bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frailty and Alzheimer’s Disease Related Plasma Biomarkers in Men from Midlife to Early Old Age
Authors: Franz Carol E , Buchholz Erik , Kremen William S. 
Published: December 2022

AbstractBackgroundAbout 7 million older American adults are affected by frailty (Bandeen‐Roche et al., 2015). Frailty places older adults at an increased risk of adverse physical and mental health outcomes, including Alzheimer’s Disease (AD). However, prior to old age, frailty or its relationship to AD biomarkers such as beta‐amyloid 40 and 42 (Aβ40, Aβ42), tau, and neurofilament light (NfL) are understudied.MethodParticipants in this prospective longitudinal observational study were community‐based men of predominantly European ancestry. Data were collected across 3 waves at average ages 56 (2002‐08), 62 (2009‐14), and 68 (2016‐19). We calculated frailty index (FI) scores using 37 out of 49 items from an index previously validated in the UK Biobank (Williams et al. 2019; Jiang et al. 2017) which assesses health deficits across multiple physiological systems. FI is calculated as a proportion of deficits out of the total, with scores ranging from 0 (no deficits) to 1 (all deficits present). AD‐related plasma biomarkers for Aβ40,and Aβ42, total tau, and NfL were assayed at average ages 56 and 68. Biomarker values were adjusted for study site and storage time.ResultAverage FI score at age 56 was .2, equivalent to having about 7 health deficits. Frailty was significantly correlated (rs=.67‐.74) over time. Higher frailty at both age 56 and 62 doubled the risk for mortality across the 12 years of the study. Age 56 frailty was significantly associated with age 56 tau. Age 68 frailty was significantly associated with age 68 NfL, tau, Aβ40 and Aβ42. In models adjusted for age, education, and ethnicity, age 56 frailty predicted age 68 NfL (B=0.64, t=2.72, p=0.007); associations with age 68 Aβ40 (B=0.39, t=1.96, p=0.0513) and Aβ42 were attenuated (B=0.27, t=1.79, p=0.0743). Age 62 frailty mediated associations between age 56 tau and age 68 tau and NfL, but not other biomarkers.ConclusionThe results are striking given the relatively young age of the sample. Even as early as one’s 50s, links between frailty and increased risk for AD emerged. Public health groups have recommended routine frailty screening in adults over 65, but it may be important to start screenings earlier.
Interrogating the role of APOE4 in Alzheimer’s disease and Down syndrome using human induced pluripotent stem cells (hiPSC)‐derived cerebral organoids
Authors: Dooling Breanna , Johnson Noah R , Joshi Molishree , Vielle Anne , Vergara M. Natalia , Potter Huntington 
Published: December 2022

AbstractBackgroundNearly all adults with Down syndrome (DS) will develop Alzheimer’s disease (AD) brain pathology by their 40s, and most will become demented by age 50‐60. The inheritance of the apolipoprotein E (apoE) ε4 allele (APOE4) is the strongest risk factor for AD other than age, whereas the ε3 allele (APOE3) does not change AD risk. ApoE is a cholesterol carrier protein, and APOE4‐positive astrocytes have been demonstrated to exhibit impaired cholesterol transport. ApoE4 has also been shown to catalyze amyloid‐beta (Aβ) polymerization. As such, the APOE4 genotype is associated with earlier and more rapid cognitive decline in individuals with DS. Understanding the molecular changes in AD neuropathology resulting from APOE4 in DS would aid in the development of therapies to alleviate dementia risk, especially in individuals with DS.MethodWe used CRISPR‐Cas9 editing to modify DS hiPSCs, or isogenic control hiPSCs disomic for chromosome 21, from an APOE3/3 genotype to APOE4/4, or to knock out the APOE gene. We developed cerebral organoids (COs) to test the effects of APOE4 on a three‐dimensional in vitro model system of AD pathology in DS. As a preliminary investigation, we also exogenously treated COs with each apoE isoform for 90 days in the culture medium to examine their effects on AD‐related pathologies.ResultOur preliminary investigation of exogenous apoE exposure of DS and control COs revealed a significant increase in apoE expression/accumulation in DS organoids, but not in control organoids, at 90 days in vitro. Amyloid‐beta production/deposition were also differentially regulated in DS and control organoids, as evaluated by immunoblotting and immunohistochemical analyses. There were also significant size differences between DS and HC organoids. These initial findings support continued investigation of APOE genotype and AD pathology in DS and control COs.ConclusionInterrogation of APOE4‐driven AD pathologies will enable the development of more targeted and proactive therapies to improve the quality of life for individuals who harbor this risk allele. Understanding differences in AD pathology in individuals with DS could enable the prevention of dementia in individuals with DS, and further elucidate the pathways by which APOE acts in conferring AD risk.
Physical Activity, Stress and Cognitive Concerns During the COVID‐19 Pandemic Among Older Adults in the United States
Authors: Guzman‐Velez Edmarie , Torres Valeria L. , Martinez Jairo E. , Vila‐Castelar Clara , Fox‐Fuller Joshua T. , Pardilla‐Delgado Enmanuelle , Pluim Celina F. , Babulal Ganesh M , Ramirez‐Gomez Liliana A. , Munera Diana , Quiroz Yakeel T. 
Published: December 2022

AbstractBackgroundThe COVID‐19 pandemic has increased psychological distress. Research shows that physical activity can reduce emotional distress and improve cognitive functioning. Yet, the pandemic has limited opportunities to engage in physical activity. In this study, we examined whether older adults who maintained physical activity during the pandemic perceived less subjective cognitive concerns and better emotional distress management compared to those who reduced or did not engage in activity. 8Method80 adults (ages 55‐94 years) from the community completed an online survey. Subjective cognitive concerns were measured using the Everyday Cognition Scale. Physical activity was measured with the question, “Have you maintained your physical activities during social isolation?” and answers were grouped into yes, no, or partially. Emotional distress was measured with the question, “How well you think you have been able to manage your emotions, worries and stress, and answers were grouped into good/very good, regular, or bad/very bad.Result54% of participants reported having maintained or increased their physical activity levels, 33% partially maintained their usual levels, and 13% reduced or did not engage in activity. 64% reported that they were managing their emotions, worry and stress good/very good, 30% regular, and 6% bad/very bad. Participants who maintained or increased their physical activity levels reported less cognitive concerns and greater ability to manage their emotions, worry and stress, compared to those who reduced, partially or did not engage in physical activity.ConclusionEncouraging individuals and providing resources for increasing physical activity may help mitigate some of the pandemic’s adverse effects on psychological well‐being.
Functional Outcomes of a Comprehensive, Individualized, Person‐Centered Management Program in Advanced Alzheimer’s Disease(AD): Results from a 52‐Week Randomized Controlled Trial
Authors: Kenowsky Sunnie , Shao Yongzhao , Zhang Qiao , Dafflisio Gianna , Vedvyas Alok , Vedvyas Gaurav , Golomb James B. , Torossian Carol , Marsh Karyn , Heller Sloane , Sadowski Martin J. , Reisberg Barry 
Published: December 2022

AbstractBackgroundWe conducted a 28‐week, single‐blind, randomized, controlled trial of the efficacy of Comprehensive, Individualized, Person‐Centered Management (CI‐PCM) and memantine treatment (Reisberg et al., Dement Geriatr Cogn Disord, 2017) in advanced AD persons. CI‐PCM and memantine was approximately 7.5 times more beneficial to AD persons on the Functional Assessment Staging Tool (FAST) (Kenowsky et. al., Alzheimer’s and Dementia, 2017) than to AD persons who received memantine alone in the memantine FDA approval pivotal trial conducted by Reisberg et. al., (NEJM 2003). We also conducted a 24‐week extension study. Herein, we report the difference in functional outcomes between the CI‐PCM and Usual Community Care (UCC+FC) groups at 52‐weeks on the FAST and the ADCS‐ADLSev‐Abv. See Figures 1 and 2.MethodAfter screening, 20 eligible subject‐carepartner dyads were randomized equally to the CI‐PCM and UCC+FC groups. All 20 dyads completed the 28‐week study and entered the 24‐week extension study. One subject in the UCC+FC group died during the extension study. The FAST and ADCS‐ADLsev‐abv were conducted at baseline, and weeks 4, 12, 28, and 52. P values were calculated using the Wilcoxon Mann Whitney test.ResultThe mean FAST total score from baseline (6.6±0.1SE) to week 52 (6.5±0.01SE) showed an improvement of functional limitations in the CI‐PCM group. The mean FAST total score for the UCC+FC group showed a functional decline from baseline (6.6±0.1SE) to week 52 (6.8±0.1SE), displaying a robustly significant difference between the two groups (p<0.0014). The mean ADCS‐ADL‐sev‐abv total score for the CI‐PCM group demonstrated a 20.9% improvement in functioning from baseline (15.3±2.0SE) to week 52 (18.5±2.5SE). The mean ADCS‐ADL‐sev‐abv total score for the UCC+FC group showed a decline of 48.6% from baseline (14.8±2.1SE) to week 52 (7.6±2.3SE), indicating a significant difference between the two groups (p<0.009).ConclusionThe CI‐PCM program is the only evidenced‐based treatment to date that can significantly improve and reverse functional deterioration in advanced AD persons. The functional success of the CI‐PCM program may primarily be attributed to care partners learning to memory coach AD persons to perform daily activities such as bathing, dressing, feeding and toileting themselves, and to become/maintain urinary and fecal continence.
Optogenetic model of tau aggregation for tauopathies
Authors: Hurtle Bryan , Donnelly Christopher , Zhang Xin , Thathiah Amantha 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) and >20 other dementias, termed tauopathies, are pathologically defined by insoluble aggregates of the microtubule‐associated protein tau (MAPT). A predictive relationship between the onset and progression of clinical AD symptoms correlates with post‐translational modifications of tau in cerebrospinal fluid and tau aggregation in the brains of AD patients. However, the biological basis for the transition of tau from a microtubule‐associated protein to an insoluble aggregate and the precise relationship between tau aggregation and neuronal dysfunction remains unknown. Recent studies have reported the development of photo‐inducible systems to control protein aggregation using photo‐oligomerizable proteins that self‐associate upon exposure to blue light. We hypothesized that the development of a photo‐inducible system, which permits temporal control of tau aggregation, would provide a novel tool to study the cause and consequence of tau aggregation.MethodsWe fused Vivid (VVD), a photoreceptor that self‐associates upon exposure to blue light, to full‐length (2N4R) tau, termed optoTAU. In addition, we generated optoTAU plasmids that contain other MAPT isoforms (e.g., 0N4R, 1N4R) and pro‐ and anti‐aggregation mutations in MAPT. We investigated the effect of blue stimulation on the soluble and insoluble aggregation of optoTAU in a cellular and neuronal model by immunoblot and immunocytochemical analysis.ResultsOptoTAU permits temporal control of tau aggregation that faithfully reproduces the isoform‐specific and dementia‐associated aggregation properties of tau. OptoTAU provides a platform to visualize the transition of tau from a soluble to an insoluble aggregate in a cellular model of tau aggregation.ConclusionsOptoTAU is a biologically‐relevant model to investigate modifiers of tau pathobiology in AD and other tauopathies and is a drug discovery platform to identify pharmacological modifiers of tau aggregation.
Cerebrospinal Fluid Markers of Neurodegeneration Associated with Postoperative Delirium in an Older Elective Arthroplasty Population
Authors: Sweeney Aoife , Passmore Anthony Peter , Beverland David , McGuinness Bernadette , McAuley Daniel F , Mawhinney Tim , Schott Jonathan M , Heslegrave Amanda , Zetterberg Henrik , Cunningham Emma L 
Published: December 2022

AbstractBackgroundPostoperative delirium (POD) is associated with subsequent cognitive decline. It is not yet clear to what extent that is because delirium indicates underlying neurodegeneration.MethodAn observational cohort study of POD in an elective arthroplasty population recruited 315 individuals. All participants were community‐dwelling adults aged over 65, without a diagnosis of dementia, undergoing hip or knee replacements. Cerebrospinal fluid (CSF) was sampled pre‐operatively at the time of spinal anaesthesia and delirium was assessed daily on days 1‐3 postoperatively. Stored CSF samples (n = 270) were analysed for markers of inflammation and neurodegeneration. Statistical analysis was carried out to determine associations of these CSF markers with POD.ResultThose who developed POD (n = 44) had significantly higher levels of CSF glial fibrillary acidic protein (GFAP; p=0.04), a marker of inflammation; CSF neurofilament light (NFL; p=0.04), a marker of axonal degeneration; and CSF triggering receptor expressed on myeloid cells 2 (sTREM2; p=0.02), a marker of age‐related neuroinflammation and tau‐related neurodegeneration and significantly lower levels of CSF amyloid‐beta 1‐42 (Aβ42; p=0.01) and CSF Aβ42/40 ratio (p=0.01) compared to participants who did not develop POD.ConclusionSignificantly higher levels of preoperative neurodegenerative CSF markers associated with dementia were found in those who developed POD following elective arthroplasty surgery. This suggests that people, without a pre‐existing diagnosis of dementia, who develop POD after elective arthroplasty surgery are more likely to have underlying neurodegeneration.
Extent ‐ A Global Spatial Distribution Measure to Estimate Progression and Demonstrate Treatment Effect in Flortaucipir Scans
Authors: Kotari Vikas , Southekal Sudeepti , Kennedy Ian Andrew , Morris Amanda , Pontecorvo Michael J. 
Published: December 2022

AbstractBackgroundWe previously reported that donanemab slows global and regional increase in flortaucipir standardized uptake value ratios (SUVRs)1. In addition to SUVR, a method to estimate spatial distribution of flortaucipir (FTP) uptake might provide valuable and complementary information. Here, we apply the previously developed Extent method to estimate the spread of FTP uptake in PET images and present comparisons against neocortical SUVR for the measurement of treatment effect in the TRAILBLAZER‐ALZ trial. We performed vertex‐wise statistical comparisons.MethodSubjects in the phase 2 TRAILBLAZER‐ALZ study completed FTP and florbetapir PET scans and MRIs at baseline and 18‐months. Flortaucipir images were processed using standard techniques2 and normalized to the cerebellum crustaneous reference region3. Each FTP image was converted to a z‐score image relative to sixteen young cognitively normal (YCN) subjects. Clusters with z‐scores smaller than a false discovery rate corrected p‐value of 0.01 were retained within a predefined neocortical mask. The neocortical mask and thresholds were selected based on previous data to maximize signal to noise ratio in 18‐month change of mild AD subjects. Extent is the ratio of voxels in this predefined mask that have abnormally elevated tau, defined as at least 2.32*SD above the mean of YCNs (values range between 0‐1). The primary outcome was 18‐month change in Extent and MUBADA2 SUVR between placebos and donanemab treated subjects. We performed vertex‐wise group comparisons to capture the differences in tau burden.ResultBoth Extent and MUBADA showed significant difference between treated and placebo subjects (Figure 1). The 18‐month change (SUVR and Extent) surface maps of the treated and placebo groups show larger spread of FTP in the superior, middle and medial orbito‐frontal regions (Figure 2 & 3). The difference and p‐value maps show clusters of vertices in the inferior temporal, parahippocampal, supramarginal, middle, medial and superior frontal regions as being significantly different.ConclusionSubjects treated with donanemab have significantly lesser flortaucipir distribution by Extent compared to placebo, and differences in surface maps of intensity and spread of FTP. Clusters in temporal, parietal, and frontal regions were significantly different. In addition to intensity differences, spatial distribution was different between treatment groups.
A novel machine learning technique using resting‐state EEG to assess and monitor cognitive impairment
Authors: Wu Yunan "Charles" , Quirk Colin , Brookshire Geoffrey , Gerrol Spencer , Merrill David A. , Caselli Richard J. , Lucero Ché 
Published: December 2022

AbstractBackgroundMonitoring changes in cognitive impairment is an important aspect of care for aging patients. Traditionally, this is done with pen‐and‐paper assessments such as the Mini‐Mental State Exam (MMSE). EEG is a low‐cost and widely available neurophysiology tool that provides a data‐rich measure of brain health, but signal complexity has limited its impact. Advances in machine learning bring new possibilities to decode those complex signals and leverage EEG in patient care. Here, we engineer novel EEG features for assessing brain health with the [Banded Fractal Variability] (BFV) technique. We use [BFV] and other EEG metrics to assess patients’ cognitive function via a continuous score (a [Cognitive Impairment Index], or [CII]). We validate the diagnostic value of the EEG features by comparing our model against reduced models lacking the EEG features.MethodThe patient sample (N=97, mean (sd) age = 69.1 (11.0), 52.6% female) was collected at the Pacific Brain Health Center. Diagnostic categories included subjective cognitive impairment (n=44), mild cognitive impairment (n=26), and dementia (n=27). Mixed disease (AD, DLB, FTD, vascular, diabetes) was common in the impaired sample, and 39.6% were diagnosed with AD. We developed a continuous [CII] model trained on patients’ MMSE scores (range = 11 to 30, mean = 26.6) using a gradient boosting model with [Banded Fractal Variability] and other EEG features computed from clinical wake EEGs. Model development and testing took place within a rigorous nested cross‐validation (NCV) procedure to prevent overfitting. Performance was compared to reduced (no‐EEG features) models using the non‐parametric Wilcoxon sign‐rank test.ResultThe approach showed a Mean Absolute Error of 1.98 (sd = 0.28) across 5 test folds in the NCV outer loops, significantly outperforming both the baseline intercept‐only model (p = 0.031) and the demographics (age and years of education) model (p = 0.031).ConclusionThese preliminary results suggest that our [CII] derived from machine‐learning and quantitative EEG using [BFV] is a viable approach to assess and track patients’ cognitive impairment regardless of disease status across all impairment levels, raising the possibility that a brief EEG scan could shed light on patient health normally accessible only through extensive cognitive and neuropsychological testing.
Mosaic Loss of Chromosome Y in Peripheral Blood Cells and Cognitive Status in the Amish
Authors: Song Yeunjoo E. , Miskimen Kristy L. , Laux Renee A. , Fuzzell M. Denise , Fuzzell Sarada L. , Miller Sherri D. , Main Leighanne R. , Osterman Michael D. , Lynn Audrey , Prough Michael B. , Slifer Susan H. , Adams Larry D. , Caywood Laura J. , Clouse Jason E. , Herington Sharlene D. , Dorfsman Daniel A. , Vance Jeffery M. , Cuccaro Michael L. , Ogrocki Paula K. , Lerner Alan J. , Scott William K. , Pericak‐Vance Margaret A. , Bush William S. , Haines Jonathan L. 
Published: December 2022

AbstractBackgroundMosaic loss of chromosome Y (mLOY) refers to acquired aneuploidy in a fraction of somatic cells. In aging men, has been suggested as a possible biomarker for increased risk of numerous diseases, including Alzheimer’s disease (AD). We investigated mLOY as a risk factor for AD in the Mid‐Western Amish, a founder population with homogeneous lifestyle, reducing the effect of confounding environmental factors.MethodThe median of the log R ratio (mLRRY) from SNP array data within the male‐specific region of chromosome Y was used to measure the degree of mLOY. A mLRRY value lower than the 99% confidence limit of the experimental distribution was scored to estimate the frequency of mLOY. The cognitive status was assigned via consensus review of cognitive examination results. Men in 3 age groups (65‐74, 75‐84, >=85) were included. The linear mixed model with a polygenic component to account for relatedness and a transformation to address non‐normality was used to estimate familial correlations and heritability. A likelihood ratio test of association was performed with age at blood sampling and age of cognitive exam as covariates.ResultAfter extensive QC, 533 participants (mean age=75.42±6.17) were included and 39 (7.9%) had a detectable level of mLOY. mLOY frequency increased with age (p<1.0x10‐6): 1.0% (65‐74; n=103), 8.4% (75‐84; n=334) and 14.3% (85+; n=96). Heritability of mLOY was 0.53 and the residual sibling correlation was 0.27 (n=201, p<1.0x10‐2). A subset of 423 individuals were assigned to the cognitively impaired (n=134) or unimpaired (n=289) groups and mLOY was significantly higher in the cognitively impaired group (p<0.0001). .ConclusionThe sibling correlation was significant for mLOY. We observed the same trend as reported in other European descent populations: mLOY increased with age and was more frequent in cognitively impaired individuals. The frequency of mLOY in Amish was lower than reported, overall and in each age stratum. Our results along with the lower prevalence of AD in Amish reinforces as a promising biomarker for the risk of AD.