bluuebunny/crossref_metadata_2025_split huggingface dataset:
Restriction of dietary protein slows the development and progression of Alzheimer’s disease in 3xTg mice
Authors: Babygirija Reji , Sonsalla Michelle M , Han Jessica , Calubag Mariah , Trautman Michaela , Green Cara , Matouska Ryan , Tobon Anna , Michael John , Yeh Yang , Lamming Dudley 
Published: December 2023

AbstractBackgroundCaloric restriction (CR) promotes health and longevity in diverse species and has been successful in ameliorating Alzheimer’s disease (AD) pathology in mouse models and non‐human primates. However, CR may be difficult to adhere to, which makes the reduction of specific macronutrients without restricting calories an attractive alternative. Low protein intake is associated with healthy aging and reduced mortality in humans, and protein restriction (PR) extends the lifespan and healthspan of many mouse models. In this study, we examined the effects of PR on metabolic health and AD pathology in the 3xTg mouse model of AD.MethodWe placed male and female 3xTg mice as well as non‐transgenic (NTg) controls on either a Control diet (21% of calories from protein) or a PR diet (7% of calories from protein) starting at 6 months of age. We assessed the effect of PR on metabolic health, cognition, and AD neuropathology along with targeted metabolomics on plasma samples to identify the abundance of metabolites and dysregulated metabolic pathways.ResultWe found that a long‐term PR diet had substantial metabolic benefits for both male and female 3xTg and NTg mice, promoting leanness and glycemic control. We also found that consumption of low protein diet significantly improved cognitive performance and reduced multiple aspects of AD neuropathology including tau phosphorylation, Aß plaques and gliosis. Phosphorylation of the mTORC1 substrate S6K1 was decreased and the major autophagy cargo receptor P62 was increased in PR‐fed 3xTg mice, which suggests that reduced mTORC1 signaling may mediate the beneficial effects of PR on AD pathology. Targeted metabolomics revealed that several metabolites involved in nucleic acid metabolism and amino acid metabolism were altered between control fed and PR fed mice in a sex specific manner.ConclusionOur findings suggest that lowering dietary protein may be a novel way to slow or even prevent AD. In addition, drugs that mimic the effects of PR may be an effective pharmaceutical approach to combat AD pathology.
Cognitively select older adults in the Dallas lifespan Brain Study exhibit higher positive personality traits and resilience to amyloid pathology
Authors: Monier Sarah A. , Smith Evan T. , Hennessee Joseph P. , Bacci Julia R. , Park Denise C. 
Published: December 2023

AbstractBackgroundIn the present study, we investigated differences in amyloid (Aβ) burden and personality traits in cognitively‐select older adults compared to average‐functioning older adults. Conscientiousness, in particular, has been linked to Alzheimer’s Disease (AD) pathology, and we hypothesized that adults who were high in cognition would exhibit enhanced conscientiousness. Of additional interest was whether high functioning older adults in the Dallas Lifespan Brain Study would evidence reduced AD pathology.MethodWe tested 285 cognitively‐normal participants (ages 55‐90) and collected conscientiousness scores using the Revised NEO Personality Inventory (NEO‐PI‐R). Participants also underwent PET imaging with radiotracer AV‐45, 18F‐Florbetapir, a radiotracer that is used to measure Aβ protein in the brain. Mean cortical SUVR was computed across 8 cortical regions of interest, normalized to cerebellar gray matter. In addition, participants completed a cognitive battery, underwent an MRI scan, and completed self‐reports for depression and fitness. We designated those participants scoring at or above the mean episodic memory of a middle‐aged (ages 35‐54) reference group, as “cognitively‐select” (N = 69), and those scoring below the mean, as “cognitively‐normal” (N = 216). Dependent variables of interest included global and regional amyloid (Aβ), cortical morphometry, depression, fitness, conscientiousness, and various cognitive measures.ResultCognitively select participants were younger (p = .043), more educated (p = .021), and had higher positive personality traits, including self‐discipline (p = .01), openness to ideas (p = .013), and competence (p = .015), compared to cognitively‐normal. Although the groups did not differ in global Aβ pathology load (p = .083), cognitively select exhibited less pathology in specific regions including lateral temporal areas (p = .049). Regression analysis controlling for sex, age, education, and MMSE, revealed a significant group by global Aβ interaction on fluid ability (p = .034), where greater Aβ load predicted lower scores in cognitively normal older adults only.ConclusionThese findings provide evidence that cognitively privileged adults show resistance to decline across many domains and demonstrate resilience to amyloid pathology. Discussion will focus on longitudinal change in amyloid accumulation, cortical thinning, and cognitive decline, as well as the concept of reserve.
Cerebrovascular reactivity in amnestic and non‐amnestic mild cognitive impairment
Authors: Umfleet Laura Glass , Cohen Alexander D , Pommy Jessica , Allen Margaret , Obarski Shawn , Mason Lilly , Berres Halle , Franczak Malgorzata , Wang Yang 
Published: December 2023

AbstractBackgroundCerebrovascular disease (CVD) is implicated in the pathogenesis and clinical presentation of Alzheimer’s Disease. Cerebrovascular reactivity (CVR) is considered a more direct estimate of cerebrovascular integrity. CVR is a potential promising biomarker for examining pathological cognitive decline in older adults though, to date, findings have been inconclusive, possibly partly due to variability in methodological approaches. In this study, we add to the limited literature on CVR in mild cognitive impairment (MCI). We provide preliminary evidence for CVR differences in MCI phenotypes compared to older adult cognitively normal controls. We hypothesized that they amnestic phenotype (aMCI) will have lower CVR than non‐amnestic (naMCI) and both groups will show lower CVR compared to controls. We also performed exploratory correlational analyses between CVR and neuropsychological test scores.MethodCVR was assessed in 22 controls, 11 aMCI, 9 naMCI cohorts using a breath‐holding task functional magnetic resonance imaging (fMRI). fMRI data were preprocessed and analyzed using AFNI. All participants underwent neuropsychological testing. T‐tests and ANOVA/ANCOVA analyses were conducted to compare controls to MCI groups on CVR metrics and cognitive tests of memory, language, processing speed, and executive functioning. Partial correlation analyses between CVR derived from regions‐of‐interest (Yeo 1‐7 ROIs) and different cognitive functions were conducted.ResultsCVR was found to be significantly lower in MCI compared to controls across all Yeo functional networks, ps < .001, which was mostly driven by the aMCI phenotype. naMCI showed intermediate patterns between aMCI and controls, though results were not significant, ps > .05. Regional CVR values along Yeo networks were positively correlated with cognitive measures of processing speed, executive functioning, and memory.ConclusionThis is the first study to evaluate CVR differences in MCI phenotypes. Consistent with previous research, we found that CVR is lower in MCI compared to controls. While group differences between naMCI and controls (also between naMCI and aMCI) did not reach statistical significance, visual inspection of CVR mean values showed preliminary evidence that naMCI had lower mean values across all ROIs compared to controls and higher mean values compared to aMCI. Future research is needed to examine differences in CVR between MCI phenotypes.
Further along the Alzheimer’s disease continuum: associations between mild behavioral impairment with hippocampal and entorhinal volume and incident cognitive decline
Authors: Guan Dylan X. , Rehman Tanaeem , Nathan Santhosh , Durrani Romella , Potvin Olivier , Duchesne Simon , Pike G. Bruce , Smith Eric E. , Ismail Zahinoor 
Published: December 2023

AbstractBackgroundMild behavioral impairment (MBI) identifies a high‐risk group for Alzheimer’s disease and related dementias (ADRD), leveraging the risk associated with later‐life emergent and persistent neuropsychiatric symptoms (NPS). MBI may act as a complementary behavioral analog to later‐life emergent cognitive symptoms (mild cognitive impairment, MCI). These constructs are not mutually exclusive and can co‐occur. We characterized the relationship between MBI, grey matter volume in the hippocampus and entorhinal cortex, and incident cognitive decline in older adults with normal cognition (NC) and MCI.MethodSeven‐hundred‐forty‐two participants were included from the National Alzheimer’s Coordinating Center Uniform Dataset. The Normative Morphometry Image Statistics tool was used to generate estimates of grey matter volume for the bilateral hippocampi and entorhinal cortices, normalized by age, sex, total intracranial volume, and image quality. NPS were evaluated using the informant‐rated Neuropsychiatric Inventory Questionnaire, from which MBI scores were derived based on a published algorithm. Associations between MBI status and the regions‐of‐interest were modelled separately in NC and MCI using multivariable linear regressions, adjusting for education and clinical‐MRI visit interval time. Associations between MBI status and incident cognitive decline were modelled using Cox proportional hazards regressions.ResultParticipant characteristics are summarized in Table 1. As per Figures 1 and 2, NC participants with MBI had lower grey matter volume in the bilateral hippocampi (B = ‐0.40, 95%CI:[‐0.66, ‐0.15], p = .004), and a greater hazard of incident MCI or dementia, than those without MBI (HR = 3.34, 95%CI:[2.04, 5.48), p<.001). NC MBI+ participants also had lower grey matter volume in the bilateral entorhinal cortices compared to NC MBI‐ participants, although not statistically significant (B = ‐0.13, 95%CI:[‐0.35, ‐0.08], p = .22). In MCI, participants with MBI had lower grey matter volume bilaterally in both the hippocampus (B = ‐0.46, 95%CI:[‐0.80, ‐0.12], p = .01) and entorhinal cortex (B = ‐0.42, 95%CI:[‐0.76, ‐0.12], p = .009), and had greater progression‐rates to dementia (HR = 4.13, 95%CI:[2.45, 6.94), p<.001), than those without MBI.ConclusionOur findings suggest that evaluating dementia‐free older adults for MBI status in conjunction with cognitive status identifies a group further along the ADRD continuum than those without MBI, who have greater baseline atrophy in key ADRD regions and greater progression rates to later cognitive stages.
Comparative Performance of the Digital Clock and Recall™ Test, Montreal Cognitive Assessment, and Saint Louis University Mental Status Among Patients in Primary Care
Authors: Hammers Dustin B. , Fowler Nicole R , Brosch Jared R. , Swartzell Kristen L , Banks Russell E , Jannati Ali , Mullavey Judy , Gomes‐Osman Joyce Rios , Murray James F , Willis Deanna R 
Published: December 2023

AbstractBackgroundDigital cognitive assessment solutions can overcome some barriers to cognitive screening in primary care by providing rapidly‐obtained objective insights without requiring specialty‐trained examiners. The Linus Health Digital Clock and Recall (DCR™) is a three‐part test consisting of three‐word immediate verbal acquisition, the Digital Clock Test (DCTclock™), and delayed recall of the three words. Our objective was to compare performance on the DCR to the Montreal Cognitive Assessment (MoCA; Nasreddine et al., 2005) and the Saint Louis University Mental Status (SLUMS; Tariq et al., 2006), two commonly used screening tests in primary care.MethodComparative analyses of DCR, MoCA (Total Score and Memory Index Score [MIS]), and SLUMS results were conducted among 80 primary care patients – 65 years and older presenting for any reason – whose DCR performance was indicative of cognitive impairment.ResultOf the 80 patients (mean age 74.0 [±7.8]; 60% female) performing as impaired or borderline impaired on the DCR, 67 completed the MoCA and 13 completed the SLUMS. Comparison between the DCR and MoCA Total Score included 78% (52/67) concordance for identifying impairment (cutoff <26). While the remaining 15 of 67 patients (22%) had normal MoCA Total Scores (≥26), 13 (87%) missed points in at least one MoCA cognitive domain and 8 (53%) missed points in multiple MoCA domains (often language and delayed recall). Comparison between DCR and SLUMS revealed that all 13 patients receiving SLUMS assessment had DCR scores 0‐1 and SLUMS scores <27 (indicating cognitive impairment). See Tables 1 and 2 for breakdown of MoCA, MIS, and SLUMS stratified by DCR performance. Logistic regression found that DCTclock metrics of information processing (z = 2.00, p = .045) and spatial reasoning (z = 2.82 p = .005) discriminated cognitive impairment on MoCA Total Score (cutoff <26). Overall, ROC analysis revealed good accuracy of DCR to identify MoCA performance (AUC = .84; Figure 1).ConclusionScreening in primary care using the DCR is feasible, takes less time to administer than MoCA or SLUMS, and shows concordant results with these more established screening tools in detecting cognitive impairment. Future research aims to investigate the criterion validity of the DCR among biomarkers for neurodegenerative disease.
Effects of cholesterol depletion, pro‐inflammatory cytokines and the apolipoprotein E isoforms on ABCA7 protein levels in human neural cell lines and brain tissue
Authors: Wiener Joel P. , Garliyev Viktor , Desire Sindy , Pratico Anna , Serrano Geidy E , Lyssenko Nicholas N. 
Published: December 2023

AbstractBackgroundStrong evidence from diverse sources points to adenosine triphosphate‐binding cassette transporter subfamily A member 7 (ABCA7) as a major risk factor in Alzheimer’s disease (AD). However, the mode of its involvement with the disease and many aspects of its function are understood incompletely.MethodHuman microglia cells C20 and HMC3 and neuronal cells SK‐N‐SH were either depleted in cholesterol using methyl‐β‐cyclodextrin and/or rosuvastatin or treated with pro‐inflammatory cytokines IL‐1β, IL‐6 or TNFα, and ABCA7 protein levels in these cells were then assessed using a validated monoclonal antibody. ABCA7 levels were also assessed using the antibody in the parietal cortex from 170 donors, who were genotyped for the APOE isoforms.ResultLarge (∼75%) reductions in intracellular cholesterol and saturating amounts of pro‐inflammatory cytokines IL‐1β and TNFα reduced ABCA7 protein by, respectively, 36.8±9.1% (mean±standard deviation, two‐tailed t test p = 0.0002, n = 4), 53.0±22.6% (p = 0.002, n = 4) and 59.2±8.0% (p = 0.0006, n = 4) in C20 cells and by similar percentages in HMC3 cells. Similarly severe cholesterol depletion had no effect on ABCA7 and IL‐1β and TNFα moderately increased ABCA7 amounts in SK‐N‐SH cells. IL‐6 had no effect on ABCA7 expression in any cell line. IL‐1β and TNFα significantly cross‐induced each other’s secretion in C20 cells. We have previously shown that ABCA7 protein levels drop suddenly during AD pathogenesis between Braak and Braak stages I and II in the human brain. Among the individuals without AD pathology or with Braak stage I pathology, ABCA7 levels were lower in APOE4 carriers without reaching statistical significance (0.74, 0.35‐2.51 vs 1.5, 0.30‐3.16 ABCA7/GAPDH ratios; median, 25%‐75% interval; Mann‐Whitney p = 0.44, n = 68 vs 14); among the individuals with Braak stages II‐V, ABCA7 was also lower in APOE4 carriers (0.21, 0.07‐1.07 vs 0.55, 0.11‐1.35; Mann‐Whitney p = 0.18, n = 53 vs 35). The comparison groups were matched for age, sex and PMI.ConclusionThe effect of cholesterol depletion on ABCA7 expression is tissue specific. ABCA7 functions are homeostatic and not compatible with inflammation in microglia. If APOE4 has an effect on ABCA7 levels, it is smaller than the reduction in ABCA7 between Braak stages I and II. These findings improve our understanding of ABCA7 pathophysiology.
Novel Framework for Brain Age Prediction using Graph Neural Networks
Authors: Sihag Saurabh , Mateos Gonzalo , Wolk David A. , Ribeiro Alejandro , McMillan Corey T 
Published: December 2023

AbstractBackgroundAging is among the largest risk factors for neurodegeneration which can be accelerated by age‐related pathologies. Hence, individuals may age at different rates reflected by a gap in biological estimates of age and actual chronological age. Graph neural networks (GNN) are deep learning models that leverage spatial information inherent in the dataset for inference. Here, we develop an MRI cortical thickness (CT) based brain age prediction framework using GNNs and illustrate that it provides a feasible mechanism to identify contributing regions leading to elevated brain age gap in Alzheimer’s disease (AD).MethodWe used ANTs to calculate CT in 100 parcels from 3T MRI of 170 healthy controls (HC; age = 64.26±8.27y, 101 females), 53 mild cognitive impairment (MCI; age = 68.56±8.58y, 22 females), and 62 AD (age = 67.25±8.83y, 30 females) individuals. A GNN model based on the anatomical covariance matrix from HC cohort was trained to predict chronological age from associated CT for HC cohort. GNN output was evaluated as an unweighted mean of entities associated with the brain regions in the final layer. Hence, individual contributions to the GNN output by each brain region could be quantified. Final brain age prediction was obtained after removing age‐bias from GNN outputs using linear regression model. For all subjects, we evaluated residuals at regional level (regional age‐gap) by comparing the contribution of each parcel with corresponding GNN output. The residual between predicted brain age and chronological age (age‐gap) was also evaluated. See Figure 1 for an overview.ResultANCOVA (with correction for age and gender) with post‐hoc analyses revealed that regional age‐gap was greater for AD relative to HC in inferior parietal, temporal pole, inferior temporal, medial temporal, and superior frontal regions (Bonferroni corrected p‐value<0.05). Also, regional age‐gap was greater for MCI relative to HC for inferior parietal and temporal pole regions (Figure 2). Subsequently, age‐gap was elevated in AD (mean = 5.64y) and MCI (mean = 2.66y) relative to HC (mean = 0y) reflecting a linear increase in age‐gap with disease stage (Figure 3).ConclusionOur novel framework identified regional CT associations with age‐gap in AD and MCI, suggesting that this GNN approach may be used to further our understanding between aging and neurodegeneration.
Hippocampal‐to‐ventricle ratio (HVR) is better related to age and cognition than Hippocampal Volume
Authors: Fernandez‐Lozano Sofia , Fonov Vladimir S , Dadar Mahsa , Collins D Louis ,   for Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundHippocampal volume (HCvol) is an important biomarker in the study of neurodegeneration (1‐3). Given its high variability (4) HCvol is commonly normalized using the intracranial volume (HCvol/ICV) (5). The Hippocampal‐to‐ventricle ratio (HVR) considers instead the nearby expanding ventricular space and has shown stronger negative association with age and positive association with delayed memory compared to HCvol in healthy aging (6).MethodUsing a Convolutional Neural Network (7) we extracted the volumes from the hippocampus and the surrounding temporal horn of the lateral ventricles to obtain the HCvol, HCvol/ICV and HVR on the baseline T1w MRI scans from the ADNI dataset (CN = 502, MCI = 814, AD = 323). We converted these measurements to Z‐scores using the mean and standard deviation of the CN cohort to facilitate comparisons. We used Pearson’s correlation coefficient to compare the relationships between each of the three Hippocampal measures with age, ADAS13, and the Immediate, Learning, Forgetting and Forgetting‐percentage metrics of the Rey’s Auditory Verbal Learning Test (RAVLT). Finally, we compared the correlations of HCvol/ICV and HVR with a bias‐corrected‐and‐accelerated bootstrap (BCa; 10,000 resamples) (8).ResultThe correlations of HCvol and HCvol/ICV were similar for age (‐.41 [‐.32, ‐.48] vs ‐.38 [‐.3, ‐.45]), ADAS13 (‐.28 [‐.19, ‐.45] vs ‐.26 [‐.17, ‐.45]) and RAVLT subtests (absolute values: .2 [0, .4] vs .2 [.01, .41]). HVR showed significantly stronger negative correlations with age compared to HCvol/ICV (Fig. 1; CN: BCa = .144 [.102‐.187]; MCI: BCa = .128 [.096‐.160]; AD: BCa = .068 [.012‐.122]). While the negative correlations between HVR and ADAS13 scores were higher than HCvol, the comparison was not statistically significant (Fig. 2). Figure 3 shows the relationships between HC measures and RAVLT subtests: HVR had stronger correlations than HCvol for CN and AD on the Immediate subtest, while HCvol’s relationship with Forgetting score was higher for MCI. None of these were statistically significant.ConclusionConsidering ventricular expansion and hippocampal shrinkage in the HVR better explains the variance related to age and cognition than using hippocampal volume by itself in healthy controls and patients with mild cognitive impairment and dementia.
The Adult Changes in Thought (ACT) Medical Records Abstraction Project: A resource for research on the aging brain and Alzheimer’s disease and related dementias
Authors: Crane Paul K , Lind Bonnie , Dodd Tammy S , Lyons Mary , Macuiba Jennifer A , Gray Shelly L , Meyers Kelly P , Kelley Ann , Nemerever Leslie C , Covey Jennifer M , Campbell Camille C , Lederman Becky , Sheridan Leigh , Tom Sarah E. , Larson Eric B , Nelson Jennifer C , LaCroix Andrea Z. , Renz Anne 
Published: December 2023

AbstractBackgroundAdult Changes in Thought (ACT) is a prospective cohort study of older adults from Seattle, Washington, USA. Participants are enrolled from Kaiser Permanente Washington membership and may consent for autopsy. Many participants have decades of medical records prior to ACT enrollment. We describe an ambitious project to abstract medical records to facilitate epidemiological investigation.MethodAbstractions include medication data preceding 1977 (the start of automated pharmacy data), laboratory data preceding 1988 (the start of automated laboratory data), women’s health history elements, blood pressures, several cardiovascular conditions, several neurological conditions, physical injuries, psychiatric conditions, and other medical conditions, among many others. Data are entered in a Microsoft Access front‐end interface linked to a Microsoft SQL Server database engine. The database comprises 15 tables in a relational structure. We summarize chart review data and other data according to dementia status.ResultWe have completed abstractions on 1329 individuals, of whom 908 had an autopsy. For the first 380 people with an autopsy, it took an average of 6.2 hours (SD 3.8 hours) to abstract >30 years of medical data. More recent electronic medical record data take longer to abstract. In this sample, 236 (62%) died without Alzheimer’s Disease or Related Dementias (ADRD) dementia, and 144 (38%) died with an ADRD dementia diagnosis. Demographic and clinical data are summarized in the Table. Over 60% had pharmacy data preceding 1977 with a median of more than a half decade’s worth. Over 90% of the cohort had additional laboratory data preceding 1988, with a median of a decade’s worth. Medical conditions were similarly common across people without and with ADRD, except cerebrovascular accidents, diabetes, depression, and confusion during hospitalization were more common among people with dementia. We will update all numbers for AAIC.ConclusionThe ACT Medical Records Abstraction Project transforms medical records into data ready for analyses of associations with outcomes derived from other data from the ACT study. For the autopsy cohort in particular, the Medical Records Abstraction Project provides unmatched detailed longitudinal clinical data to support a wide variety of epidemiological research on clinical‐pathological correlations.