bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examination of plasma YKL‐40 as a clinical biomarker for Alzheimer’s disease
Authors: Sugarman Michael A , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J. , Karikari Thomas K , Pase Matthew P. , Himali Jayandra Jung , Beiser Alexa S. , Seshadri Sudha , Budson Andrew E , O'Connor Maureen K. , Au Rhoda , Goldstein Lee E , Qiu Wei Qiao , Kowall Neil W , Stern Robert A , McKee Ann C. , Mez Jesse B. , Alosco Michael L , Aparicio Hugo J 
Published: December 2023

AbstractBackgroundBlood biomarkers represent a potential non‐invasive and cost‐effective strategy for the clinical detection and monitoring of neurodegenerative conditions including Alzheimer’s disease (AD). YKL‐40 is a secreted glycoprotein associated with inflammatory processes, and elevated cerebrospinal fluid levels have been observed in AD and other neurodegenerative conditions. Fewer studies have examined plasma YKL‐40. We examined relationships between plasma YKL‐40 and clinical indices of AD in a large cross‐sectional sample from a clinical cohort registry.MethodThe sample included 569 participants from the Boston University Alzheimer’s Disease Research Center, including participants with normal cognition (NC; n = 235), mild cognitive impairment due to suspected AD (MCI; n = 181), and AD dementia (n = 153). Blood plasma samples were analyzed using standard ELISA methods; values were log transformed and standardized into z‐scores. Cross‐sectional analyses investigated the relationships between YKL‐40 and clinical indices of functioning including diagnostic status, dementia severity (on the Clinical Dementia Rating scale [CDR]), and neuropsychological test performance. Age, sex, education, race, and APOE ε4 carrier status were included as covariates in all analyses.ResultNo significant differences in plasma YKL‐40 were observed between participants with NC, MCI, and AD dementia after accounting for covariates. The comparison between MCI and dementia was marginally significant (p = .07), with an adjusted mean difference of Z = 0.19. For participants with dementia (CDR scores 1‐3), non‐significant trends were observed for relationships between plasma YKL‐40 values and dementia severity, including for Sum of Boxes (Pearson partial correlation: r = .14, p = .10) and Total Score (ordinal logistic regression: OR = 1.38; 95% CI: [0.98,1.93]), p = .06. Modest but significant correlations were observed between YKL‐40 and performance on 4/12 neuropsychological tests including Animal Fluency (r = ‐.10), Vegetable Fluency (r = ‐.09), and Neuropsychological Assessment Battery List Learning Trials 1‐3 (r = ‐.10) and Short Delay (r = ‐.12).ConclusionPlasma YKL‐40 biomarker levels were modestly related to neuropsychological assessments of language and memory but not significantly related to cognitive diagnosis of AD or dementia severity. This biomarker may reflect underlying inflammatory processes in the context of AD. However, the use of plasma YKL‐40 to assess the presence and severity of AD in a larger cross‐sectional sample size, and using a multiple biomarker approach, warrant further study.
Amyloid and tau pathology are associated with white matter properties in cognitively unimpaired older adults at risk of AD dementia
Authors: Qiu Ting , Rheault François , Soucy Jean‐Paul , Spreng R. Nathan , Binette Alexa Pichet , Descoteaux Maxime , Villeneuve Sylvia ,   the PREVENT‐AD Research Group
Published: December 2023

AbstractBackgroundWhite matter changes are hypothesized to be among the earliest changes occurring in the course of Alzheimer’s disease (AD). We investigated associations between AD pathology, namely amyloid and tau, and white matter microstructural changes in cognitively unimpaired individuals at risk of AD dementia. We expected higher levels of pathology to be related to lower free‐water‐corrected fractional anisotropy.
MethodWe studied 223 cognitively normal older adults with PET and multi‐shell diffusion MRI from the PREVENT‐AD cohort. We first measured standardized uptake value ratios (SUVRs) in 40 brain regions for amyloid‐β (Aβ, i.e., lateral and medial prefrontal, parietal, lateral temporal, and cingulate cortical regions in both hemispheres) and 26 brain regions for tau (i.e., Braak stages I, III, and IV). We then used TractSeg, a deep learning framework, to segment 49 well‐established white matter bundles. We mapped free‐water‐corrected fractional anisotropy (FAT) in those bundles. Lastly, to explore the relationships between AD pathology and white matter microstructure across bundles, we applied two separate partial least squares analyses: one for Aβ pathology and one for tau (Figure 1).ResultWe found one significant latent variable relating Aβ pathology to FAT. Specifically, higher levels of Aβ pathology were associated with the combination of higher levels of FAT within the rostral body of the uncinate fascicle and superior longitudinal fascicle (Figure 2A). We found two significant latent variables relating tau pathology to FAT for which higher levels of tau pathology were associated with elevated FAT within the uncinate fascicle, thalamo‐occipital bundle, optic radiation, inferior occipitofrontal fascicle, inferior longitudinal fascicle, middle longitudinal fascicle, etc. (Figure 2B).ConclusionIn cognitively unimpaired individuals at risk of AD, increased Aβ and tau pathology were associated with higher levels of FAT in AD‐related bundles. These unexpected findings may suggest an inverted U‐shape pattern between AD pathology and FAT in the preclinical phase of AD for which FAT values would start by increasing before decreasing later in the course of the disease. This first increase might be a marker of early pathological processes such as neuroinflammation or swelling.
Accelerated aging in gait patterns is a leading indicator for cognitive decline
Authors: Barnard Leland R , Ali Farwa , Botha Hugo , Christianson Teresa J. , Vemuri Prashanthi , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Graff‐Radford Jonathan , Jones David T. 
Published: December 2023

AbstractBackgroundQuantified accelerated aging, or “age gap,” defined as the difference between a person’s estimated age using a biological measurement, such as a brain image, and their true age, has strong associations with multiple neurodegenerative etiologies. As an alternative to imaging‐based measurements, in this study we developed an age prediction model based on gait patterns and used this model to quantify accelerated aging as an indicator of cognitive impairment and predictor of future cognitive decline.MethodA database of 16,917 pressure sensitive walkway exams from 5,307 participants in the Mayo Clinic Study of Aging was used to develop an age estimation model that included two main components. First, a novel dimensionality reduction and feature selection algorithm was used to extract gait features. Second, a regularized linear model was trained using these features to produce a sparse, clinically interpretable estimator. This model was used to calculate a gait age gap metric, which was tested for association with measures of cognitive impairment and future cognitive decline.ResultThe distributions of gait age gap in age‐matched participants defined as having no cognitive impairment (CU, n = 573), mild cognitive impairment (MCI, n = 520), or a clinical diagnosis of dementia due to Alzheimer’s (AD, n = 53) are shown in Fig 1a. A significant shift in the mean is observed between all three groups. Fig 1b. shows the distributions of baseline gait age gap values amongst individuals categorized by cognitive decline: stable CU (n = 644), MCI converters (n = 89), stable MCI (n = 78), and significant impairment converters (SI, n = 35). The baseline gait age gap in stable CU individuals was found to be significantly lower than in the already impaired or converter groups.ConclusionIn this study, we developed a model for estimating accelerated aging from gait variables in the form of a gait age gap metric. This metric was shown to be strongly associated with AD‐driven cognitive impairment as well as predictive of future cognitive decline. These results highlight the potential clinical utility of quantitative gait analysis in behavioral neurologic assessment of cognitive impairment in AD.
The Association of Plasma Biomarkers and Survival in the Oldest Old
Authors: Lorenz Linda M.C. , Tesi Niccoló , van der Lee Sven J , Hulsman Marc , Gouda Mariam , Sikkes Sietske A.M. , Teunissen Charlotte E. , Holstege Henne 
Published: December 2023

AbstractBackgroundPrevious research showed that plasma NfL (neurofilament light chain) associated with survival. Here we perform exploratory analyses to associate a broader range of plasma biomarkers Amyloid‐βeta‐40 (Aβ40), Amyloid‐βeta‐42 (Aβ42), phosphorylated Tau‐181 (pTau‐181), NfL and glial fibrillary acidic protein (GFAP), with survival after reaching 100 years.MethodThe longitudinal Dutch 100‐plus study cohort comprises of self‐reported cognitively healthy centenarians. Biomarkers were measured in 202 centenarians (137 females, ISCED education level median [IQR] 3 [2–4]) on the Simoa platform. Information on survival was obtained via family report until January 2023. Centenarians who were alive were censored at date of last visit or date last confirmed alive. We investigated the relationship between biomarkers and survival by cox regression analyses, adjusting for age at blood draw, sex and cognitive functioning. We performed maximally selected log‐rank statistics between all plasma biomarkers and survival rate to find an optimal cut‐off, and constructed Kaplan‐Meier survival curves.ResultOf 202 centenarians (median age [IQR] at blood draw 101.4 [100.4‐102.9]), 173 (85.6%) were deceased (median age [IQR] at death 103.2 [102.0‐104.3]). The median (IQR) survival time after blood draw was 14.4 (5.5‐25.1) months. All biomarkers Aβ40, Aβ42, pTau‐181, NfL and GFAP intercorrelated (rs = 0.17–0.79; all P‐values<0.05). Cox regression analyses showed that for each standard deviation increase in NfL, adjusted for age, sex, and MMSE score, the risk of mortality increased by 28% (HR 1.28; 95% CI, 1.11–1.47; P<0.001), Table 1. Maximally selected log‐rank statistics split up NfL into survival groups high and low (cut‐off 70.34 pg/mL, M = 3.803, P = 0.003, Figure 1). The median (IQR) shorter survival time of high versus low NfL was 7.8 (5.38‐9.27) months. No statistically significant cut‐off values were identified for the remaining biomarkers.ConclusionOur results indicate that elevated levels of NfL, but not Aβ40, Aβ42, pTau‐181 and GFAP, associate with lower survival. Furthermore, we were able to find an optimal cut‐off for NfL at which survival in centenarians could be split twofold.
Hypertension is associated with reduced medial temporal lobe neural flexibility in older African Americans
Authors: Gills Joshua L. , Fausto Bernadette A. , Osiecka Zuzanna , Malin Steven K. , Gluck Mark A. 
Published: December 2023

AbstractBackgroundHypertension disproportionately affects African Americans (AA) and is an established mid‐life risk factor for Alzheimer’s disease (AD). However, previous research suggests there is inconclusive data examining late‐life hypertension and Alzheimer’s risk. Recently, a dynamic rearrangement (neural flexibility) imaging method was validated for evaluating cognitive decline in the medial temporal lobe (MTL), which is a key region affected by AD. But whether hypertension mediates MTL neural flexibility in older AA individuals is unknown. Therefore, we investigated MTL flexibility in older hypertensive and normotensive AA.MethodOne hundred and thirteen AA (60‐74y) completed demographic surveys, weight and height measurements, resting blood pressure (BP) screening procedure, and a 6‐minute walking distance test as an indirect measure of aerobic capacity. All individuals also completed a 10‐minute resting‐state functional magnetic resonance screening to assess MTL neural flexibility. Participants were separated into normotensive (systolic BP < 130mmHg, n = 36, 83% female, 64.8 ± 0.4y; 13.8 ± 0.2y of education) vs. hypertensive (systolic BP ³ 130mmHg, n = 77, 82% female, 66.4 ± 0.3y; 14.1 ± 0.1y of education). An ANCOVA was used to examine group differences in MTL neural flexibility with age, sex, and education used as covariates.ResultAlthough individuals with hypertension had a higher BMI (36.9 ± 1.8 vs. 31.3 ± 2.6 kg/m2, p = .070), this was not statistically different. However, normotensive participants had significantly higher MTL neural flexibility compared to hypertensive individuals (.42 ± .23 vs. .32 ± .25, p = .04), and this was independent of estimated aerobic capacity (14.9 ± 2.3 vs. 14.9 ± 2.5 ml/kg/min; ml/kg/min; p = .864).ConclusionHypertensive AA between the ages 60‐74 years old demonstrated lower MTL neural flexibility compared to their normotensive counterparts. These results were independent of obesity and aerobic fitness, suggesting additional work is needed to understand how blood pressure mediates neuronal connectivity to prevent and/or treat AD cognitive decline in AA.
Association of Epigenetic Aging with Cognitive Aging in Diverse Hispanics/Latinos
Authors: Xia Rui , Márquez Freddie , Tarraf Wassim , Gallo Linda C , Talavera Gregory A , Sofer Tamar , Decarli Charles , González Hector M , Fornage Myriam 
Published: December 2023

AbstractBackgroundAge‐related DNA methylation (DNAm) changes occur in specific regions of the genome and have been shown to be correlated with an individual’s chronological age. Multiple “epigenetic clocks” have been developed to estimate an individual’s DNAm age, which reflect different aspects of the multidimensional aging process. Age acceleration, the deviation of the DNAm‐estimated age from the chronological age, has been proposed as a novel biomarker of aging. We investigated the association between multiple measures of age acceleration and cognitive aging phenotypes in diverse Hispanic and Latino adults.MethodsWe estimated epigenetic age acceleration from 5 epigenetic clocks in 2188 Hispanic and Latino adults (mean age 56.7 years; 64.6% women) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) who had available blood DNA methylation data at the baseline visit and neurocognitive data. These included first generation clocks, Horvath and Hannum clocks; second generation PhenoAge and GrimAge; and third generation DunedinPACE (Pace of Aging). We used mixed models to test the association of each of these measures with a global measure of cognitive function (PC1) at the baseline visit and with mild cognitive impairment at a follow‐up visit approximately 7 years later.ResultsThere were significant cross‐sectional associations between lower global cognitive function and greater age acceleration based on Hannum, Horvath, PhenoAge, and DunedinPACE algorithms. In addition, a greater age acceleration based on DunedinPACE was strongly associated with a higher risk of MCI 7 years later (Table).ConclusionBiological aging is associated with lower cognitive function and risk of MCI in diverse Hispanic and Latino adults. DunedinPACE, a third generation epigenetic clock, may be a more sensitive predictor of cognitive aging outcomes than previous generation clocks.
The cytoskeletal protein Plectin regulates Tau‐induced neurotoxicity in Alzheimer’s Disease
Authors: Lee Tom V , Chen Catherine , Allison Katherine S , Li Yarong , Al‐Ramahi Ismael , Bagchi Pritha , Levey Allan I. , Botas Juan , Seyfried Nicholas T , Shulman Joshua M 
Published: December 2023

AbstractBackgroundThe genetic causes for most cases of Alzheimer’s disease (AD) and the underlying biology of pathogenesis remain unknown. Recent large scale proteomics studies on AD patient brains have identified novel protein networks and targets that are highly correlated with AD diagnosis and neuropathology. The most significantly AD‐correlated protein network identified contains the cytoskeletal protein Plectin (PLEC) as a network hub. PLEC functions to crosslink different cytoskeletal components and plays a role in axonal transport of synaptic proteins. Considering that microtubule associated protein‐Tau (MAPT) dysfunction is an AD hallmark, we hypothesize that PLEC dysfunction increases AD susceptibility by disrupting cytoskeletal homeostasis and synaptic function.MethodUtilizing a combination of genetic and proteomic analyses, we validate Plectin as a potential AD risk factor. We assessed the role of PLEC in Tau‐induced neurotoxicity in the animal model Drosophila melanogaster and human neuronal cell culture. Furthermore, we have also elucidated PLEC mutant neurodegenerative phenotypes independent of Tau overexpression in the fly. Immunoprecipitation‐mass spectrometry (IP‐MS) analysis was performed to define a Drosophila Plectin protein‐protein interaction network in adult brains. This network will serve as the basis for cross‐species analysis of protein networks.ResultThe Drosophila homolog of Plectin (dPLEC) is ubiquitously expressed within the adult brain with strong enrichment in neuronal rich tissues. Using Drosophila models of human tauopathy, dPLEC regulates age dependent Tau‐induced neurotoxicity and locomotor dysfunction. Plus, altering levels dPLEC regulates Tau‐phosphorylation in both adult Drosophila brains and human neurons. In the absence of Tau overexpression, dPLEC functions in light‐induced neuronal transmission confirming its role in normal neuronal function. Continued mechanistic analysis in both Drosophila and human neuronal cultures will determine PLEC’s role in AD neuropathogenesis and elucidate the underlying role of the cytoskeleton in AD susceptibility. To that end, we generated an endogenous GFP‐tagged dPLEC (dPLEC‐GFP) and performed immunoprecipitation‐mass spectrometry (IP‐MS) analysis to identify dPLEC protein interactors. Several cytoskeletal and synaptic proteins were identified and are currently being tested for their role in Tau‐induced neurodegeneration and synaptic dysfunction.ConclusionWe functionally validate the AD target PLEC as a regulator of Tau‐induced neurodegeneration and identify PLEC as a regulator of Tau dynamics and neuronal function.
The dynamics of auditory working memory impairment in logopenic aphasia and Alzheimer’s disease
Authors: Levett Benjamin , Kalian Iris , Core Lucy , Jiang Jessica , Warren Jason D , Hardy Chris JD 
Published: December 2023

AbstractBackgroundImpaired auditory verbal working memory is a diagnostic hallmark and integral driver of the clinical phenotype in logopenic aphasia. However, the physiology of the working memory buffer in this syndrome is poorly characterised. Here we addressed the temporal dynamics of auditory verbal working memory in patients with logopenic aphasia and typical Alzheimer’s disease.MethodIn a cohort of patients with logopenic aphasia and typical Alzheimer’s disease and in healthy age‐matched controls, we assessed how temporal manipulations of standard auditory verbal working memory tasks (forward and reverse digit span and phrasal repetition) affected performance. We varied tempo of delivery and inter‐trial gap and performed a detailed analysis of error types. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultCompared with healthy controls, patients with logopenic aphasia and Alzheimer’s disease showed increased sensitivity to temporal manipulation of auditory verbal working memory tasks and error profiles suggesting a dynamic physiological lesion of the working memory buffer. These effects were particularly marked in the logopenic group.ConclusionOur findings open a novel physiological window on working memory dynamics in Alzheimer’s disease syndromes. Further work is warranted to assess how this dynamic deficit impacts communication in patients’ daily lives, how it can best inform management interventions and its potential as a novel, rapid read‐out of neural function in the era of disease‐modifying therapies.
Spatial proteomics and cell‐type specific changes in the basal ganglia of different neuropathologic vascular dementing lesions
Authors: Zamudio Carlos , Danner Benjamin , Ajroud Kaouther , Pladies Erica , Matos Arleen , Spencer Callen , White Lon R , Flanagan Margaret E 
Published: December 2023

AbstractBackgroundVascular dementia (VD) is the second most common cause of dementia behind Alzheimer’s disease. VD has been associated with various cardiovascular maladies, which are thought to contribute to the white matter abnormalities associated with dementia. Cerebrovascular impairment disrupts CNS blood supply resulting in inflammation, oxidative stress, and hypoxia. The aim of this project is to study the impact of the cytotoxic environment created by disruptions to the CNS vasculature, which could be detrimental to glial (microglia, astrocyte) viability and function. We examined age and sex‐matched VD and control human autopsy brain from the Honolulu Asia Aging Study.MethodUtilizing Nanostring’s GeoMx™ Digital Spatial Profiling (DSP), we analyzed autopsy brain to compare neuropathologic vascular dementia lesions (lacunar, macro, and chronic microinfarcts) in the basal ganglia across the disease spectrum (absent/mild, moderate, severe). DSP enables spatial analysis of expression levels for 73 proteins in multiple regions of interest on formalin‐fixed paraffin‐embedded sections. Morphology markers were IBA1 (microglia) and GFAP (astrocytes) (Figure 1a‐b).Indica Labs’ HALO object co‐localization module was used to determine astrocyte, microglia, and total nuclei counts.ResultFor chronic microinfarct severity, astrocyte and microglial counts decreased as the number of microinfarcts increased. By contrast, for macroinfarcts, astrocyte counts increased in addition to microglia steadily decreasing as the number of macroinfarcts increased. Analyses comparing increasing chronic microinfarct severity revealed numerous proteins with differential expression in both microglia and astrocytes, including pTauS404, IDE, p62, ATG5 and P2RX7 (Figure 2 microglia; Figure 3 astrocytes).ConclusionUsing a spatial proteomic technique, we demonstrated that various vascular dementing lesions have unique glial autophagy and inflammatory profiles at different disease stages. Overall, lower levels of vascular dementia lesions display lower levels of inflammation and increased upregulation of protective pathways that may contribute to maintenance of cognitive function. We also demonstrated basal ganglia cell population changes across different disease severities for chronic microinfarcts and macroinfarcts. Findings suggest that there is progressive astrocyte and microglial loss in the setting of chronic microinfarcts and increased astrogliosis in the setting of macroinfarcts. Whether there is a definitive inverse relationship in astrocyte counts between chronic microinfarcts and macroinfarcts remains unclear.