bluuebunny/crossref_metadata_2025_split huggingface dataset:
The moderating effect of APOE E4 on the association of plasma biomarkers with markers of cognition and brain health in Alzheimer’s disease
Authors: Sanchez Erlan , Wilkinson Tim , Coughlan Gillian T , Baril Andree‐Ann , Binns Malcolm , Bartha Robert , Symons Sean , Hegele Robert , McLaughlin Paula , Kwan Donna , Black Sandra E. , Freedman Morris , Kvartsberg Hlin , Zetterberg Henrik , Munoz Douglas , Masellis Mario 
Published: December 2023

AbstractBackgroundDue to low success rates in clinical trials for Alzheimer’s disease (AD), there is a need to apply precision medicine approaches, such as stratifying based on APOE genotype, in order to assess its effects on outcome measures. Herein, we aim to better understand how plasma biomarkers of AD and neurodegenerative pathology are associated with cognition and neurodegeneration in APOE E4 carriers compared to non‐carriers.MethodPatients from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) diagnosed with AD were included (n = 126, age = 71.0±8.2, 55%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using Simoa assays. Composite cognitive domain scores (attention & working memory, executive function, language, memory, and visuospatial function) were computed from a comprehensive neuropsychological assessment. Volumes of regional grey matter, ventricular cerebrospinal fluid, white matter hyperintensities, perivascular spaces, lacunes and strokes were extracted from 3T structural MRI sequences using the SABRE pipeline. Linear regression models with an interaction term, controlling for age, sex and education were used to test the moderating effect of the APOE E4 allele on the association of plasma biomarkers with cognitive and MRI variables. When interaction effects were significant, post‐hoc models stratified by APOE E4 carrier status and controlling for age, sex and education were assessed.ResultThe APOE E4 allele moderated the association of GFAP, NfL and p‐tau181 with memory. Further stratification revealed that higher levels of GFAP, NfL and p‐tau181 were all associated with worse memory only in APOE E4 carriers. APOE E4 was also found to moderate the association of GFAP and p‐tau181 with many imaging markers. Further stratification revealed that higher levels of GFAP were associated with increased white matter hyperintensities, ventricular expansion and grey matter atrophy (temporal lobe, occipital lobe, hippocampus, basal ganglia and thalamus) only in APOE E4 carriers. Higher levels of p‐tau181 were also associated with increased temporal, parietal, and hippocampal atrophy only in APOE E4 carriers.ConclusionPlasma biomarkers, especially GFAP and p‐tau181, appear to be significantly more predictive of memory deficits and brain neurodegeneration in APOE E4 carriers compared to non‐carriers in AD.
Examining the Driving Habits of Older Canadians as Captured by the COMPASS‐ND Study
Authors: Saryazdi Raheleh , Yung Stephanie , Pereira April , Naglie Gary , Rapoport Mark J. , Stasiulis Elaine , Campos Jennifer L. 
Published: December 2023

AbstractBackgroundDriving is associated with a sense of autonomy and good quality of life in older adults. However, older adults often change their driving habits, such as regulating how often, how far, and under what conditions (e.g., time of day, weather) they drive, in part due to changes in cognition. Our study describes data from the first large‐scale Canadian cohort study to investigate differences in driving habits across cognitive groups, including cognitively healthy older adults (control), Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and Alzheimer’s Disease (AD).MethodWe analyzed data from the Comprehensive Assessment of Neurodegeneration and Dementia study (COMPASS‐ND, Chertkow et al., 2019), a population‐based study of Canadians with various cognitive and functional abilities (May 2021 Data Release). The final sample analyzed included 317 participants (55% Females, Meanage = ∼72). We report the responses for the following driving‐related questions: licensing status (no longer have license, drive with or without restrictions), driving frequency, driving distance, and driving restrictions (e.g., bad weather).ResultMost participants across all groups reported that they have a driver’s license without restrictions, including the AD group (AD: ∼61%, remaining groups: >90%). The following analyses only included current drivers. In terms of the frequency of driving and the distance travelled, as expected, the AD group drove the least often and the shortest distances. The most frequent restriction types selected by all groups were bad weather and nighttime driving. The number of restriction types increased with the severity of cognitive decline. Interestingly, driving restrictions reported by the SCD group more closely approximated the cognitively impaired groups (MCI and AD) than the control group.ConclusionAlthough many of the AD group participants still had a license, they also reported the greatest number of driving restrictions. Further, the SCD group and MCI group were quite similar in their responses for several items, indicating that even SCD may be associated with differences in driving habits. Implications of driving‐related limitations include reduced independence, socialization, participation, and access to resources (e.g., medical care, groceries).
Longitudinal Locus Coeruleus Imaging across the Alzheimer’s Spectrum
Authors: Sibahi Ahmad , Rosa‐Neto Pedro , Tardif Christine L , Cassidy Clifford 
Published: December 2023

AbstractBackgroundNoradrenergic neurons of the locus coeruleus (LC) may play a critical role in the pathophysiology of Alzheimer’s Disease (AD). LC imaging with MRI is a promising in vivo method to study the role of this system in AD. Here we investigate longitudinal change in LC integrity across the AD spectrum.MethodThis study included 291 participants from the TRIAD cohort at the McGill Research Center for Studies in Aging (cognitively normal: n = 166, mild cognitive impairment: n = 79, AD: n = 46). Follow‐up data was available for 123 participants. All participants underwent MR imaging including a turbo spin echo (TSE) sequence for LC imaging, tau positron emission tomography (using [18F]MK6240), and clinical and cognitive assessment including the Mini Mental State Exam (MMSE). LC signal contrast was assessed relative to a pontine reference region. Linear regression analyses related LC signal to clinical measures.ResultConsistent with prior work in an earlier version of this sample, at baseline, LC signal was reduced in tau positive participants (t(285) = ‐4.56, p<0.0001) and negatively correlated to AD severity (Braak stage: t(253) = ‐4.79, p<0.0001; MMSE score: t(254) = 4.30, p<0.0001). There was no significant change in LC signal over time (t(122) = 1.36, p = 0.18) and no significant impact of tau status on LC change (t(119) = 0.39, p = 0.70). Counterintuitively, there was evidence of increasing LC signal in the most severe participants, as those with low MMSE score (<27) showed a significant signal increase over time (t(16) = 2.16, p = 0.046). Moreover, increasing LC signal in tau positive participants was correlated to reduction in MMSE performance over time (t(35) = ‐2.13, p = 0.040). In contrast, tau negative participants showed the opposite trend (t(52) = 1.97, p = 0.054).ConclusionWhile cross‐sectional analyses found the expected negative correlation between LC signal and AD severity, longitudinal analyses obtained the surprising result that increasing signal correlated to worsening AD severity. This finding could suggest that the LC imaging sequence used (TSE) may imperfectly capture LC degeneration and signal increases could be driven by other factors occuring simultaneously with LC degeneration (perhaps elevated neuromelanin or tau deposition). Future work could determine if different types of LC sequence (TSE versus magnetization transfer) differ in their ability to capture degeneration and provide complementary information.
Effect of SUVR reference region selection on sampled iterative local approximation estimates of amyloid onset age
Authors: Teague Jordan P , De Chavez Elena Ruiz , Irizarry‐Pagan Erica E , Cody Karly Alex , Asthana Sanjay , Johnson Sterling C , Christian Bradley T. , Langhough Rebecca E , Betthauser Tobey J 
Published: December 2023

AbstractBackgroundAmyloid PET imaging quantifies Aβ plaques informing longitudinal modeling methods such as sampled iterative local approximation (SILA) that provide individualized estimated amyloid onset age (EAOA). EAOA is defined as the transition to abnormal Aβ accumulation that occurs in Alzheimer’s disease. This work investigates the effect of SUVR reference region selection on EAOA by comparing DVR‐trained versus SUVR‐trained SILA models with three different SUVR reference regions.MethodN = 585 participants (mean (SD) baseline age = 66.40 (7.89) years, 512 unimpaired, 44 MCI, 28 dementia, 1 unknown) from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center underwent T1‐weighted MRI and dynamic 11C‐Pittsburgh Compound B (PiB) amyloid PET imaging (0‐70 minutes after bolus injection). Reconstructed dynamic PET time series were processed and quantified using MR‐guided imaging pipelines optimized for DVR (Logan, k2’ = 0.149 min−1, cerebellum gray matter (CBLM‐GM) reference region) and SUVR (50‐70 min frames) quantification with CBLM‐GM, whole cerebellum (WHOLE‐CBLM), or subcortical white matter (WM) as a reference region. Mean cortical PiB DVR and SUVR were each calculated by averaging across eight bilateral ROIs. Group‐based trajectory modeling was applied to longitudinal DVR data to establish an amyloid positivity (A+) threshold (DVR>1.14; equivalent to 14 centiloids). LME was used to define the relationship between DVR and SUVR and translate the DVR threshold to SUVR (SUVRCBLM GM>1.28; SUVRWHOLE CBLM>1.07; SUVRWM>0.68). Within‐person paired differences between EAOADVR and EAOASUVR_REFERENCE_REGION are reported as (mean; [95% CI]).ResultEAOA derived from DVR and SUVR were compared for n = 198 (34%) DVR A+ participants. Amyloid vs. age data are shown for each quantification approach in Figure 1. EAOASUVR‐WHOLE‐CBLM (‐1.29 years; [‐1.51, ‐1.08]) had the highest agreement with EAOADVR compared to EAOASUVR‐CBLM‐GM (‐1.44 years; [‐1.75, ‐1.12]) and EAOASUVR‐WM (‐0.67 years; [‐2.13, 0.79]; Figure 2). EAOA variability was highest for DVR>1.8 where fewer longitudinal observations were available for model training.ConclusionSUVR with whole cerebellum as a reference region resulted in the smallest difference in EAOA compared to DVR from the SILA model. Future work is ongoing to define SUVR thresholds that will optimize agreement with DVR‐trained EAOA results for harmonization of temporal estimates.
Pathologic Features of Asymptomatic Limbic‐Predominant Age‐Related TDP‐43 Encephalopathy Neuropathologic Change (LATE‐NC)
Authors: Culhane Jessica E. , Mock Charles , Chan Kwun Chuen Gary , Chen Yen‐Chi , Kukull Walter A. 
Published: December 2023

AbstractBackgroundLATE‐NC is a newly‐defined TDP‐43 proteinopathy that is common in older adults and associated with amnestic dementia syndrome. To our knowledge, no prior study has studied individuals resilient to LATE‐NC (participants with Stage 2 or 3 LATE‐NC but no cognitive impairment at autopsy). The extensive autopsy dataset at the National Alzheimer’s Coordinator Center (NACC) uniquely positions us to examine these rare individuals. To determine if asymptomatic participants have lower levels of other neuropathologic diseases, we compared neuropathologic features against participants with clinical dementia.MethodWe included autopsied participants from NACC’s Uniform Data Set whose last visit was within two years of death or had clinical dementia at their last visit. Participants were excluded if they had rare neuropathologic diseases or were not evaluated for each neuropathologic feature. For asymptomatic (normal cognition, 75+ years old, stage 2 or 3 LATE‐NC) individuals, we calculated the odds of having non‐LATE pathologic features against a control group (stage 2 or 3 LATE‐NC, clinical dementia), adjusting for age at death, sex, education, and presence of APOE e4 allele(s). Features included Alzheimer’s pathology (amyloid plaques and neurofibrillary tangles) vascular pathology (number of infarcts and microinfarcts; severity of arteriosclerosis, atherosclerosis, and cerebral amyloid angiopathy), and Lewy body disease (LBD) staging.ResultOf participants who met inclusion criteria, 20 were asymptomatic and 505 were controls. In unadjusted analyses, asymptomatic participants had lower severity of amyloid plaques, tau tangles, LBD, microinfarcts, and arteriosclerosis, and were less likely to have an APOE e4 allele. In adjusted logistic regression analysis, associations remained only for tau tangles, LBD, and APOE. Interestingly, we found no association of asymptomatic LATE‐NC with amyloid plaques (Thal phase or CERAD score).ConclusionResilience to LATE‐NC is associated with lower odds of other neuropathologic disease, including neurofibrillary tangles and Lewy bodies. This supports prior research indicating an interactive effect of multiple neuropathologic diseases on risk of dementia. Severity of amyloid plaques was not associated with risk of dementia in participants with LATE‐NC, indicating that amyloid‐reducing therapies may not be an effective way to prevent LATE symptoms.
Association of birth weight with incident dementia: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study
Authors: Emanuel Olivia M , Lee Mark , Lutsey Pamela L. , Sullivan Kevin J , Groechel Renee C. , Mosley Thomas H. , Schneider Andrea LC , Wong Dean F. , Gottesman Rebecca F. 
Published: December 2023

AbstractBackgroundEarly life factors, such as birth weight (BW), may have long‐term health consequences, but the importance of these factors in dementia risk is poorly understood. Our objective was to prospectively examine the association of BW with dementia incidence over mid‐ to late‐adulthood in the ARIC study. We hypothesized that participants who report lower BW experience more incident dementia than participants who report normal BW, and this association may differ by race.Method10,789 participants who were dementia‐free at ARIC baseline (Visit 1: 1987‐1989; ages 45‐64) and followed through 2019 were included. Participants were asked their BW through standard interviews at Visit 4 (1996‐1998), but if unable to recall, they selected their BW category: low (<5.5 lbs.), medium (normal) (5.5‐9.0 lbs.), or high (>9.0 lbs.), and to identify if they were premature (yes/no). Adjudicated dementia cases from baseline through 2019 were classified using in‐person cognitive evaluations, informant interviews, and phone assessments as well as hospitalization codes and death certificate codes. The associations between having high or low (vs medium) BW and dementia, or premature birth status and dementia were investigated using Cox proportional hazards models, with testing for interaction by race.ResultOur overall population was 54 yo at baseline, 56% female, and 20% Black; 2,255 dementia cases were identified over a median of 28.2 years. Participants who reported a low BW had 1.2 times (95% CI 1.02, 1.41) increased risk of incident dementia compared to those with medium BW in demographic‐ and APOE‐adjusted models (Table 1). This association was no longer significant when the model additionally adjusted for vascular risk factors. The risk for dementia was not increased among participants who reported having been born premature (vs not premature). When stratified by race, the risk of incident dementia was elevated in Black participants reporting high (vs medium) BW, but not in White participants reporting high BW (p‐interaction = 0.006) (Table 2).ConclusionIn this cohort, low BW was associated with risk of dementia in minimally adjusted models. The association was attenuated after accounting for vascular risk factors. High BW was associated with risk of dementia in Black participants only.
INCREASED CATALASE ACTIVITY IN AGING ADULTS WITH DOWN SYNDROME: ASSOCIATIONS WITH AGE AND COGNITIVE DECLINE
Authors: Sarno Tamires Alves , Cordeiro Augusto Magno Tranquezi , Pereira Cícero Augusto Costa , Talib Leda Leme , Forlenza Orestes Vicente 
Published: December 2023

AbstractBackgroundThe aging process in Down syndrome (DS) is associated with a high prevalence of dementia, which is regarded as a variant form of early‐onset Alzheimer’s disease (AD). In addition to the central role played by amyloid pathology, DS‐dementia (DS‐D) may also be related to abnormal regulation of oxidative stress. The copper/zinc‐dependent superoxide dismutase (SOD1) gene is also located on chromosome 21, and studies have suggested an association of SOD1 overexpression with disrupted redox homeostasis. We hypothesize that such abnormalities may be further related to cognitive decline in DS.Method30 aging adults with DS were enrolled to the study, of whom 14 were cognitively stable (DS‐S) and 16 had evidence of cognitive decline (DS‐D). Two comparison groups were constituted with euploid volunteers, i.e., 30 age‐matched, cognitively healthy subjects (euploid controls, EU‐C); and 60 MCI and AD patients (EU‐MCI‐AD). We used an enzymatic assay to determine catalase activity.ResultAs compared to euploid controls, catalase activity was increased in DS irrespective of the presence of cognitive decline (p<0.004). This finding was also observed when the DS group was stratified according to the presence of cognitive decline (EU‐C vs. DS‐S, p<0.001; EU‐C vs. DS‐D, p<0.01). Catalase activity was also increased among cognitively stable DS as compared to MCI‐AD (DS‐S vs. EU‐MCI‐AD, p<0.027).When the DS group was stratified by age (18‐34y, 35‐49y, and ≥ 50y), catalase activity was found to be increased in younger and middle‐aged DS‐S as compared to EU‐C (18‐34y, p<0.01; 35‐49y, p<0.01) and in middle‐aged DS‐S as compared to SD‐D (35‐49y: p< 0.03).ConclusionOur preliminary findings suggest a systemic pro‐oxidant status in DS, evidenced by the increased catalase activity, presumably as a physiological compensation for redox imbalance due to the upregulation of SOD1 (data not shown). Furthermore, antioxidant defense functions decline with aging in the DS carrying. Thus, catalase could be a predictive biomarker candidate for AD.
The Built Environment’s Role in Supporting Dementia Inclusive Communities: A Case Study of Canterbury‐Bankstown City
Authors: Karamacoska Diana , Shatnawi Eman , Caballero Gabriela , Woodward Jeannette , Vu Thi Hang , Pham Ho Trong Nhan , Morrison Nicky , Siette Joyce , Steiner‐Lim Genevieve Z. , DiGiacomo Michelle , Dadich Ann ,   Canterbury‐Bankstown Dementia Alliance
Published: December 2023

AbstractBackgroundInclusive and enabling cities are fundamental to the wellbeing of people impacted by dementia. How we implement these ideals in multicultural communities through the built environment remains understudied. The experience of place must be considered in the context of dementia‐friendly community (DFC) models to fully enable people experiencing dementia to remain autonomous, integrated, and connected. This study aimed to explore how diverse individuals with dementia perceive the built environment and its impacts on everyday activities using a mixed methods approach.MethodThis study was set in Canterbury‐Bankstown, New South Wales, Australia where a high proportion of people impacted by dementia speak English, Arabic, and/or Vietnamese. Seventeen people experiencing dementia, their care partners, and former carers (English: n = 7; Arabic: n = 5; Vietnamese: n = 5) were recruited for a semi‐structured interview, and two of these dyads (English: n = 1; Vietnamese n = 1) audited a local shopping centre and hospital using the DFC‐environmental assessment tool (DFC‐EAT). Interviews and audits were conducted in‐language with bilingual researchers, who then transcribed the data into English for analysis. Similarities and differences were identified across the interview transcripts and audit data to identify issues with the existing built environment and improvement opportunities.ResultWe found that participants would limit or avoid going outdoors for everyday activities because of safety concerns (especially when using paths and carparks). Furthermore, overwhelming indoor experiences were characterised by unfamiliar designs and fittings (particularly with bathroom facilities), unsupported movement and way‐finding due to excessive or insufficient signage, poor lighting, and high noise. Participants recommended greater access to door‐to‐door transport that caters to people experiencing dementia, establishing quiet resting areas, and improving navigation through signage that uses standardised symbols (e.g., for toilet facilities).ConclusionPeople experiencing dementia and carers reported an array of issues concerning built environment design and accessibility features that excluded them from everyday activities. These findings were translated into an implementation plan that informed the City of Canterbury‐Bankstown Council’s community planning efforts and the shopping centre’s facility operations. Critical areas for improvement in the built environment would benefit from co‐design practices that are inclusive and representative of the community.
Biobanking best practices for research, Banner Sun Health Research Institute Brain and Body Donation Program standards and journey
Authors: Serrano Geidy E 
Published: December 2023

AbstractThe Arizona Study of Aging and Neurodegenerative Disease (AZSAND)/Brain and Body Donation Program (BBDP) is a unique clinicopathological study of aging and neurodegenerative disease based in Sun City, AZ since 1987. The BBDP has made rapid autopsy a priority, with a constitutive 24‐7 rapid autopsy team and a 3.0‐hour median postmortem interval for the entire collection. Tissue quality is correspondingly high, with a median RNA Integrity Number (RIN) for frozen brain tissue of 8.9. The current holdings include fixed and frozen brain and body tissue, as well as biofluids from more than 850 Alzheimer’s Disease (AD) cases, 250 Parkinson’s Disease (PD) cases and more than 350 elderly control subjects. The program supports and leads national and international research focused on AD, AD related dementias and other debilitating neurodegenerative diseases. It provides basic scientists with de‐identified annual comprehensive standardized cognitive, motor, and non‐motor assessments data and neuropathologically characterized human samples that are suitable for the elucidation of the molecular mechanisms of disease and novel therapeutic targets. The BBDP is committed to distributing human samples and accompanying clinicopathological data to as many researchers as possible. All collected data are available to researchers through the program’s website https://www.brainandbodydonationregistration.org/ and personalized consultations.