {2574-3805},
}