bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apolipoprotein E ε4 associates with microglial activation in early Braak regions independently of amyloid‐β and tau
Authors: Ferrari‐Souza João Pedro , Lussier Firoza Z , Tissot Cécile , Leffa Douglas Teixeira , Ferreira Pamela C.L. , Bellaver Bruna , Brum Wagner S. , Benedet Andréa Lessa , Therriault Joseph , Wang Yi‐Ting , Chamoun Mira , Servaes Stijn , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Rahmouni Nesrine , Pallen Vanessa , Poltronetti Nina Margherita , Souza Diogo O. , Gauthier Serge , Zimmer Eduardo R , Rosa‐Neto Pedro , Pascoal Tharick A 
Published: December 2022

AbstractBackgroundRecent evidence suggests that microglial activation sets the stage for tau spread in Alzheimer’s disease (AD). However, the underpinnings of microglial activation in early regions of tau accumulation are poorly understood. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for sporadic AD and influences microglial response in animal models of AD. Here, we tested the hypothesis that APOE ε4 carriership is associated with microglial activation in early Braak regions independently of amyloid‐β (Aβ) and tau pathologies.MethodWe assessed 118 participants [79 cognitively unimpaired (CU), 23 with mild cognitive impairment (MCI), and 16 with AD dementia] with 50 years of age or older from the McGill TRIAD cohort. Individuals had available positron emission tomography (PET) for Aβ ([18F]AZD4694), tau tangles ([18F]MK6240), and microglial activation ([11C]PBR28), as well as magnetic resonance imaging (MRI) and APOE genotyping. Braak I (transentorhinal) and Braak II (entorhinal and hippocampus) were defined as early regions of tau tangles accumulation.ResultVoxel‐wise analysis revealed that APOE ε4 carriership was associated with microglial activation mainly in regions corresponding to early Braak stages (e.g., transentorhinal, entorhinal, and hippocampus; Figure 1). In these regions, we observed that APOE ε4 carriership was associated with microglial activation independently of Aβ and tau pathologies (Braak I: β = 0.087, P < 0.001; Braak II: β = 0.053, P = 0.026; Table 1). Furthermore, structural equation modeling demonstrated that microglial activation mediated the Aβ‐independent effect of APOE ε4 carriership on tau accumulation in regions corresponding to Braak I‐II (mediation effect size = 34.1%; Figure 2).ConclusionOur results suggest a deleterious effect of APOE ε4 carriership on AD progression by contributing to microglial activation in regions of early tau accumulation (transentorhinal, entorhinal, and hippocampus). These findings can help to understand the influence of the APOE ε4 allele on AD pathogenesis, as well as provide insights for the development of drugs targeting the interplay between APOE ε4 and microglial activation.
Mapping entorhinal cortex circuitry in mouse models of Alzheimer’s Disease
Authors: Macchia Desiree , Beier Kevin 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is one of the most common neurodegenerative diseases worldwide that comes with significant personal and economic burdens. Unfortunately, the brain circuitry underlying AD pathophysiology is yet to be fully understood. Elucidating the circuits that change before the onset of cognitive deficits would help to identify neuronal populations that change early in disease progression. After the identification of these brain regions and cell types, they can be selectively targeted to reverse both the anatomical pathology and eventual behavioral decline.MethodHere we used a novel viral‐genetic method, rabies virus (RABV) tracing, which maps the inputs of targeted starter cell populations. We utilized this method in two mouse models of AD to measure circuit changes in the entorhinal cortex, which is one of the earliest brain regions to degenerate in Alzheimer’s. We implemented RABV mapping at three different time points, using aging as a key measure of comparison between circuit states. In using RABV tracing throughout disease progression, we were able to capture how these circuits look before any overt behavioral or histopathological deficits, as well as at a more advanced stage of the disease when both cognitive and pathological deficits are present.ResultOur preliminary results have identified key cells and circuits that are disrupted related to AD pathogenesis as targets to slow or prevent the development of the disease.ConclusionKey cells and circuits change early on in AD pathogenesis elucidated by rabies virus tracing.
Monitoring DHA and AA Brain Uptake in ApoE4 Mice with 18F‐Fluorinated PET Tracers
Authors: Duro Marlon Vincent V. , Van Valkenburgh Juno S. , Kerman Bilal E. , Wang Shaowei , Liu Xiaodan , Sta Naomi , Zanderigo Francesca , Jacobs Russell E. , Chen Kai , Yassine Hussein N. 
Published: December 2022

AbstractBackgroundPolyunsaturated fatty acids (PUFAs) are the precursors of various lipid mediators of inflammation. Brain imaging techniques for monitoring the brain’s uptake of PUFAs would not only uncover the effects of risk factors for excessive neuroinflammation associated with Alzheimer’s disease (AD) and related dementia but also direct the development of methods to prevent or treat AD. Radiosynthesized 11C‐docosahexaenoic acid (DHA) and 11C‐arachidonic acid (AA) have already been utilized in positron emission tomography (PET) studies in humans [1, 2]. Because 18F has a longer half‐life than 11C, fluorinated PUFA derivatives would be more favorable alternatives for PET studies of brain uptake.MethodsWe prepared 18F‐fluorinated analogues of DHA (18F‐FDHA) and AA (18F‐FAA) as PUFA PET tracers. Radiosynthesis was performed via a nucleophilic fluorination scheme using the tosylate ester derivatives as precursors. We then performed bolus injection of each tracer into 16‐month‐old APOE4 knock‐in mice and scanned them by dynamic PET‐MRI over 45 min to assess region‐specific uptake. PUFA uptake kinetics in the cerebral region was evaluated using the time‐dependent activity in the lumen of the right ventricle as the image‐derived input function and using an irreversible two‐tissue compartment model to calculate the incorporation coefficient (Ki).ResultsBoth 18F‐FDHA and 18F‐FAA were successfully synthesized in high radiochemical purity (≥98%) and were found to be stable in the formulation and mouse serum for 2 hr. The mean Ki values for the cerebral region were determined to be 6.31 ± 0.98 µL mL‐1 min‐1 for 18F‐FDHA (n = 4) and 6.75 ± 0.68 µL mL‐1 min‐1 for 18F‐FAA (n = 5).ConclusionUsing an image‐based method with 18F‐fluorinated PUFA tracers, we were able to determine Ki values for both AA and DHA. The use of these PUFA PET tracers has the potential to elucidate deleterious changes in PUFA metabolism during various phases of AD as well as effects due to dietary interventions and drug treatment.
References
1. Yassine, H.N. et al. (2017). DHA brain uptake and APOE4 status: a PET study with [1‐11C]‐DHA. Alzheimers Res Ther 9, 23.2. Zanderigo, F. et al. (2018). [11C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use. Synapse 72.
Alterations to gut microbiota in mice lacking C5aR1 in Alzheimer’s mouse model do not account for protective effects in disease progression.
Authors: Petrisko Tiffany J , Chu Shu‐Hui , Selvan Purnika , Tenner Andrea J 
Published: December 2022

AbstractBackgroundThe complement (C’) system contributes to enhanced inflammation and cognitive decline in Alzheimer’s disease (AD). Previous studies demonstrated that genetic ablation of downstream receptor C5aR1 provides protection from cognitive decline in AD animal models. C’ activation and associated cell‐signaling may influence the composition of the gut microbiome, modulating systemic inflammation, and ultimately inducing behavioral and cognitive changes. The objective of this study was to determine if deletion of C5aR1 (C5aR1KO) alters the fecal microbiome in the Arctic (Arc) model of AD which could contribute to the previously observed protection from cognitive decline (Hernandez et al., 2017).MethodAs the coprophagic nature of mice results in microbiome synchronization between cohoused mice, we sought to determine the impact on the microbiome when WT/Arc C5aR1KO and WT/Arc C5aR1‐sufficient (C5aR1+/+) animals were housed separately or together. Fecal samples were collected at 10 mo and subjected to microbial focused Illumina sequencing. Taxonomy was assigned using RDP18 followed by downstream analysis in R.ResultWhen housed separately, WT C5aR1KO animals had a significantly reduced alpha‐diversity (ie. reduced number of species within their microbiome) compared to WT C5aR1+/+ mice, with a trending decrease observed in Arc C5aR1KO mice compared to Arc controls. Beta‐diversity indicated significant variation in species between the genotypes. Further analysis revealed alterations in the serotonin modulating bacteria. C5aR1+/+ mice had increased levels of Alistipes (serotonin‐increasing) compared to both WT and Arc C5aR1KO mice, while WT C5aR1KO had elevated levels of Turicibacter (serotonin‐decreasing) compared to WT and Arc C5aR1+/+ animals. In contrast, when cohoused, no difference in alpha‐ or beta‐ diversity, nor Alistipes and Turicibacter were observed.ConclusionWhile deletion of C5aR1 can influence the fecal microbiome these effects are overcome when C5aR1KO and C5aR1+/+ mice are cohoused. In previous studies, Arc mice displayed cognitive impairment compared to WT cagemates, which was rescued by C5aR1 ablation. As there was no difference in the microbiome of co‐housed WT/Arc C5aR1+/+ animals, we can conclude that the cognitive improvement resulting from ablation of C5aR1 was unlikely to have resulted from differences in the microbiome. Further, our studies highlight the importance of cohousing mice to fully eliminate microbiome from CNS causal effects.
Intergenerational interventions during Covid‐19: impact on children’s drawings of the elderly and dementia
Authors: Bormans Kasper , Zwakhalen Sandra 
Published: December 2022

AbstractBackgroundPositive qualities of children can be used to lighten the burden of dementia for society. Almost every child knows a person with dementia. The primary objective of this study is to connect generations and increase positive interaction by translating the ‘hidden victims of the disease’ into ‘hidden resources’.MethodWe developed a mobile application (‘MemoryHome’) based on the ancient mnemonic ‘the method of loci’ (MoL). The application allows children (n = 31) to construct personalized memory walks throughout the known environment of grandparents and dementia patients. The visual‐audio‐guide encourages communication between the elder person and the child. The youngsters made drawings of elderly people before and after the combination of meetings with grandparents and an educational trajectory regarding positive ageing of 12 weeks. The current study took place in autumn 2021.ResultThis study supports research indicating that perceptions of the elderly are malleable and open to change. The predicted a positive shift in the way children view old age after interaction. Findings however showed that older people in the post‐test were portrayed more negatively: significantly smaller, more sedentary and in the absence of positive symbols.ConclusionThese findings may suggest that the context of the pandemic further embedded negative stereotypical notions of the elderly. Positive interventions are a crucial and urgent antidote to reshape children’s attitudes towards ageing.
LatAm FINGERS: Overcoming Barriers for a Dementia Prevention Trial Startup
Authors: Calandri Ismael Luis , Crivelli Lucia , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Ortiz Ana Luisa Sosa , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Velilla Lina M , Yassuda Monica Sanches , Sevlever Gustavo , Allegri Ricardo Francisco ,   LatAm FINGERS initiative
Published: December 2022

AbstractBackgroundThe LatAm‐FINGERS initiative is a non‐pharmacological intervention trial to prevent cognitive impairment in 12 Latin American countries. Our aim is to describe the challenges faced when launching a multi‐country trial and the strategies used to tackle them. The principal challenges included: 1) Training personnel from the different teams in trial procedures, 2) Assessing the training results, and 3) To provide support regarding the trial set‐up on the different sites. Another barrier is that centers are separated in distance and time zones and languages (Spanish, Portuguese, and English).MethodA set of technological solutions were selected to face the challenges due to COVID‐19 restrictions. a) Specialists provided online training for the different interventions, the training sessions were recorded, and subtitles in the alternate language were provided. b) Training was assessed using a web‐based campus with questionnaires and certifications. c) Support was provided through two ad‐hoc designed platforms. We created a WhatsApp Chatbot to assist investigators 24/7, automatically answering questions, sending resources, and reporting difficulties. The Chatbot also includes a database system to register adverse events reports, and report them to the clinical core. Finally, a LatAm FINGERS Consulting Room was built to provide weekly online sessionsResultUntil now, 16 in‐vivo online sessions were provided to 203 trainees, 15 multilingual videos summarizing essential aspects of intervention, and six tutorials solving the most common problems were uploaded in the web‐based campus with multiple language subtitles. A total of 93 participants received complete certification for the trial. Nine Consulting Room meetings have been carried out, and more than 30 conflicts have been solved. Chatbot has answered a mean of 12 daily questions since its implementation.ConclusionThe LatAm Fingers team was able to launch in December 2021, overcoming the challenges and barriers generated by the COVID‐19 pandemic. Results show how feasibility can be achieved for a study encompassing a vast territory of low‐income countries with diverse ethnic backgrounds in pandemic times. The set of innovative tools implemented could work as inspiration to other trials and collaborate to make the research in the region feasible.
Plasma ptau231 predicts locus coeruleus integrity earlier in life than other Alzheimer’s disease plasma markers: a 7T MRI study across the adult lifespan
Authors: Jacobs Heidi I.L. , Riphagen Joost M. , Ashton Nicholas J. , Janelidze Shorena , Sperling Reisa A. , Johnson Keith A. , Yang Hyun‐Sik , Blennow Kaj , Hansson Oskar , Zetterberg Henrik , Van Egroo Maxime 
Published: December 2022

AbstractBackgroundAutopsy studies indicated that the locus coeruleus (LC) is one of the first regions to accumulate pretangle material, and imaging work demonstrated that the LC MRI‐signal correlates with entorhinal tau in cognitively normal individuals. Recently developed phosphor‐tau (ptau) blood‐based biomarkers correlated well with cortical tau‐PET and have been suggested as early markers of aberrant tau phosphorylation. Here we evaluated the relationship between LC‐MRI signal intensity and plasma markers of tau (ptau231, ptau217, ptau181), neurodegenerative processes (total tau (t‐tau), neurofilament light (NfL)) and amyloidosis (Aβ42/40).Method99 cognitively normal individuals across the lifespan (30‐85 years, n=52 female) underwent dedicated 7T LC‐imaging and fasting blood draw. A sample‐specific template for the LC was generated and transformed into a surface. All plasma markers were quantified in duplicate using Single molecule array methods (Simoa, Quanterix) or Meso‐Scale Discovery. Voxel‐wise robust regressions associated LC intensity values with plasma markers, adjusted for age and sex (or Aβ42/40). Interactions between Aβ42/40 and ptau, t‐tau or NfL were also tested. Multiple comparisons were corrected using Threshold‐Free‐Cluster‐Enhancement (p<0.001). Bootstrapped sliding window analyses determined the age‐window of significant plasma marker–LC intensity associations.ResultOlder age was associated with higher ptau181, NfL and lower Aβ42/40 (Figure 1). Higher ptau231 was associated with lower LC intensity in bilateral dorso‐rostral clusters. Ptau181, ptau217 and t‐tau correlated negatively with LC intensity in right dorso‐rostral clusters. Small clusters of negative associations between LC intensity and NfL were distributed across the length of the LC. LC intensity was not associated with Aβ42/40 (Figure 2). Adjusting for Aβ42/40 did not change these results. We did not find interactions between Aβ42/40 and ptau, t‐tau or NfL. The association between LC intensity and ptau231 became significant from age 55.5 years, and for ptau181 and ptau217 from age 60 years (Figure 3).ConclusionPlasma ptau231 showed robust and earlier relationships with LC intensity compared to ptau217 or ptau181 in asymptomatic individuals across the lifespan. Given that tau phosphorylation at threonine 231 is one of the earliest events in the phosphorylation cascade hindering tubulin assembly, these findings suggest that LC intensity may reflect processes related to early tau aggregation.
Elucidating the role of MMP9 in hyperhomocysteinemia induced degradation of the neurovascular unit
Authors: Gearon Mary D , Early Alexandria N , Weekman Erica M , Lee Tiffany , Wilcock Donna M 
Published: December 2022

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) is one of the leading causes of dementia. Hyperhomocysteinemia has been identified as a risk factor for VCID though the mechanism behind this connection has yet to be determined. Hyperhomocysteinemia increases inflammation inducing the upregulation of matrix metalloproteinase 9 (MMP9) activity. MMP9 has been shown to degrade several substrates along the neurovascular unit including claudin 5, collagen 4, occludin and β‐dystroglycan. I hypothesize that increased MMP9 activity following the induction of hyperhomocysteinemia leads to the cleavage of important anchoring proteins along the neurovascular unit weakening the integrity of the blood brain barrier which contributes to the progression of VCID pathology.MethodC57BL6 WT and MMP9 knockout mice were placed on a control diet or a diet deficient in vitamins B6, B12 and folate and enriched in methionine to induce hyperhomocysteinemia for 4, 8, 12 and 16 weeks. Western blot analysis was performed to investigate the substrates of MMP9 including claudin, occludin, and β‐dystroglycan.ResultStudies are underway to examine if MMP9 activation contributes to blood brain barrier dysfunction directly by degrading tight junction proteins leading to a weakened endothelial cell barrier and/or indirectly by cleaving proteins responsible for maintaining the connection between astrocytic end feet and the endothelial basement membrane.ConclusionOur findings suggest that increased levels of MMP9 activity may impact several aspects of the neurovascular unit to contribute to VCID pathology. Further investigations focused on inhibition of MMP9 activation could provide the field with an important target for mitigating progression of this disease.
Developing a universal phenotyping algorithm to identify patients with clinically diagnosed and probable Alzheimer’s disease using electronic health record data
Authors: Thakkar Rut , Liu Ge , Zhao Juan , Ong Henry H. , Li Bingshan , Wen Zhexing , Wei Wei‐Qi 
Published: December 2022

AbstractBackgroundDespite significant advancements in our understanding of Alzheimer’s disease (AD) over the last decade, no disease‐modifying treatments exist for it. Rich clinical information on patients with AD is currently available in electronic health records (EHR) worldwide. Our aim is to develop a portable phenotyping algorithm to mine EHRs and identify patients with clinical and probable preclinical AD. Identified patients can subsequently be used as cohorts in future biomedical research studies.MethodWe developed an algorithm using the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). This enables other institutes using this standardized EHR data representation to avail the algorithm with minimum effort for local implementation. The algorithm’s backbone is based on ubiquitous information readily derived from EHRs such as ICD‐10 billing codes, medication history, cognitive test scores (Mini‐Mental State Exam), imaging reports and lab results. The model classifies identified patients into three categories based on high (category 1), intermediate (category 2) and low (category 3) probability with AD. The algorithm was applied to a deidentified EHR database at the Vanderbilt University Medical Center (VUMC) with clinical information from over 3 million individuals. We performed an manual chart review on 100 randomly selected samples of each category’s AD cases to assess its predictive value.ResultImplementation of the phenotyping algorithm yielded 274,000 patients with probable Alzheimer’s disease. 4169 patients were identified based on category 1 criteria, 13270 patients were identified using category 2 and 256,302 patients were identified in category 3. Independent chart review resulted in a PPV of 94% for category 1, 86% for category 2 and 8% for category 3 patients. Majority of false positive cases occurred because of mild cognitive impairment (MCI) patients in category 3 who were selected through broad billing codes and medication history.ConclusionA portable phenotyping algorithm can help identify large cohorts of patients with diagnosed and probable Alzheimer’s disease for research use by mining EHRs. Based on preliminary results, our algorithm is a promising attempt to achieve this goal. We aim to improve on it till it selects AD patients with an even higher predictive value (>95%).
Health and minority stress in explaining change in executive function: Results from the Canadian Longitudinal Study on Aging (CLSA)
Authors: Stinchcombe Arne , Hammond Nicole G , Hopper Shawna 
Published: December 2022

AbstractBackgroundAlzheimer’s disease is characterized by deficits in multiple cognitive domains, one being executive function (e.g., planning, inhibition, decision making). Maintaining executive functions is important for autonomy and independence in daily living. Minority stress is linked to cross‐sectional differences in executive function, but less is known about the potential role of minority stress in changes in executive functioning over time.MethodUsing data from the Canadian Longitudinal Study on Aging (CLSA), a large cohort of mid‐aged and older adults, we examined changes in executive function over a 3‐year period. Specifically, we focused on the role of health (e.g., medical conditions, modifiable health behaviors) and minority stress factors (sexual orientation, gender identity, race, and perceived social standing) in explaining these changes. Demographic, health, and minority stress variables were collected at baseline. The Mental Alteration Test (MAT), a cognitive switching task, was administered to measure executive function at baseline (2011‐2015) and follow‐up (2015‐2018). Using the MAT, we computed a reliable change index, accounting for practice effects and variability in scores at follow‐up. Negative scores reflect a more reliable decline in executive function. We used multivariable linear regression and the analytic sample was n = 27,714.ResultOlder age, higher household income, and greater educational attainment predicted reliable declines in executive function. There were no sex differences. Surprisingly, there were also no health factors (e.g., depression symptoms, physical activity levels) or minority stress variables (sexual orientation, gender identity, race, and perceived social standing) that predicted change in executive function.ConclusionAlthough previous cross‐sectional research has established that older minoritized individuals tend to have lower cognitive performance compared to majority peers, minoritized identities do not appear to explain changes in executive function over a short follow‐up period. Additional longitudinal data is needed to understand better the long‐term impact of minority stress on cognitive aging.