bluuebunny/crossref_metadata_2025_split huggingface dataset:
The regional relationship between CSF VEGF and white matter microstructural integrity in older adults: A voxelwise DTI study
Authors: Tubi Meral A , Hare Evan , Nir Talia M , Sagare Abhay P , Wang Xinhui , Schneider Lon S. , Joe Elizabeth B , Toga Arthur W. , Harrington Michael G , Zlokovic Berislav V , Chui Helena C , Braskie Meredith N 
Published: December 2022

AbstractBackgroundBoth white matter (WM) micro‐ and macro‐ structural abnormalities occur in Alzheimer’s disease (AD) with micro‐structural abnormalities likely preceding macrostructural changes in the AD cascade. Diffusion tensor imaging (DTI) fractional anisotropy (FA) ‐ which is sensitive to factors such as myelination, fiber coherence, and fiber density‐ within an MRI voxel may be used to detect AD‐specific deficits. However, mechanisms driving loss of WM microstructural integrity in AD are poorly understood. Vascular endothelial growth factor (VEGF) is a multi‐function vascular protein linked to early AD brain and cognition biomarkers. VEGF provides neurotrophic support via glia and is also secreted by glial cells essential for maintaining myelin. However, in humans, the relationship between VEGF and WM microstructural integrity has yet to be mapped. We evaluated whether cerebrospinal fluid (CSF) VEGF levels were associated with voxelwise WM FA in older adults without dementia.MethodWe evaluated 72 older adults without dementia from the USC Alzheimer’s Disease Research Center (ADRC) (mean age 65.7; 47‐82 years old) with a clinical dementia rating (CDR) score of 0 (n=56) or 0.5 (n=16) who had both CSF VEGF‐A levels and a 3 T diffusion MRI scan (64‐direction (b=1000 s/mm2) DWI volumes). MRI scans were pre‐processed to reduce artifacts related to motion, distortion, eddy currents, bias field, and susceptibility artifacts. Tract‐based spatial statistics, using FSL software, was implemented to derive skeletonized FA maps along WM tracts. The association between VEGF and voxelwise FA WM integrity was evaluated using FSL’s general linear model tool. We covaried for age, sex, and CDR. FA significance cluster maps were corrected for voxelwise multiple comparisons.ResultHigher CSF VEGF levels were associated with lower DTI FA, indicative of poorer WM microstructural integrity, in the left and right superior longitudinal fasciculus, left anterior thalamic radiation, and left inferior frontal occipital fasciculus (p<0.05) (Figure 1).ConclusionThese results demonstrate for the first time in humans that VEGF levels are related to WM microstructure in older adults without dementia, primarily in long range association fibers connecting temporal, parietal, and frontal lobes. These pathways are essential for memory, language, attention and emotional control.
Amyloid, tau, cerebrovascular disease, neurodegeneration, and cognition in middle‐aged adults from a racially and ethnically diverse, community‐based study
Authors: Lao Patrick J. , Lippert Rafael , Benavides Andrea , Berroa Joncarlos , Igwe Kay C , Schupf Nicole , Mayeux Richard , Manly Jennifer J , Brickman Adam M. 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) pathophysiology (i.e., amyloid‐induced tau) and cerebrovascular disease drive neurodegeneration and cognitive impairment. Our objective was to investigate moderation and mediation pathways among amyloid PET, tau PET, vascular MRI, and structural MRI in a middle‐aged, racially and ethnically diverse sample.MethodsIn an ongoing study, participants (n=63; 61±6 years old, 68% women, 13±4 years of education, 12% Non‐Latinx White/25% Non‐Latinx Black/63% Latinx) underwent amyloid PET (weighted average Florbetaben SUVR in Thaal phase regions), tau PET (average MK‐6240 SUVR in Braak stage I), vascular MRI (white matter hyperintensity (WMH) volume), and structural MRI (AD‐signature cortical thickness) in the Offspring Study of Racial and Ethnic Disparities in Alzheimer’s Disease. Serial parallel mediation was used to assess two pathways from age to neurodegeneration (i.e., age to amyloid to tau to neurodegeneration; age to WMH to tau to neurodegeneration).ResultsOlder age was associated with greater amyloid (7E‐3 [3E‐3, 0.01], p=0.001), which was in turn trend level associated with greater tau (0.55 [‐0.1, 1.2], p=0.09); tau was not associated with cortical thickness (‐6E‐3 [‐0.09, 0.08], p=0.88). The total indirect effect of this amyloid pathway was not significant (‐2E‐5 [‐3E‐4, 3E‐4], p=0.88). Older age was associated with greater WMH (0.01 [2E‐4, 0.02], p=0.048), but WMH was not associated with tau (0.01 [‐0.20, 0.22], p=0.91) or cortical thickness (‐8E‐3 [‐0.08, 0.06], p=0.82). The total indirect effect of this vascular pathway was not significant (‐9E‐7 [‐2E‐5, 2E‐5], p=0.93). The direct effect from age to neurodegeneration, given both indirect pathways, was significant (‐5E‐3 [‐9E‐3, ‐1E‐3], p=0.005).ConclusionsIn midlife, there is evidence of age‐related increases in cerebrovascular disease and amyloid‐induced tau, but the two pathways do not have an effect on neurodegeneration in this age group. Older age is the strongest predictor of neurodegeneration, but AD and cerebrovascular pathology may become stronger predictors later in the AD continuum.
Teleneuropsychology in the memory clinic setting: evidence for reliability and usability of videoconference‐based neuropsychological testing
Authors: Butterbrod Elke , Zevenhoven Pia , Waterink Lisa , van Leeuwenstijn Mardou , van der Flier Wiesje M. , van den Heuvel Dominique M.J. , Sikkes Sietske A.M. 
Published: December 2022

AbstractBackgroundRemote neuropsychological assessment through video teleconferencing (VTC) can improve accessibility to dementia care, even beyond the COVID‐19 pandemic. Evidence for the usability and reliability of VTC is still limited in a memory clinic population, particularly for tests assessing non‐memory and non‐verbal functions. This study aims to investigate stability of performances on neuropsychological tests across in‐person and VTC modality, as well as VTC user experiences, in memory clinic patients.MethodPatients were included at the Alzheimer Center Amsterdam between August 2020 and February 2021. Patients underwent in‐person neuropsychological assessment, and subsequently through VTC within 4 months. Stability of performances on all tests across assessments was investigated with intraclass correlations coefficients/percentage agreement and independent samples t‐tests/Wilcoxon signed‐rank tests. Rank order stability was investigated with Pearson or Spearman correlation/Chi‐square tests. For each test, we converted standardized (T‐)scores into seven performance classes (see Figure 1) and described the proportion of patients showing a clinically relevant difference in performance class. Furthermore, we described stability of patients’ overall assessment performance (no impairment, single‐domain impairment, multi‐domain impairment). User friendliness and system usability were assessed with questionnaires by patients and neuropsychologists. Scores were set against previously defined acceptability cut‐offs, and compared across diagnostic groups (subjective cognitive decline [SCD] vs. MCI/dementia) with independent samples t‐tests.ResultThirty‐one patients (62±6.7 years, 55% male, 58% SCD, 42% MCI/dementia) completed VTC assessment. Intraclass correlation coefficients ranged from moderate (0.5; TMT index) to excellent (>0.9; RAVLT, LDST), see Table 1.Significant differences in mean performances were observed for Digit span and Stroop test (SCD group only). For all tests, the majority of patients showed no clinically relevant difference in performance (Figure 1, 61%‐100% stable). Nineteen patients (61%) had the same overall assessment performance across modalities (Figure 2). User friendliness (mean total scores patients/psychologists:164/143) and usability (mean item scores patients/psychologists:3.0/3.0) reached acceptability and did not differ between diagnostic groups.ConclusionVTC assessment may serve as an accessible and user friendly method to test cognitive functioning in the memory clinic, with largely similar reliability coefficients as in‐person assessments. Implications of VTC assessment for the evaluation of impairment severity, and possibly diagnosis, should be further investigated.
Default‐mode connectivity mediates the association between cardiovascular and metabolic risks and cognition: a pilot study
Authors: Rashid Barnaly , Glasser Matthew F. , Nichols Thomas , Van Essen David , Juttukonda Meher R , Schwab Nadine A , Yacoub Essa , Lovely Allison , Terpstra Melissa , Harms Michael P , Bookheimer Susan Y. , Ances Beau M , Arnold Steven E. , Salat David H 
Published: December 2022

AbstractBackgroundPrior studies have linked increased vulnerability to cognitive decline later in life with exposure to cardiovascular and metabolic disease risk factors. Further, these classic risk factors are associated with alteration to brain structure and function. This project investigates whether altered default‐mode network (DMN) functional connectivity (FC) mediates the association between cardiovascular and metabolic (CVM) health and cognition.MethodStructural, Resting‐state fMRI, and fieldmap scans were collected in a large sample of 930 healthy volunteers aged 36 to 90+ years old (mean ± SD: 61.6 ± 16 years; female= 55.6%) from the Human Connectome Project in Aging (HCP‐A) study. Data were preprocessed using the currently recommended HCP‐A pipelines, including precise spatial preprocessing, multi‐modal cross‐subject alignment, and selective temporal denoising. FC values were computed using full correlation with FSLNets amongst the neocortical brain areas of HCP‐A’s multi‐modal parcellation and standard FreeSurfer subcortical structures and converted to z‐scores with the Fisher transform. A composite CVM index (CVMI) was computed with variables related to general CVM health, and a cognitive composite index (CCI) encompassed measures of general cognition, memory, processing speed, and executive functioning. Figure 1 presents the mediation model implemented using MATLAB. The mediation effects were assessed in the full sample (FDR corrected, p<0.05), as well as separately in ‘younger’ participants below 65 years (n = 546) and ‘older’ participants aged 65+ years (n = 384) with and without sex stratification (uncorrected).ResultFigure 2 highlights an indirect effect between CVMI and CCI that is mediated by DMN FC. In the full sample, the CVMI shows a significant negative direct effect on CCI (b=‐0.54, p<.001). This effect is mediated by DMN FC as seen in Figure 2(a), which is well‐replicated in the sex‐stratified analyses. Similar overlapping effects are observed in the younger and older groups. Figure 3 presents an example of connectivity and age association differences between low and high CCI groups.ConclusionOur results indicate that cardiovascular and metabolic health impacts cognitive functioning, and that this is, at least in part, mediated by DMN FC.
Functional fitness predicts global cognition scores
Authors: Gray Michelle , Paulson Sally , Gills Joshua L. , Jones Megan , Campitelli Anthony , Rodgers Charles , Madero Erica N. , Myers Jennifer Rae , Glenn Jordan M. , Bryk Kelsey Nicole 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the 5th leading cause of death and the 6th most burdensome disease among US older adults. Given the concern with public health, understanding modifiable risk factors contributing to cognitive decline is imperative. With preliminary symptoms of cognitive decline occurring long before diagnosis, the ability to identify modifiable risk factors is key to primary prevention and maintenance of cognition. Often among individuals with AD, physical function is concurrently impaired. Thus, the primary aim of the present investigation is to determine the ability to predict global cognition scores from commonly used physical function assessments.MethodCommunity‐dwelling adults 60 years and older completed all assessments. Global cognition (percentile score) was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). All participants were free from mild cognitive impairment, dementia, and probable dementia. Physical function variables included maximal hand grip strength (average of right and left hands), lower‐body peak force development during a sit‐to‐stand task, and 10‐mfast walking time. Linear regression analysis was performed to determine the proportion of variance accounted for by the independent variables (sex, hand grip strength, peak force, 10‐meter walk time). Semi‐partial correlations were performed to determine the unique contribution from each independent variable.Result27% of the variance in global cognition was accounted for when including all independent variables. Semi‐partial correlations revealed the largest unique contribution was from the 10‐meter fast walking time, accounting for 19% of the variance (p < .001). Lower‐body peak force production accounted for 9% (p < .001). Sex accounted for 2.6% (p =.04) and hand grip strength accounted for 2% (p = .055).ConclusionThe current investigation provides support for the predictive capabilities of physical function assessments on cognitive ability—in particular, the time to complete a 10‐meter walk. This is paramount to future efficacious treatments with the inconsistent nature of current cognitive testing and implementation, primarily because of difficulties accessing qualified neuropsychological professionals. The physical function assessments presented here are cost effective and may serve as an early warning sign to cognitive decline.
Four‐year cognitive decline in mild cognitive impairment patients with distinct baseline neuroanatomical atrophy profiles: A MEMENTO and QyScore® study.
Authors: Gordon Elizabeth , Cavedo Enrica , dos Santos Clarisse Longo , Samper‐González Jorge , Schwarz Adam J. ,   the MEMENTO Study Group
Published: December 2022

AbstractBackgroundNeuroanatomical atrophy profile is increasingly recognized as a valuable characterization in mild cognitive impairment (MCI) individuals and may provide prognostic information about cognitive decline.Method1153 MCI participants from the MEMENTO memory clinic study with 48‐month longitudinal follow‐up were included (mean (sd) Age=70.6 (8.2), 60% female, CDR‐SB=0.63 (0.72)). QyScore® volumetric quantification was applied to baseline 3DT1 images and four recognized neuroanatomical subtypes defined based on regional atrophy with respect to an internal normative database (z<‐1.64) [1,2]: no/minimal atrophy [N‐] (n=1,012), limbic predominant: LP (n=37), hippocampal sparing: HS (n=84) and combined hippocampal and cortical atrophy [typical/diffuse: TD] (n=20). 145 participants were amyloid positive (A+) via CSF or PET (Age = 73.7 (5.9): 47% female: N‐=114, LP=8, HS=21 and TD=2). All participants underwent cognitive and functional assessments at baseline and 48 months, including mini‐mental state examination (MMSE), clinical dementia rating (CDR), Free and Cued Selective Reminding Test (FCRST) and Instrumental Activities of Daily Living (IADL) scale. Linear regression analysis (correcting for age, sex and baseline performance) investigated the relationship between baseline neuroanatomical subtype and subsequent 4‐year cognitive decline. Bonferroni correction was applied.ResultAt month 48, all subtypes demonstrated significant decline across memory, orientation, and executive function. Severity of decline varied across subscales and subtype and was particularly marked in A+ LP individuals (Figure 1). IADL remained stable for the N‐ and TD subgroups. 143 participants converted to dementia [102=N‐, 18=LP, 15=HS, and 8=TD subtypes, representing 10%, 49%, 18% and 40% of the total N‐, LP, HS and TD atrophy subtypes respectively]. HS and N‐ individuals also demonstrated the least decline across all domains and did not significantly differ on any tests. LP atrophy subtype demonstrated the greatest decline across all cognitive domains as well as global CDR and IADL (p<0.001 compared with N‐ and HS subtypes). Similarly, TD phenotypes showed significant decline across multiple cognitive subscales compared with N‐ and HS subtypes (p<0.001) particularly for orientation and global CDR.ConclusionEarly atrophy profiles in MCI populations can provide insights into the domains and severity of future patient progression over 4 years.[1] Planche et al., (2020)[2] Schwarz et al., (AAIC2022)
Assessing a Network‐Specific Polygenic Risk Score for Alzheimer’s Disease in the Midwestern Amish and Across Diverse Ancestries
Authors: Osterman Michael D. , Song Yeunjoo E. , Wheeler Nicholas R. , Laux Renee A. , Adams Larry D. , Caywood Laura J. , Prough Michael B. , Clouse Jason E. , Herington Sharlene D. , Slifer Susan H. , Lynn Audrey , Bartlett Jacquelaine , Fuzzell M. Denise , Fuzzell Sarada L. , Hochstetler Sherri D. , Miskimen Kristy L. , Main Leighanne R. , Dorfsman Daniel A. , Ogrocki Paula K. , Lerner Alan J. , Vance Jeffery M. , Cuccaro Michael L. , Bush William S. , Scott William K. , Pericak‐Vance Margaret A. , Haines Jonathan L. ,   Alzheimer's Disease Sequencing Project (ADSP)
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD), the most common type of dementia, has a complex etiology with a strong genetic component. Many genetic risk variants for AD have been identified including APOE, the largest known genetic risk factor. However, most of this research has examined only broad populations of individuals with European ancestry and there is mounting evidence that effect sizes vary by population. Here, we investigate the transferability of polygenic risk scores (PRSs), including a network‐specific PRS, in the midwestern Amish and across diverse ancestries.MethodData from 1,091 Amish adults with AD diagnosis by consensus were considered for analysis from the Collaborative Amish Aging & Memory Project. Genotype data (Illumina GSA and MEGAEX) were imputed using the Haplotype Reference Consortium panel. We also analyzed 15,745 individuals from the Alzheimer’s Disease Sequencing Project (ADSP) r3 with three predominant race/ethnicity groups: African American (AA; n=2,937), Hispanic (n=3,047), and non‐Hispanic White (NHW; n=9,708). An AD network‐specific PRS was constructed by including variants from AD‐implicated molecular networks in the Kyoto Encyclopedia of Genes and Genomes. A comprehensive pruning and thresholding PRS considering all variants was calculated for comparison. Effect estimates from Kunkle et al. (2019) were used. PRS‐only models, sex and age covariate‐only, and full models were constructed for each group and the full ADSP data.ResultWe observed that PRS‐only predictive ability was similar between the comprehensive PRS (AUC=0.56) and the network‐specific PRS (AUC=0.55) in the full ADSP r3 data. Network‐specific PRS performance was similar in the Amish (AUC=0.55). However, we observed better predictive ability with the comprehensive PRS compared to the network‐specific PRS in each of the subgroups (Amish AUC: 0.61 vs. 0.55; NHW: 0.70 vs. 0.53; AA: 0.56 vs. 0.53, Hispanic: 0.61 vs. 0.56). These trends were consistent after inclusion of sex and age covariates.ConclusionWe demonstrated that a network‐specific PRS performed similarly to a comprehensive PRS in a combined diverse population and the Amish but confers less predictive ability when investigating individual subgroups. Thus, the network‐specific PRS has potential as a component of a risk model in diverse populations because it may successfully account for effects that are consistent across subgroups.
The M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator (PAM) VU0453595 and M4 PAM VU0467154 Normalize Sleep‐Wake Architecture Deficits in Aged Mice
Authors: Russell Jason K , Bubser Michael , Ingram Shalonda , Newhouse Paul A , Lindsley Craig W , Jones Carrie K 
Published: December 2022

AbstractBackgroundDeclining basal forebrain cholinergic integrity has been associated with disturbances in sleep‐wake architecture in Alzheimer’s Disease (AD). Acetylcholinesterase inhibitors (AChEIs) provide symptomatic treatment for the cognitive deficits in AD through nonselective enhancement of cholinergic signaling. Additionally, AChEIs promote wakefulness, but reduce NREM sleep quality and produce dose limiting side effects through nonselective activation of peripheral muscarinic acetylcholine receptors (mAChR). Selectively targeting different mAChRs with positive allosteric modulators (PAMs) provides an alternate approach. In the current study, we assessed the effects of the M1 PAM VU0453595 and the M4 PAM VU0467154 on sleep‐wake architecture and arousal following dosing across the circadian cycle in aged mice.MethodsYoung (3‐4 month‐old, n = 13‐14 per group) and aged (19‐21 month‐old, n = 14 per group) C57/BL6 mice were implanted with HD‐X02 telemetry devices (DSI) for electroencephalography (EEG) recording. The M1 PAM VU0453595 (3‐30mg/kg IP) or the M4 PAM VU0467154 (1‐30mg/kg IP) were dosed 2‐hours into the active or inactive phases of the circadian cycle. EEG was recorded for 24‐hours, with sleep stages scored in 5‐second epochs. Arousal was assessed through changes in gamma power during wake, and sleep quality was measured through changes in delta power during NREM sleep. Statistical comparisons involved repeated measures one‐ or two‐way ANOVAs as appropriate, with Dunnett’s or Sidak’s multiple comparisons applied in all cases.ResultsThe M1 PAM VU0453595 increased wakefulness and arousal with inactive phase dosing in young and aged mice. During the active phase, VU0453595 increased wakefulness and arousal only in aged mice. The M4 PAM VU0467154 increased NREM sleep in young and aged mice when dosed in both phases. In the inactive phase, suppression of REM sleep in young and aged mice is also observed. During NREM sleep, VU0467154 increased delta power in young and aged mice.ConclusionThese findings suggest that M1 and M4 PAMs may be valuable as treatments in AD at different phases of the circadian cycle. M1 PAMs could be beneficial with morning dosing in clinical populations as they enhanced wakefulness and arousal. M4 PAMs could be advantageous with evening dosing in clinical population as they enhanced NREM sleep quantity and quality.