bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal cascades of Alzheimer disease biomarkers across the entire adult lifespan among cognitively normal adults
Authors: Xiong Chengjie , Luo Jingqin , Agboola Folasade , Grant Elizabeth A. , Masters Colin L. , Albert Marilyn S. , Johnson Sterling C. , McDade Eric , Fagan Anne M. , Benzinger Tammie L.S. , Hassenstab Jason , Bateman Randall J. , Moulder Krista L. , Perrin Richard J. , Cruchaga Carlos , Morris John C. 
Published: December 2021

AbstractBackgroundThe temporal cascade of Alzheimer disease (AD) biomarkers among cognitively normal individuals, including cerebral spinal fluid (CSF) Aβ42, Aβ40, total tau (Tau) and phosphorylated tau (pTau), standardized uptake value ratio (SUVR) from the molecular imaging of cerebral fibrillar β‐amyloid with positron emission tomography (PET) using the [11C] benzothiazole tracer, Pittsburgh Compound‐B (PiB), magnetic resonance imaging (MRI)‐based hippocampal volume and cortical thickness, and cognition has been hypothesized, but not yet fully tested with longitudinal data.MethodLeveraging a large harmonized database of 2703 cognitively normal individuals 18 to 103 years of age from 8 longitudinal studies with a median follow up of 5∼6 years, we estimated the longitudinal trajectories of all major AD biomarkers as functions of baseline age, located the age window at which the longitudinal change accelerated by comparing it across adjacent age bins, and examined possible modifying effects of apolipoprotein E (APOE) genotypes.ResultParticipants 18 to 45 years of age at baseline exhibited ‘learning effects’ on both cognition and all but the MRI‐based biomarkers. The earliest acceleration of longitudinal change occurred for CSF Aβ42 and Aβ42/Aβ40 ratio at the baseline age of 45 to 50 years, followed by hippocampal volume at the baseline age of 55 to 60 years, further by CSF Tau, PET PiB mean cortical SUVR, cortical thickness, and cognition at the baseline age of 65 to 70 years. The accelerated longitudinal changes remained in the covariate‐adjusted analyses. APOE ε4 modified the observed ‘learning effects’ from 18 to 45 years. Further, there was preliminary evidence that APOE ε4 carriers may have experienced the first significant acceleration of the longitudinal change in almost all major AD markers within the baseline age window of 45 to 55 years, whereas among APOE ε4 non‐carriers, only PiB PET SUVRs and cortical thickness and the cognitive composite showed the earliest longitudinal acceleration of change at the same baseline age interval.ConclusionOur results characterize the temporal cascades of longitudinal changes for all major AD biomarkers across entire adult lifespan, and address the modifying effect of APOE ε4. These findings may better inform the design of prevention trials on AD.
Encouraging interim results at 9 months from an open‐label study of simufilam in patients with Alzheimer’s disease
Authors: Burns Lindsay H , Doehner Tamara , Puente John , Beck Brian , Gonzalez‐Rojas Yaneicy , Lopez‐Brignoni Evelyn , Nikolov Boris , Wang Hoau‐Yan , Pei Zhe , Hernandez Antonio , Crowley Carrie A , Friedmann Nadav 
Published: December 2021

AbstractBackgroundSimufilam is a novel drug candidate for Alzheimer’s disease (AD). This small molecule reverses an altered conformation of filamin A in the AD brain, reducing tau hyperphosphorylation and neuroinflammation initiated by Aβ42. In a prior randomized, controlled trial in 64 patients with mild‐to‐moderate AD, simufilam significantly improved eleven CSF biomarkers of AD pathology, neurodegeneration, neuroinflammation and blood‐brain barrier integrity over 28 days, with no safety issues. A one‐year, open‐label, multi‐center study is now evaluating simufilam’s long‐term safety and tolerability and following cognition and neuropsychiatric symptoms of dementia. The study has pre‐planned interim analyses at 6 and 9 months.MethodApproximately 150 patients with mild‐to‐moderate AD, MMSE 16 to 26, will be enrolled across 16 sites in the US and Canada. Study participants receive 100 mg twice‐daily oral simufilam for one year. In addition to safety, patients are assessed on the 11‐item Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog11) and the 10‐item Neuropsychiatric Inventory (NPI10).ResultInterim results summarize data from the first 50 patients to complete at least 9 months of treatment. Simufilam was safe and well‐tolerated, consistent with prior safety results. Six months of treatment improved patients’ cognition scores by ‐1.6 points on ADAS‐Cog11, a 10% mean improvement from baseline (negative score indicates improvement). At 9 months, ADAS‐Cog11 scores improved by ‐3.0 points, a 19% mean improvement from baseline. At 9 months, 69% of patients showed improved or stable ADAS‐Cog11 scores from baseline. Mean baseline ADAS‐Cog11 score for these 50 patients was 16. Mean baseline MMSE was 22. Six months of treatment also improved NPI scores by ‐1.3 points, a 29% mean improvement from baseline (negative score indicates improvement). At 9 months, NPI scores improved by ‐0.7 points, a 16% mean improvement from baseline. At 9 months, 76% of patients showed improved or stable NPI scores from baseline. Mean baseline NPI10 score was 4.5.ConclusionInterim analyses at 6 and 9 months indicate open‐label treatment with simufilam 100 mg improved scores of cognition and neuropsychiatric symptoms in patients with Alzheimer’s disease, with no safety issues. This work was funded by NIA grant AG065152.
Investigating white matter connectomes in amnestic and non‐amnestic Alzheimer's disease clinical variants
Authors: Bharne Pandurang R. , Kinney Nikolas G. , Da Re Fulvio , Spotorno Nicola , Olm Christopher A. , Cook Philip , Irwin David J. , McMillan Corey T. , Grossman Murray , Phillips Jeffrey S. 
Published: December 2021

AbstractBackgroundRecent models propose that spread of Alzheimer's disease (AD) pathology may be mediated by white matter connectivity. AD clinical variants exhibit partially distinct patterns of gray matter atrophy. However, it is less clear whether phenotypic differences extend to patients' white matter connectomes. We hypothesized that white matter connectivity would differ between healthy controls, amnestic AD (aAD), and non‐amnestic AD (naAD), including behavioral variant Alzheimer's disease (bvAD), logopenic‐variant primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA).MethodWe examined white matter connectomes in 194 participants (controls=60, aAD=42, bvAD=25, lvPPA=39, PCA=28). All participants with dementia had evidence of AD pathologic change based on autopsy, Aβ1–42 from cerebrospinal fluid, or [18]F‐florbetaben positron emission tomography. T1‐weighted and diffusion tensor images were collected using a 3 Tesla scanner. We calculated gray matter volume for cortical regions of interest and median fractional anisotropy (FA) for the tract connecting every pair of regions. Tracts with the most variable FA values across participants were excluded to yield graphs with 30% density. Linear regressions adjusted for sex and age were used to investigate group differences in degree and betweenness centrality as well as the relationship between gray matter volume and FA measures. Phenotypic differences in tractwise FA were evaluated using t‐tests.ResultBoth node and edge metrics indicated significant (p<.05, corrected) widespread differences between patient groups and controls. In contrasts between disease groups, aAD patients had reduced degree in multiple occipital and inferior temporal regions; and higher betweenness centrality in bilateral frontal and parietal regions relative to naAD phenotypes. Tractwise FA values did not differ between patient groups. Across groups, endpoint gray matter volume was correlated with tractwise FA measures.ConclusionBoth node‐ and edge‐based metrics suggested patients’ white matter connectomes exhibited degeneration relative to controls. Phenotypic differences between patient populations were few, suggesting that AD clinical variants with distinct patterns of gray matter disease nevertheless had broadly similar patterns of white matter degeneration. Gray matter atrophy was closely associated with lower values of FA of white matter tracts connecting atrophied regions, consistent with Wallerian degeneration of white matter.
Neighborhood environment and cognition in older adults: Exploring the mediating effect of physical activity
Authors: Fausto Bernadette A , Yu Kexin 
Published: December 2021

AbstractBackgroundEmerging evidence suggests neighborhood environment may shape both health behaviors and outcomes. Neighborhood environment could be particularly influential for community‐dwelling older adults who prefer to age in place. Recent studies report that neighborhood social and built environment characteristics significantly influence older adults’ cognition. However, the underlying mechanisms by which neighborhood environment affects cognition are not well understood. Regular physical activity in late life is associated with a lower risk for cognitive decline and may be affected by neighborhood amenities and resources. This study examined how the neighborhood social and built environment affects cognition in older adulthood and explored whether physical activity levels mediated these relationships.MethodThe cross‐sectional analyses included older adults from Wave 2 of the National Social Life, Health, and Aging Project (N = 3,196; mean age = 73.17, SD = 7.34; 52.6% female; median education = high school diploma; 77.3% Caucasian). We tested a structural equation model to examine associations among neighborhood social and built environment and cognition as measured by the Montreal Cognitive Assessment. Built environment was operationalized as a latent variable of living density, litter, noise, traffic, pollution, and conditions of respondents’ building and other buildings nearby. The social environment latent variable was constructed with social cohesion, social ties, and perceived neighborhood danger. We tested whether self‐reported frequency of rigorous physical activity mediated these environment‐cognition relationships.ResultThe results indicated (1) greater disadvantages in the neighborhood built environment were associated with worse cognition (est = ‐0.05, p < .001) and with lower levels of physical activity (est = ‐0.03, p = .001); (2) greater advantages in the neighborhood social environment were associated with better cognition (est = 0.03, p < .001) and higher levels of physical activity (est = 0.02, p < .001); however, (3) physical activity levels were not significantly associated with cognition (est = ‐0.02, p = .17).ConclusionThese results highlight the influence of neighborhood environment on both physical activity and cognition in older adulthood. While physical activity was not an underlying mechanism by which environment influences cognition, future studies should test for mediation using objectively‐measured physical activity.
Analysis of exclusion criteria in NIA‐funded Alzheimer’s disease and Alzheimer’s disease‐related dementias clinical trials
Authors: Mitchell Alexandra K , Massett Holly A , Shakur Mujaahida , Lockett Jaron , Han Sae H 
Published: December 2021

AbstractBackgroundEligibility criteria are an integral component of clinical trials, ensuring participant safety and reducing factors that may confound results. Research suggests that unnecessarily restrictive exclusion criteria may disphroportionately exclude African Americans (AA) and Hispanics/Latinos (H/L), reduce generalizability, and prevent timely enrollment. This may be of particular concern for Alzheimer’s and related dementias (AD/ADRD), as AA and H/L are at greater risk than non‐Hispanic Whites for AD/ADRD yet underrepresented in clinical trials (CT). This abstract analyzes exclusion criteria proposed within active National Institute on Aging (NIA)‐funded AD/ADRD CTs (N=235) to document the most widely used criteria and to analyze the potential impact on AA and H/L CT participation.MethodCT exclusion criteria and study design were obtained from NIA grant folders and ClinicalTrials.gov. A codebook was developed using a sample of CTs to identify key exclusion categories (N=47 categories; intercoder reliability=92%) and used to code the 235 trials. A review of published literature was also conducted to identify which categories have documented ethno‐racial disparities (e.g., diabetes is more prevalent among H/L).ResultA median of 8 exclusion criteria were listed per CT (range=1‐41). The top categories/conditions were: 1) psychiatric (64% of trials, top ranked: depression, bipolar), 2) neurological (52%, top ranked: head/spinal injury, abnormal EEG/brain MRI), and 3) dementia/cognitive impairment (49%). Literature identifies almost half (47%) of all categories as disproportionately affecting AA and H/L, including psychological disorders and cardiovascular disease. Of 47 exclusion categories, AA have the potential to be disproportionately eliminated by 19 categories (40%) and H/L by 16 (34%). Additional analyses will be presented by trial population, phase, enrollment, and intervention type.ConclusionOur findings demonstrate commonly used exclusion criteria in active NIA‐funded AD/ADRD CTs. We found many criteria that disproportionately affect AA and H/L, which may play a role in their reduced enrollment in AD/ADRD trials. Similar to an effort in the oncology field (Kim, 2017), AD/ADRD stakeholders should undertake a concerted effort to jointly address the use of overly restrictive criteria, advocate for the use of clear rationale when establishing criteria, and implement more equitable, scientifically justified exclusion criteria for AD/ADRD CTs.
HDL particle morphology in Alzheimer’s disease patients compared to healthy human subjects and chemically modified HDL
Authors: Zheng Jack Jingyuan , Hong Brian V. , Agus Joanne , Guo Fei , Cavicchi Richard E. , Jin Lee‐Way , Maezawa Izumi , Lebrilla Carlito B. , Harvey Danielle J. , Zivkovic Angela M. 
Published: December 2021

AbstractBackgroundIn various chronic diseases including Alzheimer’s disease, a common clinical manifestation is defective high‐density lipoprotein (HDL) status. Published evidence suggests that HDL particles from Alzheimer’s patients are functionally deficient, as measured by impaired cholesterol efflux capacity. However, the structural and compositional alterations of HDL particles that contribute to this loss of function in Alzheimer’s disease are currently not well understood.MethodIn this study, we investigated the morphological characteristics of HDL particles from 7 patients confirmed with Alzheimer’s disease and 3 age‐matched healthy subjects using transmission electron microscopy. We also analyzed how oxidation, glycation, deglycosylation, and acidification alter the morphology of HDL isolated from healthy human subjects and compared these chemically treated HDL with HDL from Alzheimer’s patients and controls.ResultDistinct treatment‐specific variation patterns of HDL particles, including particle size change, aggregation, and disintegration, were observed. Most prominently, HDL incubated at a pH of 5.5 for 18 hours had an increased average HDL particle diameter from 10.65 ± 2.22 nm to 13.08 ± 2.77 nm (P<0.001). In addition, both glycation and oxidation treatment caused HDL to form aggregates. HDL isolated from patients with Alzheimer’s disease and age‐matched, cognitively normal subjects displayed aggregate structures that resembled those of chemically glycated and oxidized HDL. These aggregated HDL structures were found in both patients and controls.ConclusionFurther studies with larger sample sizes are needed to better characterize the morphological, structural, and compositional alterations that cause the loss of HDL function in patients with Alzheimer’s disease.
Persistent pain is associated with lower locus coeruleus integrity in older adults
Authors: Bell Tyler Reed , Elman Jeremy A. , Puckett Olivia K. , Franz Carol E. , Kremen William S. 
Published: December 2021

AbstractBackgroundPersistent pain has been recently linked to increased Alzheimer’s disease (AD) risk, calling for the identification of related AD biomarkers. One biomarker of interest is integrity of the locus coeruleus (LC), a brainstem region that is thought to be the earliest site of tau deposition in the brain. The LC is also the main projection site for norepinephrine (NE), a major neurotransmitter inhibiting pain via rostral and caudal LC projections. A recently proposed mechanism suggests that persistent pain alters LC‐NE function and advances AD pathology in this region, explaining increased AD risk. Here we examined the association between persistent pain and LC integrity in older adults.MethodData were derived from the Vietnam Era Twin Study of Aging (VETSA) in which community‐dwelling men were assessed across up to 12 years in 3 waves. At the third wave, 426 community‐dwelling men (mean age = 67.55) underwent MRI‐assessment sensitive to neuromelanin, a byproduct of LC NE production. Using neuromelanin signal intensities, we calculated contrast‐to‐noise ratios between LC regions (i.e., rostral and caudal) and a pontine tegmentum reference region. Higher contrast‐to‐noise ratios indicate better LC integrity. Persistent pain was defined as reporting 2 or more waves of moderate‐to‐severe pain on the SF‐36 Bodily Pain Scale (n = 80, 16.5%). Generalized linear models examined associations between persistent pain and LC integrity after weighting for survival effects and adjusting for demographic (i.e., age, race, young adult general cognitive ability, income) and health confounders (i.e., comorbidities, depressive symptoms, opioid use), and nested twin observations.ResultPersistent pain was associated with .21 standard deviation lower rostral LC integrity (95% CI: ‐.40 to ‐.03) and .23 standard deviation lower caudal LC integrity at the third wave (95% CI: ‐.44 to ‐.04).ConclusionPersistent pain was associated with worse LC integrity in older adults. Persistent pain related to worse integrity in both the rostral and caudal LC regions. These associations are consistent with the recent proposed mechanism emphasizing the role of pain on LC‐NE dysfunction, but this relationship may also be bidirectional. Longitudinal designs would be informative, as would studies looking at later dementia trajectories.
APOE ε4 allele status similarly predicts a latent dementia index as clinical diagnosis of dementia
Authors: Beam Christopher R , Saenz Joseph , Kim Alice J 
Published: December 2021

AbstractBackgroundLatent dementia index (LDI) variables are increasingly popular, mainly because they make it possible to quantify a continuous measure of dementia risk using cognitive and functional ability variables when no clinical gold standard is available. Validation studies of LDI variables tend to include clinical gold standard outcomes and demographic variables (e.g., age and gender). No studies to date, however, have validated LDI variables using APOE ε4 allele status. To the extent that effects are similar, we can claim greater convergent validity of the LDI. The purpose of this study is evaluate whether effects of APOE ε4 allele status on LDI is similar to effects of e4 status on clinical gold standard.MethodThe study included 856 participants from the 2001‐2003 Aging, Demographics, and Memory Study (ADAMS), a subsample from the United States Health and Retirement Study. Respondents completed a comprehensive neuropsychological battery, including tests evaluating cognitive ability across multiple cognitive domains (such as memory, executive function, orientation, attention, spatial ability, and language). Informants provided data on functional ability. The LDI was modeled as a latent variable indicated by task specific cognitive scores and functional ability tasks. Lower LDI scores indicate greater risk of dementia. APOE status was an ordinal variable to indicate the absence (0 alleles) or presence (1 or 2 alleles) of ε4 allele status. Clinical gold standard was determined by neuropsychological assessment, which included medical, functioning, cognitive, and physical exams. Regression analyses were performed to test the correlation between APOE ε4 allele status and both measures of dementia.ResultAPOE ε4 allele status significantly predicted clinical gold standard (OR: 1.44 [.95CI: 1.23, 1.69]). APOE ε4 allele status also significantly predicted LDI (β = ‐0.15, SE =0.04, p < .001). APOE ε4 allele status accounted for approximately half the amount of the variance in LDI (2%) as in clinical gold standard (3.6%).ConclusionBased on the similarity of the effects of APOE ε4 allele status on LDI and clinical gold standard, the LDI appears to be a valid continuous proxy measure of dementia.
Acute inositol‐stabilized arginine silicate supplementation may elicit benefits on cognitive tasks
Authors: Gills Joshua L , Campitelli Anthony , Jones Megan , Paulson Sally , McWilliams Dalton L , Dale Stephanie , Madero Erica N , Myers Jennifer Rae , Glenn Jordan M , Gray Michelle 
Published: December 2021

AbstractBackgroundAlzheimer’s disease and related dementias exhibit similar pathologies such as decreases in cerebral blood circulation and aluminum accumulation leading to decreases in cognitive ability. Acute inositol‐stabilized arginine silicate (ASI) purportedly enhances cerebral blood flow and removes aluminum from the brain. Moreover, ASI supplementation demonstrated the ability to increase processing speed in young adults. While processing speed is important, ASI’s ability to improve other domains of cognitive function remain unknown. Therefore, the purpose of this current investigation is to evaluate the acute effects of ASI supplementation in young healthy adults on various cognitive tasks.MethodEight young adults participated in this randomized, double‐blind, placebo‐controlled crossover study. Each participant completed the Repeatable Battery for the Assessment of Neuropsychological Status before and after the supplement (placebo 8g of dextrose or 1.5g ASI and 8g of dextrose) was consumed. Paired samples t‐test were utilized to assess the differences between language (LAN), attention (ATT), and delayed memory (DM) in each supplement group. Percent differences were used to assess differences between supplement trials.ResultPaired samples t‐test showed a significant difference (p < 0.05) for DM index scores in both supplement groups; statistical trends were noticed in LAN (p = .05) and ATT (p = .07) domains after ASI supplementation. ATT improved by 8% after ASI supplementation compared to 0% in the control group; additionally, LAN scores increased by ∼8% for both supplement groups. DM scores decreased in both trials pre to post examination; but the percent decrease was less in the ASI trial (8%) compared to the placebo trial (12%).ConclusionOur preliminary results demonstrated no significant differences between placebo and ASI trials. However, a larger sample size could illustrate significant findings during language and attention tasks while supplementing with ASI. Further research is needed to determine ASIs effect on brain health and ability to improve cognition in healthy younger adults.