@article {pmid34129637,
year = {2021},
author = {Triunfol, M and Gouveia, FC},
title = {What's not in the news headlines or titles of Alzheimer disease articles? #InMice.},
journal = {PLoS biology},
volume = {19},
number = {6},
pages = {e3001260},
doi = {10.1371/journal.pbio.3001260},
pmid = {34129637},
issn = {1545-7885},
abstract = {There is increasing scrutiny around how science is communicated to the public. For instance, a Twitter account @justsaysinmice (with 70.4K followers in January 2021) was created to call attention to news headlines that omit that mice, not humans, are the ones for whom the study findings apply. This is the case of many headlines reporting on Alzheimer disease (AD) research. AD is characterized by a degeneration of the human brain, loss of cognition, and behavioral changes, for which no treatment is available. Around 200 rodent models have been developed to study AD, even though AD is an exclusively human condition that does not occur naturally in other species and appears impervious to reproduction in artificial animal models, an information not always disclosed. It is not known what prompts writers of news stories to either omit or acknowledge, in the story's headlines, that the study was done in mice and not in humans. Here, we raised the hypothesis that how science is reported by scientists plays a role on the news reporting. To test this hypothesis, we investigated whether an association exists between articles' titles and news' headlines regarding the omission, or not, of mice. To this end, we analyzed a sample of 623 open-access scientific papers indexed in PubMed in 2018 and 2019 that used mice either as models or as the biological source for experimental studies in AD research. We found a significant association (p < 0.01) between articles' titles and news stories' headlines, revealing that when authors omit the species in the paper's title, writers of news stories tend to follow suit. We also found that papers not mentioning mice in their titles are more newsworthy and significantly more tweeted than papers that do. Our study shows that science reporting may affect media reporting and asks for changes in the way we report about findings obtained with animal models used to study human diseases.},
}

@article {pmid34128081,
year = {2021},
author = {Hallinan, GI and Hoq, MR and Ghosh, M and Vago, FS and Fernandez, A and Garringer, HJ and Vidal, R and Jiang, W and Ghetti, B},
title = {Structure of Tau filaments in Prion protein amyloidoses.},
journal = {Acta neuropathologica},
volume = {},
number = {},
pages = {},
pmid = {34128081},
issn = {1432-0533},
support = {P30-AG010133/AG/NIA NIH HHS/United States ; U01-NS110437/NS/NINDS NIH HHS/United States ; RF1-AG071177/NS/NINDS NIH HHS/United States ; },
abstract = {In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann-Sträussler-Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.},
}

@article {pmid34127064,
year = {2021},
author = {Bayat, S and Babulal, GM and Schindler, SE and Fagan, AM and Morris, JC and Mihailidis, A and Roe, CM},
title = {GPS driving: a digital biomarker for preclinical Alzheimer disease.},
journal = {Alzheimer's research & therapy},
volume = {13},
number = {1},
pages = {115},
pmid = {34127064},
issn = {1758-9193},
support = {R01AG056466, R01AG068183, R01AG067428//Foundation for the National Institutes of Health/ ; P30AG066444; P01AG003991; P01AG026276; U19AG032438; and U19AG024904//Foundation for the National Institutes of Health/ ; R01AG056466, R01AG068183, R01AG067428//Foundation for the National Institutes of Health/ ; K23AG053426//Foundation for the National Institutes of Health/ ; A2021142S//BrightFocus Foundation/ ; A2021142S//BrightFocus Foundation/ ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia. Preclinical AD is the period during which early AD brain changes are present but cognitive symptoms have not yet manifest. The presence of AD brain changes can be ascertained by molecular biomarkers obtained via imaging and lumbar puncture. However, the use of these methods is limited by cost, acceptability, and availability. The preclinical stage of AD may have a subtle functional signature, which can impact complex behaviours such as driving. The objective of the present study was to evaluate the ability of in-vehicle GPS data loggers to distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD using machine learning methods.

METHODS: We followed naturalistic driving in cognitively normal older drivers for 1 year with a commercial in-vehicle GPS data logger. The cohort included n = 64 individuals with and n = 75 without preclinical AD, as determined by cerebrospinal fluid biomarkers. Four Random Forest (RF) models were trained to detect preclinical AD. RF Gini index was used to identify the strongest predictors of preclinical AD.

RESULTS: The F1 score of the RF models for identifying preclinical AD was 0.85 using APOE ε4 status and age only, 0.82 using GPS-based driving indicators only, 0.88 using age and driving indicators, and 0.91 using age, APOE ε4 status, and driving. The area under the receiver operating curve for the final model was 0.96.

CONCLUSION: The findings suggest that GPS driving may serve as an effective and accurate digital biomarker for identifying preclinical AD among older adults.},
}

@article {pmid34127063,
year = {2021},
author = {Li, Y and Zhu, K and Li, N and Wang, X and Xiao, X and Li, L and Li, L and He, Y and Zhang, J and Wo, J and Cui, Y and Huang, H and Zhang, J and Wang, W and Wang, X and Zheng, Y},
title = {Reversible GABAergic dysfunction involved in hippocampal hyperactivity predicts early-stage Alzheimer disease in a mouse model.},
journal = {Alzheimer's research & therapy},
volume = {13},
number = {1},
pages = {114},
pmid = {34127063},
issn = {1758-9193},
support = {81971004//National Natural Science Foundation of China/ ; 81571038//National Natural Science Foundation of China/ ; 81771145//National Natural Science Foundation of China/ ; 5202006//Natural Science Foundation of Beijing Municipality/ ; 2016YFC1306300//National Key Research and Development Program of China/ ; },
abstract = {BACKGROUND: Neuronal hyperactivity related to β-amyloid (Aβ) is considered an early warning sign of Alzheimer disease (AD). Although increasing evidence supports this opinion, the underlying mechanisms are still unknown.

METHODS: Here, we recorded whole-cell synaptic currents and membrane potentials using patch clamping of acute hippocampal slices from human amyloid precursor protein (APP)/presenilin-1 transgenic (5XFAD) mice and their wild-type littermates. Biochemical methods, electron microscopic imaging, behavioral tests, and intraventricular drug delivery applied with osmotic pumps were used in this study.

RESULTS: We confirmed hyperactivity of hippocampal CA1 pyramidal neurons in 5XFAD mice using whole-cell electrophysiological recording at 2.5 months old, when local Aβ-positive plaques had not developed and only mild cognitive dysfunction occurred. We further discovered attenuated inhibitory postsynaptic currents and unchanged excitatory postsynaptic currents in CA1 pyramidal neurons, in which the intrinsic excitability was unchanged. Moreover, the density of both γ-aminobutyric acid A (GABAA) receptor subunits, α1 and γ2, was reduced in synapses of the hippocampus in transgenic mice. Intriguingly, early intervention with the GABAA receptor agonist gaboxadol reversed the hippocampal hyperactivity and modestly ameliorated cognitive performance in 5XFAD mice under our experimental conditions.

CONCLUSIONS: Inhibitory postsynaptic disruption critically contributes to abnormalities in the hippocampal network and cognition in 5XFAD mice and possibly in AD. Therefore, strengthening the GABAergic system could be a promising therapy for AD in the early stages.},
}

@article {pmid34126028,
year = {2021},
author = {Zaritsky, R},
title = {To Alois Alzheimer, From Auguste Deter.},
journal = {Annals of internal medicine},
volume = {174},
number = {6},
pages = {843},
doi = {10.7326/M20-3816},
pmid = {34126028},
issn = {1539-3704},
}

@article {pmid34123738,
year = {2021},
author = {Kim, H and Chung, JY},
title = {Pathobiolgy and Management of Alzheimer's Disease.},
journal = {Chonnam medical journal},
volume = {57},
number = {2},
pages = {108-117},
pmid = {34123738},
issn = {2233-7385},
abstract = {Amyloid and tau protein abnormalities have been identified as the main causes of Alzheimer's disease but exact mechanisms remain to be revealed. Especially, amyloid beta and tau protein coupling and neuroinflammatory and neurovascular contributions to Alzheimer disease are quite mysterious. Many animal models and basic biological research are trying to solve these puzzles. Known as aging processes, autophagy, mitochondrial degeneration with generation of reactive oxygen species, and age-related epigenetic modifications are also known to be associated with development of Alzheimer's disease. Environmental factors such as bacterial and viral infections, heavy metal ions, diet, sleep, stress, and gut microbiota are also risk factors of Alzheimer's disease. Future development of preventive and therapeutic modalities may be dependent on the pathobiology of Alzheimer's disease.},
}

@article {pmid34122052,
year = {2021},
author = {Yin, J and Ibrahim, S and Petersen, F and Yu, X},
title = {Autoimmunomic Signatures of Aging and Age-Related Neurodegenerative Diseases Are Associated With Brain Function and Ribosomal Proteins.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {679688},
pmid = {34122052},
issn = {1663-4365},
abstract = {Biological aging is a complex process featured by declined function of cells and tissues, including those of the immune system. As a consequence, aging affects the expression and development of autoantibodies and autoreactive T cells, which can be seen in their sum as the autoimmunome of an individual. In this study we analyzed whether sets of autoimmune features are associated with specific phenotypes which form autoimmunomic signatures related to age and neurodegenerative diseases. The autoantibody profile data of healthy subjects and patients from the GEO database was used to explore autoimmunomic signatures of aging and three neurodegenerative diseases including Parkinson's disease (PD), Alzheimer disease (AD) and Multiple Sclerosis (MS). Our results demonstrate that the autoimmunomic signature of aging is featured by an undulated increase of IgG autoantibodies associated with learning and behavior and a consistent increase of IgG autoantibodies related to ribosome and translation, and the autoimmunomic signature of aging are also associated with age-related neurodegenerative diseases. Intriguingly, Differential Expression-Sliding Window Analysis (DE-SWAN) identified three waves of changes of autoantibodies during aging at an age of 30, 50, and 62 years, respectively. Furthermore, IgG autoantibodies, in particular those against ribosomal proteins, could be used as prediction markers for aging and age-related neurodegenerative diseases. Therefore, this study for the first time uncovers comprehensive autoimmunomic signatures for aging and age-related neurodegenerative diseases.},
}

@article {pmid34121996,
year = {2021},
author = {Contini, C and Olianas, A and Serrao, S and Deriu, C and Iavarone, F and Boroumand, M and Bizzarro, A and Lauria, A and Faa, G and Castagnola, M and Messana, I and Manconi, B and Masullo, C and Cabras, T},
title = {Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease.},
journal = {Frontiers in neuroscience},
volume = {15},
number = {},
pages = {668852},
pmid = {34121996},
issn = {1662-4548},
abstract = {Alzheimer disease (AD) is the most prevalent neurodegenerative disease in the elderly, characterized by accumulation in the brain of misfolded proteins, inflammation, and oxidative damage leading to neuronal cell death. By considering the viewpoint that AD onset and worsening may be influenced by environmental factors causing infection, oxidative stress, and inflammatory reaction, we investigated the changes of the salivary proteome in a population of patients with respect to that in healthy controls (HCs). Indeed, the possible use of saliva as a diagnostic tool has been explored in several oral and systemic diseases. Moreover, the oral cavity continuously established adaptative and protective processes toward exogenous stimuli. In the present study, qualitative/quantitative variations of 56 salivary proteoforms, including post-translationally modified derivatives, have been analyzed by RP-HPLC-ESI-IT-MS and MS/MS analyses, and immunological methods were applied to validate MS results. The salivary protein profile of AD patients was characterized by significantly higher levels of some multifaceted proteins and peptides that were either specific to the oral cavity or also expressed in other body districts: (i) peptides involved in the homeostasis of the oral cavity; (ii) proteins acting as ROS/RNS scavengers and with a neuroprotective role, such as S100A8, S100A9, and their glutathionylated and nitrosylated proteoforms; cystatin B and glutathionylated and dimeric derivatives; (iii) proteins with antimicrobial activity, such as α-defensins, cystatins A and B, histatin 1, statherin, and thymosin β4, this last with a neuroprotective role at the level of microglia. These results suggested that, in response to injured conditions, Alzheimer patients established defensive mechanisms detectable at the oral level. Data are available via ProteomeXchange with identifier PXD021538.},
}

@article {pmid34120907,
year = {2021},
author = {Richard Chen, X and Shao, Y and Sadowski, MJ and , },
title = {Segmented Linear Mixed Model Analysis Reveals Association of the APOEɛ4 Allele with Faster Rate of Alzheimer's Disease Dementia Progression.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-210434},
pmid = {34120907},
issn = {1875-8908},
abstract = {BACKGROUND: APOEɛ4 allele carriers present with increased risk for late-onset Alzheimer's disease (AD), show cognitive symptoms at earlier age, and are more likely to transition from mild cognitive impairment (MCI) to dementia but despite this, it remains unclear whether or not the ɛ4 allele controls the rate of disease progression.

OBJECTIVE: To determine effects of the ɛ4 allele on rates of cognitive decline and brain atrophy during MCI and dementia stages of AD.

METHODS: A segmented linear mixed model was chosen for longitudinal modeling of cognitive and brain volumetric data of 73 ɛ3/ɛ3, 99 ɛ3/ɛ4, and 39 ɛ4/ɛ4 Alzheimer's Disease Neuroimaging Initiative participants who transitioned during the study from MCI to AD dementia.

RESULTS: ɛ4 carriers showed faster decline on MMSE, ADAS-11, CDR-SB, and MoCA scales, with the last two measures showing significant ɛ4 allele-dose effects after dementia transition but not during MCI. The ɛ4 effect was more prevalent in younger participants and in females. ɛ4 carriers also demonstrated faster rates of atrophy of the whole brain, the hippocampus, the entorhinal cortex, the middle temporal gyrus, and expansion of the ventricles after transitioning to dementia but not during MCI.

CONCLUSION: Possession of the ɛ4 allele is associated with a faster progression of dementia due to AD. Our observations support the notion that APOE genotype not only controls AD risk but also differentially regulates mechanisms of neurodegeneration underlying disease advancement. Furthermore, our findings carry significance for AD clinical trial design.},
}

@article {pmid34119804,
year = {2021},
author = {Montazeri, K and Farhadi, M and Fekrazad, R and Akbarnejad, Z and Chaibakhsh, S and Mahmoudian, S},
title = {Transcranial photobiomodulation in the management of brain disorders.},
journal = {Journal of photochemistry and photobiology. B, Biology},
volume = {221},
number = {},
pages = {112207},
doi = {10.1016/j.jphotobiol.2021.112207},
pmid = {34119804},
issn = {1873-2682},
abstract = {Transcranial photobiomodulation (tPBM) is the process of delivering light photons through the skull to benefit from its modifying effect. Brain disorders are important health problems. The aim of this review was to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Parkinson, and Alzheimer's disease as the common brain disorders. Four online databases, including Cochrane, Pub Med, Embase, and Google scholar were searched according to the Preferred Reporting Items for Systematic Reviews and meta-analyses (PRISMA) guidelines. 4728 articles were obtained in the initial search. Only those articles that were published until September 2020 and designed as randomized clinical trials (RCTs) or animal-controlled studies were included. 6 RCTs, 2 related supplementary articles, and 38 controlled animal studies met the inclusion criteria of this study. No RCTs were performed in the fields of Alzheimer's and Parkinson's diseases. The human RCTs and animal studies reported no adverse events resulted from the use of tPBM. Useful parameters of tPBM were identified according to the controlled animal studies. Since the investigated RCTs had no homogenous results, making an evidence-based decision for definite therapeutic application of tPBM is still unattainable. Altogether, these data support the need for large confirmatory well-designed RCTs for using tPBM as a novel, safe, and easy-to-administer treatment of brain disorders.

EVIDENCE BEFORE THIS STUDY: High prevalence and complications of brain disorders and also side effects of neuropsychiatric medications have encouraged researchers to find alternative therapeutic techniques which tPBM can be one of them. In present review we tried to determine the existing evidence of effectiveness, useful parameters, and safety of tPBM in the management of traumatic brain injury, stroke, Alzheimer, and Parkinson's disease as common brain disorders. Four online databases, including "Cochrane", "Pub Med", "Embase", and "Google scholar" were searched. Only those articles that were published until September 2020 and designed as RCTs or animal-controlled studies were included. Search keywords were the followings: transcranial photobiomodulation" OR "transcranial low-level laser therapy" AND "stroke" OR "traumatic brain injury" OR "Alzheimer" OR "Parkinson". Several studies have confirmed effectiveness of tPBM in treatment of different brain disorders but the level of evidence of its effectiveness remain to be determined.

ADDED VALUE OF THIS STUDY: In this study we systematically reviewed human RCTs to determine the existing evidence of tPBM effectiveness in management of four mentioned brain disorders. Since the outcomes of the reviewed RCTs were not homogeneous, further well-designed RCTs are required to decide more definitively on the evidence of this noninvasive and probably safe therapeutic intervention. We hypothesized that non-homogeneous outcomes could be due to inefficiency of PBM parameters. Controlled animal studies have the advantage of using objective tests to evaluate the results and compare them with the control group. We determined useful tPBM parameters based on these studies.

This research is part of our main project of tinnitus treatment using photobiomodulation (PBM). Evidence of central nervous system involvement in tinnitus led us to believe that treatment protocol of tinnitus should also include transcranial PBM. The determined useful parameters can be helpful in designing more efficient tPBM protocols in the management of brain disorders and tinnitus as a common debilitating symptom that can be associated with these disorders.},
}

@article {pmid34118168,
year = {2021},
author = {Brunori, M},
title = {From Kuru to Alzheimer: a personal outlook.},
journal = {Protein science : a publication of the Protein Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/pro.4145},
pmid = {34118168},
issn = {1469-896X},
abstract = {Seventy years ago we learned from Chris Anfinsen that the stereochemical code necessary to fold a protein is embedded into its amino acid sequence. In water, protein morphogenesis is a spontaneous reversible process leading from an ensemble of disordered structures to the ordered functionally competent protein; conforming to Aristotle's definition of substance, the synolon of matter and form. The overall process of folding is generally consistent with a two state transition between the native and the denatured protein: not only the denatured state is an ensemble of several structures, but also the native protein populates distinct functionally relevant conformational (sub)states. This two-state view should be revised, given that any globular protein can populate a peculiar third state called amyloid, characterized by an overall architecture that at variance with the native state, is by-and-large independent of the primary structure. In a nut shell, we should accept that beside the folded and unfolded states, any protein can populate a third state called amyloid which gained centre stage being the hallmark of incurable neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases as well as others. These fatal diseases are characterized by clear-cut clinical differences, yet display some commonalities such as the presence in the brain of amyloid deposits constituted by one misfolded protein specific for each disease. Some aspects of this complex problem are summarized here as an excursus from the prion's fibrils observed in the brain of aborigines who died of Kuru to the amyloid detectable in the cortex of Alzheimer's patients. This article is protected by copyright. All rights reserved.},
}

@article {pmid34117482,
year = {2021},
author = {Romoli, M and Sen, A and Parnetti, L and Calabresi, P and Costa, C},
title = {Amyloid-β: a potential link between epilepsy and cognitive decline.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {34117482},
issn = {1759-4766},
abstract = {People with epilepsy - in particular, late-onset epilepsy of unknown aetiology - have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease (AD), supporting the concept of an epileptic AD prodrome. However, the relationship between epilepsy and cognitive decline remains controversial, with substantial uncertainties about whether epilepsy drives cognitive decline or vice versa, and whether shared pathways underlie both conditions. Here, we review evidence that amyloid-β (Aβ) forms part of a shared pathway between epilepsy and cognitive decline, particularly in the context of AD. People with epilepsy show an increased burden of Aβ pathology in the brain, and Aβ-mediated epileptogenic alterations have been demonstrated in experimental studies, with evidence suggesting that Aβ pathology might already be pro-epileptogenic at the soluble stage, long before plaque deposition. We discuss the hypothesis that Aβ mediates - or is at least a major determinant of - a continuum spanning epilepsy and cognitive decline. Serial cognitive testing and assessment of Aβ levels might be worthwhile to stratify the risk of developing dementia in people with late-onset epilepsy. If seizures are a clinical harbinger of dementia, people with late-onset epilepsy could be an ideal group in which to implement preventive or therapeutic strategies to slow cognitive decline.},
}

@article {pmid34116955,
year = {2021},
author = {Kim, JI and Zhu, D and Barry, E and Kovac, E and Aboumohamed, A and Agalliu, I and Sankin, A},
title = {Intravesical Bacillus Calmette-Guérin Treatment Is Inversely Associated With the Risk of Developing Alzheimer Disease or Other Dementia Among Patients With Non-muscle-invasive Bladder Cancer.},
journal = {Clinical genitourinary cancer},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clgc.2021.05.001},
pmid = {34116955},
issn = {1938-0682},
abstract = {BACKGROUND: The immune system plays an important role in the pathogenesis of Alzheimer disease (AD), but it remains unclear whether bacillus Calmette-Guérin (BCG) may affect the risk of AD or not.

METHODS: Using retrospective chart review, we collected data regarding demographics, comorbidities, cancer diagnosis, BCG treatment, and subsequent diagnosis of AD or other dementia in a racially/ethnically diverse cohort of patients with non-muscle-invasive bladder cancer (NIMBC) receiving treatment between 1984 and 2020 in the Bronx, New York. We used Cox proportional hazard models to examine association between BCG treatment and risk of incident AD or other dementia, adjusting for age, gender, race/ethnicity, and major comorbidities.

RESULTS: In our cohort of 1290 patients with NMIBC, a total of 99 (7.7%) patients developed AD or other dementia during follow-up. Patients who received BCG treatment (25%) had a 60% lowered incidence of AD or other dementia (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.21-0.80) in comparison to those who did not receive BCG. There was also suggestive evidence that the reduction in risk of AD or other dementia associated with BCG treatment was stronger in men (adjusted HR, 0.34; 95% CI, 0.15-0.81) but not in women (adjusted HR, 0.75; 95% CI 0.25-2.24). When we stratified the patients who received BCG by type of treatments, patients who received both induction and maintenance rounds of BCG had a further lowered incidence of AD or other dementia (HR, 0.23; 95% CI, 0.06-0.96) than patients who did not receive BCG.

CONCLUSIONS: To our knowledge, our study is one of the first to suggest that BCG treatment is associated with a reduced risk of developing AD or other dementia in a multiethnic population, independent of significant comorbidities. Larger cohort studies are needed to corroborate our findings.},
}

@article {pmid34116363,
year = {2021},
author = {Moyle, W and Murfield, J and Lion, K},
title = {The effectiveness of smart home technologies to support the health outcomes of community-dwelling older adults living with dementia: A scoping review.},
journal = {International journal of medical informatics},
volume = {153},
number = {},
pages = {104513},
doi = {10.1016/j.ijmedinf.2021.104513},
pmid = {34116363},
issn = {1872-8243},
abstract = {OBJECTIVES: To map the current state-of-knowledge about the effectiveness of smart home technologies to support the health outcomes of community-dwelling older adults living with dementia.

DESIGN: A scoping review following the methodological frameworks described by Arksey and O'Malley (2005) and Levac et al. (2010).

DATA SOURCES: Electronic databases and online sources were searched in April 2020 using database specific medical subject headings and keywords about 'smart homes' and 'dementia'.

METHODS: Empirical peer-reviewed articles were included if they were written in English; used a quantitative, qualitative, or mixed method design; and presented the effects of a smart home technology on the health outcomes of community-dwelling adults living with dementia. Methodological and reporting quality of studies was assessed using the Mixed Methods Appraisal Tool - Version 2018.

RESULTS: Five studies described evaluations of five smart home technology systems with a total of n = 617 community-dwelling people living with dementia. Collectively, studies showed potential effectiveness of the technologies on a range of health outcomes (physical activity, activities of daily living, sleep, anxiety, depression, agitation, irritability, risk of falls, cognitive functioning, night-time injury, unattended home exits). However, the overall methodological and reporting quality of studies was low and profiled a research field lacking in rigorous evaluation.

CONCLUSIONS: Based on current evidence, the success of smart home technologies to support people with dementia to live at home remains unclear. Recommendations are provided to inform future research into smart home technologies for community-based dementia care.},
}

@article {pmid34114602,
year = {2021},
author = {Schumacher, J and Gunter, JL and Przybelski, SA and Jones, DT and Graff-Radford, J and Savica, R and Schwarz, CG and Senjem, ML and Jack, CR and Lowe, VJ and Knopman, DS and Fields, JA and Kremers, WK and Petersen, RC and Graff-Radford, NR and Ferman, TJ and Boeve, BF and Thomas, AJ and Taylor, JP and Kantarci, K},
title = {Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awab218},
pmid = {34114602},
issn = {1460-2156},
abstract = {Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of α-synuclein aggregates, but many DLB cases show concurrent Alzheimer's disease (AD) pathology in the form of β-amyloid plaques and tau neurofibrillary tangles. The first objective of this study was to investigate the effect of AD co-pathology on functional network changes within the default mode network (DMN) in DLB. Secondly, we studied how the distribution of tau pathology measured with PET relates to functional connectivity in DLB. Twenty-seven DLB, 26 AD, and 99 cognitively unimpaired (CU) participants (balanced on age and sex to the DLB group) underwent tau-PET with AV-1451 (flortaucipir), β-amyloid-PET with Pittsburgh compound-B (PiB), and resting state (rs)-fMRI scans. The rs-fMRI data were used to assess functional connectivity within the posterior DMN. This was then correlated with overall cortical flortaucipir-PET and PiB-PET standardized uptake value ratio (SUVr). The strength of inter-regional functional connectivity was assessed using the Schaefer atlas. Tau-PET covariance was measured as the correlation in flortaucipir SUVr between any two regions across participants. The association between region-to-region functional connectivity and tau-PET covariance was assessed using linear regression. Additionally, we identified the region with highest and the region with lowest tau SUVrs (tau hot- and coldspot) and tested whether tau SUVr in all other brain regions was associated with the strength of functional connectivity to these tau hot- and coldspots. A reduction in posterior DMN connectivity correlated with overall higher cortical tau- (r=-0.39, p = 0.04) and amyloid-PET uptake (r=-0.41, p = 0.03) in the DLB group, i.e. DLB patients with more concurrent AD pathology showed a more severe loss of DMN connectivity. Higher functional connectivity between regions was associated with higher tau covariance in CU, AD, and DLB. Furthermore, higher functional connectivity of a target region to the tau hotspot (i.e. inferior/medial temporal cortex) was related to higher flortaucipir SUVRs in the target region whereas higher functional connectivity to the tau coldspot (i.e. sensory-motor cortex) was related to lower flortaucipir SUVr in the target region. Our findings suggest that a higher burden of AD co-pathology in DLB patients is associated with more AD-like changes in functional connectivity. Furthermore, we found an association between the brain's functional network architecture and the distribution of tau pathology which has recently been described in AD. We show that this relationship also exists in DLB patients, indicating that similar mechanisms of connectivity-dependent occurrence of tau pathology might be at work in both diseases.},
}

@article {pmid34114049,
year = {2021},
author = {Zwirner, J and Lier, J and Franke, H and Hammer, N and Matschke, J and Trautz, F and Tse, R and Ondruschka, B},
title = {GFAP positivity in neurons following traumatic brain injuries.},
journal = {International journal of legal medicine},
volume = {},
number = {},
pages = {},
pmid = {34114049},
issn = {1437-1596},
abstract = {Glial fibrillary acidic protein (GFAP) is a well-established astrocytic biomarker for the diagnosis, monitoring and outcome prediction of traumatic brain injury (TBI). Few studies stated an accumulation of neuronal GFAP that was observed in various brain pathologies, including traumatic brain injuries. As the neuronal immunopositivity for GFAP in Alzheimer patients was shown to cross-react with non-GFAP epitopes, the neuronal immunopositivity for GFAP in TBI patients should be challenged. In this study, cerebral and cerebellar tissues of 52 TBI fatalities and 17 controls were screened for immunopositivity for GFAP in neurons by means of immunohistochemistry and immunofluorescence. The results revealed that neuronal immunopositivity for GFAP is most likely a staining artefact as negative controls also revealed neuronal GFAP staining. However, the phenomenon was twice as frequent for TBI fatalities compared to non-TBI control cases (12 vs. 6%). Neuronal GFAP staining was observed in the pericontusional zone and the ipsilateral hippocampus, but was absent in the contralateral cortex of TBI cases. Immunopositivity for GFAP was significantly correlated with the survival time (r = 0.306, P = 0.015), but no correlations were found with age at death, sex nor the post-mortem interval in TBI fatalities. This study provides evidence that the TBI-associated neuronal immunopositivity for GFAP is indeed a staining artefact. However, an absence post-traumatic neuronal GFAP cannot readily be assumed. Regardless of the particular mechanism, this study revealed that the artefact/potential neuronal immunopositivity for GFAP is a global, rather than a regional brain phenomenon and might be useful for minimum TBI survival time determinations, if certain exclusion criteria are strictly respected.},
}

@article {pmid34113981,
year = {2021},
author = {Lefèvre-Arbogast, S and Dhana, K and Aggarwal, NT and Zhang, S and Agarwal, P and Liu, X and Laranjo, N and Carey, V and Sacks, F and Barnes, LL and Arfanakis, K},
title = {Vitamin D Intake and Brain Cortical Thickness in Community-Dwelling Overweight Older Adults: A Cross-Sectional Study.},
journal = {The Journal of nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1093/jn/nxab168},
pmid = {34113981},
issn = {1541-6100},
abstract = {BACKGROUND: Vitamin D is critical to brain health and a promising candidate to prevent cognitive decline and onset of Alzheimer disease (AD), although the underlying brain mechanisms are unclear.

OBJECTIVES: This study aimed to determine the association between vitamin D intake and brain cortical thickness in older adults.

METHODS: This was a cross-sectional investigation of 263 cognitively unimpaired participants, aged 65 y and older, participating in the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) trial (an ongoing study testing the effects of a 3-y diet intervention on cognitive decline). Vitamin D intake, from diet and supplements, was ascertained from an FFQ. Linear regression analysis, adjusted for age, sex, race, education, income, cognitive and physical activities, and cardiovascular disease risk factors, was used to determine the association between vitamin D intake and cortical thickness of the whole brain, lobes, and AD signature.

RESULTS: Total vitamin D intake was associated with cortical thickness of the temporal lobe and AD signature. Compared with individuals in the lowest quartile of total vitamin D intake [median: 140 international units (IU)/d], those in the highest quartile (median: 1439 IU/d) had a 0.038-mm (95% CI: 0.006, 0.069 mm) thicker temporal lobe and 0.041-mm (95% CI: 0.012, 0.070 mm) thicker AD signature. Most vitamin D intake was from supplements, and supplemental intake was also associated with cortical thickness. Compared with those who used no supplement, individuals taking 800-1000 IU/d and >1000 IU/d of supplemental vitamin D had a 0.039-mm (95% CI: 0.013, 0.066 mm) and 0.047-mm (95% CI: 0.013, 0.081 mm) thicker temporal lobe and a 0.037-mm (95% CI: 0.013, 0.061 mm) and 0.046-mm (95% CI: 0.015, 0.077 mm) thicker AD signature, respectively. Dietary vitamin D was not related to brain cortical thickness in our sample.

CONCLUSIONS: In cognitively unimpaired older adults, total and supplemental vitamin D intakes were associated with cortical thickness in regions vulnerable to AD.This trial was registered at clinicaltrials.gov as NCT02817074.},
}

@article {pmid34112972,
year = {2021},
author = {DeMichele-Sweet, MAA and Klei, L and Creese, B and Harwood, JC and Weamer, EA and McClain, L and Sims, R and Hernandez, I and Moreno-Grau, S and Tárraga, L and Boada, M and Alarcón-Martín, E and Valero, S and , and Liu, Y and Hooli, B and Aarsland, D and Selbaek, G and Bergh, S and Rongve, A and Saltvedt, I and Skjellegrind, HK and Engdahl, B and Stordal, E and Andreassen, OA and Djurovic, S and Athanasiu, L and Seripa, D and Borroni, B and Albani, D and Forloni, G and Mecocci, P and Serretti, A and De Ronchi, D and Politis, A and Williams, J and Mayeux, R and Foroud, T and Ruiz, A and Ballard, C and Holmans, P and Lopez, OL and Kamboh, MI and Devlin, B and Sweet, RA},
title = {Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {34112972},
issn = {1476-5578},
support = {AG027224//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG066468//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG030653//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; MH116046//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; MH057881//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.},
}

@article {pmid34112945,
year = {2021},
author = {Mullard, A},
title = {FDA approval for Biogen's aducanumab sparks Alzheimer disease firestorm.},
journal = {Nature reviews. Drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/d41573-021-00099-3},
pmid = {34112945},
issn = {1474-1784},
}

@article {pmid34112537,
year = {2021},
author = {Chávez-Pérez, C and Ceballos-Ramírez, A and Suárez-Castro, A},
title = {[Effects of the use of 17 β-estradiol and genistein in Alzheimer's disease in women with menopause].},
journal = {Revista espanola de geriatria y gerontologia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.regg.2021.04.005},
pmid = {34112537},
issn = {1578-1747},
abstract = {The use of 17 β-estradiol and genistein in women with menopause helps in the reduction of vasomotor symptoms and cognitive improvement. There is evidence on the use of certain flavonoids such as genistein, which has a potentially neuroprotective role in neurodegenerative diseases such as Alzheimer's. Scientific evidence on the effects of phytoestrogens and genistein during menopause and their effect on cognition are scarce, however, in the present review it was found that the intervention with 17 β-estradiol has positive effects on cognition in women with Alzheimer's disease. In addition, the use of genistein, daidzein or any supplement based on isoflavones may influence vasomotor symptoms. 17 β-estradiol supplements in women in early menopause and with some degree of cognitive impairment may have beneficial effects.},
}

@article {pmid34111056,
year = {2021},
author = {Diez-Sepulveda, JC and Uribe-Buritica, FL and Angel-Isaza, AM and Bustamante-Cristancho, LA and Mejia-Herrera, F and Watts-Pajaro, FA and Rojas-Martinez, MF},
title = {An 80-Year-Old Woman with Alzheimer Disease and Accidental Poisoning with Pyrethroid Pesticide Successfully Treated with Intravenous Lipid Emulsion.},
journal = {The American journal of case reports},
volume = {22},
number = {},
pages = {e928420},
doi = {10.12659/AJCR.928420},
pmid = {34111056},
issn = {1941-5923},
abstract = {BACKGROUND Pesticides are commonly used in the agricultural industry. Overdose can be lethal due to its effects generating closure of the voltage-gated sodium channels in the axonal membranes. Most case reports of toxicity refer to skin exposure and there are very few that refer to effects due to its oral intake. CASE REPORT We report the case of an elderly woman with Alzheimer disease who accidentally swallowed 50 g of Lambda Cyhalothrin (GOLPE 5 M E®), a pyrethroid of medium toxicity containing a cyano group. It severely harmed the woman's health, causing severe central nervous system depression and refractory vasodilated shock requiring the use of vasopressors. Its management was challenging, requiring orotracheal intubation, vasopressors, and admission to the Intensive Care Unit (ICU). The emergency care team decided to use intravenous lipid emulsion, which clearly helped with the recovery and successful discharge of the patient. CONCLUSIONS The use of intravenous lipid emulsion for the treatment of pyrethroid poisoning can lead to successful outcomes, as described in this case report.},
}

@article {pmid34110247,
year = {2021},
author = {Bourdenx, M and Gavathiotis, E and Cuervo, AM},
title = {Chaperone-mediated autophagy: a gatekeeper of neuronal proteostasis.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/15548627.2021.1935007},
pmid = {34110247},
issn = {1554-8635},
abstract = {Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular proteostasis and cellular function remains unknown. In this work, we have investigated the consequences of failure of chaperone-mediated autophagy (CMA) in neurons and compared the impact, on the neuronal proteome, of CMA loss to that of macroautophagy loss. We found that these autophagic pathways are non-redundant and that CMA is the main one responsible for maintenance of the metastable proteome (the one at risk of aggregation). We demonstrate that loss of CMA, as the one that occurs in aging, has a synergistic effect with the proteotoxicity associated with neurodegenerative conditions such as Alzheimer disease (AD) and, conversely, that, pharmacological enhancement of CMA is effective in improving both behavior and pathology in two different AD mouse models.},
}

@article {pmid34108875,
year = {2021},
author = {Alvarenga, MOP and Frazão, DR and de Matos, IG and Bittencourt, LO and Fagundes, NCF and Rösing, CK and Maia, LC and Lima, RR},
title = {Is There Any Association Between Neurodegenerative Diseases and Periodontitis? A Systematic Review.},
journal = {Frontiers in aging neuroscience},
volume = {13},
number = {},
pages = {651437},
doi = {10.3389/fnagi.2021.651437},
pmid = {34108875},
issn = {1663-4365},
abstract = {Background: Neurodegenerative diseases are a group of progressive disorders that affect the central nervous system (CNS) such as Alzheimer, Parkinson, and multiple sclerosis. Inflammation plays a critical role in the onset and progression of these injuries. Periodontitis is considered an inflammatory disease caused by oral biofilms around the tooth-supporting tissues, leading to a systemic and chronic inflammatory condition. Thus, this systematic review aimed to search for evidence in the association between neurodegenerative disorders and periodontitis. Methods: This systematic review was registered at International Prospective Register of Systematic Reviews (PROSPERO) under the code CRD 42016038327. The search strategy was performed in three electronic databases and one gray literature source-PubMed, Scopus, Web of Science, and OpenGrey, based on the PECO acronym: observational studies in humans (P) in which a neurodegenerative disease was present (E) or absent (C) to observe an association with periodontitis (O). The Fowkes and Fulton checklist was used to critically appraise the methodological quality and the risk of bias of individual studies. The quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: From 534 articles found, 12 were included, of which eight were case-control, three were cross-sectional, and one was a cohort, giving a total of 3,460 participants. All the included studies reported an association between some neurodegenerative diseases and periodontitis and presented a low risk of bias. According to the GRADE approach, the level of evidence of probing pocket depth was considered very low due to the significant heterogeneity across the studies' upgrading imprecision and inconsistency. Conclusions: Although all the included studies in this review reported an association between neurodegenerative diseases and periodontitis, the level of evidence was classified to be very low, which suggests a cautious interpretation of the results.},
}

@article {pmid34108560,
year = {2021},
author = {Kosyakovsky, J},
title = {The neural economics of brain aging.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {12167},
pmid = {34108560},
issn = {2045-2322},
abstract = {Despite remarkable advances, research into neurodegeneration and Alzheimer Disease (AD) has nonetheless been dominated by inconsistent and conflicting theory. Basic questions regarding how and why the brain changes over time remain unanswered. In this work, we lay novel foundations for a consistent, integrated view of the aging brain. We develop neural economics-the study of the brain's infrastructure, brain capital. Using mathematical modeling, we create ABC (Aging Brain Capital), a simple linear simultaneous-equation model that unites aspects of neuroscience, economics, and thermodynamics to explain the rise and fall of brain capital, and thus function, over the human lifespan. Solving and simulating this model, we show that in each of us, the resource budget constraints of our finite brains cause brain capital to reach an upper limit. The thermodynamics of our working brains cause persistent pathologies to inevitably accumulate. With time, the brain becomes damaged causing brain capital to depreciate and decline. Using derivative models, we suggest that this endogenous aging process underpins the pathogenesis and spectrum of neurodegenerative disease. We develop amyloid-tau interaction theory, a paradigm that bridges the unnecessary conflict between amyloid- and tau-centered hypotheses of AD. Finally, we discuss profound implications for therapeutic strategy and development.},
}

@article {pmid34108080,
year = {2021},
author = {Litke, R and Garcharna, LC and Jiwani, S and Neugroschl, J},
title = {Modifiable Risk Factors in Alzheimer Disease and Related Dementias: A Review.},
journal = {Clinical therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clinthera.2021.05.006},
pmid = {34108080},
issn = {1879-114X},
abstract = {PURPOSE: Although Alzheimer disease and related dementias (ADRDs) have long been considered nonpreventable and even an inevitable consequence of aging, recent findings from longitudinal studies indicate a downtrend in age-adjusted incidence and prevalence of ADRDs in Western countries. This remarkable trend might be the result of improved management of so-called modifiable risk factors. The aim of this review is to present evidence of modifiable factors of ADRDs in a life-course approach.

METHODS: A PubMed database search was conducted between November and December 2020 to identify relevant studies evaluating the role of modifiable risk factors in the development of ADRDs. Key words (Alzheimer's disease and modifiable risk factors) were used and specific inclusion and exclusion criteria applied.

FINDINGS: This review identifies modifiable factors for ADRDs divided into early-life, middle-life, and late-life risk factors, depending on the available window of preventive action. According to life course exposure, factors can be protective or deleterious for ADRDs that participate in the underlying pathophysiologic complexity of these diseases as well as the complexity for public health measures implementations.

IMPLICATIONS: The available evidence derived from epidemiologic, preclinical, interventional studies suggest that modifiable risk factors for ADRDs offer opportunities for therapeutic and preventive actions.},
}

@article {pmid34107398,
year = {2021},
author = {Bijttebier, S and Theunis, C and Jahouh, F and Martins, DR and Verhemeldonck, M and Grauwen, K and Dillen, L and Mercken, M},
title = {Development of immunoprecipitation - two-dimensional liquid chromatography - mass spectrometry methodology as biomarker read-out to quantify phosphorylated tau in cerebrospinal fluid from Alzheimer disease patients.},
journal = {Journal of chromatography. A},
volume = {1651},
number = {},
pages = {462299},
doi = {10.1016/j.chroma.2021.462299},
pmid = {34107398},
issn = {1873-3778},
abstract = {In Alzheimer's disease (AD) brain, one of the histopathological hallmarks is the neurofibrillary tangles consisting of aggregated and hyperphosphorylated tau. Currently many tau binding antibodies are under development to target the extracellular species responsible for the spreading of the disease in the brain. As such, an in-house developed antibody JNJ-63733657 with picomolar affinity towards tau phosphorylated at both T212 and T217 (further named p217+tau) was recently tested in phase I clinical trial NCT03375697. Following multiple dose administration in healthy subjects and subjects with AD, there were dose dependant reductions in free p217+tau fragments in cerebrospinal fluid (CSF) following antibody administration, as measured with a novel single molecule ELISA assay (Simoa PT3 x PT82 assay), demonstrating epitope engagement of the therapeutic antibody [Galpern, Haeverans, Janssens, Triana-Baltzer, Kolb, Li, Nandy, Mercken, Van Kolen, Sun, Van Nueten, 2020]. Total p217+tau levels also were reduced in CSF as measured with the Simoa PT3 x PT82 assay. In this study we developed an orthogonal immunoprecipitation - liquid chromatography - triple quadrupole mass spectrometry (IP-LC-TQMS) assay to verify the observed reductions in total p217+ tau levels. In this assay, an excess of JNJ-63733657 is added to the clinical CSF to ensure all p217+tau is bound by the antibody instead of having a pool of bound and unbound antigen and to immunoprecipitate all p217+tau, which is followed by on-bead digestion with trypsin to release surrogate peptides. Tryptic peptides with missed cleavages were monitored when phosphorylation occurred close to the cleavage site as this induced miscleavages. Compared with acidified mobile phases typically used for peptide analysis, reversed phase LC with mobile phase at basic pH resulted in sharper peaks and improved selectivity and sensitivity for the target peptides. With this setup a diphospho-tau tryptic peptide SRTPSLPTPPTREPK*2 could be measured with pT217 accounting for at least one of the phospho-sites. This is the first time that the presence of a diphopsho-tau peptide is reported to be present in human CSF. A two-dimensional LC-TQMS method was developed to remove matrix interferences. Selective trapping of diphospho-peptides via a metal oxide chromatography mechanism was achieved in a first dimension with a conventional reversed phase stationary phase and acidified mobile phase. Subsequent elution at basic pH enabled detection of low picomolar p217+tau levels in human CSF (lower limit of quantification: 2 pM), resulting in an approximate 5-fold increase in sensitivity. This enabled the quantification of total p217+tau in CSF leading to the confirmation that in addition to reductions in free p217+tau levels total p217+tau levels were also reduced following administration of the tau mAb JNJ-63733657, correlating with the previous measurement with the PT3 x PT82 Simoa assay. An orthogonal sample clean-up using offline TiO2/ZrO2 combined with 1DLC-TQMS was developed to confirm the presence of mono-ptau (pT217) tryptic peptides in CSF.},
}

@article {pmid34106590,
year = {2021},
author = {Lee, JY and Kim, JY and Lee, JY and Jung, JH and Jung, IC},
title = {Efficacy of Jihwangeumja (Dihuang Yinzi) on cognitive function and activities of daily living in patients with Alzheimer disease: A protocol for a systematic review and meta-analysis.},
journal = {Medicine},
volume = {100},
number = {19},
pages = {e25592},
doi = {10.1097/MD.0000000000025592},
pmid = {34106590},
issn = {1536-5964},
support = {HB16C0044//Ministry of Health and Welfare/ ; },
abstract = {BACKGROUND: This systematic review protocol describes the methods proposed to evaluate the efficacy and safety of Jihwangeumja in patients with Alzheimer disease.

METHODS: The following databases, PubMed, EMBASE, CENTRAL, Cumulative Index to Nursing and Allied Health Literature, China National Knowledge Infrastructure, National Digital Science Library, Korean Information Service System, and Korean Medical Database will be searched for relevant publications without language or publication status restrictions. Search terms will be based on "Alzheimer" for participants and "Jihwangeumja" or "Dihuang Yinzi" for interventions. Two researchers will independently extract the study data from the included studies and only randomized controlled trials will be included. The risk of bias will also be assessed independently by 2 researchers using the Cochrane risk of bias tool. We will use RevMan software random-effects and fixed-effect models for the assessment of heterogeneity and data synthesis. Any changes in the plan for documenting significant protocol amendments will require the researchers to have a revision agreement and register the international prospective register of systematic review modification.

RESULTS: The treatment effect and safety will be measured by meta-analysis and the quality of the included studies will be reviewed.

CONCLUSION: This systematic review will provide evidence regarding the efficacy and safety of Jihwangeumja.

ETHICS AND DISSEMINATION: Ethical approval is not required because individual patient data will not be included in this paper. The study findings will be disseminated through conference presentations.

OSF REGISTRATION: DOI: 10.17605/OSF.IO/HXA58.},
}

@article {pmid34103899,
year = {2021},
author = {Weng, G and Zhou, B and Liu, T and Huang, Z and Huang, S},
title = {Tetramethylpyrazine Improves Cognitive Function of Alzheimer's Disease Mice by Regulating SSTR4 Ubiquitination.},
journal = {Drug design, development and therapy},
volume = {15},
number = {},
pages = {2385-2399},
doi = {10.2147/DDDT.S290030},
pmid = {34103899},
issn = {1177-8881},
abstract = {Purpose: Many researches have investigated the functions of tetramethylpyrazine (TMP) in Alzheimer's disease (AD). This study aimed to discuss the underlying mechanism of TMP in AD mice.

Methods: TMP (200 mg/kg) was administered to 6-month-old APP/PS1 transgenic mice, and behavioral changes and hippocampal nerve injury in AD mice were detected. Apoptosis and autophagy-related protein levels were detected. Changes in gene expression before and after TMP treatment were compared using transcriptome sequencing. The effects of Cullin 4B (CUL4B) overexpression and somatostatin receptor 4 (SSTR4) silencing on AD symptoms and SSTR4 ubiquitination in APP/PS1 mice were observed. SH-SY5Y and PC12 cells were treated with 25 μmol/L Aβ25-35 and TMP to observe cell viability, apoptosis, and autophagy. Cell viability and apoptosis were measured again after treatment with proteasome inhibitor MG132 or lysosomal inhibitor 3-mA.

Results: TMP treatment improved the behavioral cognition of APP/PS1 mice and improved the neuronal apoptosis and damage in brain tissue. CUL4B was significantly upregulated in APP/PS1 mouse brain tissue, and SSRT4 protein was downregulated, and the levels of CUL4B and SSRT4 were negatively correlated. TMP treatment downregulated CUL4B, inhibited SSRT4 ubiquitination and upregulated SSRT4 protein level in APP/PS1 mouse brain tissue, while CUL4B overexpression or SSRT4 silencing reversed the effect of TMP. TMP and MG132 improved the decreased activity, increased apoptosis and increased SSRT4 protein in SH-SY5Y and PC12 cells treated with Aβ25-35, but not 3-mA. CUL4B overexpression promoted the ubiquitination of SSTR4 in cells, which partially reversed the effect of TMP.

Conclusion: TMP could improve the cognitive ability of AD mice by inhibiting CUL4B expression and the ubiquitination degradation of SSTR, and alleviating neuronal apoptosis and injury. This study may offer a new therapeutic option for AD treatment.},
}

@article {pmid34103713,
year = {2021},
author = {Gubert, C and Hannan, AJ},
title = {Exercise mimetics: harnessing the therapeutic effects of physical activity.},
journal = {Nature reviews. Drug discovery},
volume = {},
number = {},
pages = {},
pmid = {34103713},
issn = {1474-1784},
abstract = {Exercise mimetics are a proposed class of therapeutics that specifically mimic or enhance the therapeutic effects of exercise. Increased physical activity has demonstrated positive effects in preventing and ameliorating a wide range of diseases, including brain disorders such as Alzheimer disease and dementia, cancer, diabetes and cardiovascular disease. This article discusses the molecular mechanisms and signalling pathways associated with the beneficial effects of physical activity, focusing on effects on brain function and cognitive enhancement. Emerging therapeutic targets and strategies for the development of exercise mimetics, particularly in the field of central nervous system disorders, as well as the associated opportunities and challenges, are discussed.},
}

@article {pmid34103702,
year = {2021},
author = {Crunkhorn, S},
title = {Predicting Alzheimer disease dementia.},
journal = {Nature reviews. Drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/d41573-021-00105-8},
pmid = {34103702},
issn = {1474-1784},
}

@article {pmid34103557,
year = {2021},
author = {Saleh, RA and Eissa, TF and Abdallah, DM and Saad, MA and El-Abhar, HS},
title = {Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl3-induced Alzheimer-like pathology model.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {12040},
pmid = {34103557},
issn = {2045-2322},
abstract = {Peganum harmala (P. harmala) is a folk medicinal herb used in the Sinai Peninsula (Egypt) as a remedy for central disorders. The main constituents, harmine and harmaline, have displayed therapeutic efficacy against Alzheimer's disease (AD); however, the P. harmala potential on sensitizing central insulin to combat AD remains to be clarified. An AD-like rat model was induced by aluminum chloride (AlCl3; 50 mg/kg/day for six consecutive weeks; i.p), whereas a methanolic standardized P. harmala seed extract (187.5 mg/kg; p.o) was given to AD rats starting 2 weeks post AlCl3 exposure. Two additional groups of rats were administered either the vehicle to serve as the normal control or the vehicle + P. harmala seed extract to serve as the P. harmala control group. P. harmala enhanced cognition appraised by Y-maze and Morris water maze tests and improved histopathological structures altered by AlCl3. Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 (pS307-IRS-1). Besides, P. harmala increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. The extract also curtailed the hippocampal content of beta amyloid (Aβ)42, glycogen synthase (GSK)-3β and phosphorylated tau. It also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione. In conclusion, combating insulin resistance by P. harmala is a novel machinery in attenuating the insidious progression of AD by enhancing both insulin and GLP-1 trajectories in the hippocampus favoring GLUT4 production.},
}

@article {pmid34103175,
year = {2021},
author = {Majoka, MA and Schimming, C},
title = {Effect of Social Determinants of Health on Cognition and Risk of Alzheimer Disease and Related Dementias.},
journal = {Clinical therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clinthera.2021.05.005},
pmid = {34103175},
issn = {1879-114X},
abstract = {Social determinants of health are the conditions in which people are born, work, live, and age and the wider set of forces and systems that shape the conditions of daily life. They affect every area of life, particularly health and health care. There is increasing focus on modifiable factors that affect cognition and risk of Alzheimer disease and related dementias (ADRDs). This article examines the impact of various social determinants of health, which are potentially reversible, on the incidence, prevalence, and risk of ADRDs and cognition. Various social determinants of health affect cognition and risk of ADRDs. Lower socioeconomic status (SES) and less education are associated with a higher incidence of ADRDs, whereas higher SES and education level appear to be protective, leading to a deceleration of time to diagnosis. In terms of employment, manual labor is associated with a higher risk of ADRDs. Higher body mass index in midlife and a decreasing body mass index in old age are associated with a higher risk of ADRDs. Furthermore, lower food security in early and late life is associated with a higher risk of ADRD diagnosis. Neighborhoods that are economically disadvantaged with fewer physical resources are associated with a higher risk of ADRDs. Higher levels of social engagement have a protective effect on diagnosis of ADRDs. Higher levels of stress are associated with a higher likelihood of developing ADRDs. Early-life adversity is associated with an increased risk of ADRDs, and further work in this area will be illuminating. Racial discrimination also leads to higher risk of ADRDs through the direct effect of discrimination and indirectly through lower SES, educational level, employment, and residential segregation. With an aim of reducing of ADRDs, future work in enhancing education, improving socioeconomic conditions, work, and neighborhood environments, and eliminating racial discrimination could potentially have a drastic impact.},
}

@article {pmid34102977,
year = {2021},
author = {Kulkarni, NP and Vaidya, B and Narula, A and Sharma, SS},
title = {Neuroprotective Potential of Caffeic Acid Phenethyl Ester (CAPE) in CNS Disorders: Mechanistic and Therapeutic Insights.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/1570159X19666210608165509},
pmid = {34102977},
issn = {1875-6190},
abstract = {Neurological disorders like Alzheimer's disease (AD), Parkinson's disease (PD), stroke, amyotrophic lateral sclerosis, Huntington's disease (HD), epilepsy, traumatic brain injury (TBI), depression and anxiety are responsible for thousands of deaths worldwide every year. With the increase in life expectancy, there has been a rise in the prevalence of these disorders. Age is one of the major risk factors for these neurological disorders and with the aged population is set to rise to 1.25 billion by 2050. There is a growing concern to look for new therapeutic molecules to treat age-related diseases. Caffeic acid phenethyl ester (CAPE) is a molecule obtained from a number of botanical sources such as the bark of conifer trees as well as propolis which is extracted from beehives. Though CAPE remains relatively unexplored in human trials, it possesses antioxidant, anti-inflammatory, antimitogenic and anti-cancer activities as shown by preclinical studies. Apart from this, it also exhibits tremendous potential for the treatment of neurological disorders through modulation of multiple molecular pathways and attenuation of behavioural deficits. In the present article, we have reviewed the therapeutic potential of CAPE and its mechanisms in the treatment of neurological disorders.},
}

@article {pmid34102969,
year = {2021},
author = {Mao, C and Li, J and Dong, L and Huang, X and Lei, D and Wang, J and Chu, S and Liu, C and Peng, B and Román, GC and Cui, L and Gao, J},
title = {Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/1567205018666210608120339},
pmid = {34102969},
issn = {1875-5828},
abstract = {BACKGROUND: Alzheimer's disease with a causative genetic mutation (AD-CGM) is an un- common form, characterized by a heterogeneous clinical phenotype and variations in the genotype of racial groups affected.

OBJECTIVE: We aimed to systemically describe the phenotype variance and mutation spectrum in the large sample size of the Peking Union Medical College Hospital (PUMCH) cohort, Beijing, China.

METHOD: Next-generation sequencing (NGS) was carried out in 1108 patients diagnosed with dementia. A total of 40 Han Chinese patients with three AD gene mutations were enrolled. A systemic review of all the patients was performed, including clinical history, neurocognitive assessment, brain magnetic resonance imaging, and cerebrospinal fluid (CSF) biomarkers.

RESULTS: We studied the following gene mutation variants: 12 AβPP, 13 PSEN1, and 9 PSEN2, and 23 among them were novel. Most of them were early-onset, but PSEN1 mutation carriers had the youngest onset age. The commonest symptoms were similar to those of AD, including an amnestic syndrome, followed by psychiatric symptoms and movement disorder. On MRI, parietal and posterior temporal atrophy was prominent in PSEN1 and PSEN2 mutation carriers, while AβPP mutation carriers had more vascular changes. The CSF biomarkers profile was indistinguishable from sporadic AD.

CONCLUSION: We identified a small group of AD-CGM subjects representing 3.6% among more than 1000 demented patients in the PUMCH cohort. These subjects usually presented with early-onset de- mentia and exhibited significant clinical and genetic heterogeneity. Identification required complete screening of genetic mutations using NGS. Although family history was usually present, we found non-familial cases of all three genetic mutations.Recent Advances in Anti-Infective Drug Discovery.},
}

@article {pmid34102642,
year = {2021},
author = {Kumai, K and Kawabata, N and Meguro, K and Takada, J and Nakamura, K and Yamaguchi, S},
title = {Mental and Physical Self-Awareness of Alzheimer Patients: Decreased Awareness of Amnesia and Increased Fear of Falling Compared to Views of Families: The Tajiri and Wakuya Projects.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-6},
doi = {10.1159/000516656},
pmid = {34102642},
issn = {1421-9824},
abstract = {INTRODUCTION: The purpose of this study is to examine self-awareness of patients with Alzheimer disease (AD) regarding forgetfulness and physical status, with the goal of further psychological understanding of these patients.

METHODS: The 255 subjects included 33 healthy volunteers and 48 patients with mild cognitive impairment who were elderly community residents selected from the 2017 Wakuya Project and 174 consecutive outpatients with AD at the Tajiri Clinic. Test data were selected from a pooled database. Results from the Mini-Mental State Examination, Clinical Dementia Rating (CDR), Short Falls Efficacy Scale International (FES), and Everyday Memory Checklist (EMC) were used in the study. FES and EMC data were also obtained from family members for comparison.

RESULTS: EMC scores in the AD groups (mild to moderate and moderate to severe) were significantly higher (more complaining memory impairment) than those in the CDR 0 (healthy) group and significantly lower (less self-awareness for memory impairment) than the corresponding EMC scores of families of the subjects. In contrast, FES scores of the AD groups did not differ significantly from those of the CDR 0 group, and these scores were higher (more fear of falling) than those of family members. Additionally, family-FES scores of the AD groups were higher than those of the CDR 0 and 0.5 groups.

CONCLUSION: The results showed an evidence of the heterogeneity of awareness, an emotional response (concern or fear, FES), and a cognitive appraisal of function (EMC). These may be explained whereby awareness of/fear of falling increases with AD due to a preserved emotional awareness, whereas awareness of cognitive impairment is impaired due to memory deficits.},
}

@article {pmid34102318,
year = {2021},
author = {Cordeiro, MF and Hill, D and Patel, R and Corazza, P and Maddison, J and Younis, S},
title = {Detecting retinal cell stress and apoptosis with DARC: Progression from lab to clinic.},
journal = {Progress in retinal and eye research},
volume = {},
number = {},
pages = {100976},
doi = {10.1016/j.preteyeres.2021.100976},
pmid = {34102318},
issn = {1873-1635},
abstract = {DARC (Detection of Apoptosing Retinal Cells) is a retinal imaging technology that has been developed within the last 2 decades from basic laboratory science to Phase 2 clinical trials. It uses ANX776 (fluorescently labelled Annexin A5) to identify stressed and apoptotic cells in the living eye. During its development, DARC has undergone biochemistry optimisation, scale-up and GMP manufacture and extensive preclinical evaluation. Initially tested in preclinical glaucoma and optic neuropathy models, it has also been investigated in Alzheimer, Parkinson's and Diabetic models, and used to assess efficacy of therapies. Progression to clinical trials has not been speedy. Intravenous ANX776 has to date been found to be safe and well-tolerated in 129 patients, including 16 from Phase 1 and 113 from Phase 2. Results on glaucoma and AMD patients have been recently published, and suggest DARC with an AI-aided algorithm can be used to predict disease activity. New analyses of DARC in GA prediction are reported here. Although further studies are needed to validate these findings, it appears there is potential of the technology to be used as a biomarker. Much larger clinical studies will be needed before it can be considered as a diagnostic, although the relatively non-invasive nature of the nasal as opposed to intravenous administration would widen its acceptability in the future as a screening tool. This review describes DARC development and its progression into Phase 2 clinical trials from lab-based research. It discusses hypotheses, potential challenges, and regulatory hurdles in translating technology.},
}

@article {pmid34101795,
year = {2021},
author = {Kosaner Kließ, M and Martins, R and Connolly, MP},
title = {Major Cost Drivers in Assessing the Economic Burden of Alzheimer's Disease: A Structured, Rapid Review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {8},
number = {3},
pages = {362-370},
doi = {10.14283/jpad.2021.17},
pmid = {34101795},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's Disease is the most common cause of dementia, affecting memory, thinking and behavior. Symptoms eventually grow severe enough to interfere with daily tasks. AD is predicted to increase healthcare spending and costs associated with formal and informal caregiving. The aim of this study was to identify and quantify the contribution of the different cost components associated with AD.

METHODS: A structured literature review was conducted to identify studies reporting the economic burden of Alzheimer`s Disease beyond the healthcare setting. The search was conducted in Medline, Embase and EconLit and limited to studies published in the last 10 years. For each identified cost component, frequency weighted mean costs were calculated across countries to estimate the percentage contribution of each component by care setting and disease severity. Results obtained by each costing approach were also compared.

RESULTS: For community-dwelling adults, the percentage of healthcare, social care and indirect costs to total costs were 13.9%, 17.4% and 68.7%, respectively. The percentage of costs varied by disease severity with 26.0% and 10.4% of costs spent on healthcare for mild and severe disease, respectively. The proportion of total spending on indirect costs changed from 60.7% to 72.5% as disease progressed. For those in residential care, the contribution of each cost component was similar between moderate and severe disease. Social care accounted on average for 85.9% of total costs.

CONCLUSION: The contribution of healthcare costs to the overall burden was not negligible; but was generally exceeded by social and informal care costs.},
}

@article {pmid34101793,
year = {2021},
author = {Zhou, S and Wang, K},
title = {Childhood Secondhand Smoke Exposure and Risk of Dementia, Alzheimer's Disease and Stroke in Adulthood: A Prospective Cohort Study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {8},
number = {3},
pages = {345-350},
doi = {10.14283/jpad.2021.10},
pmid = {34101793},
issn = {2426-0266},
abstract = {BACKGROUND: This study aimed to investigate the associations between secondhand smoke exposure and dementia, Alzheimer's disease (AD) and stroke.

METHODS: This prospective study analyzed Framingham Offspring (FHS-OS) cohort participants with parents in the original Framingham Heart Study (FHS) cohort with known smoking status during offspring childhood. Surveillance for incident events, including dementia and stroke, among offspring participants exposed to parental smoking up to the age of 18 years commenced at examination 9 through 2014 and continued for approximately 30 years.

RESULTS: At baseline, a total of 1683 (56.2%) subjects were not exposed to any secondhand smoke, whereas 670 (22.4%) subjects were exposed to 0-1 packs (20 cigarettes)/day, and 640 (21.4%) were exposed to over 1 pack/day. On follow-up (median: 31 years), 2993 patients developed dementia, including 103 with AD dementia and 315 with stroke. After adjusting for a wide range of established risk factors, participants with the highest exposure to secondhand smoke exhibited increased risks of all dementia, AD dementia and stroke compared with individuals with no exposure [HR 2.86 (2.00-4.09) for dementia; HR 3.13 (1.80-5.42) for AD dementia; HR 1.89 (1.37-2.61) for stroke]. The results remained comparable in the subgroup for individuals with median exposure to secondhand smoke.

CONCLUSION: Exposure to secondhand smoke may be associated with increased risks of dementia, AD dementia and stroke.},
}

@article {pmid34099509,
year = {2021},
author = {Kikuchi, K and Tatebe, T and Sudo, Y and Yokoyama, M and Kidana, K and Chiu, YW and Takatori, S and Arita, M and Hori, Y and Tomita, T},
title = {GPR120 signaling controls amyloid-β degrading activity of matrix metalloproteinases.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2595-20.2021},
pmid = {34099509},
issn = {1529-2401},
abstract = {Alzheimer disease (AD) is characterized by the extensive deposition of amyloid-β peptide (Aβ) in the brain. Brain Aβ level is regulated by a balance between Aβ production and clearance. The clearance rate of Aβ is decreased in the brains of sporadic AD patients, indicating that the dysregulation of Aβ clearance mechanisms affects the pathological process of AD. Astrocytes are among the most abundant cells in the brain and are implicated in the clearance of brain Aβ via their regulation of the blood-brain barrier, glymphatic system, and proteolytic degradation. The cellular morphology and activity of astrocytes are modulated by several molecules, including ω3 polyunsaturated fatty acids, such as docosahexaenoic acid, which is one of the most abundant lipids in the brain, via the G protein-coupled receptor GPR120/FFAR4. In this study, we analyzed the role of GPR120 signaling in the Aβ-degrading activity of astrocytes. Treatment with the selective antagonist upregulated the matrix metalloproteinase (MMP) inhibitor-sensitive Aβ-degrading activity in primary astrocytes. Moreover, the inhibition of GPR120 signaling increased the levels of Mmp2 and Mmp14 mRNAs, and decreased the expression levels of tissue inhibitor of metalloproteinases 3 (Timp3) and Timp4, suggesting that GPR120 negatively regulates the astrocyte-derived MMP network. Finally, the intracerebral injection of GPR120 specific antagonist substantially decreased the levels of Tris-buffered saline-soluble Aβ in male AD model mice, and this effect was canceled by the coinjection of an MMP inhibitor. These data indicate that astrocytic GPR120 signaling negatively regulates the Aβ degrading activity of MMPs.SIGNIFICANT STATEMENTThe level of amyloid β (Aβ) in the brain is a crucial determinant of the development of Alzheimer disease. Here we found that astrocytes, which are the most abundant cell type in the central nervous system, harbors degrading activity against amyloid β, which is regulated by GPR120 signaling. GPR120 is involved in the inflammatory response and obesity in peripheral organs. However, the pathophysiological role of GPR120 in Alzheimer disease remains unknown. We found that selective inhibition of GPR120 signaling in astrocytes increased the Aβ-degrading activity of matrix metalloproteases. Our results suggest that GPR120 in astrocytes is a novel therapeutic target for the development of anti-Aβ therapeutics.},
}

@article {pmid34098912,
year = {2021},
author = {Jan, H and Usman, H and Shah, M and Zaman, G and Mushtaq, S and Drouet, S and Hano, C and Abbasi, BH},
title = {Phytochemical analysis and versatile in vitro evaluation of antimicrobial, cytotoxic and enzyme inhibition potential of different extracts of traditionally used Aquilegia pubiflora Wall. Ex Royle.},
journal = {BMC complementary medicine and therapies},
volume = {21},
number = {1},
pages = {165},
pmid = {34098912},
issn = {2662-7671},
abstract = {BACKGROUND: Himalayan Columbine (Aquilegia pubiflora Wall. Ex Royle) is a medicinal plant and have been used as traditional treatments for various human diseases including skin burns, jaundice, hepatitis, wound healing, cardiovascular and circulatory diseases. Till now there is no report available on phytochemical investigation of Himalayan Columbine and to the best of our knowledge, through present study we have reported for the first time, the phytochemical analysis and pharmacological potentials of different leaf extracts of Aquilegia pubiflora.

METHODS: Four types of extracts were prepared using solvent of different polarities (Distilled water APDW, Methanol APM, Ethanol APE and Ethyl acetate APEA), and were evaluated to determine the best candidate for potent bioactivity. Phytochemical constituents in prepared extracts were quantified through HPLC analysis. Subsequently, all four types of leaf extracts were then evaluated for their potential bioactivities including antimicrobial, protein kinase inhibition, anti-inflammatory, anti-diabetic, antioxidant, anti-Alzheimer, anti-aging and cytotoxic effect.

RESULTS: HPLC analysis demonstrated the presence of dvitexin, isovitexin, orientin, isoorientin, ferulic acid, sinapic acid and chlorogenic acid in varied proportions in all plant extracts. Antimicrobial studies showed that, K. pneumonia was found to be most susceptible to inhibition zones of 11.2 ± 0.47, 13.9 ± 0.33, 12.7 ± 0.41, and 13.5 ± 0.62 measured at 5 mg/mL for APDW, APM, APE and APEA respectively. A. niger was the most susceptible strain in case of APDW with the highest zone of inhibition 14.3 ± 0.32, 13.2 ± 0.41 in case of APM, 13.7 ± 0.39 for APE while 15.4 ± 0.43 zone of inhibition was recorded in case of APEA at 5 mg/mL. The highest antioxidant activity of 92.6 ± 1.8 μgAAE/mg, 89.2 ± 2.4 μgAAE/mg, 277.5 ± 2.9 μM, 289.9 ± 1.74 μM for TAC, TRP, ABTS and FRAP, respectively, was shown by APE. APM, APE and APEA extracts showed a significant % cell inhibition (above 40%) against HepG2 cells. The highest anti-inflammatory of the samples was shown by APE (52.5 ± 1.1) against sPLA2, (41.2 ± 0.8) against 15-LOX, followed by (38.5 ± 1.5) and (32.4 ± 0.8) against COX-1 and COX-2, respectively.

CONCLUSIONS: Strong antimicrobial, Protein Kinase potency and considerable α-glucosidase, α-amylase, and cytotoxic potential were exhibited by plant samples. Significant anti-Alzheimer, anti-inflammatory, anti-aging, and kinase inhibitory potential of each plant sample thus aware us for further detailed research to determine novel drugs.},
}

@article {pmid34088777,
year = {2021},
author = {Meier, SR and Sehlin, D and Roshanbin, S and Lim Falk, V and Saito, T and Saido, TC and Neumann, U and Rokka, J and Eriksson, J and Syvanen, S},
title = {11C-PIB and 124I-antibody PET provide differing estimates of brain amyloid-beta after therapeutic intervention.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.121.262083},
pmid = {34088777},
issn = {1535-5667},
abstract = {Positron emission tomography (PET) imaging of amyloid-β (Aβ) has become an important component of Alzheimer's disease (AD) diagnosis. 11C-Pittsburgh compound B (11C-PiB) and analogs bind to fibrillar Aβ. However, levels of nonfibrillar, soluble aggregates of Aβ, appear more dynamic during disease progression and more affected by Aβ reducing treatments. The aim of this study was to compare an antibody-based PET ligand, targeting nonfibrillar Aβ, with 11C-PiB after β-secretase (BACE-1) inhibition in two AD mouse models at an advanced stage of Aβ pathology. Methods: Transgenic ArcSwe mice (16 months) were treated with the BACE-1 inhibitor NB-360 for 2 months, while another group was kept as controls. A third group was analyzed at the age of 16 months as baseline. Mice were PET scanned with 11C-PiB to measure Aβ plaque load followed by a scan with the bispecific radioligand 124I-RmAb158-scFv8D3 to investigate nonfibrillar aggregates of Aβ. The same study design was then applied for another mouse model, AppNL-G-F. In this case, NB-360 treatment was initiated at the age of 8 months and animals were scanned with 11C-PiB-PET and 125I-RmAb158-scFv8D3 single-photon emission computer tomography (SPECT). Brain tissue was isolated after scanning and Aβ levels were assessed. Results:124I-RmAb158-scFv8D3 concentrations measured with PET in hippocampus and thalamus of NB-360 treated ArcSwe mice were similar to those observed in baseline animals and significantly lower than concentrations observed in same-age untreated controls. Reduced 125I-RmAb158-scFv8D3 retention was also observed with SPECT in hippocampus, cortex and cerebellum of NB-360 treated AppNL-G-F mice. Radioligand in vivo concentrations corresponded with postmortem brain tissue analysis of soluble Aβ aggregates. For both models, mice treated with NB-360 did not display a reduced 11C-PiB signal compared to untreated controls, and further, both NB-360 and control mice tended, although not reaching significance, to show higher 11C-PiB signal than the baseline groups. Conclusion: This study demonstrated the ability of an antibody-based radioligand to detect changes in brain Aβ levels after anti-Aβ therapy in ArcSwe and AppNL-G-F mice with pronounced Aβ pathology. In contrast, the decreased Aβ levels could not be quantified with 11C-PiB PET, suggesting that these ligands detect different pools of the Aβ.},
}

@article {pmid34082625,
year = {2021},
author = {Angioni, D and Cesari, M and Raffin, J and Virecoulon Giudici, K and Mangin, JF and Bouyahia, A and Chupin, M and Fischer, C and Gourieux, E and Rolland, Y and De Breucker, S and Vellas, B and de Souto Barreto, P and , },
title = {Neuroimaging correlates of persistent fatigue in older adults: A secondary analysis from the Multidomain Alzheimer Preventive Trial (MAPT) trial.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/13607863.2021.1932737},
pmid = {34082625},
issn = {1364-6915},
abstract = {OBJECTIVES: Fatigue has been suggested as a marker of biological aging. It seems plausible that this symptom might be associated with changes in brain health. The objective of this study was to examine the associations between persistent fatigue and neuroimaging correlates in a non-disease-specific population of community-dwelling older adults.

METHODS: We performed a cross-sectional analysis using data from The Multidomain Alzheimer Preventive Trial (MAPT). We included 458 subjects. Persistent fatigue was defined as meeting exhaustion criterion of Fried frailty phenotype in two consecutive clinical visits six months apart between study baseline and one year. Brain imaging correlates, assessed by magnetic resonance imaging (MRI), were the outcomes. The associations between persistent fatigue and brain correlates were explored using mixed model linear regressions with random effect at the center level.

RESULTS: The mean age of the participants was 74.8 ± 4 years old, and 63% of the subjects were women. Forty-seven participants (10%) exhibited a persistent fatigue profile. People with persistent fatigue were older compared to subjects without persistent fatigue (76.2 years ± 4.3 vs.74.7 ± 3.9 p = 0.009). Persistent fatigue was associated with higher white matter hyperintensity volume in the fully adjusted analysis. We did not find any cross-sectional association between persistent fatigue and sub-cortical volumes and global and regional cortical thickness.

CONCLUSION: Persistent fatigue was cross-sectionnally associated with higher white matter hyperintensity volume in older adults. Further longitudinal studies, using an assessment tool specifically designed and validated for measuring fatigue, are needed to confirm our findings.},
}

@article {pmid34098334,
year = {2021},
author = {Yu, X and Xia, L and Zhang, S and Zhou, G and Li, Y and Liu, H and Hou, C and Zhao, Q and Dong, L and Cui, Y and Zeng, Q and Wang, A and Liu, L},
title = {Fluoride exposure and children's intelligence: Gene-environment interaction based on SNP-set, gene and pathway analysis, using a case-control design based on a cross-sectional study.},
journal = {Environment international},
volume = {155},
number = {},
pages = {106681},
doi = {10.1016/j.envint.2021.106681},
pmid = {34098334},
issn = {1873-6750},
abstract = {BACKGROUND: Excessive fluoride exposure has been associated with intelligence loss, but little is known about gene-fluoride interactions on intelligence at SNP-set, gene and pathway level.

OBJECTIVES: Here we conducted a population-based study in Chinese school-aged children to estimate the associations of fluoride from internal and external exposures with intelligence as well as to explore the gene-fluoride interactions on intelligence at SNP-set, gene and neurodevelopmental pathway level.

METHODS: A total of 952 resident children aged 7 to 13 were included in the current study. The fluoride contents in drinking water, urine, hair and nail were measured using the ion-selective electrode method. LASSO Binomial regression was conducted to screen the intelligence-related SNP-set. The gene-fluoride interactions at gene and pathway levels were detected by the Adaptive Rank Truncated Product method.

RESULTS: The probability of high intelligence was inversely correlated with fluoride contents in water, urine, hair and nail (all P < 0.001). The SNP-set based on rs3788319, rs1879417, rs57377675, rs11556505 and rs7187776 was related to high intelligence (P = 0.001) alone and by interaction with water, urinary and hair fluoride (P = 0.030, 0.040, 0.010), separately. In gene level, CLU and TOMM40 interacted with hair fluoride (both P = 0.017) on intelligence. In pathway level, Alzheimer disease pathway, metabolic pathway, signal transduction pathway, sphingolipid signaling pathway and PI3K-AKT signaling pathway interacted with fluoride on intelligence in men.

CONCLUSIONS: Our study suggests that fluoride is inversely associated with intelligence. Moreover, the interactions of fluoride with mitochondrial function-related SNP-set, genes and pathways may also be involved in high intelligence loss.},
}

@article {pmid34095977,
year = {2021},
author = {Wallon, D and Boluda, S and Rovelet-Lecrux, A and Thierry, M and Lagarde, J and Miguel, L and Lecourtois, M and Bonnevalle, A and Sarazin, M and Bottlaender, M and Mula, M and Marty, S and Nakamura, N and Schramm, C and Sellal, F and Jonveaux, T and Heitz, C and Le Ber, I and Epelbaum, S and Magnin, E and Zarea, A and Rousseau, S and Quenez, O and Hannequin, D and Clavaguera, F and Campion, D and Duyckaerts, C and Nicolas, G},
title = {Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers.},
journal = {Acta neuropathologica},
volume = {},
number = {},
pages = {},
pmid = {34095977},
issn = {1432-0533},
support = {DEQ20170336711//Fondation pour la recherche médicale/ ; },
abstract = {Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.},
}

@article {pmid34094647,
year = {2021},
author = {Wang, WW and Han, R and He, HJ and Wang, Z and Luan, XQ and Li, J and Feng, L and Chen, SY and Aman, Y and Xie, CL},
title = {Delineating the Role of Mitophagy Inducers for Alzheimer Disease Patients.},
journal = {Aging and disease},
volume = {12},
number = {3},
pages = {852-867},
doi = {10.14336/AD.2020.0913},
pmid = {34094647},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia in elderly that serves to be a formidable socio-economic and healthcare challenge in the 21st century. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes contributing to the development of AD pathologies, namely amyloid-β plaques (Aβ) and neurofibrillary tangles (NFT). Here, we highlight the recent advances in the association between impaired mitophagy and AD, as well as delineate the potential underlying mechanisms. Furthermore, we conduct a systematic review the current status of mitophagy modulators and analyzed their relevant mechanisms, evaluating on their advantages, limitations and current applications in clinical trials for AD patients. Finally, we describe how deep learning may be a promising method to rapid and efficient discovery of mitophagy inducers as well as general guidance for the workflow of the process.},
}

@article {pmid34094601,
year = {2021},
author = {Neubauer, NA and Miguel-Cruz, A and Liu, L},
title = {Strategies to Locate Lost Persons with Dementia: A Case Study of Ontario First Responders.},
journal = {Journal of aging research},
volume = {2021},
number = {},
pages = {5572764},
doi = {10.1155/2021/5572764},
pmid = {34094601},
issn = {2090-2204},
abstract = {Information on strategies and practices in the search of missing persons with dementia is inconsistent which creates challenges for first responders, such as police, when they choose appropriate search and rescue approaches. The purpose of this study was to describe current strategies among police services in Ontario. Telephone interviews with police were conducted. Questions included what strategies were used for locating missing persons living with dementia, and what gaps exist in search practices. Participants described they used high- and low-tech solutions in search and rescue. They identified gaps in education and awareness, proactive strategies, resources, and funding. Information collected from the interviews was used to develop a practice guideline for police in partnership with the Alzheimer Society of Ontario.},
}

@article {pmid34093133,
year = {2021},
author = {Mathoux, J and Henshall, DC and Brennan, GP},
title = {Regulatory Mechanisms of the RNA Modification m6A and Significance in Brain Function in Health and Disease.},
journal = {Frontiers in cellular neuroscience},
volume = {15},
number = {},
pages = {671932},
doi = {10.3389/fncel.2021.671932},
pmid = {34093133},
issn = {1662-5102},
abstract = {RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N6-methyladenosine (m6A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m6A, how this influences neuronal development and function and how aberrant m6A signaling may contribute to neurological disease. M6A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m6A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m6A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m6A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m6A, although there in vivo activity and the dynamic nature of this modification requires further study. M6A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m6A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m6A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.},
}

@article {pmid34093032,
year = {2021},
author = {Svob Strac, D and Konjevod, M and Sagud, M and Nikolac Perkovic, M and Nedic Erjavec, G and Vuic, B and Simic, G and Vukic, V and Mimica, N and Pivac, N},
title = {Personalizing the Care and Treatment of Alzheimer's Disease: An Overview.},
journal = {Pharmacogenomics and personalized medicine},
volume = {14},
number = {},
pages = {631-653},
doi = {10.2147/PGPM.S284615},
pmid = {34093032},
issn = {1178-7066},
abstract = {Alzheimer's disease (AD) is a progressive, complex, and multifactorial neurodegenerative disorder, still without effective and stable therapeutic strategies. Currently, available medications for AD are based on symptomatic therapy, which include acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist. Additionally, medications such as antipsychotic drugs, antidepressants, sedative, and hypnotic agents, and mood stabilizers are used for the management of behavioral and psychological symptoms of dementia (BPSD). Clinical research has been extensively investigated treatments focusing on the hallmark pathology of AD, including the amyloid deposition, tau hyperphosphorylation, neuroinflammation, and vascular changes; however, so far without success, as all new potential drugs failed to show significant clinical benefit. The underlying heterogeneous etiology and diverse symptoms of AD suggest that a precision medicine strategy is required, which would take into account the complex genetic, epigenetic, and environmental landscape of each AD patient. The article provides a comprehensive overview of the literature on AD, the current and potential therapy of both cognitive symptoms as well as BPSD, with a special focus on gut microbiota and epigenetic modifications as new emerging drug targets. Their specific patterns could represent the basis for novel individually tailored approaches aimed to optimize precision medicine strategies for AD prevention and treatment. However, the successful application of precision medicine to AD demands a further extensive research of underlying pathological processes, as well as clinical and biological complexity of this multifactorial neurodegenerative disorder.},
}

@article {pmid34092631,
year = {2021},
author = {Ben Ayed, I and Castor-Guyonvarch, N and Amimour, S and Naija, S and Aouichaoui, C and Ben Omor, S and Tabka, Z and El Massioui, F},
title = {Acute Exercise and Cognitive Function in Alzheimer's Disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-201317},
pmid = {34092631},
issn = {1875-8908},
abstract = {BACKGROUND: Many studies have shown the impact of acute aerobic exercises (AAE) on cognition in healthy adults or at a pre-dementia stage. Few studies, however, have explored the positive effects of AAE in moderate Alzheimer's disease (ADM) patients.

OBJECTIVE: Evaluating the effect of AAE on cognitive functions in ADM patients.

METHODS: Overall, 79 (age: 69.62±0.99) ADM patients were recruited. Participants were divided into three groups according to the task: aerobic exercises done alone or combined with cognitive games presented on a screen, and a control group who performed a reading task. The aerobic exercise protocol consisted of a 20-min cycling exercise of moderate intensity, corresponding to 60%of the individual target maximal heart rate recorded in a 6-minute walking test. The participants' cognition was monitored before and after the intervention using the Tower of Hanoi, Digit Span, and Stroop tasks.

RESULTS: After the exercise, the participants' attention in both the physical and combined groups improved for the Stroop, the forward and backward Digit Span tasks, as well as the time taken to solve the Tower of Hanoi, although no significant differences were found in the number of moves taken in the latter. By contrast, the control group did not show any significant improvement for most of the cognitive tasks after the reading session.

CONCLUSION: Current evidence suggests that AAE may help to improve cognitive functions in ADM patients. This improvement is enhanced when the exercise is combined with cognitive games. Safe and progressive types of exercises should be promoted among ADM patients.},
}

@article {pmid34092630,
year = {2021},
author = {Callahan, BL and McLaren-Gradinaru, M and Burles, F and Iaria, G},
title = {How Does Dementia Begin to Manifest in Bipolar Disorder? A Description of Prodromal Clinical and Cognitive Changes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-201240},
pmid = {34092630},
issn = {1875-8908},
abstract = {BACKGROUND: Older adults with bipolar disorder (BD) have increased dementia risk, but signs of dementia are difficult to detect in the context of pre-existing deficits inherent to BD.

OBJECTIVE: To identify the emergence of indicators of early dementia in BD.

METHODS: One hundred and fifty-nine non-demented adults with BD from the National Alzheimer Coordinating Center (NACC) data repository underwent annual neuropsychological assessment up to 14 years (54.0 months average follow-up). Cognitive performance was examined longitudinally with linear mixed-effects models, and yearly differences between incident dementia and controls cases were examined in the six years prior to diagnosis.

RESULTS: Forty participants (25.2%) developed dementia over the follow-up period ('incident cases'). Alzheimer's disease was the most common presumed etiology, though this was likely a result of sampling biases within NACC. Incident cases showed declining trajectories in memory, language, and speeded attention two years prior to dementia onset.

CONCLUSION: In a sample of BD patients enriched for Alzheimer's type dementia, prodromal dementia in BD can be detected up to two years before onset using the same cognitive tests used in psychiatrically-healthy older adults (i.e., measures of verbal recall and fluency). Cognition in the natural course of BD is generally stable, and impairment or marked decline on measures of verbal episodic memory or semantic retrieval may indicate an early neurodegenerative process.},
}

@article {pmid34090726,
year = {2021},
author = {Long, EM and Hale, RL},
title = {Improving nursing students' confidence in caring for persons with dementia.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.gerinurse.2021.04.017},
pmid = {34090726},
issn = {1528-3984},
abstract = {BACKGROUND: Nursing students need experiences providing patient centered care for persons with dementia.

METHODS: Students were provided with a voluntary opportunity to complete an online educational module that focused on caring for persons with dementia. Dementia knowledge was measured with the Alzheimer Dementia and Knowledge Scale and confidence was assessed with the Sense of Competence in Dementia Care Staff Scale.

RESULTS: Data suggested that students developed an increased confidence in caring for persons with dementia after the education. Key to person centered care, students demonstrated an increased ability to sustain person hood and build relationships.

CONCLUSIONS: The growing complexity and needs of persons with dementia in various practice settings requires a nursing workforce able to apply clinical reasoning and provide person centered care. Further studies are needed exploring the effects of online educational opportunities on learning outcomes and clinical reasoning to build confidence in caring for persons with dementia.},
}

@article {pmid34089652,
year = {2021},
author = {Jenny Wei, YJ and Chen, C and Fillingim, RB and DeKosky, ST and Schmidt, S and Pahor, M and Solberg, L and Winterstein, AG},
title = {Uncontrolled Pain and Risk for Depression and Behavioral Symptoms in Residents With Dementia.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jamda.2021.05.010},
pmid = {34089652},
issn = {1538-9375},
abstract = {OBJECTIVES: Limited cohort studies have assessed the association between uncontrolled pain and risk for behavioral and psychological symptoms of dementia (BPSDs). We conducted a longitudinal cohort study to examine whether associations exist between uncontrolled pain and risk for 2 common BPSDs-depression and behavioral symptoms-among long-term care (LTC) residents with Alzheimer disease and related dementia (ADRD).

DESIGN: This retrospective cohort study analyzed quarterly data from the 5% Medicare sample linked to Minimum Data Set (MDS) 3.0 between January 1, 2011, and December 31, 2015.

SETTING AND PARTICIPANTS: LTC residents aged 50 years or older with ADRD who had chronic pain and at least 2 quarterly MDS 3.0 assessments.

METHODS: LTC residents were followed up quarterly from first observed quarterly MDS 3.0 until first outcome event or last observed quarterly MDS 3.0. Uncontrolled pain was defined as numerical rating scale >4, verbal descriptor scale of moderate or severe pain, or ≥1 pain indicators on the Checklist of Nonverbal Pain Indicators. Depression was defined as ≥10 on the Patient Health Questionnaire 9; behavioral symptoms were defined as the presence of psychotic (delusions or hallucinations) or disruptive behaviors (rejection of care, or physical, verbal, or other aggressive behaviors). Generalized linear models (GLMs) with marginal structural modeling (MSM) stabilized weights were used to examine uncontrolled pain and outcome risk.

RESULTS: The incidence rate of depression and behavioral symptoms during follow-up was 9.4 and 23.1 per 100 resident-years, respectively. Results from the MSM-GLMs showed that LTC residents with uncontrolled pain had a higher risk than those with controlled pain for developing depression (hazard ratio 1.67, 95% confidence interval [CI] 1.54-1.81) and behavioral symptoms (hazard ratio 1.28, 95% CI 1.19-1.37).

CONCLUSIONS AND IMPLICATIONS: Uncontrolled pain was associated with elevated risk for depressive and behavioral symptoms in dementia, underscoring the importance of pain assessment and control among LTC residents with ADRD.},
}

@article {pmid34080526,
year = {2021},
author = {Manandhar, S and Priya, K and Mehta, CH and Nayak, UY and Kabekkodu, SP and Pai, KSR},
title = {Repositioning of antidiabetic drugs for Alzheimer's disease: possibility of Wnt signaling modulation by targeting LRP6 an in silico based study.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/07391102.2021.1930583},
pmid = {34080526},
issn = {1538-0254},
abstract = {Alzheimer disease (AD) is the most common, irreversible and progressive form of dementia for which the exact pathology and cause are still not clear. At present, we are only confined to symptomatic treatment, and the lack of disease-modifying therapeutics is worrisome. Alteration of Wnt signaling has been linked to metabolic diseases as well as AD. The crosstalk between Canonical Wnt signaling and insulin signaling pathway has been widely studied and accepted from several clinical and preclinical studies that have proven the beneficial effect of antidiabetic medications in the case of memory and cognition loss. This structure-based in silico study was focused on exploring the link between the currently available FDA approved antidiabetic drugs and the Wnt signaling pathway. The library of antidiabetics was obtained from drug bank and was screened for their binding affinity with protein (PDB ID: 3S2K) LRP6, a coreceptor of the Wnt signaling pathway using GLIDE module of Schrodinger. The top molecules, with higher docking score, binding energy and stable interactions, were subjected to energy-based calculation using MMGBSA, followed by a molecular dynamics-based simulation study. Drugs of class α-glucosidase inhibitors and peroxisome proliferator-activated receptors (PPARs) agonists were found to have a strong affinity towards LRP6 proteins, highlighting the possibility of the modulation of Wnt signaling by antidiabetics as one of the possible mechanisms for use in AD. However, further experimental based in vitro and in vivo studies are warranted for verification and support.Communicated by Ramaswamy H. Sarma.},
}

@article {pmid34080437,
year = {2021},
author = {Lu, L and Dai, WZ and Zhu, XC and Ma, T},
title = {Analysis of Serum miRNAs in Alzheimer's Disease.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {36},
number = {},
pages = {15333175211021712},
doi = {10.1177/15333175211021712},
pmid = {34080437},
issn = {1938-2731},
abstract = {This paper was aimed to analyze the microRNA (miRNA) signatures in Alzheimer disease (AD) and find the significant expressions of miRNAs, their target genes, the functional enrichment analysis of the confirmed genes, and potential drug treatment. The miRNA expression information of the gene expression profile data was downloaded from the Gene Expression Omnibus database. The total data sample size is 1309, including 1021 AD samples and 288 normal samples. A total of 21 differentially expressed miRNAs were obtained, of which 16 (hsa-miR-6761-3p, hsa-miR-6747-3p, hsa-miR-6875-3p, hsa-miR-6754-3p, hsa-miR-6736-3p, hsa-miR-6762-3p, hsa-miR-6787-3p, hsa-miR-208a-5p, hsa-miR-6740-3p, hsa-miR-6778-3p, hsa-miR-595, hsa-miR-6753-3p, hsa-miR-4747-3p, hsa-miR-3646, hsa-miR-6716-3p and hsa-miR-4435) were up-regulated and 5 (hsa-miR-125a-3p, hsa-miR-22-3p, hsa-miR-24-3p, hsa-miR-6131 and hsa-miR-125b-1-3p) were down-regulated in AD. A total of 6 miRNAs (hsa-miR-595, hsa-miR-3646, hsa-miR-4435 hsa-miR-125a-3p, hsa-miR-22-3p and hsa-miR-24-3p) and 78 miRNA-disease-related gene sub-networks were predicted, and 116 ceRNA regulatory relationship pairs, and the ceRNA regulatory network were obtained. The results of enrichment analysis suggested that the main target pathways of several miRNAs differentially expressed in AD were mitogen-activated protein kinase signal pathway. According to the prediction results of Drug-Gene Interaction database 2.0, we obtained 53 pairs of drug-gene interaction, including 7 genes (PTGS2, EGFR, CALM1, PDE4D, FGFR2, HMGCR, cdk6) and 53 drugs. We hope our results are helpful to find a viable way to prevent, delay the onset, diagnose, and treat AD.},
}

@article {pmid34079697,
year = {2021},
author = {Guo, XY and Chang, Y and Kim, Y and Rhee, HY and Cho, AR and Park, S and Ryu, CW and San Lee, J and Lee, KM and Shin, W and Park, KC and Kim, EJ and Jahng, GH},
title = {Development and evaluation of a T1 standard brain template for Alzheimer disease.},
journal = {Quantitative imaging in medicine and surgery},
volume = {11},
number = {6},
pages = {2224-2244},
doi = {10.21037/qims-20-710},
pmid = {34079697},
issn = {2223-4292},
abstract = {Background: Patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) have high variability in brain tissue loss, making it difficult to use a disease-specific standard brain template. The objective of this study was to develop an AD-specific three-dimensional (3D) T1 brain tissue template and to evaluate the characteristics of the populations used to form the template.

Methods: We obtained 3D T1-weighted images from 294 individuals, including 101 AD, 96 amnestic MCI, and 97 cognitively normal (CN) elderly individuals, and segmented them into different brain tissues to generate AD-specific brain tissue templates. Demographic data and clinical outcome scores were compared between the three groups. Voxel-based analyses and regions-of-interest-based analyses were performed to compare gray matter volume (GMV) and white matter volume (WMV) between the three participant groups and to evaluate the relationship of GMV and WMV loss with age, years of education, and Mini-Mental State Examination (MMSE) scores.

Results: We created high-resolution AD-specific tissue probability maps (TPMs). In the AD and MCI groups, losses of both GMV and WMV were found with respect to the CN group in the hippocampus (F >44.60, P<0.001). GMV was lower with increasing age in all individuals in the left (r=-0.621, P<0.001) and right (r=-0.632, P<0.001) hippocampi. In the left hippocampus, GMV was positively correlated with years of education in the CN groups (r=0.345, P<0.001) but not in the MCI (r=0.223, P=0.0293) or AD (r=-0.021, P=0.835) groups. WMV of the corpus callosum was not significantly correlated with years of education in any of the three subject groups (r=0.035 and P=0.549 for left, r=0.013 and P=0.821 for right). In all individuals, GMV of the hippocampus was significantly correlated with MMSE scores (left, r=0.710 and P<0.001; right, r=0.680 and P<0.001), while WMV of the corpus callosum showed a weak correlation (left, r=0.142 and P=0.015; right, r=0.123 and P=0.035).

Conclusions: A 3D, T1 brain tissue template was created using imaging data from CN, MCI, and AD participants considering the participants' age, sex, and years of education. Our disease-specific template can help evaluate brains to promote early diagnosis of MCI individuals and aid treatment of MCI and AD individuals.},
}

@article {pmid34079609,
year = {2021},
author = {Bethell, J and O'Rourke, HM and Eagleson, H and Gaetano, D and Hykaway, W and McAiney, C},
title = {Social Connection is Essential in Long-Term Care Homes: Considerations During COVID-19 and Beyond.},
journal = {Canadian geriatrics journal : CGJ},
volume = {24},
number = {2},
pages = {151-153},
doi = {10.5770/cgj.24.488},
pmid = {34079609},
issn = {1925-8348},
abstract = {COVID-19 has had a profound impact on long-term care (LTC) homes in Canada. But the measures put in place to control infection within LTC homes have also had devastating impacts on the health and well-being of residents through the effects on social connection. Here, we offer guiding principles to enable social connection and promote health and quality of life for LTC residents during COVID-19 and beyond. These principles were generated by a working group of the COVID-19 and Dementia Task Force, convened by the Alzheimer Society of Canada to identify the urgent and emerging issues raised by COVID-19 for Canadians with dementia.},
}

@article {pmid34079471,
year = {2021},
author = {Guo, Y and Zhang, C and Wang, C and Huang, Y and Liu, J and Chu, H and Ren, X and Kong, L and Ma, H},
title = {Thioredoxin-1 Is a Target to Attenuate Alzheimer-Like Pathology in Diabetic Encephalopathy by Alleviating Endoplasmic Reticulum Stress and Oxidative Stress.},
journal = {Frontiers in physiology},
volume = {12},
number = {},
pages = {651105},
doi = {10.3389/fphys.2021.651105},
pmid = {34079471},
issn = {1664-042X},
abstract = {Varying degrees of central nervous system neuropathy induced by diabetes mellitus (DM) contribute to a cognitive disorder known as diabetic encephalopathy (DE), which is also one of the independent risk factors for Alzheimer's disease (AD). Endoplasmic reticulum stress (ERS) plays a critical role in the occurrence and development of DE and AD. However, its molecular mechanism remains largely unknown. This study aims to investigate whether thioredoxin-1 (Trx-1) could alleviate DE and AD through ERS, oxidative stress (OS) and apoptosis signaling pathways. Mice were randomly divided into a wild-type group (WT-NC), a streptozotocin (STZ)-treated DM group (WT-DM), a Trx-1-TG group (TG-NC) and a Trx-1-TG DM group (TG-DM). Diabetic animals showed an increase in the time spent in the target quadrant and the number of platform crossings as well as AD-like behavior in the water maze experiment. The immunocontent of the AD-related protein Tau and the levels of cell apoptosis, β-amyloid (Aβ) plaque formation and neuronal degeneration in the hippocampus of the diabetic group were increased. Some key factors associated with ERS, such as protein disulfide isomerase (PDI), glucose-regulated protein 78 (GRP78), inositol-requiring enzyme 1α (IRE1α), tumor necrosis factor receptor-associated factor 2 (TRAF2), apoptosis signal-regulating kinase-1 (ASK1), c-Jun N-terminal kinase (JNK), protein kinase RNA (PKR)-like ER kinase (PERK), and C/EBP homologous protein (CHOP), were upregulated, and other factors related to anti-oxidant stress, such as nuclear factor erythroid 2-related factor (Nrf2), were downregulated in the DM group. Moreover, DM caused an increase in the immunocontents of caspase-3 and caspase-12. However, these changes were reversed in the Trx-1-tg DM group. Therefore, we conclude that Trx-1 might be a key factor in alleviating DE and AD by regulating ERS and oxidative stress response, thus preventing apoptosis.},
}

@article {pmid34077500,
year = {2021},
author = {Akbor, MM and Kurosawa, N and Tanaka, M and Isobe, M},
title = {Polymorphic SERPINA3-R124C reduces pathogenesis of its wild type by shortening the life time of oligomeric Aβ.},
journal = {Bioscience, biotechnology, and biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1093/bbb/zbab101},
pmid = {34077500},
issn = {1347-6947},
abstract = {Amyloid beta (Aβ) 42 peptide accumulated in Alzheimer disease (AD) patients' brain, often colocalized with serine protease inhibitor family A member 3 (SERPINA3). Being a chaperon, SERPINA3 accelerated Aβ42 fibrillization. While analyzing chaperon activity of human SERPINA3 polymorphisms, we found SERPINA3-R124C played a role in protecting cells from Aβ42 cytotoxicity. SH-SY5Y cells exposed to Aβ42 preincubated with wild type SERPINA3 (SERPINA3-WT) resulted in extended toxicity leading cell death whereas Aβ42 with SERPINA3-R124C resulted in less cytotoxicity. Transmission electron microscope and thioflavin T assay revealed that SERPINA3-R124C shortened life time of small soluble oligomer and maintained β-sheet rich protofibril-like aggregates for longer time compared to that of with SERPINA3-WT. Western blot assay confirmed that SERPINA3-R124C converted Aβ42 mostly into high molecular aggregates. Here, we demonstrate first time that polymorphic SERPINA3 acts as a benign chaperon by modulating the transition states of Aβ42, which may contribute to the reduction of AD risk.},
}

@article {pmid34074863,
year = {2021},
author = {Veldkamp, R and Goetschalckx, M and Hulst, HE and Nieuwboer, A and Grieten, K and Baert, I and Leone, C and Moumdjian, L and Feys, P},
title = {Cognitive-motor Interference in Individuals With a Neurologic Disorder: A Systematic Review of Neural Correlates.},
journal = {Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology},
volume = {34},
number = {2},
pages = {79-95},
pmid = {34074863},
issn = {1543-3641},
abstract = {BACKGROUND: Performing a cognitive task and a motor task simultaneously is an everyday act that can lead to decreased performance on both tasks.

OBJECTIVE: To provide insight into the neural correlates associated with cognitive-motor dual tasking in individuals with a neurologic disorder.

METHOD: We searched the PubMed and Web of Science databases for studies that had been published up to January 16th, 2019. Studies investigating the neural correlates of cognitive-motor dual task performance in individuals with a variety of neurologic disorders were included, independently from whether the study included healthy controls. Clinical and imaging data were abstracted for the comparison between single tasks and a dual task in the individuals with a neurologic disorder and for the comparison between the healthy controls and the individuals with a neurologic disorder.

RESULTS: Eighteen studies met the inclusion criteria. Study populations included individuals with Parkinson disease, multiple sclerosis, mild cognitive impairment, Alzheimer disease, traumatic brain injury, and stroke. Neuroimaging types used to study the neural correlates of cognitive-motor dual tasking during upper limb or gait tasks included fMRI, functional near-infrared spectroscopy, EEG, and PET.

CONCLUSION: Despite large heterogeneity in study methodologies, some recurrent patterns were noted. Particularly, in neurologic patients, an already higher brain activation during single tasks was seen compared with healthy controls, perhaps compromising the patients' ability to further adapt brain activation with increasing load during dual tasking and resulting in reduced behavioral dual task performance.},
}

@article {pmid34074373,
year = {2021},
author = {Cheng, L and Song, C and Li, X and Shi, M and Zhao, H},
title = {[Protective effect of 1, 25(OH)_2D_3 on Aβ_(1-42)-induced pyrolysis in PC12 cells].},
journal = {Wei sheng yan jiu = Journal of hygiene research},
volume = {50},
number = {3},
pages = {483-487},
doi = {10.19813/j.cnki.weishengyanjiu.2021.03.023},
pmid = {34074373},
issn = {1000-8020},
abstract = {OBJECTIVE: To investigate the protective effect of 1, 25(OH)_2D_3 on Aβ_(1-42)-induced pyrolysis in PC12 cells.

METHODS: The Alzheimer& apos; s disease model in PC12 cells was established with 20 μmol/L Aβ_(1-42). The experiment was divided into control group, model group(20 μmol/L Aβ_(1-42)) and 1, 25(OH)_2D_3 groups(1, 10, 100 nmol/L 1, 25(OH)_2D_3+20 μmol/L Aβ_(1-42)). Cell activity was detected by CCK-8, cell membrane permeability was detected by AO/EB staining, lactic dehydrogenase(LDH)and interleukin-1β(IL-1β)were detected by colorimetry and ELISA, NOD-like receptor family protein 1(NLRP1), cysteinyl aspartate specific proteinase-1(caspase-1)and gasdermin D(GSDMD)protein expression were detected by Western Blot.

RESULTS: Compared with the control group, the cell activitywas significantly decreased(P& lt; 0. 01), cell membrane permeability, the level of LDH and IL-1β, and the expression of NLRP1, caspase-1 and GSDMD were significantly increased(P& lt; 0. 01). Compared with the model group, the cell activity was significantly increased(P& lt; 0. 01), cell membrane damage was decreased in PC12 cells exposed to 1, 25(OH)_2D_3. The level of LDH and IL-1β were significantly decreased(P& lt; 0. 01) in PC12 cells exposed to 10 and 100 nmol/L 1, 25(OH)_2D_3. The expression of NLRP1 and GSDMD in 1 nmol/L 1, 25(OH)_2D_3 group was decreased(P& lt; 0. 05), and the decrease was more significant in 10 and 100 nmol/L 1, 25(OH)_2D_3 groups(P& lt; 0. 01). The expression of caspase-1 was significantly decreased in 10 and 100 nmol/L 1, 25(OH)_2D_3 groups(P& lt; 0. 05, P& lt; 0. 01).

CONCLUSION: 1, 25(OH)_2D_3 exerts a significant protective effect against Aβ_(1-42)-induced PC12 cells injury through inhibition of neuronal pyrolysis.},
}

@article {pmid34072107,
year = {2021},
author = {Giovannini, MG and Lana, D and Traini, C and Vannucchi, MG},
title = {The Microbiota-Gut-Brain Axis and Alzheimer Disease. From Dysbiosis to Neurodegeneration: Focus on the Central Nervous System Glial Cells.},
journal = {Journal of clinical medicine},
volume = {10},
number = {11},
pages = {},
doi = {10.3390/jcm10112358},
pmid = {34072107},
issn = {2077-0383},
support = {RICATEN (MGV2020)//University of Florence/ ; B/2019/0236//Intesa san paolo/ ; 2020.1456//FCRF/ ; },
abstract = {The microbiota-gut system can be thought of as a single unit that interacts with the brain via the "two-way" microbiota-gut-brain axis. Through this axis, a constant interplay mediated by the several products originating from the microbiota guarantees the physiological development and shaping of the gut and the brain. In the present review will be described the modalities through which the microbiota and gut control each other, and the main microbiota products conditioning both local and brain homeostasis. Much evidence has accumulated over the past decade in favor of a significant association between dysbiosis, neuroinflammation and neurodegeneration. Presently, the pathogenetic mechanisms triggered by molecules produced by the altered microbiota, also responsible for the onset and evolution of Alzheimer disease, will be described. Our attention will be focused on the role of astrocytes and microglia. Numerous studies have progressively demonstrated how these glial cells are important to ensure an adequate environment for neuronal activity in healthy conditions. Furthermore, it is becoming evident how both cell types can mediate the onset of neuroinflammation and lead to neurodegeneration when subjected to pathological stimuli. Based on this information, the role of the major microbiota products in shifting the activation profiles of astrocytes and microglia from a healthy to a diseased state will be discussed, focusing on Alzheimer disease pathogenesis.},
}

@article {pmid34071695,
year = {2021},
author = {Zuin, M and Cervellati, C and Trentini, A and Passaro, A and Rosta, V and Zimetti, F and Zuliani, G},
title = {Association between Serum Concentrations of Apolipoprotein A-I (ApoA-I) and Alzheimer's Disease: Systematic Review and Meta-Analysis.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {11},
number = {6},
pages = {},
doi = {10.3390/diagnostics11060984},
pmid = {34071695},
issn = {2075-4418},
abstract = {BACKGROUND: A wealth of experimental and epidemiological evidence suggest that Apolipoprotein A-I (ApoA-I), the main protein constituent of high-density lipoprotein (HDL), may protect against Alzheimer disease (AD). To investigate this potential role, we conducted a meta-analysis of the published studies on the relationship between serum ApoA-I and AD occurrence.

METHODS: We screened MEDLINE, EMBASE, Web of Science, and Scopus, for cross-sectional studies published from inception to 1 March 2021, comparing the ApoA-I serum levels between patients with AD and cognitively normal controls.

RESULTS: From an initial screening of 245 articles, 5 studies, including 397 AD patients (mean age 75.0 years, 234 females) and 367 controls (mean age 69.2 years, 182 females), met the inclusion criteria. Compared to healthy controls, AD subjects had a lower ApoA-I serum level. The pooled weighted mean difference from a random-effects model was -0.31 g/L (p < 0.0001) (95% Confidence Interval: [-0.62-0.01], with high heterogeneity (I2 = 100%). The Egger's test confirmed an absence of publication bias (t = 0.62, p = 0.576).

CONCLUSIONS: Our study showed that AD patients present lower serum levels of ApoA-I compared to cognitively normal individuals. Further studies on large population samples are required to support this finding.},
}

@article {pmid34070808,
year = {2021},
author = {Martín-Belmonte, A and Aguado, C and Alfaro-Ruiz, R and Albasanz, JL and Martín, M and Moreno-Martínez, AE and Fukazawa, Y and Luján, R},
title = {The Density of Group I mGlu5 Receptors Is Reduced along the Neuronal Surface of Hippocampal Cells in a Mouse Model of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {22},
number = {11},
pages = {},
doi = {10.3390/ijms22115867},
pmid = {34070808},
issn = {1422-0067},
support = {RTI2018-095812-B-I00//Ministerio de Ciencia y Tecnología/ ; PID2019-109206GB-I00//Ministerio de Ciencia y Tecnología/ ; SBPLY/17/180501/000229//Junta de Comunidades de Castilla-La Mancha/ ; SBPLY/19/180501/000251//Junta de Comunidades de Castilla-La Mancha/ ; 19K22469//University of Fukui/ ; 20H05058//University of Fukui/ ; },
abstract = {Metabotropic glutamate receptor subtype 5 (mGlu5) is implicated in the pathophysiology of Alzheimer´s disease (AD). However, its alteration at the subcellular level in neurons is still unexplored. Here, we provide a quantitative description on the expression and localisation patterns of mGlu5 in the APP/PS1 model of AD at 12 months of age, combining immunoblots, histoblots and high-resolution immunoelectron microscopic approaches. Immunoblots revealed that the total amount of mGlu5 protein in the hippocampus, in addition to downstream molecules, i.e., Gq/11 and PLCβ1, was similar in both APP/PS1 mice and age-matched wild type mice. Histoblots revealed that mGlu5 expression in the brain and its laminar expression in the hippocampus was also unaltered. However, the ultrastructural techniques of SDS-FRL and pre-embedding immunogold demonstrated that the subcellular localisation of mGlu5 was significantly reduced along the neuronal surface of hippocampal principal cells, including CA1 pyramidal cells and DG granule cells, in APP/PS1 mice at 12 months of age. The decrease in the surface localisation of mGlu5 was accompanied by an increase in its frequency at intracellular sites in the two neuronal populations. Together, these data demonstrate, for the first time, a loss of mGlu5 at the plasma membrane and accumulation at intracellular sites in different principal cells of the hippocampus in APP/PS1 mice, suggesting an alteration of the excitability and synaptic transmission that could contribute to the cognitive dysfunctions in this AD animal model. Further studies are required to elucidate the specificity of mGlu5-associated molecules and downstream signalling pathways in the progression of the pathology.},
}

@article {pmid34069029,
year = {2021},
author = {Zampar, S and Wirths, O},
title = {Characterization of a Mouse Model of Alzheimer's Disease Expressing Aβ4-42 and Human Mutant Tau.},
journal = {International journal of molecular sciences},
volume = {22},
number = {10},
pages = {},
doi = {10.3390/ijms22105191},
pmid = {34069029},
issn = {1422-0067},
support = {16013//Alzheimer Forschung Initiative/ ; //Alzheimer Stiftung Göttingen/ ; T0323-28.817//Gerhard Hunsmann Stiftung/ ; },
abstract = {The relationship between the two most prominent neuropathological hallmarks of Alzheimer's Disease (AD), extracellular amyloid-β (Aβ) deposits and intracellular accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFT), remains at present not fully understood. A large body of evidence places Aβ upstream in the cascade of pathological events, triggering NFTs formation and the subsequent neuron loss. Extracellular Aβ deposits were indeed causative of an increased tau phosphorylation and accumulation in several transgenic models but the contribution of soluble Aβ peptides is still controversial. Among the different Aβ variants, the N-terminally truncated peptide Aβ4-42 is among the most abundant. To understand whether soluble Aβ4-42 peptides impact the onset or extent of tau pathology, we have crossed the homozygous Tg4-42 mouse model of AD, exclusively expressing Aβ4-42 peptides, with the PS19 (P301S) tau transgenic model. Behavioral assessment showed that the resulting double-transgenic line presented a partial worsening of motor performance and spatial memory deficits in the aged group. While an increased loss of distal CA1 pyramidal neurons was detected in young mice, no significant alterations in hippocampal tau phosphorylation were observed in immunohistochemical analyses.},
}

@article {pmid34067882,
year = {2021},
author = {De Gaetano, A and Gibellini, L and Zanini, G and Nasi, M and Cossarizza, A and Pinti, M},
title = {Mitophagy and Oxidative Stress: The Role of Aging.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {10},
number = {5},
pages = {},
doi = {10.3390/antiox10050794},
pmid = {34067882},
issn = {2076-3921},
support = {19786//Associazione Italiana per la Ricerca sul Cancro/ ; },
abstract = {Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer's and Parkinson's diseases. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria.},
}

@article {pmid34067632,
year = {2021},
author = {Testai, L and Martelli, A and Flori, L and Cicero, AFG and Colletti, A},
title = {Coenzyme Q10: Clinical Applications beyond Cardiovascular Diseases.},
journal = {Nutrients},
volume = {13},
number = {5},
pages = {},
doi = {10.3390/nu13051697},
pmid = {34067632},
issn = {2072-6643},
abstract = {Coenzyme Q10 (CoQ10) is an essential cofactor in oxidative phosphorylation (OXPHOS), present in mitochondria and cell membranes in reduced and oxidized forms. Acting as an energy transfer molecule, it occurs in particularly high levels in the liver, heart, and kidneys. CoQ10 is also an anti-inflammatory and antioxidant agent able to prevent the damage induced by free radicals and the activation of inflammatory signaling pathways. In this context, several studies have shown the possible inverse correlation between the blood levels of CoQ10 and some disease conditions. Interestingly, beyond cardiovascular diseases, CoQ10 is involved also in neuronal and muscular degenerative diseases, in migraine and in cancer; therefore, the supplementation with CoQ10 could represent a viable option to prevent these and in some cases might be used as an adjuvant to conventional treatments. This review is aimed to summarize the clinical applications regarding the use of CoQ10 in migraine, neurodegenerative diseases (including Parkinson and Alzheimer diseases), cancer, or degenerative muscle disorders (such as multiple sclerosis and chronic fatigue syndrome), analyzing its effect on patients' health and quality of life.},
}

@article {pmid34065393,
year = {2021},
author = {Merighi, S and Poloni, TE and Terrazzan, A and Moretti, E and Gessi, S and Ferrari, D},
title = {Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?.},
journal = {Cells},
volume = {10},
number = {5},
pages = {},
doi = {10.3390/cells10051267},
pmid = {34065393},
issn = {2073-4409},
abstract = {Alzheimer's disease (AD) is a widespread neurodegenerative pathology responsible for about 70% of all cases of dementia. Adenosine is an endogenous nucleoside that affects neurodegeneration by activating four membrane G protein-coupled receptor subtypes, namely P1 receptors. One of them, the A2A subtype, is particularly expressed in the brain at the striatal and hippocampal levels and appears as the most promising target to counteract neurological damage and adenosine-dependent neuroinflammation. Extracellular nucleotides (ATP, ADP, UTP, UDP, etc.) are also released from the cell or are synthesized extracellularly. They activate P2X and P2Y membrane receptors, eliciting a variety of physiological but also pathological responses. Among the latter, the chronic inflammation underlying AD is mainly caused by the P2X7 receptor subtype. In this review we offer an overview of the scientific evidence linking P1 and P2 mediated purinergic signaling to AD development. We will also discuss potential strategies to exploit this knowledge for drug development.},
}

@article {pmid34064783,
year = {2021},
author = {Saretz, S and Basset, G and Useini, L and Laube, M and Pietzsch, J and Drača, D and Maksimović-Ivanić, D and Trambauer, J and Steiner, H and Hey-Hawkins, E},
title = {Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue.},
journal = {Molecules (Basel, Switzerland)},
volume = {26},
number = {10},
pages = {},
doi = {10.3390/molecules26102843},
pmid = {34064783},
issn = {1420-3049},
support = {doctoral fellowship for L.U.//Deutscher Akademische Austauschdienst/ ; HE 1376/38-1//Deutsche Forschungsgemeinschaft/ ; STE 847/6-1//Deutsche Forschungsgemeinschaft/ ; S.S., L.U.//Graduate School BuildMoNa/ ; 451-03-68/2020-14/200007//Ministry of Education, Science and Technological Development of the Republic of Serbia/ ; Helmholtz Cross-Programme Initiative "Technology and Medicine-Adaptive Systems"//Helmholtz Association/ ; },
abstract = {All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer's disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood-brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood-brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.},
}

@article {pmid34059876,
year = {2021},
author = {Strand, H and Garabet, L and Bjelke, B and Sithiravel, C and Hardang, IM and Moe, MK},
title = {β-Amyloid in Cerebrospinal Fluid: How to Keep It Floating (Not Sticking) by Standardization of Preanalytic Processes and Collection Tubes.},
journal = {The journal of applied laboratory medicine},
volume = {},
number = {},
pages = {},
doi = {10.1093/jalm/jfab024},
pmid = {34059876},
issn = {2576-9456},
abstract = {BACKGROUND: Phosphorylated tau (pTau), total tau (tTau), and β-amyloid (Aβ) are established cerebrospinal fluid (CSF) biomarkers used to help diagnose Alzheimer disease. Preanalytic workups of CSF samples lack harmonization, making interlaboratory comparison of these biomarkers challenging. The Aβ adsorbs to sample tubes, yielding underestimated concentrations, and may result in false Alzheimer disease diagnosis. Our primary aim was to compare Aβ recovery across multiple polypropylene tubes and to test the stability of tTau, pTau, and Aβ in the best performing tube.

METHODS: Eight polypropylene tubes were tested using 3 CSF pools with Aβ concentrations <500, 500-1000, and >1000 ng/L. All samples were analyzed in duplicate. Tubes were cut open to assess their different infrared adsorption spectra. Freshly drawn CSF from 14 patients was distributed into 4 Sarstedt 5-mL (no. 63.504.027; Sar5CSF) tubes, left at room temperature for up to 7 days, and analyzed for pTau, tTau, and Aβ by ELISA.

RESULTS: Two Sarstedt 5-mL tubes and a Sarstedt 10-mL (Sar10CSF) tube showed significantly higher Aβ recovery at all 3 concentrations compared with the 5 other tubes. The infrared adsorption spectra of Sar10CSF and Sar5CSF tubes were practically identical, unlike the other tubes. No significant loss of pTau, tTau, and Aβ was observed in CSF left at room temperature for up to 7 days (P > 0.05).

CONCLUSIONS: Recovery of Aβ from Sar5CSF tubes is equivalent to Aβ recovery from Sar10CSF tubes. Levels of pTau, tTau, and Aβ were stable for at least 7 days at room temperature but not at 37 °C.},
}

@article {pmid34062171,
year = {2021},
author = {Blanco-Paniagua, E and García-Lino, AM and García-Mateos, D and Álvarez, AI and Merino, G},
title = {Role of the Abcg2 transporter in plasma levels and tissue accumulation of the anti-inflammatory tolfenamic acid in mice.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {109537},
doi = {10.1016/j.cbi.2021.109537},
pmid = {34062171},
issn = {1872-7786},
abstract = {The Breast Cancer Resistance Protein (BCRP/ABCG2) is an ATP-binding cassette efflux transporter that is expressed in the apical membrane of cells from relevant tissues involved in drug pharmacokinetics such as liver, intestine, kidney, testis, brain and mammary gland, among others. Tolfenamic acid is an anti-inflammatory drug used as an analgesic and antipyretic in humans and animals. Recently, tolfenamic acid has been repurposed as an antitumoral drug and for use in chronic human diseases such as Alzheimer. The aim of this work was to study whether tolfenamic acid is an in vitro of Abcg2 substrate, and to investigate the potential role of Abcg2 in plasma exposure, secretion into milk and tissue accumulation of this drug. Using in vitro transepithelial assays with cells transduced with Abcg2, we showed that tolfenamic acid is an in vitro substrate of Abcg2. The in vivo effect of this transporter was tested using wild-type and Abcg2-/- mice, showing that after oral and intravenous administration of tolfenamic acid, its area under the plasma concentration-time curve in Abcg2-/- mice was between 1.7 and 1.8-fold higher compared to wild type-mice. Abcg2-/- mice also showed higher liver and testis accumulation of tolfenamic acid after intravenous administration. In this study, we demonstrate that tolfenamic acid is transported in vitro by Abcg2 and that its plasma levels as well as its tissue distribution are affected by Abcg2, with potential pharmacological and toxicological consequences.},
}

@article {pmid34061824,
year = {2021},
author = {Jin, X and He, W and Zhang, Y and Gong, E and Niu, Z and Ji, J and Li, Y and Zeng, Y and Yan, LL},
title = {Association of APOE ε4 genotype and lifestyle with cognitive function among Chinese adults aged 80 years and older: A cross-sectional study.},
journal = {PLoS medicine},
volume = {18},
number = {6},
pages = {e1003597},
doi = {10.1371/journal.pmed.1003597},
pmid = {34061824},
issn = {1549-1676},
abstract = {BACKGROUND: Apolipoprotein E (APOE) ε4 is the single most important genetic risk factor for cognitive impairment and Alzheimer disease (AD), while lifestyle factors such as smoking, drinking, diet, and physical activity also have impact on cognition. The goal of the study is to investigate whether the association between lifestyle and cognition varies by APOE genotype among the oldest old.

METHODS AND FINDINGS: We used the cross-sectional data including 6,160 oldest old (aged 80 years old or older) from the genetic substudy of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) which is a national wide cohort study that began in 1998 with follow-up surveys every 2-3 years. Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score less than 18. Healthy lifestyle profile was classified into 3 groups by a composite measure including smoking, alcohol consumption, dietary pattern, physical activity, and body weight. APOE genotype was categorized as APOE ε4 carriers versus noncarriers. We examined the associations of cognitive impairment with lifestyle profile and APOE genotype using multivariable logistic regressions, controlling for age, sex, education, marital status, residence, disability, and numbers of chronic conditions. The mean age of our study sample was 90.1 (standard deviation [SD], 7.2) years (range 80-113); 57.6% were women, and 17.5% were APOE ε4 carriers. The mean MMSE score was 21.4 (SD: 9.2), and 25.0% had cognitive impairment. Compared with those with an unhealthy lifestyle, participants with intermediate and healthy lifestyle profiles were associated with 28% (95% confidence interval [CI]: 16%-38%, P < 0.001) and 55% (95% CI: 44%-64%, P < 0.001) lower adjusted odds of cognitive impairment. Carrying the APOE ε4 allele was associated with 17% higher odds (95% CI: 1%-31%, P = 0.042) of being cognitively impaired in the adjusted model. The association between lifestyle profiles and cognitive function did not vary significantly by APOE ε4 genotype (noncarriers: 0.47 [0.37-0.60] healthy versus unhealthy; carriers: 0.33 [0.18-0.58], P for interaction = 0.30). The main limitation was the lifestyle measurements were self-reported and were nonspecific. Generalizability of the findings is another limitation because the study sample was from the oldest old in China, with unique characteristics such as low body weight compared to populations in high-income countries.

CONCLUSIONS: In this study, we observed that healthier lifestyle was associated with better cognitive function among the oldest old regardless of APOE genotype. Our findings may inform the cognitive outlook for those oldest old with high genetic risk of cognitive impairment.},
}

@article {pmid34061820,
year = {2021},
author = {Han, F and Chen, J and Belkin-Rosen, A and Gu, Y and Luo, L and Buxton, OM and Liu, X and , },
title = {Reduced coupling between cerebrospinal fluid flow and global brain activity is linked to Alzheimer disease-related pathology.},
journal = {PLoS biology},
volume = {19},
number = {6},
pages = {e3001233},
doi = {10.1371/journal.pbio.3001233},
pmid = {34061820},
issn = {1545-7885},
abstract = {The glymphatic system plays an important role in clearing the amyloid-β (Aβ) and tau proteins that are closely linked to Alzheimer disease (AD) pathology. Glymphatic clearance, as well as Aβ accumulation, is highly dependent on sleep, but the sleep-dependent driving forces behind cerebrospinal fluid (CSF) movements essential to the glymphatic flux remain largely unclear. Recent studies have reported that widespread, high-amplitude spontaneous brain activations in the drowsy state and during sleep, which are shown as large global signal peaks in resting-state functional magnetic resonance imaging (rsfMRI), are coupled with CSF movements, suggesting their potential link to glymphatic flux and metabolite clearance. By analyzing multimodal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project, here we showed that the coupling between the global fMRI signal and CSF influx is correlated with AD-related pathology, including various risk factors for AD, the severity of AD-related diseases, the cortical Aβ level, and cognitive decline over a 2-year follow-up. These results provide critical initial evidence for involvement of sleep-dependent global brain activity, as well as the associated physiological modulations, in the clearance of AD-related brain waste.},
}

@article {pmid34061149,
year = {2021},
author = {Chen, MH and Yang, FC and Liang, CS},
title = {APOE Allele Testing and Alzheimer Disease.},
journal = {JAMA},
volume = {325},
number = {21},
pages = {2210-2211},
doi = {10.1001/jama.2021.4919},
pmid = {34061149},
issn = {1538-3598},
}

@article {pmid34061147,
year = {2021},
author = {Choudhury, P and Ramanan, VK and Boeve, BF},
title = {APOE Allele Testing and Alzheimer Disease-Reply.},
journal = {JAMA},
volume = {325},
number = {21},
pages = {2211},
doi = {10.1001/jama.2021.4925},
pmid = {34061147},
issn = {1538-3598},
}

@article {pmid34061007,
year = {2021},
author = {Schade, N and Koch, P and Ansideri, F and Krystof, V and Holzer, M and Hilgeroth, A},
title = {Evaluation of Novel Substituted Furopyridines as Inhibitors of Protein Kinases Related to Tau Pathology in Alzheimer´s Disease.},
journal = {Medicinal chemistry (Shariqah (United Arab Emirates))},
volume = {},
number = {},
pages = {},
doi = {10.2174/1573406417666210601144510},
pmid = {34061007},
issn = {1875-6638},
abstract = {BACKGROUND: Alzheimer´s disease (AD) is characterized by a progressive neuronal degeneration caused by two pathological hallmarks, hyperphosphorylated tau protein aggregated into tau filaments and amyloid precursor protein derived beta amyloid peptides aggregated into extracellular amyloid plaques. All attempts so far to find effective drugs failed in clinical trials. AD is a multifactorial disease, so that selective drugs to target one AD-relevant structure alone may not be sufficient.

OBJECTIVE: We built novel furopyridines with various substitution patterns to evaluate them as protein kinases inhibitors of enzymes related to tau pathology.

METHOD: Furopyridine derivatives were synthesized and purified using column chromatography. The protein kinase inhibitory properties were determined in ATP-competition assays with determined affinity constants for the most active compounds.

RESULTS: The compounds were prepared in simple two-component reactions of substituted 1,4- dihydropyridines and respective quinones to obtain various substitutions of the molecular furopyridine scaffold. The substituent effects on the determined kinase inhibitory properties of cdk1, cdk2, Fyn, JNK3 and gsk-3β are discussed.

CONCLUSION: Various 3-substitutions were found most sensitive for the protein kinase inhibition depending on the length, nature and a substituent positioning within. We identified compounds as inhibitors of several kinases as a tool to potentially combat the disease progress in a multitargeting approach.},
}

@article {pmid34057082,
year = {2021},
author = {Wei, W and Liu, Y and Dai, C and Baazaoui, N and Tung, YC and Liu, F and Iqbal, K},
title = {Neurotrophic Treatment Initiated During Early Postnatal Development Prevents the Alzheimer-Like Behavior and Synaptic Dysfunction.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {},
doi = {10.3233/JAD-201599},
pmid = {34057082},
issn = {1875-8908},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction.

OBJECTIVE: To explore strategies for early intervention to prevent Alzheimer's disease.

METHODS: In the present study, we investigated the effect of treatment during early development with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLAG-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated.

RESULTS: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice.

CONCLUSION: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies.},
}

@article {pmid34055897,
year = {2021},
author = {Tanaka, M and Chock, PB},
title = {Oxidative Modifications of RNA and Its Potential Roles in Biosystem.},
journal = {Frontiers in molecular biosciences},
volume = {8},
number = {},
pages = {685331},
doi = {10.3389/fmolb.2021.685331},
pmid = {34055897},
issn = {2296-889X},
abstract = {Elevated level of oxidized RNA was detected in vulnerable neurons in Alzheimer patients. Subsequently, several diseases and pathological conditions were reported to be associated with RNA oxidation. In addition to several oxidized derivatives, cross-linking and unique strand breaks are generated by RNA oxidation. With a premise that dysfunctional RNA mediated by oxidation is the pathogenetic molecular mechanism, intensive investigations have revealed the mechanism for translation errors, including premature termination, which gives rise to aberrant polypeptides. To this end, we and others revealed that mRNA oxidation could compromise its translational activity and fidelity. Under certain conditions, oxidized RNA can also induce several signaling pathways, to mediate inflammatory response and induce apoptosis. In this review, we focus on the oxidative modification of RNA and its resulting effect on protein synthesis as well as cell signaling. In addition, we will also discuss the potential roles of enzymatic oxidative modification of RNA in mediating cellular effects.},
}

@article {pmid34054698,
year = {2021},
author = {Pietrowski, MJ and Gabr, AA and Kozlov, S and Blum, D and Halle, A and Carvalho, K},
title = {Glial Purinergic Signaling in Neurodegeneration.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {654850},
doi = {10.3389/fneur.2021.654850},
pmid = {34054698},
issn = {1664-2295},
abstract = {Purinergic signaling regulates neuronal and glial cell functions in the healthy CNS. In neurodegenerative diseases, purinergic signaling becomes dysregulated and can affect disease-associated phenotypes of glial cells. In this review, we discuss how cell-specific expression patterns of purinergic signaling components change in neurodegeneration and how dysregulated glial purinergic signaling and crosstalk may contribute to disease pathophysiology, thus bearing promising potential for the development of new therapeutical options for neurodegenerative diseases.},
}

@article {pmid34053209,
year = {2021},
author = {Kim, SH and Ko, YJ and Kim, JY and Sim, YJ},
title = {Treadmill Running Improves Spatial Learning Memory Through Inactivation of Nuclear Factor Kappa B/Mitogen-Activated Protein Kinase Signaling Pathway in Amyloid-β-Induced Alzheimer Disease Rats.},
journal = {International neurourology journal},
volume = {25},
number = {Suppl 1},
pages = {S35-43},
doi = {10.5213/inj.2142164.082},
pmid = {34053209},
issn = {2093-4777},
support = {//Ministry of Education/ ; 2018S1A5A2A01032722//National Research Foundation of Korea/ ; },
abstract = {PURPOSE: Exercise is known to reduce proinflammatory cytokines production and apoptosis. We investigated the effect of treadmill running on spatial learning memory in terms of activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathway in Alzheimer disease (AD) rats. We also evaluated the effect of treadmill running on proinflammatory cytokine production and apoptosis.

METHODS: Using the stereotaxic frame, amyloid-β (Aβ) was injected into the lateral ventricle of the brain. The rats belong to treadmill running groups were forced to run on a motorized treadmill for 30 minutes per a day during 4 weeks, starting 3 days after Aβ injection. Morris water maze task was done for the determination of spatial learning memory. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry for cleaved caspase-3, and western blot for NF-κB, inhibitory protein of NF-κB (IκB), MAPK signaling pathway, tumor necrosis factor (TNF)-α, interleukin (IL)-1β were done.

RESULTS: Induction of AD increased proinflammatory cytokine secretion by activating the NF-κB/MAPK signaling pathway. These changes induced apoptosis in the hippocampus and reduced spatial learning memory. In contrast, treadmill running inactivated the NF-κB/MAPK signaling pathway and suppressed proinflammatory cytokine production. These changes inhibited apoptosis and improved spatial learning memory.

CONCLUSION: Current results showed that treadmill running promoted spatial learning memory through suppressing proinflammatory cytokine production and apoptosis via inactivation of NF-κB/MAPK signaling pathway. Treadmill exercise can be considered an effective intervention for symptom relieve of AD.},
}

@article {pmid34052752,
year = {2021},
author = {Saber, FR and Mohsen, E and El-Hawary, S and Eltanany, BM and Elimam, H and Sobeh, M and Elmotayam, AK},
title = {Chemometric-enhanced metabolic profiling of five Pinus species using HPLC-MS/MS spectrometry: Correlation to in vitro anti-aging, anti-Alzheimer and antidiabetic activities.},
journal = {Journal of chromatography. B, Analytical technologies in the biomedical and life sciences},
volume = {1177},
number = {},
pages = {122759},
doi = {10.1016/j.jchromb.2021.122759},
pmid = {34052752},
issn = {1873-376X},
abstract = {Detailed metabolic profiling of needles of five Pinus species was investigated using complementary HPLC-MS/MS techniques together with supervised and unsupervised chemometric tools. This resulted in putative identification of 44 compounds belonging to flavonoids, phenolics, lignans, diterpenes and fatty acids. Unsupervised principal component analysis showed that differences were maintained across the metabolites characteristic of each Pinus species, are mainly related to di-O-p-coumaroyltrifolin, p-coumaroyl quinic acid derivative, arachidonic acid, hydroxypalmitic acid, isopimaric acid and its derivative. A supervised Partial Least Squares regression analysis was performed to correlate HPLC-MS/MS profiles with the variation observed in the in vitro anticholinesterase, antiaging and anti-diabetic potential. All investigated Pinus extracts exerted their antiaging activity via increasing telomerase and TERT levels in normal human melanocytes cells compared to the control (untreated cells). Profound inhibition activities of acetylcholinesterase and dipeptidyl peptidase-4 were also observed with P. pinea and P. canariensis extracts having comparable antidiabetic activities to sitagliptin as a standard antidiabetic drug. Our findings suggested that pine needles are a good source of phenolics and diterpenoids that have possible health promoting activities in management and alleviation of diabetic conditions and Alzheimer disease.},
}

@article {pmid34052296,
year = {2021},
author = {Abd El-Fatah, IM and Abdelrazek, HMA and Ibrahim, SM and Abdallah, DM and El-Abhar, HS},
title = {Dimethyl fumarate abridged tauo-/amyloidopathy in a D-Galactose/ovariectomy-induced Alzheimer's-like disease: Modulation of AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, Adiponectin/Adipo1R, and NF-κB/IL-1β/ROS trajectories.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {105082},
doi = {10.1016/j.neuint.2021.105082},
pmid = {34052296},
issn = {1872-9754},
abstract = {Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aβ42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1β, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3β, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.},
}

@article {pmid34044035,
year = {2021},
author = {Souders, CL and Rushin, A and Sanchez, CL and Toth, D and Adamovsky, O and Martyniuk, CJ},
title = {Mitochondrial and transcriptome responses following exposure to the insecticide fipronil on rat dopaminergic neural cells.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuro.2021.05.011},
pmid = {34044035},
issn = {1872-9711},
abstract = {The phenylpyrazole fipronil is an insecticide that inhibits γ -amino-butyric acid (GABA) ionotropic receptors in the central nervous system. Experimental evidence suggests that fipronil acts as a neurotoxin and it is implicated in neurodegenerative diseases; however, the mechanisms of neurotoxicity are not fully elucidated. The objective of this study was to quantify mechanisms of fipronil-induced neurotoxicity in dopamine cells. Rat primary immortalized mesencephalic dopaminergic cells (N27) were treated with fipronil (0.25 up to 500 µM depending on the assay). We measured endpoints related to mitochondrial bioenergetics, mitophagy, mitochondrial membrane potential, and ATP production in addition to discerning transcriptome responses to the pesticide. Fipronil reduced cell viability at 500 µM after 24 -h exposure and caspase 3/7 activity was significant increased after 6 and 12 hours by 250 and 500 µM fipronil. Subsequent endpoints were thus assessed at concentrations that were below cytotoxicity. We measured oxidative respiration of N27 cells following a 24 -h exposure to one dose of either 0.25, 2.5, 25, or 50 µM fipronil. Oxygen consumption rates (OCR) were not different between vehicle-control and 0.25 or 2.5 µM fipronil treatments, but there was a ∼40 to 60% reduction in basal respiration, as well as reduced oligomycin-induced ATP production at 50 µM. The reduction in OCR is hypothesized to be related to lower mitochondrial mass due to mitophagy. Mitochondrial membrane potential was also sensitive to fipronil, and it was compromised at concentrations of 2.5 µM and above. To further elucidate the mechanisms linked to neurotoxicity, we conducted transcriptomics in dopamine cells following treatment with 25 µM fipronil. Fipronil suppressed transcriptional networks associated with mitochondria (damage, depolarization, permeability, and fission), consistent with its effects on mitochondrial membrane potential. Altered gene networks also included those related to Alzheimer disease, inflammatory disease, nerve fiber degeneration, and neurofibrillary tangles. This study clarifies molecular targets of fipronil-induced neurotoxicity and supports, through multiple lines of evidence, that fipronil acts as a mitochondrial toxicant in dopamine cells. This is important as exposure to fipronil is associated with the progressive loss of nigrostriatal dopaminergic neurons in rodents.},
}

@article {pmid34043628,
year = {2021},
author = {Varma, VR and Wang, Y and An, Y and Varma, S and Bilgel, M and Doshi, J and Legido-Quigley, C and Delgado, JC and Oommen, AM and Roberts, JA and Wong, DF and Davatzikos, C and Resnick, SM and Troncoso, JC and Pletnikova, O and O'Brien, R and Hak, E and Baak, BN and Pfeiffer, R and Baloni, P and Mohmoudiandehkordi, S and Nho, K and Kaddurah-Daouk, R and Bennett, DA and Gadalla, SM and Thambisetty, M},
title = {Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study.},
journal = {PLoS medicine},
volume = {18},
number = {5},
pages = {e1003615},
doi = {10.1371/journal.pmed.1003615},
pmid = {34043628},
issn = {1549-1676},
abstract = {BACKGROUND: While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis.

METHODS AND FINDINGS: We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings.

CONCLUSIONS: We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.},
}

@article {pmid34042795,
year = {2021},
author = {Lettry, E and Ehrler, F and Szilas, N},
title = {A Tutorial for an Interactive Narrative Simulation for Alzheimer's Disease's Caregivers: Development and Evaluation.},
journal = {Studies in health technology and informatics},
volume = {281},
number = {},
pages = {855-859},
doi = {10.3233/SHTI210300},
pmid = {34042795},
issn = {1879-8365},
abstract = {Alzheimer Care Trainer (ACT) is an interactive narrative simulation for caregivers of patients with Alzheimer's disease. It aims to support family caregivers by letting them practice difficult situations of daily life in a training environment. In order to ensure its accessibility to its target audience, which may be unfamiliar with new technologies, we have created a tutorial. The aim of the tutorial is to teach users the main mechanics of the simulation. Considered to be an introductory level to ACT, it is built in 2 parts, a dirigiste first part and an exploratory, second part. Several tutorial elements, such as context-sensitive information or a help page, have been integrated. The evaluation of the tutorial by 14 participants revealed that interaction mechanics were well understood although the state of the visual element remains confusing. Generated positive affects were stronger than the negative ones and most of the participants were confident to play the game after the tutorial. Ensuring accessibility to all populations is essential especially when targeting seniors. A well-conceived tutorial has the potential to familiarize users with our intervention, reducing the risk of excluding people that could benefit from it.},
}

@article {pmid34042725,
year = {2021},
author = {Shaji, S and Ganapathy, N and Swaminathan, R},
title = {Differentiation of Alzheimer Conditions in MR Brain Images Using a Single Inception Module Network.},
journal = {Studies in health technology and informatics},
volume = {281},
number = {},
pages = {158-162},
doi = {10.3233/SHTI210140},
pmid = {34042725},
issn = {1879-8365},
abstract = {In this study, an attempt has been made to differentiate Alzheimer's Disease (AD) stages in structural Magnetic Resonance (MR) images using single inception module network. For this, T1-weighted MR brain images of AD, mild cognitive impairment and Normal Controls (NC) are obtained from a public database. From the images, significant features are extracted and classified using an inception module network. The performance of the model is computed and analyzed for different input image sizes. Results show that the single inception module is able to classify AD stages using MR images. The end-to-end network differentiates AD from NC with 85% precision. The model is found to be effective for varied sizes of input images. Since the proposed approach is able to categorize AD stages, single inception module networks could be used for the automated AD diagnosis with minimum medical expertise.},
}

@article {pmid34042019,
year = {2021},
author = {de Oliveira, OV and Gonçalves, ADS and Almeida, NEC},
title = {Insights into β-amyloid transition prevention by cucurbit[7]uril from molecular modeling.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/07391102.2021.1932600},
pmid = {34042019},
issn = {1538-0254},
abstract = {In this study, comparable molecular dynamic (MD) simulations of 1.2 microseconds were performed to clarify the prevention of the β-amyloid peptide (Aβ1-42) aggregation by cucurbit[7]uril (CB[7]). The accumulation of this peptide in the brain is one of the most harmful in Alzheimer's disease. The inhibition mechanism of Aβ1-42 aggregation by different molecules is attributed to preventing of Aβ1-42 conformational transition from α-helix to the β-sheet structure. However, our structural analysis shows that the pure water and aqueous solution of the CB[7] denature the native Aβ1-42 α-helix structure forming different compactness and unfolded conformations, not in β-sheet form. On the other hand, in the three CB[7]@Aβ1-42 complexes, it was observed the encapsulation of N-terminal (Asp1), Lys16, and Val36 by CB[7] along the MD trajectory, and not with aromatic residues as suggested by the literature. Only in one CB[7]@Aβ1-42 complex was observed stable Asp23-Lys28 salt bridge with an average distance of 0.36 nm. All CB[7]@Aβ1-42 complexes are very stable with binding free energy lowest than ∼-50 kcal/mol between the CB[7] and Aβ1-42 monomer from MM/PBSA calculation. Therefore, herein we show that the mechanism of the prevention of elongation protofibril by CB[7] is due to the disruption of the Asp23-Lys28 salt bridge and steric effects of CB[7]@Aβ1-42 complex with the fibril lattice, and not due to the transition from α-helix to β-sheet following the dock-lock mechanism.Communicated by Ramaswamy H. Sarma.},
}

@article {pmid34041783,
year = {2021},
author = {Lin, BSZ and Sur, S and Liu, P and Li, Y and Jiang, D and Hou, BSX and Darrow, J and Pillai, JJ and Yasar, S and Rosenberg, P and Albert, M and Moghekar, A and Lu, H},
title = {Blood-brain barrier breakdown in relationship to Alzheimer and vascular disease.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.26134},
pmid = {34041783},
issn = {1531-8249},
abstract = {OBJECTIVE: Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer's and vascular diseases, is still poorly understood. The present study measured human BBB function in mild-cognitive-impairment (MCI) patients at two molecular scales, specifically BBB's permeability to water and albumin molecules.

METHODS: 55 elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new MRI technique, water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST). BBB permeability to albumin was determined using CSF/serum albumin ratio. Cognitive performance was assessed by domain specific composite scores. AD pathology (including CSF Aβ and ptau) and vascular risk factors were examined.

RESULTS: Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aβ and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function.

INTERPRETATION: These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. This article is protected by copyright. All rights reserved.},
}

@article {pmid34040575,
year = {2021},
author = {Vichianin, Y and Khummongkol, A and Chiewvit, P and Raksthaput, A and Chaichanettee, S and Aoonkaew, N and Senanarong, V},
title = {Accuracy of Support-Vector Machines for Diagnosis of Alzheimer's Disease, Using Volume of Brain Obtained by Structural MRI at Siriraj Hospital.},
journal = {Frontiers in neurology},
volume = {12},
number = {},
pages = {640696},
doi = {10.3389/fneur.2021.640696},
pmid = {34040575},
issn = {1664-2295},
abstract = {Background: The determination of brain volumes using visual ratings is associated with an inherently low accuracy for the diagnosis of Alzheimer's disease (AD). A support-vector machine (SVM) is one of the machine learning techniques, which may be utilized as a classifier for various classification problems. This study exploratorily investigated the accuracy of SVM classification models for AD subjects using brain volume and various clinical data as features. Methods: The study was designed as a retrospective chart review. A total of 201 eligible subjects were recruited from the Memory Clinic at Siriraj Hospital, Thailand. Eighteen cases were excluded due to incomplete MRI data. Subjects were randomly assigned to a training group (AD = 46, normal = 46) and testing group (AD = 45, normal = 46) for SVM modeling and validation, respectively. The results in terms of accuracy and a receiver operating characteristic curve analysis are reported. Results: The highest accuracy for brain volumetry (62.64%) was found using the hippocampus as a single feature. A combination of clinical parameters as features provided accuracy ranging between 83 and 90%. However, a combination of brain volumetry and clinical parameters as features to the SVM models did not improve the accuracy of the result. Conclusions: In our study, the use of brain volumetry as SVM features provided low classification accuracy with the highest accuracy of 62.64% using the hippocampus volume alone. In contrast, the use of clinical parameters [Thai mental state examination score, controlled oral word association tests (animals; and letters K, S, and P), learning memory, clock-drawing test, and construction-praxis] as features for SVM models provided good accuracy between 83 and 90%.},
}

@article {pmid34040515,
year = {2021},
author = {Anwar, F and Saleem, U and Rehman, AU and Ahmad, B and Froeyen, M and Mirza, MU and Kee, LY and Abdullah, I and Ahmad, S},
title = {Toxicity Evaluation of the Naphthalen-2-yl 3,5-Dinitrobenzoate: A Drug Candidate for Alzheimer Disease.},
journal = {Frontiers in pharmacology},
volume = {12},
number = {},
pages = {607026},
doi = {10.3389/fphar.2021.607026},
pmid = {34040515},
issn = {1663-9812},
abstract = {The presented study was designed to probe the toxicity potential of newly identified compound naphthalen-2-yl 3,5-dinitrobenzoate (SF1). Acute, subacute toxicity and teratogenicity studies were performed as per Organization of economic cooperation and development (OECD) 425, 407, and 414 test guidelines, respectively. An oral dose of 2000 mg/kg to rats for acute toxicity. Furthermore, 5, 10, 20, and 40 mg/kg doses were administered once daily for 28 days in subacute toxicity study. Teratogenicity study was performed with 40 mg/kg due to its excellent anti-Alzheimer results at this dose. SF1 induced a significant rise in Alkaline Phosphatases (ALP), bilirubin, white blood cells (WBC), and lymphocyte levels with a decrease in platelet count. Furthermore, the reduction in urea, uric acid, and aspartate transaminase (AST) levels and an increase in total protein levels were measured in subacute toxicity. SF1 increased spermatogenesis at 5 and 10 mg/kg doses. Teratogenicity study depicted no resorptions, early abortions, cleft palate, spina bifida and any skeletal abnormalities in the fetuses. Oxidative stress markers (Superoxide dismutase (SOD), Catalase (CAT), and glutathione (GSH) were increased in all the experiments, whereas the effect on melanoaldehyde Malondialdehyde (MDA) levels was variable. Histopathology further corroborated these results with no change in the architectures of selected organs. Consequently, a 2000 mg/kg dose of SF1 tends to induce minor liver dysfunction along with immunomodulation, and it is well below its LD50 . Moreover, it can be safely used in pregnancy owing to its no detectable teratogenicity.},
}

@article {pmid34039035,
year = {2021},
author = {Rost, NS and Meschia, JF and Gottesman, R and Wruck, L and Helmer, K and Greenberg, SM and , },
title = {Cognitive Impairment and Dementia After Stroke: Design and Rationale for the DISCOVERY Study.},
journal = {Stroke},
volume = {},
number = {},
pages = {STROKEAHA120031611},
doi = {10.1161/STROKEAHA.120.031611},
pmid = {34039035},
issn = {1524-4628},
abstract = {Stroke is a leading cause of the adult disability epidemic in the United States, with a major contribution from poststroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID's overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent preexisting brain pathology related to cerebrovascular and Alzheimer disease or related dementia. Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent it, and for informing future clinical trial design. The DISCOVERY study (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery), a collaborative network of thirty clinical performance clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID will address this critical challenge. DISCOVERY is a prospective, multicenter, observational, nested-cohort study of 8000 nondemented ischemic and hemorrhagic stroke patients enrolled at the time of index stroke and followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research magnetic resonance imaging and positron emission tomography and comprehensive genetic/genomic and fluid biomarker testing. The overall scientific objective of this study is to elucidate mechanisms of brain resilience and susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, preexisting burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation.},
}

@article {pmid34036518,
year = {2021},
author = {Elfouly, A and Awny, M and Ibrahim, MK and Aboelsaad, M and Tian, J and Sayed, M},
title = {Effects of Long-Acting Testosterone Undecanoate on Behavioral Parameters and Na + , K+-ATPase mRNA Expression in Mice with Alzheimer`s Disease.},
journal = {Neurochemical research},
volume = {},
number = {},
pages = {},
pmid = {34036518},
issn = {1573-6903},
abstract = {Previous studies have shown that testosterone attenuates stress-induced mood dysfunction and memory deterioration. However, the exact mechanism is still unknown. This study was conducted to investigate the role of long-term testosterone undecanoate on the behavioral responses in AD induced by AlCl3 + D-galactose administration and the possible alteration of the gene expression level of the Na/K ATPase pump. Adult male mice received AlCl3 in drinking water (10 mg/kg/day) and (D-gal 200 mg/kg/day), subcutaneously for 90 consecutive days, then received a single intramuscular (I.M) injection of castor oil (vehicle) on day 91, while treated groups received a single I.M injection of either low (100 mg/kg/45 days) or high dose (500 mg/kg/45 days) respectively of long-acting testosterone undecanoate on day 91. The time spent in the interaction zone during the open field test, preference index to novel objects in the novel object recognition test, spontaneous alternation percentage (SAP) in Y-maze test, and escape latency time in the Morris water maze test were used to measure the locomotor activity, long-term memory, and spatial memory in mice, respectively. The results showed that testosterone undecanoate treatment improved locomotor activity, improved preference to novel objects, improved spatial memory, and reversed anxiety and depression induced by AlCl3 + D-galactose administration in male mice, suggesting the enhancement of behavioral and memory functions brought by testosterone treatment. Moreover, testosterone undecanoate treatment did alter gene expression levels of Na/K ATPase isoforms in the brain hippocampus. In most cases, altered gene expression was significant and correlated with the observed behavioral changes. Taken together, our findings provide new insight into the effects of long-acting testosterone undecanoate administration on locomotor activity, long-term memory, anxiety, and spatial memory in male mice with Alzheimer's disease.},
}

@article {pmid34035132,
year = {2021},
author = {Pavisic, IM and Lu, K and Keuss, SE and James, SN and Lane, CA and Parker, TD and Keshavan, A and Buchanan, SM and Murray-Smith, H and Cash, DM and Coath, W and Wong, A and Fox, NC and Crutch, SJ and Richards, M and Schott, JM},
title = {Subjective cognitive complaints at age 70: associations with amyloid and mental health.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2020-325620},
pmid = {34035132},
issn = {1468-330X},
abstract = {OBJECTIVE: To investigate subjective cognitive decline (SCD) in relation to β-amyloid pathology and to test for associations with anxiety, depression, objective cognition and family history of dementia in the Insight 46 study.

METHODS: Cognitively unimpaired ~70-year-old participants, all born in the same week in 1946 (n=460, 49% female, 18% amyloid-positive), underwent assessments including the SCD-Questionnaire (MyCog). MyCog scores were evaluated with respect to 18F-Florbetapir-PET amyloid status (positive/negative). Associations with anxiety, depression, objective cognition (measured by the Preclinical Alzheimer Cognitive Composite, PACC) and family history of dementia were also investigated. The informant's perspective on SCD was evaluated in relation to MyCog score.

RESULTS: Anxiety (mean (SD) trait anxiety score: 4.4 (3.9)) was associated with higher MyCog scores, especially in women. MyCog scores were higher in amyloid-positive compared with amyloid-negative individuals (adjusted means (95% CIs): 5.3 (4.4 to 6.1) vs 4.3 (3.9 to 4.7), p=0.044), after accounting for differences in anxiety. PACC (mean (SD) -0.05 (0.68)) and family history of dementia (prevalence: 23.9%) were not independently associated with MyCog scores. The informant's perception of SCD was generally in accordance with that of the participant.

CONCLUSIONS: This cross-sectional study demonstrates that symptoms of SCD are associated with both β-amyloid pathology, and more consistently, trait anxiety in a population-based cohort of older adults, at an age when those who are destined to develop dementia are still likely to be some years away from symptoms. This highlights the necessity of considering anxiety symptoms when assessing Alzheimer's disease pathology and SCD.},
}

@article {pmid34034963,
year = {2021},
author = {Horvath, AA and Papp, A and Zsuffa, J and Szucs, A and Luckl, J and Radai, F and Nagy, F and Hidasi, Z and Csukly, G and Barcs, G and Kamondi, A},
title = {Subclinical epileptiform activity accelerates the progression of Alzheimer's disease: A long-term EEG study.},
journal = {Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clinph.2021.03.050},
pmid = {34034963},
issn = {1872-8952},
abstract = {OBJECTIVE: While many studies suggest that patients with Alzheimer's disease have a higher chance for developing epileptic seizures, only a few studies are available examining independent epileptic discharges. The major aims of our study was to determine the prevalence of subclinical epileptiform activity (SEA) in AD compared to healthy elderly controls with the hypothesis that SEA is more frequent in AD than in cognitively normal individuals. Another aim was to analyze the effect of baseline SEA captured with electroencephalography on the progression of the disease with longitudinal cognitive testing.

METHODS: We investigated 52 Alzheimer patients with no history of epileptic seizures and 20 healthy individuals. All participants underwent a 24-hour electroencephalography, neurology, neuroimaging and neuropsychology examination. Two independent raters analyzed visually the electroencephalograms and both raters were blind to the diagnoses. Thirty-eight Alzheimer patients were enrolled in a 3-year long prospective follow-up study with yearly repeated cognitive evaluation.

RESULTS: Subclinical epileptiform discharges were recorded significantly (p:0.018) more frequently in Alzheimer patients (54%) than in healthy elderly (25%). Epileptiform discharges were associated with lower performance scores in memory. Alzheimer patients with spikes showed 1.5-times faster decline in global cognitive scores than patients without (p < 0.001). The decline in cognitive performance scores showed a significant positive correlation with spike frequency (r:+0.664; p < 0.001).

CONCLUSIONS: Subclinical epileptiform activity occurs in half of Alzheimer patients who have never suffered epileptic seizures. Alzheimer patients with subclinical epileptiform activity showed accelerated cognitive decline with a strong relation to the frequency and spatial distribution (left temporal) of spikes.

SIGNIFICANCE: Our findings suggest the prominent role of epileptiform discharges in the pathomechanism of Alzheimer's disease which might serve as potential therapeutic target.},
}

@article {pmid34034613,
year = {2021},
author = {Oliveira, FF and de Almeida, SS and Smith, MC and Bertolucci, PHF},
title = {Behavioural effects of the ACE insertion/deletion polymorphism in Alzheimer's disease depend upon stratification according to APOE-ϵ4 carrier status.},
journal = {Cognitive neuropsychiatry},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/13546805.2021.1931085},
pmid = {34034613},
issn = {1464-0619},
abstract = {Introduction: The inherited risk of late-onset Alzheimer's disease (AD) is genetically determined. We aimed to examine associations of genetic variants of APOE and ACE with age at AD onset and with neuropsychiatric symptoms according to each dementia stage.Methods: Consecutive outpatients with AD were assessed for demographic features, Clinical Dementia Rating scores, and the 10-item Neuropsychiatric Inventory, and genotyped for rs7412 and rs429358 (APOE haplotypes, Real-Time Polymerase Chain Reactions), and the ACE insertion/deletion polymorphism (Polymerase Chain Reactions). Combined genetic variants of APOE and ACE were associated with age at dementia onset, and with neuropsychiatric symptoms in each dementia stage (adjusted for sex and age at dementia onset).Results: Over two-thirds of the 238 patients were women, whereas the mean age at dementia onset was 73.82 ± 6.2 years-old. APOE-ϵ4/ϵ4 carriers had earlier dementia onset (p<.001). The ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=.37) but was not associated with age at dementia onset, regardless of APOE-ϵ4 carrier status. The only results that survived corrections for false discovery rates were higher scores of dysphoria for APOE-ϵ4 carriers (n=122) who also carried ACE deletion/deletion (p=.031). No results survived corrections for false discovery rates for APOE-ϵ4 non-carriers (n=116).Conclusions: Though only the APOE-ϵ4/ϵ4 haplotype affected AD onset, effects of the ACE insertion/deletion polymorphism over behavioural features might differ according to APOE-ϵ4 carrier status in genetic associations.},
}

@article {pmid34033708,
year = {2021},
author = {Burke, AD},
title = {Can Emerging Therapies Resolve Unmet Needs With Current Treatment in Early-stage AD?.},
journal = {The Journal of clinical psychiatry},
volume = {82},
number = {3},
pages = {},
doi = {10.4088/JCP.BG20044WC3C},
pmid = {34033708},
issn = {1555-2101},
abstract = {While no current medications for Alzheimer disease (AD) can modify the disease, the agents do slow symptom progression. The earlier the medications are started for patients diagnosed with AD, the greater the potential benefit. Clinical trials are in progress on drugs with a variety of mechanisms that may modulate the disease course: neuronal protection; protein synthesis or aggregation inhibition; immunologic priming with antibodies; vaccines; and secretase inhibition. Early diagnosis, whether in the primary care setting or the specialty setting, continues to be critical to give patients their best chance at managing their illness. Although current treatments cannot give patients back what they have already lost, in the near future, drugs may be able to slow or even halt their cognitive and functional decline if clinicians identify AD early enough in the disease process.},
}

@article {pmid34032945,
year = {2021},
author = {Anuradha, U and Kumar, A and Singh, RK},
title = {The clinical correlation of proinflammatory and anti-inflammatory biomarkers with Alzheimer disease: a meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {34032945},
issn = {1590-3478},
abstract = {BACKGROUND: Numerous studies have indicated the role of inflammation in the pathogenesis of Alzheimer's disease (AD). However, the exact role of inflammatory markers in AD is still unclear.

OBJECTIVE: The main objective of the current study was to find out the association between the level of inflammatory markers and AD.

MATERIAL AND METHODS: The relevant articles have been extracted from PubMed as per the inclusion and exclusion criteria of the study. The mean value with standard deviation and number of participants in AD and control groups were extracted from relevant articles. The inverse variance was used as a statistical method and standard mean difference (SMD) as effect measure with 95% C.I. The random effect model was used and all analyses were done using Rev. Man 5.0.

RESULTS: A total of 38 articles have been found relevant and selected for analysis. The overall estimate results have shown that the level of IL-6, TGF-β1, and IL-1α were increased significantly in AD patients as compared to the control group among all other pro-inflammatory, inflammatory and anti-inflammatory mediators.

CONCLUSION: The findings of the current study suggest that IL-6, TGF-β1, and IL-1α may be a useful early marker in AD. However, further studies are required to confirm the exact utility of these inflammatory markers.},
}

@article {pmid34032549,
year = {2021},
author = {Kandil, LS and Hanafy, AS and Farid, RM and Elgammal, S},
title = {Intranasal galantamine/chitosan complex nanoparticles elicit neuroprotection potentials in rat brains via antioxidant effect.},
journal = {Drug development and industrial pharmacy},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/03639045.2021.1934861},
pmid = {34032549},
issn = {1520-5762},
abstract = {BACKGROUND: Alzheimer's disease is a common cause of dementia in the elderly. Galantamine hydrobromide (GH) is an anti-Alzheimer cholinesterase inhibitor that has an intrinsic antioxidant effect. In a previous study, GH was complexed with chitosan to prepare intranasal GH/chitosan complex nanoparticles (CX-NP2). The nanoparticles were located in rat brains 1 h after nasal administration and showed pharmacological superiority to GH nasal solution without showing histopathological toxicity. Objective: This study aimed to investigate whether the long-term administration of CX-NP2 leads to biochemical toxicity in rat brains compared to GH nasal solution. Methods: CX-NP2 dispersion and GH solution were administrated intranasally to male Wistar rats for 30 days (3 mg/kg/day). Malondialdehyde(MDA), lipid peroxidation marker, glutathione (GSH), superoxide dismutase (SOD) activity and tumor necrosis factor-α (TNF-α) were assessed in the brain extracts in all groups. Results: There was statistically insignificant difference between the CX-NP2 and GH nasal solution treated groups in all biochemical toxicity parameters assessed. Interestingly, MDA and TNF-α levels in CX-NP2-treated group significantly decreased compared to the control group. Also, GSH level and SOD activity were significantly enhanced in CX-NP2 treated group compared to the control group. Conclusions: CX-NP2 did not induce a statistically significant oxidative stress or neuroinflammation in rat brains after 30-day treatment, they rather elicited neuroprotective potentials.HighlightsIntranasal GH/chitosan complex nanoparticles (CX-NP2) show promising potential as a brain targeting carrier.Compared to GH nasal solution, nasal CX-NP2 formulation did not exert oxidative stress nor neuroinflammation when administered for 30 days.},
}

@article {pmid34032430,
year = {2021},
author = {He, H and Liu, Y and Sun, Y and Ding, F},
title = {Misfolding and Self-Assembly Dynamics of Microtubule-Binding Repeats of the Alzheimer-Related Protein Tau.},
journal = {Journal of chemical information and modeling},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jcim.1c00217},
pmid = {34032430},
issn = {1549-960X},
abstract = {Pathological aggregation of intrinsically disordered tau protein, driven by the interactions between microtubule-binding (MTB) domains, is associated with Alzheimer's disease. The MTB domain contains either three or four repeats with sequence similarities. Compared to amyloid β, many aspects of the misfolding and aggregation mechanisms of tau are largely unknown. In this study, we systematically investigated the dynamics of monomer misfolding and dimerization of each MTB repeat using atomistic discrete molecular dynamic simulations. Our results revealed that all the four repeat monomers (R1-R4) were very dynamic, featuring frequent conformational conversion and lacking stable conformations. While R1, R2, and R4 monomers occasionally adopted partially helical conformations, R3 monomers frequently formed β-sheets. In dimerization simulations, R3 displayed the strongest aggregation propensity with high β-sheet contents, while R1 was the least prone to aggregation. The R2 and R4 dimers contained both helix and β-sheet structures. The β-sheets in R4 assemblies were dominant with β-hairpin conformation. In R2 and R3 dimers, intermolecular β-sheets were mainly driven by residues around the paired helical filament (PHF) regions. Residues around the PHF6* in R2 and PHF6 in R3 had significantly higher intermolecular contacts than other regions, suggesting that these residues play a key role in the amyloid aggregation of tau. Our results on the structural ensembles and early aggregation dynamics of each tau MTB repeat will help understand the nucleation and fibrillization of tau.},
}

@article {pmid34031961,
year = {2021},
author = {Vicente de Sousa, O and Mendes, J and Freitas do Amaral, T},
title = {Association between nutritional and functional status indicators with caregivers' burden in Alzheimer's disease.},
journal = {Nutrition & dietetics: the journal of the Dietitians Association of Australia},
volume = {},
number = {},
pages = {},
doi = {10.1111/1747-0080.12679},
pmid = {34031961},
issn = {1747-0080},
abstract = {AIM: To investigate the association between nutritional and functional status of Alzheimer's disease patients and caregivers' burden.

METHODS: A cross-sectional study was conducted among 79 community-dwelling Alzheimer's disease patients living with their caregivers. Caregivers' burden was assessed using the Zarit Burden-Interview. Multinomial logistic regressions were carried out using caregivers' burden as the dependent variable.

RESULTS: Caregivers' severe overload was strongly associated with weight loss of more than 3 kg during the previous 3 months (OR = 7.34; 95% CI: 2.02-26.65), lower values of calf girth (OR = 3.20; 95% CI: 1.03-9.93), sarcopenia status (OR = 3.50; 95% CI: 1.09-11.22), and lower gait speed values (OR = 3.83; 95% CI: 1.18-12.47). Otherwise, overweight or obesity (OR = 0.21; 95% CI: 0.05-0.83), was related to lower odds of higher caregivers' burden.

CONCLUSION: In community-dwelling older adults with Alzheimer's disease, the nutritional and functional status impairments were strongly associated with increasing caregivers' burden, whereas overweight conferred protection.},
}

@article {pmid34031193,
year = {2021},
author = {Hughes, TM and Hajjar, I},
title = {Is Late-onset Alzheimer Disease Spelled "ATV(N)"?.},
journal = {Neurology},
volume = {},
number = {},
pages = {},
doi = {10.1212/WNL.0000000000012259},
pmid = {34031193},
issn = {1526-632X},
}