bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease
Authors: Sadaghiani Shokufeh , Dolui Sudipto , Khandelwal Pulkit , Taghvaei Mohammad , Shakibajahromi Banafsheh , Das Sandhitsu R. , Yushkevich Paul A. , Wolk David A. , Detre John A.
Published: December 2022

Background

Brain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function.

Method

76 cognitively intact subjects age 65 ± 15 years were scanned using a hybrid 7T/3T protocol. CMIs were counted by visual inspection on T1‐weighted MP2RAGE (0.7mm3) and FLAIR (0.8mm3) scans obtained at 7T. T1‐weighted MPRAGE, FLAIR and 3D arterial spin labeling (ASL) data were also acquired at 3T and were used to calculate cortical thickness, WMH volume, and regional CBF. Spearman and Pearson bivariate tests were used for statistical analyses.

Result

185 CMIs were detected in 63 of 76 (83%) 7T scans (range:0‐8, 66% multiple CMIs). Age and sex were not significantly correlated with CMI number.

A significant positive Pearson correlation was seen between the number of CMIs and log‐transformed WMH volume (r(74)= 0.23, p=0.04) and a more significant negative correlation between the number of CMIs and PVWM CBF normalized to global CBF was also observed (r(74)= ‐0.37, p=0.003).

Significant negative correlations between CMI number and mean cortical thickness in Brodmann area 35 (BA35) (r(73)= ‐0.24, p=0.04) and parahippocampal cortex (r(73)= ‐0.26, p=0.03) was observed with nonsignificant trends in BA36 and entorhinal cortex.

Conclusion

Significant correlations between the CMI number and both relative PVWM CBF and WMH volume suggests a contribution of small vessel ischemic disease in the development of CMIs. The negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for CMIs and Alzheimer’s disease that may be mediated by cerebral amyloid angiopathy.
The Asian Cohort for Alzheimer’s Disease (ACAD) Pilot Study
Authors: Wang Li‐San , Ho Pei‐Chuan , Tee Boon Lead , Li Clara , Gu Yian , Yokoyama Jennifer S. , Vardarajan Badri N. , Reyes‐Dumeyer Dolly , Faber Kelley M. , Lee Wan‐Ping , Tzuang Marian , Choi Yun‐Beom , Feldman Howard H. , Henderson Victor , Hsiung Ging‐Yuek Robin , Mayeux Richard , Rosen Howard J. , Varma Rohit , Foroud Tatiana M. , Kukull Walter A. , Peavy Guerry M. , Lee Haeok , Yu W. Haung , Chui Helena C , Jun Gyungah R , Park Van Ta , Chow Tiffany W
Published: December 2022

Background

Asian Americans and Canadians (ASACs) are the fastest growing minority group in the US and Canada. ASACs are under‐sampled in Alzheimer’s disease (AD) research. Culturally appropriate, community‐based approaches to recruit these understudied communities are urgently needed, and in 2021 the Asian Cohort for Alzheimer’s Disease (ACAD) began recruitment to the first large dementia genetics cohort to examine genetic and non‐genetic risk factors for AD among ASACs. Our clinical and community‐based participatory research (CPBR) scientists have a long collaborative history and specific experience in leading AD and CBPR research.

Method

The ACAD pilot study has 8 recruiting sites (6 US and 2 Canadian), a coordinating site, and an analysis site. ACAD piloted a data collection packet (DCP) and pre‐screening/sample collection procedures. The Outreach workgroup translated the forms and an outreach campaign into Chinese (Mandarin and Cantonese), Vietnamese and Korean. Data Management created a central RedCap database. The Training workgroup developed a curriculum for the administration of the DCP and for culturally appropriate approaches to recruitment. We recruited in collaboration with community partners, clinics, and nursing homes that serve Asian communities.

Result

ACAD’s pilot study has consented 216 participants (142 Chinese, 20 Vietnamese and 54 Korean), and 126 (58%) have completed the DCP. The majority the consent (64.3%) were given by women. The age range of the sample is 60‐93 years. 60.3% have college or graduate level education. 101 of the 126 participants provided saliva (51) or blood (50) biosamples. Data entry is complete, with Consensus Diagnoses fully reviewed on 18 participants. Among 34 diagnosed participants, there are 19 healthy controls, 11 Subjective Cognitive Complaints, 3 Mild Cognitive Impairments, and 1 Probable or Possible AD case.

Conclusion

Lessons learned during the pilot phase of ACAD will provide guidance for future studies to explore risk factors for AD and related dementias. In collaboration with ongoing consortium efforts in Alzheimer’s Disease Genetics Consortium (ADGC), insights from ACAD may identify potential novel, population‐specific therapeutic pathways for AD. Our long‐term goal will be to expand ACAD to have a larger sample size and include other Asian American subgroups .
Amyloid and tau‐driven signatures in hippocampal GFAP‐positive astrocytes
Authors: Bellaver Bruna , De Bastiani Marco Antônio , Brum Wagner S. , Ferreira Pamela C.L. , Povala Guilherme , da Rocha Andreia Silva , Ferrari‐Souza João Pedro , de Souza Débora Guerini , Karikari Thomas K , Rosa‐Neto Pedro , Pascoal Tharick A , Zimmer Eduardo R
Published: December 2022

Background

Despite the known heterogeneity of astrocyte responses to injuries, Alzheimer’s disease (AD) pre‐clinical and clinical research relies on the glial fibrillary acidic protein (GFAP) as a proxy of astrocyte reactivity. Recently, it was demonstrated that plasma GFAP levels differentially relate to AD hallmarks, associating with amyloid‐β (Aβ), but not with tau pathology. However, the molecular underpinnings behind this specificity are still unexplored. Here, we aim to uncover the molecular signatures of GFAP‐positive astrocytes driven by either by Aβ or tau pathology.

Method

Hippocampal GFAP‐positive astrocytes data from 6 month‐old TauP301S (n = 5), 11.5 months‐old APP/PS2 (n = 5) and their wild‐type littermates (WT, n = 5) were acquired from GEO datasets (GSE129770;GSE129797) and used to identify differentially expressed genes (DEGs) and enriched biological processes. DEGs were evaluated using the DESeq2 method. Further data analysis included Gene Ontology (GO) functional evaluation.

Result

Principal component analysis clearly differentiated gene expression of GFAP‐positive astrocytes from APP/PS2, TauP301S and their WT controls (Fig.1A). Interestingly, only 30 DEGs overlapped among GFAP‐positive astrocytes from these two transgenic mouse models, revealing multiple DEGs specifically associated with Tau or Aβ (Fig.1B). The functional enrichment analysis revealed 36 GO terms enriched with DEGs altered in the PS2APP mice compared to WT. The most significantly enriched terms include processes such as “protein localization to cell periphery and plasma membrane”, “interleukin−6 production and regulation”, “exocytosis” and “neuron death” (Fig.1C). For the comparison of the TauP301S mice versus WT controls, the functional enrichment analysis using DEGs revealed 95 terms. Among the most significantly enriched terms, we found “learning”, “cognition”, and “small GTPase mediated signal transduction” (Fig.1C).

Conclusion

Overall, we observed a small overlap of DEGs between the Aβ and tau mouse models, indicating the unique nature of GFAP‐positive astrocytic responses to different aspects of AD pathology. The findings presented in this study allowed the identification of functional categories and biological processes particular to Aβ or tau burden. Characterizing how these upstream triggers influence GFAP‐positive astrocyte phenotypes may contribute to the biological interpretation of GFAP as a biomarker of AD pathology and pave the way to unravel novel mechanisms and context‐specific astrocyte biomarkers for AD.
Standardized preprocessed derivatives for the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) Study
Authors: Lussier Désirée , Clarke Natasha , Wang Hao‐Ting , Boré Arnaud , Tetrel Loic , Duchesne Simon , Devenyi Gabriel A. , Chakravarty M. Mallar , Descoteaux Maxime , Dixon Roger A. , Badhwar AmanPreet , Bellec Pierre
Published: December 2022

Background

The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) cohort of the pan‐Canadian Consortium on Neurodegeneration in Aging (CCNA) provides imaging on participants following a standardized protocol. This imaging contribution to deep phenotyping is done to study the full spectrum of age‐related dementias in more than 1,100 individuals (50‐90y) with subjective or mild cognitive impairment, Alzheimer’s disease, other dementias, or otherwise cognitively unimpaired. To accelerate discovery, we propose to release biomarkers extracted from these acquisitions. Here we present preliminary (N=385, AD=39) preprocessing methods, quality control, and available derivatives of the resting‐state functional (rsfMRI), diffusion weighted (DWI), and structural magnetic resonance images.

Method

fMRI data was preprocessed using fMRIprep v20.2.1. Sørensen–Dice similarity measure was computed between individual masks and group templates using our internal BIDS app. Functional connectome of 101 regions from Dictionary of Functional Modes (DiFuMo) 64 dimension atlas were calculated with confounds removed. Mean network connectivity for the Yeo7 networks was summarized from connectomes. DWI data underwent robust quality control and preprocessing using Tractoflow. Bundle extraction and mean metric computation was done using freewater_flow, rbx_flow and tractometry_flow. Structural scans were preprocessed and segmented using iterativeN3 and MAGeT‐brain to obtain subcortical and cerebellar volumes. As a validation, a subset of variables associated with aging in the literature was tested for association with participant age using simple correlation.

Result

The functional Dice score was 0.915 (SD=0.017, N=390) and structural was 0.988 (SD=0.004, N=381). Age was significantly associated with mean DMN connectivity (r=‐0.226, p<0.001), bilateral inferior fronto‐occipital fasciculus freewater (r=0.533, p<0.001), and bilateral thalamus volume (r=‐0.243, p<0.001).

Conclusion

Derivatives obtained include: functional connectomes using DiFuMo64, network connectivity from Yeo7, DWI measures for major fiber tracts, and segmented subcortical and cerebellar volumes. The results of the quality and validity checks indicate the derivatives would be useful for the study of age‐related dementias. Full quality control and release of the complete COMPASS‐ND preprocessed imaging dataset and derivatives should be completed in 2022. For information on access see ccna‐ccnv.ca.
Apolipoprotein E moderates the association between Non‐APOE Polygenic Risk Score for Alzheimer’s Disease and Aging on Preclinical Cognitive Function
Authors: Xu Yuexuan , Vasiljevic Eva , Deming Yuetiva , Jonaitis Erin M. , Koscik Rebecca Langhough , Lu Qiongshi , Johnson Sterling C. , Engelman Corinne D
Published: December 2022

Background

Apolipoprotein E4 (APOE‐ε4) is the strongest known risk factor for late‐onset Alzheimer’s disease (LOAD). Variation in cognitive decline patterns among cognitively unimpaired individuals suggests that additional LOAD‐related genetic factors may interact with APOE‐ε4 to influence cognitive decline during asymptomatic aging. In the present study, we aim to investigate whether any genome‐wide association studies (GWAS) and p‐value threshold (pT)‐informed non‐APOE polygenic risk scores (PRS) moderate associations between APOE‐ε4 and longitudinal cognition.

Methods

We leveraged 12 years of longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention, and we built eight PRSs under various pTs for single nucleotide polymorphism selection using summary statistics from three GWAS meta‐analyses: International Genomics of Alzheimer’s Project (IGAP) case‐control study, UK‐biobank (UKBB) AD‐by‐proxy study, and a combined sample that merges IGAP and UKBB study results. All association analyses were fitted using a linear mixed effects model and adjusted for within‐individual/family correlation among 1,190 cognitively unimpaired individuals at baseline (Table 1). A set of sensitivity analyses were performed to assess the robustness of the main findings.

Results

We found that the adverse effect of non‐APOE PRS on overall and memory‐related cognitive domains is more evident among APOE‐ε4 carriers as people age (Figure 1). There is a gradual, statistically significant difference in the rate of overall and memory‐related cognitive decline per unit change of non‐APOE PRSs between APOE‐ε4 carriers and non‐carriers for people over the age of 70 (Figure 2). Our study findings are consistent with a relatively stringent pT (p <= 5e‐8) and more evident when the PRSs are constructed using the case‐control GWAS study results, despite the smaller sample size (“Kunkle significant variants only” in Figures 1 and 2). Our findings are also robust to various sensitivity checks when we replace the dichotomous APOE‐ε4 predictor with the APOE genotype, use different PRS clumping parameters, and exclude cognitive measurements from the last test occasion, which has a smaller sample size.

Conclusion

We recommend considering the interaction between non‐APOE PRS, APOE status, and age in modeling pre‐clinical cognitive phenotypes for LOAD. We also recommend leveraging a conservative p‐value threshold and using case‐control GWAS results in constructing the LOAD PRS.
Healthcare Resource Utilization Among Veterans with Alzheimer’s Disease
Authors: Aguilar Byron J. , Li Mingfei , Wang Ying , Morin Peter , Berlowitz Dan , Monfared Amir Abbas Tahami , Zhang Quanwu , Xia Weiming
Published: December 2022

Background

We evaluated healthcare utilization patterns to understand the care pathways for Veterans with Alzheimer’s disease (AD) from the Department of Veterans Affairs (VA) healthcare system.

Method

VA electronic health records (EHR) were used to extract data from clinical notes and identify patients with AD. The patient cohort was merged with the VA Informatics and Computing Infrastructure (VINCI) administrative database from October 2008–to October 2021 to obtain systematic healthcare utilization records including total inpatient admissions and outpatient visits. A control group was extracted for comparison and matched to the patient cohort using the propensity score on age, sex, and race. A linear mixed‐effects model was used to compare the total outpatient and inpatient utilization, adjusting for patient demographics and comorbidities.

Result

We extracted 21,442 AD patients from the EHR clinical notes. A cohort of 85,684 non‐AD and non‐dementia Veterans was constructed as a control group. In the AD vs control groups, the mean age was 82 vs 79 years, 83 vs 84% was White, and 97% were male in both groups. The number of annual outpatient visits 1 year before, and at 1 and 2 years after the first AD diagnosis code was 30, 34 and 27, respectively. The control group maintained 12 annual outpatient visits throughout the three‐year period. The average annual hospital admission rate was 1.8 vs 1.7 in the AD vs control group. The average length of inpatient stay in the year prior to the first AD diagnostic code was 23.1 days, increased to 27.4 days at year 1 after AD diagnosis, and declined back to 20.5 days at year 2, as compared to 13.1, 13.0, and 11.9 days, respectively, in the control group. The mixed‐effects analysis showed significantly higher healthcare utilization trends across VA outpatient and inpatient care settings (p<0.001) in the AD vs control groups, after controlling for age, gender, race, ethnicity, and select comorbidities.

Conclusion

Healthcare resource utilization in patients with AD identified from the medical notes is more than doubled that in outpatient care and nearly doubled in inpatient length of stay relative to the matched controls in the VA healthcare system.
Identification of Novel Modifiers of Tau Aggregation and Pathology using a Proximity Proteomics Approach
Authors: Lee Jannifer H , Morderer Dmytro , Khalil Bilal , Liu Feilin , Tsai Chih‐Wei , Croft Cara L , Carlomagno Yari , DeTure Michael , Salemi Michelle , Cook Casey , Phinney Brett , Dickson Dennis W. , Golde Todd E , Petrucelli Leonard , Rossoll Wilfried
Published: December 2022

Background

Alzheimer's disease (AD) and related neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates. A defining hallmark of AD is the formation of neurofibrillary tangles (NFTs) by aggregation of the microtubule‐associated protein tau into pathological oligomers and fibrils. Although NFTs are believed to play a pivotal role in the disease process, we have a poor understanding of how their formation, toxicity, and spread across brain regions is regulated. Recent data suggest that the seeding behavior of tau is governed by patterns of posttranslational modifications and varying filament structures. Understanding how tau‐associated proteins regulate the oligomerization, pathological accumulation, and seeding of tau in affected neurons and glia is of critical importance for therapy development.

Method

To profile the interactome of tau aggregates, we have established proximity‐dependent biotin‐identification (BioID) as a novel method to identify the composition and proximal molecular environment of insoluble protein aggregates in the context of living brain cells and tissue. Using an in vitro and ex vivo model approach coupled with mass spectrometry, we are generating datasets containing top identified proteins, stratified based on significance and molecular pathway. Once we validate their co‐localization with NFTs in the context of human AD pathology, functional characterization of putative modifiers will be performed to assess their impact on tau‐aggregate and toxicity.

Result

To determine the physiological and aggregate specific interacting partners of tau, we are comparing wild type tau (TauWT) with mutant tau (Tau3xMUT) carrying three tauopathy‐associated mutations (A152T/P301L/S320F) that form hyper‐phosphorylated and thioflavin S‐positive aggregates even in the absence of seeding. The proteomic analysis from our pilot study revealed that significantly changed proteins included candidates involved in RNA processing, as well as protein ubiquitination and proteasome degradation.

Conclusion

This study provides novel insights into cellular pathways and molecular mechanisms of neurodegeneration, by identifying in the context of living neurons and brain tissue different functional classes of tau‐associated proteins with relevance for AD pathophysiology. These are expected to include proteins that may mediate the toxic effect of NFTs, facilitate the formation or degradation of pathological tau aggregates, and catalyze posttranslational modifications of tau oligomers and associated proteins.
A Cross‐sectional HABS‐HD study of Plasma Biomarkers of Cognitive Decline across Diagnoses in a Diverse Community Cohort
Authors: Hall James , Petersen Melissa , Johnson Leigh , O'Bryant Sid E.
Published: December 2022

Background

Due to their low cost, less invasive nature and ready availability, plasma biomarkers of Alzheimer’s disease have been proposed as one time screening tools for clinical trials and research. The impact of ethnoracial factors on these biomarkers has received little attention. The current study investigated the levels of Aβ40, Aβ42, total tau and NfL across diagnoses for each of the three major ethnoracial groups in the US in a community based cohort of older adults.

Method

1862 participants (852 Mexican Americans (MA); 775 Non‐Hispanic Whites (NHW) and 235 African Americans (AA)) drawn from The Health & Aging Brain Study – Health Disparities (HABS‐HD) study were included. Diagnoses were assigned using an algorithm (decision tree) verified by consensus review. Plasma samples were assayed using Simoa technology. Data were analyzed using ANOVA comparing the level of each biomarker across the cognitive diagnoses (Normal Cognition (NC), MCI & Dementia) within each ethnoracial group co‐varying age and sex.

Result

For NHW there were no significant differences between NC, MCI and Dementia groups in levels of Aβ40 or Aβ42. For t tau, MCI t tau was significantly higher than NC. The t tau level did not differ between the two cognitively impaired groups. There was a significant effect for diagnosis for NfL with the MCI NfL and the Dementia NfL level being significantly higher than the NC NfL level. The impaired groups did not differ in NfL between the impaired groups. For the MA significant differences across diagnoses were found only for NfL. The Dementia NfL level was significantly higher than the NC and significantly higher than the MCI. The only biomarker showing significant differences across diagnoses for AA was NfL. The Dementia NfL level was significantly higher than the NC and MCI levels.

Conclusion

Although cross‐sectional, the results suggest different patterns of plasma biomarkers across diagnoses for NHW as compared to MA and AA. NfL levels were highest in the Dementia group for all. Ongoing longitudinal research will show how biomarkers change as cognition declines.
ABCA7‐reducing mutation carriers have reduced CSF amyloid biomarker levels, suggestive of increased amyloid deposition
Authors: Duchateau Lena , Bjerke Maria , Timmers Maarten , Engelborghs Sebastiaan , Sleegers Kristel
Published: December 2022

Background

The Alzheimer’s disease (AD) risk gene ABCA7 has suggested functions in lipid metabolism and the immune system. Rare premature termination codon (PTC) mutations and an expansion of a variable number of tandem repeats (VNTR) polymorphism in the gene, both likely cause a lower ABCA7 expression and hereby increased risk for AD. However, the exact mechanism‐of‐action remains unclear. By studying CSF biomarkers reflecting different types of AD‐related pathological processes, we aim to get a better insight in those processes and establish a biomarker profile of mutation carriers.

Method

The study population consisted of 228 AD patients (27 PTC mutation and 16 pathogenic expansion carriers) for whom CSF was available and ABCA7 sequencing and VNTR genotyping had been performed. CSF levels of amyloid β (Aβ) 40 and 42, sAPP‐α and ‐β, YKL‐40 and hFABP were determined using ELISA and Meso Scale Discovery assays. We compared differences in levels of these biomarkers AD patients with or without an ABCA7 PTC mutation or expansion, and further stratified on APOE e4 status.

Result

Carriers of ABCA7 mutations/expansions had significantly lower Aβ42 levels (p= 0.0031) and amyloid ratio (p=0.020) compared to non‐carrier patients, and were threefold more likely to have abnormal Aβ42 values. The effect on amyloid biomarkers remained significant when considering PTC mutations or VNTR expansions separately. APOE e4 carriers had significantly lower Aβ42 (p=0.0013) and amyloid ratio (p<0.001) compared to non‐APOE e4 carriers. When combined, both APOE e4 allele and ABCA7 carrier status influenced amyloid ratio and Aβ42 levels. Remarkably, within non‐APOE e4 carriers, ABCA7 mutation/expansion carriers did have significantly reduced Aβ42 levels (mean=540 pg/mL) compared to ABCA7 non‐carriers (812 pg/mL; p=0.0051), attaining lower levels as e4 carriers (612 pg/mL). Finally, in carriers of the pathogenic expansion we observed lower YKL40 levels (p=0.011), suggesting reduced neuroinflammation.

Conclusion

Our results highlight that carriers of ABCA7 PTC mutations and repeat expansions show more pronounced abnormalities in CSF amyloid beta markers than non‐carrier patients, especially in non‐APOE e4 carriers. Expansion carriers also had a decrease in neuroinflammation marker YKL40. Our results suggest that reduced ABCA7 expression leads to increase in amyloid pathology and potentially a reduced inflammatory response to damage.
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

Background

Recent 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.

Method

We 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.

Result

Voxel‐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).

Conclusion

Our 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

Background

Alzheimer’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.

Method

Here 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.

Result

Our 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.

Conclusion

Key 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

Background

Polyunsaturated 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.

Methods

We 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).

Results

Both 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).

Conclusion

Using 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

Background

The 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).

Method

As 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.

Result

When 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.

Conclusion

While 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

Background

Positive 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’.

Method

We 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.

Result

This 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.

Conclusion

These 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

Background

The 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).

Method

A 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 sessions

Result

Until 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.

Conclusion

The 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

Background

Autopsy 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).

Method

99 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.

Result

Older 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).

Conclusion

Plasma 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

Background

Vascular 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.

Method

C57BL6 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.

Result

Studies 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.

Conclusion

Our 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

Background

Despite 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.

Method

We 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.

Result

Implementation 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.

Conclusion

A 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

Background

Alzheimer’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.

Method

Using 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.

Result

Older 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.

Conclusion

Although 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.