bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of primary age‐related tauopathy defined by neuroimaging biomarkers
Authors: Jung Joon Hyung , Yi Dahyun , Byun Min Soo , Kim Min Jung , Kong Nayeong , Park Seo Hee , Jung Gijung , Lee Yun‐Sang , Lee Dong Young ,   for the KBASE Research Group
Published: December 2022

AbstractBackgroundPrimary age‐related tauopathy (PART) is a neuropathological entity with neurofibrillary tangles (NFTs) in the absence of amyloid (Aβ) plaques in the brain. Recent advance of neuroimaging makes it possible to identify PART in living human brain. We tried to investigate the frequency and clinical characteristics including rate of cognitive decline of non‐demented older adults with PART defined by neuroimaging biomarkers.MethodA total of 113 non‐demented older individuals recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) were included in the analysis. All participants underwent [11C] PiB PET and [18F] AV‐1451 PET with comprehensive clinical assessment. Global cognition was measured annually using MMSE, from 2 years before to 2 years after the PET scans. PART was defined when beta‐amyloid deposition is negative and tau burden corresponds to Braak stage I‐IV.ResultAmong 113 participants, 40 (35.4%) were classified as PART, 29 (25.7%) as no Alzheimer's disease (AD)‐ pathology (amyloid‐negative, Tau Braak stage 0), and 44 (38.9%) as AD (amyloid‐positive). Compared to PART and no‐AD associated pathology group, AD group had higher apolipoprotein E ε4 positivity (13.8%, 12.5%, and 59.1% for PART, no‐AD pathology, and AD, respectively). In regard of cognitive decline rate over 4 years, PART was similar to no‐AD pathology, but significantly slower than AD.ConclusionOur findings indicate that PART is relatively common in non‐demented older adults. In regard of genetic risk and progression rate, PART appears closer to no‐AD pathology condition rather than AD.
Cerebral Perfusion and Cortical Thickness Predict Cognitive Impairment in a Community‐dwelling Cohort
Authors: Okonmah‐Obazee Stephanie E. , Duran Tugce , Rundle Melissa M. , Williams Benjamin J. , Peavey Jeremy J. , Bateman James R. , Whitlow Christopher T. , Craft Suzanne , Lockhart Samuel N. 
Published: December 2022

AbstractBackgroundNeurodegeneration and cerebral perfusion are key neuroimaging biomarkers in the Alzheimer’s Disease continuum. ASL (arterial spin labeling) explores cerebral blood flow (CBF) and has aided in elucidating cerebrovascular health amongst people at risk of cognitive decline. Reduced cortical thickness (CT) on MRI is a neurodegeneration biomarker that also implicated in cognitive impairment. The influence of cortical thickness and perfusion in AD‐related regions on cognitive status is poorly understood. We explored markers to investigate the roles they had in cognitive impairment.MethodParticipants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N= 535, Table 1) underwent baseline T1/ASL MRI. Participants were adjudicated as cognitively impaired (CI: mild cognitive impairment or AD) or cognitively unimpaired (CU) using NIA‐AA criteria by a consensus panel of experts. CT in an AD‐related temporal lobe meta‐ROI (region of interest) was calculated on T1 using FreeSurfer v5.3 and standardized. A homologous set of AD‐sensitive temporal lobe ROIs was used to extract mean CBF, which was log transformed for normality. A one‐way MANOVA (covariates: age, education, sex) assessed effects of CT and CBF on cognitive impairment. Bivariate models evaluated the associations of CT and CBF in relation to age, education, sex, and cognitive impairment. Linear regression was used to analyze whether cognitive impairment was predicted by CT and CBF (adjusted).ResultWe found both CBF and CT were associated with age (r2= ‐0.142, p<0.01; r2= ‐0.339; p<0.01) and cognitive status (r2= ‐0.188, p<0.01; r2= ‐0.264; p<0.01); respectively. CBF was also associated with sex (r2= 0.083; p=0.055) such that women had higher CBF. We also found that higher CBF was marginally associated with higher CT (r2= 0.083; p=0.055); this relationship was not significant when age, sex, and education were included in the model (r2= 0.886; p=0.376). Finally, we found both CT and CBF predicted cognitive impairment (p<0.01; both unadjusted and adjusted, in models where each MRI marker was used to predict cognition), such that CBF and CT were higher in CU; further, both CBF and CT independently predicted cognitive status when together in a model (p<0.008).ConclusionCortical thickness and CBF are predictive of cognitive impairment.
Effect of APOE genotype on the Association between Sleep Disturbance and Cognition across Racial/Ethnic groups
Authors: Bubu Omonigho Michael M , Umasabor‐Bubu Ogie Queen , Mbah Alfred , Kaur Sonya , Turner Arlener D. , Williams Natasha , Jean‐Louis Girardin A , Osorio Ricardo 
Published: December 2022

AbstractBackgroundAPOE alleles are associated with cognitive‐decline and Alzheimer’s disease in Whites. We examined the effect of APOE‐genotype on the association between sleep disturbance (SD) and cognition across racial/ethnic groups.MethodWe conducted a cross‐sectional analysis of baseline data on 10,254 (i.e., 7900 non‐Hispanic Whites, 1428 Black/African‐Americans, 627 Hispanics and 299 Asians) cognitive‐normal subjects from the National Alzheimer’s Coordinating Center Uniform Dataset. We characterized SD using an item on the Neuropsychiatric Inventory‐Questionnaire. Generalized linear models examined SD‐group differences (i.e., SD vs. no SD) on psychometric tests performance between‐and‐within racial categories. The interactive associations of APOE genotype, SD, and race on psychometric tests performance was also examined. All models included age, sex, education, hypertension, and diabetes.ResultOverall, the mean (sd) age was 71.1 (10.3) years and education was 15.7 (3.0) years. Prevalence of SD was 10% (Whites), 6.1% (Blacks), 18.2% (Hispanics), and 7.4% (Asians). SD subjects were at increased risk for worse psychometric scores in: executive, and language domains (p < 0.02 for all) among Whites; language domain (p = 0.001) among Blacks; memory, executive, and language domains (p ≤0.05 for all) among Hispanics; and visuospatial memory domain (p ≤0.001) among Asians. The interactive associations of APOE genotype, SD, and race on psychometric tests performance were significant (p ≤0.001 for all). Within racial groups, only Hispanic SD subjects with 1 or 2 APOE ε4 alleles were at increased risk for worse psychometric scores in memory, executive function, visuospatial, attention, processing speed and language domains (p ≤0.001 for all). Compared to Whites and Asians, Hispanic and Black SD subjects were at increased risk for worse psychometric scores across all domains (p ≤0.001 for all), regardless of APOE‐ε4 status.ConclusionIn this sample of cognitive‐normal older‐adults, SD subjects were at increased risk for worse psychometric scores in specific cognitive domains that varied by race/ethnicity. Hispanic and Black SD subjects were at increased risk for worse psychometric scores regardless of APOE‐ε4 status. APOE‐ε4 effect on SD‐cognition association worsened psychometric scores and occurred only within Hispanics. These findings suggest that APOE‐ε4 interacts with sleep to effect varying cognitive domain outcomes within‐and‐between racial/ethnic groups.
Cerebrospinal fluid glial fibrillary acidic protein (GFAP) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in Alzheimer’s Disease and Related Dementias (ADRD)
Authors: Jain Lavanya , Khrestian Maria , Tuason Elizabeth D. , Pillai Jagan A. , Rao Stephen M. , Leverenz James B. , Bekris Lynn M. 
Published: December 2022

AbstractBackgroundDiscerning Dementia with Lewy Bodies (DLB) from Alzheimer's disease (AD) can be a challenge for the clinician and represents a critical unmet medical need. Diagnosis of DLB is especially challenging in early stages due to variable core features and coexistent pathologies such as AD. A variable immune response has been implicated in AD/ADRD. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a myeloid cell activity marker, has been genetically linked to AD risk and glial fibrillary acidic protein (GFAP), an astrocyte activity marker, is liked to astrogliosis in a number of neurologic disorders. Our objective was to explore differences in cerebrospinal fluid (CSF) values of both sTREM2 and GFAP in AD/ADRD. This included individuals clinically diagnosed with AD, DLB, mild‐cognitive impairment (MCI), Parkinson’s Disease (PD), and cognitively normal controls (CN).MethodCohorts included participants from the Cleveland Clinic‐based Dementia with Lewy Body Consortium (DLBC), the Lou Ruvo Center for Brain Health Aging and Neurodegenerative Disease biobank (LRCBH‐biobank) and the Cleveland Alzheimer's Disease Research Center (CADRC). Patients were clinically characterized based on CSF biomarkers, clinical symptoms, and consensus review. Analytes measured included: CSF GFAP, CSF sTREM2, CSF a‐synuclein (aSyn) and plasma neurofilament light chain (NfL) using multiple platforms such as the Luminex/Millipore and Meso Scale Discovery systems.ResultIn this AD/ADRD cohort, CSF aSyn was higher in MCI than both PD and DLB, while lower in DLB than CN and AD. CSF sTREM2 was higher in MCI, AD and DLB than CN. GFAP was higher in MCI than either CN or DLB, while AD was higher than DLB. sTREM2/GFAP ratio was higher in DLB than CN, MCI, AD and PD.ConclusionThese findings suggest that inflammatory factors, CSF sTREM2 and GFAP are altered in both AD and DLB. Future study of the relationship between CSF amyloid or tau and the immune response will help tease apart the potential influence of co‐existent AD‐related pathology on inflammatory factors in DLB. The findings will help inform possible immunotherapeutic strategies that seek to target the immune response in AD/ADRD.
Interplay of genetic and epigenetic factors in regulating immune‐related pathways in Alzheimer’s disease
Authors: Han Seonggyun , Nho Kwangsik , LEE YOUNGHEE 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a major cause of dementia and among the most complex of diseases, featuring various heterogeneous molecular mechanisms. Not only genetic but also non‐genetic factors (i.e., epigenetics) contribute to progression in the human brain; dysregulation of gene expression by single nucleotide polymorphisms (SNPs) and altered DNA methylation is often observed in AD patients. Although genetic and epigenetic regulators have each independently received intensive study for their roles in AD progression, their interactive contributions to expression regulation are not yet fully understood. In this study, we aimed to elucidate the interplay of SNPs and DNA methylation in determining transcript‐level expression status in AD.MethodWe performed integrative analysis of whole‐genome sequencing (WGS), RNA‐seq, and methylation data from the dorsolateral prefrontal cortex in AD patients (n=495), obtained from the ROSMAP project. We tested a set of 160,126 SNPs having minor allele frequency (MAP) > 0.05 for interaction with 208,911 methylation loci within promoter regions (+3000 to ‐200 bp) related to expression status of 81,715 transcripts having transcripts per million (TPM) values. Likelihood ratio tests (LRTs) were used to determine the statistical significance of differences between linear models with and without the interaction term, with false discovery rate (FDR) < 0.05 for significance criteria.ResultWe identified 511 SNP‐methylation probe pairs as having interactions with statistically significant impacts on the expression of 76 transcripts (56 unique genes). Genes in the HLA family (e.g., HLA‐A, HLA‐B, HLA‐C, HLA‐DPA1, HLA‐DRB1, and HLA‐DMA) were found to be especially associated with the interplay of SNPs and methylation. For example, the SNP rs1126511 and DNA methylation locus cg13581859 interact in regulating expression of the HLA‐DPA1 transcript ENST0000419277: neither the SNP nor the methylation locus alone impacted its expression, but transcript levels tended to be significantly decreased under the combination of SNP allele T and low methylation. In addition, gene‐set enrichment analysis found that interaction‐regulated genes were significantly enriched in immune‐related pathways.ConclusionOur study provides a new molecular insight into the crosstalk between genetic and epigenetic elements that are involved in transcript expression status in AD and suggests that immune‐related pathways may especially be regulated by such interactions.
Neurotoxic mechanisms of glyphosate exposure
Authors: Limberger Christian , Roginski Ana Cristina , Amaral Alexandre U. , Venturin Gianina Teribele , Wajner Moacir , daCosta Jaderson Costa , Zimmer Eduardo R. , Souza Diogo O. , de Souza Débora Guerini 
Published: December 2022

AbstractBackgroundHuman exposure to pesticides is increasing, especially glyphosate‐based herbicides (GBH). Thus, it is of great interest to characterize whether glyphosate (Gly) exerts neurotoxic effects. Besides Gly, GBH formulations contain adjuvants, mainly POEA, a surfactant. We hypothesize adjuvants may enhance glyphosate neurotoxicity. Therefore, we aimed at investigating the neurotoxic properties of Gly and its adjuvants.MethodGly, POEA, Gly+POEA, and GBH were orally administered into male Wistar rats (90‐day‐old, n = 30) for 28 days (5 mg/kg/day). Controls received vehicle. Then, we assessed the working memory via Y‐maze test, glial fibrillary acidic protein (GFAP), inducible nitric oxide synthase (iNOS), and glutamate transporter 1 (GLT‐1) immunocontent in cortex and hippocampus via Western blot, mitochondrial respiration via high‐resolution respirometry in cortex and brain metabolism via FDG‐PET (pons as reference region).ResultGFAP and iNOS in the cortex were higher in Gly (p= 0.0053 and p=0.0012, respectively) compared to GBH (Figures A, B), whereas GLT‐1 was higher in the GBH (p=0.0004), compared to Gly (Figure C). Hippocampus showed no changes in GFAP, iNOS, and GLT‐1 expression in any group. The POEA group showed impaired working memory in the Y‐maze test (p=0.005) (Figure D). The respiratory control ratio was affected in the cortices of POEA (p=0.0212) and Gly+POEA (p=0.0281) groups (Figure E). Brain metabolism was not altered in cortical and hippocampal regions. However, the striatum presented hypermetabolism in POEA (p=0.0492) group (Figure F).ConclusionEnvironmental factors may contribute to the onset of neurodegenerative diseases in later life, including AD. Our preliminary results reveal individual toxic effects of Gly, POEA, and GBH, highlighting the overlooked role that adjuvants may have in herbicides toxicity. It seems that different subsets of reactive astrocytes result from each treatment. Mitochondrial uncoupling and striatum hypermetabolism may underlie working memory deficits. The study of potential pathways of neurotoxicity is fundamental for translational findings since the general population is chronically exposed to low doses of complex glyphosate formulations.
Sensory and Motor Differences in A Cognitive Aging Sample
Authors: Ho Emily , Mather Molly A , Weintraub Sandra , Gershon Richard C. 
Published: December 2022

AbstractBackgroundAging is associated with many different types of sensory, motor, and sensorimotor changes.Recent evidence suggests such behavior may be able to predict the risk of developing Alzheimer’s Disease, potentially even before cognitive symptoms manifest. Existing studies have generally examined only particular facets of sensation and motor, rendering comprehensive comparisons of sensorimotor behavior in this sample difficult. To fill this gap, we use the NIH Toolbox® Motor and Sensation Batteries in three groups: normal controls (NC), Mild Cognitive Impairment (MCI), and dementia of the Alzheimer type (DAT).MethodParticipants (N = 336) were consensus diagnosed and grouped into either NC (N = 161), MCI (N = 104), and DAT (N = 71). Participants completed the NIH Toolbox Motor and Sensation Batteries. The motor battery included measures of Standing Balance, Grip Strength for both dominant and non‐dominant hands, Pegboard (dexterity) for both dominant and nondominant hands, the Walk 2 Minute, and the Walk 4 Meter. The sensation battery included measures of Odor, Visual Acuity (vision), Words‐in‐Noise, and Pain Interference. One‐way ANOVAs were conducted for each measure; effect sizes were also calculated.ResultFor all motor measures with the exception of Standing Balance, there were significant diffrences. For grip strength, NC exhibited higher strength than those in the DAT sample (medium effect). For Pegboard, DAT exhibited the weakest performance, followed by MCI (medium to large effect). In general, the DAT walked slower than MCI and NC (large effect), respectively. For sensation measures, there were no differences in visual acuity or pain interference across cognitive groups. DAT participants had decreased olfactory capacity compared with MCI and MCI to NC (large effect). The DAT group and MCI group had more difficulty distinguishing noise from words than the NC counterparts (large effect).ConclusionThis represents one of the first studies to comprehensively characterize sensory and motor changes in a cross‐sectional sample of cognitive aging. Motor changes dominated; cognitive decline appeared more sensitive to both finer motor movements such as the pegboard task and gross movement such as walking. Sensation results were more mixed. We conclude with implications for sensorimotor changes and its relationship with cognitive performance in the latter life span.
Multi‐ethnic differences in brain and biopsychosocial risk factors for ADRD in UK immigrants from the Middle East and North Africa (MENA)
Authors: Jahanshad Neda , Haddad Elizabeth , Zhu Alyssa H , Nir Talia M , Bhatt Ravi R , Nourollahimoghadam Elnaz , Thompson Paul M , Salminen Lauren , Medland Sarah E , Gupta Arpana 
Published: December 2022

AbstractBackgroundThe populations of the Middle East and North Africa countries (MENA) are predicted to contribute to the world’s sharpest increases in rates of Alzheimer’s disease and related dementias (ADRD) in the coming years (GBD 2022), yet this group is underrepresented in health studies. The UK Biobank provides one of the largest and well‐characterized datasets on aging immigrants in the UK. We compare risk factors for ADRDs between UK immigrants from MENA countries to those of immigrants from other countries.MethodImmigrants from MENA countries (N = 3557), India (N = 2959), Germany (N = 1103), and genetically‐determined British individuals (N = 1929) born outside of the UK in any of the three areas of interest were included in the study. There are multiple definitions of MENA: here, MENA was defined broadly to include the union of all included countries; Figure 1 highlights the distribution in this sample. We focused on variables associated with suboptimal brain aging and ADRD risk: APOE genotypes; education; an algorithmically defined diet quality score (Zhuang, 2021); BMI; incidence of parental death before 65 years; and the Townsend deprivation index (TDI) as a proxy of socioeconomic status (SES). Chi‐squared or Mann‐Whitney tests provided statistics on distribution discrepancies for categorical or continuous data, respectively. We also charted hippocampal volumes with age for the subset of each ethnic group who underwent neuroimaging.ResultFigure 2 highlights group demographics and distributions. Compared to all other groups (Figure 3), MENA groups had higher TDI (lower SES), lowest diet quality, and highest BMIs; these differences remained even in college educated individuals. MENA also reported a greater incidence of maternal deaths before age 65. German immigrants were more highly educated than all other groups. ApoE4 alleles were significantly less prevalent in MENA and Indian countries than groups of European ancestry (Figure 4). Hippocampal volumes, adjusted for intracranial volume, had similar age‐trends across groups.ConclusionMany ADRD risk factors differ substantially across different ethnic groups, even when the proportion with a college education is not different. It is imperative to understand underlying lifestyle and sociological factors associated with immigration, to provide adequate healthcare for all aging individuals.
Validity of a remote supervised preclinical Alzheimer’s disease cognitive composite (PACC) score in preclinical and prodromal Alzheimer’s disease.
Authors: Maruff Paul , Lim Yen Ying , Masters Colin L. , Robertson Joanne 
Published: December 2022

AbstractBackgroundNeuropsychological tests administered to individuals in locations different from the assessor (i.e., remote assessment) can provide substantial reductions in patient burden, study cost and barriers to access. However, such tests must be optimized and validated for use in remote settings. The preclinical cognitive composite score (PACC) is derived from neuropsychological tests of episodic memory, complex attention, and general mental status. This study determined whether a set of neuropsychological tests of these domains, which can provide a PACC score, can be given in a remote supervised setting and remain sensitive to AD related cognitive impairment.MethodOlder adults classified as cognitively unimpaired (CU, n = 30), preclinical AD (n = 30) or prodromal AD (n = 25), with conventional PACC scores known, completed three computerized tests; the International Shopping list Test (ISLT), Continuous Paired Associate Learning Test (CPAL) and the International Digit Symbol Substitution Test, while supervised by a neuropsychologist in in‐clinic and remote settings. All individuals then completed the remote assessments two more times 7days (+/‐4 days) apartResultMain performance measure from each test on each assessment was standardized using the mean and SD of the CU group, assessed under supervision, at baseline. Standardized scores for each assessment were then averaged to yield a PACC score. There was no difference in rates of missing data or group mean score on individual test scores or PACC score, between in‐clinic and remote settings. Compared to the CU group, impairment in performance on the digital PACC in the prodromal AD was substantial (z = ‐1.56) but equivalent between in clinic (9z = 1.57) and remote (z = ‐1.56) settings. Performance on the digital PACC was slightly worse in the preclinical AD group (z = –0.42) but did not differ for settings. The reliability of the digital PACC score was very high (r = 0.87).ConclusionThe digital PACC derived from neuropsychological tests given in remote supervised contexts is acceptable, valid, reliable and sensitive to AD related cognitive impairment when given in‐clinic or remotely.