bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longer TOMM40 poly‐T variants associated with decreased regional gray matter in cognitively normal older APOE E3/E3 adults
Authors: Honea Robyn A , Vidoni Eric D , Morris Jill K , Michaelis Elias K , Burns Jeffrey M , Swerdlow Russell H 
Published: December 2020

AbstractBackgroundThe TOMM40 poly‐T is a polymorphism of the TOMM40 gene at rs10524523 (“523”), in linkage disequilibrium with APOE. The role of TOMM40 in Alzheimer’s disease risk is still controversial. We sought to use whole brain voxel‐based methods to investigate if older individuals with the absence of an APOE e4 allele with varying lengths of the TOMM40 Poly‐T allele had gray matter volume differences indicative of Alzheimer’s disease risk.MethodWe studied individuals without cognitive impairment (n=69) from our KU Alzheimer’s Disease Center whose apolipoprotein (APOE) genotype was e3/e3, and who were Caucasian. The participants were grouped according to poly‐T length polymorphisms at “523” homozygous for S (S/S; n=25), homozygous for VL (VL/VL; n=19), and heterozygous (S/VL; n=25). All individuals were scanned for T1‐weighted MPRAGE structural images using a 3T Skyra Siemens. Images were preprocessed and analyzed using CAT12, a Computational Anatomy Toolbox (http://www.neuro.uni‐jena.de/cat/) running under SPM12 and MATLAB (R2020a). To investigate associations between genotype and regional GM volume, we performed voxel‐based morphometry (VBM). In order to investigate associations between TOMM40 Poly‐T group and gray matter volume differences we included age, sex, and total intracranial volume (TIV), as variables of no interest in our full factorial model. The statistical threshold was set at Pheight < 0.05, corrected (FDR).ResultAll groups were similar and not significantly different in mean age, education, MMSE, and overall brain volume. Brain magnetic resonance scans were analyzed using the CAT12 program within SPM software. Individuals with a VL/VL genotype had lower precuneus volumes (p=.023 FDR corrected, k=213, ‐29, ‐84, 36) and temporal cortex volumes (p=.005 FDR corrected, k =362, ‐45, ‐40, ‐32) compared to S/S individuals.ConclusionTOMM40 “523” VL variants are related to reduced gray matter volume in the precuneus and temporal cortex in healthy individuals with an APOE e3/e3genotype. This is especially interesting as the precuneus has been identified in other studies, and it may be particularly sensitive to dysfunction in bioenergetic changes associated with faulty mitochondria. This adds to a growing literature implicating TOMM40 “523” and mitochondrial function in late‐onset Alzheimer’s disease progression.
Usefulness of the physical fitness test for screening cognitive impairment in the Korean elderly
Authors: Choi Muncheong , Chun Buong‐O , Moon So Young , Lee Sun Min , Sun Kyunghwa , Jeong Jee Hyang , Park Hee Kyung , Park Yoo Kyoung , Hong Chang Hyung , Na Hae Ri , Park Kyung‐Won , Kim Byeong‐Chae , Cho Soo Hyun , Choi Seong Hye , Song Hong‐Sun 
Published: December 2020

AbstractBackgroundPhysical performance as well as cognitive function decline as people are getting older. We aimed to evaluate usefulness of physical fitness measures for screening cognitive impairment in Korean elders.MethodA total of 88 not‐demented individuals (Female: 80.0%, age: 70.6±5.1 yrs, Clinical Dementia Rating (CDR): 0(33%), 0.5(67%), Body Mass Index: 24.2±2.9 kg/m2)were recruited. Their physical fitness was assessed by grip power, sit‐to‐stand for 30 seconds, walking in place for 2 minutes, bending the upper body forward, standing on one foot while lifting the other knee up, 3m timed‐up‐and‐go (TUG), fast walking on an “8”‐ shaped trajectory (F8WT), T‐wall test and bioelectrical impedance analysis. In addition, their cognitive function was evaluated by Mini‐Mental State Examination (MMSE) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Correlation analysis was conducted to analyze the association between physical fitness and cognitive function. The receiver operating characteristic (ROC) analysis was applied to reveal diagnostic accuracy and optimal cutoff of each physical fitness test for cognitive impairment which was defined as CDR 0.5.ResultIn T‐wall test, time taken for 100 hits was negatively correlated with MMSE total score (r=‐0.497) and RBANS total score (r=‐0.532). The time taken for F8WT was significantly correlated with MMSE (r=‐0.405). F8WT, TUG, as well as T‐wall test showed large Area under the curve for defining cognitive impairment (TUG=.768, 95%CI= .650∼.885; F8WT=.735, 95%CI=.612∼.857; T‐wall=.682, 95%CI=.545∼.819). The optimal cut‐off to predict cognitive impairment was 6.0 sec in TUG (sensitivity=73.2%, specificity=73.1%), 26.3 sec in F8WT (sensitivity=71.4%, specificity=73.1%) and 94.5 sec in T‐wall test (sensitivity=62.5%, specificity=65.4%).ConclusionF8WT, TUG, as well as T‐wall test were found to be accurate and portable measures for screening cognitive impairment in Korean elders, and may be particularly useful for screening cognitive impairment in elderly populations with wide variation in educational levels.
A panel of blood lipids associated with cognitive performance, brain atrophy and diagnosis: A longitudinal study of elders without dementia
Authors: Ma Ya‐Hui , Yu Jin‐Tai , Tan Lan , Dong Qiang , Xu Wei , Tan Lin , Shen Xue‐Ning 
Published: December 2020

AbstractBackgroundBlood metabolites have been suggested as promising biomarkers of Alzheimer’s disease. Identifying diagnostic and predictive lipids can provide new spots in worse cognitive decline fields.MethodTotal 579 plasma lipid signatures were sampled in 374 participants without dementia at baseline enrolled in the Alzheimer’s Disease Neuroimaging Initiative cohort over 10 years. Ten‐fold cross‐validated least absolute shrinkage and selection operator‐logistic regression selected a subset of lipids that best classified individuals with worse slopes of cognitive decline determined by linear mixed models. Multivariable adjusted model examined associations between lipids and neuropsychiatric assessments, CSF biomarkers, brain structural measures and diagnostic categories.ResultIn a training and a validation set, a panel of seventeen lipids classified cognitively declined individuals with favorable prediction (training set: area under curve [AUC]=0.768, 95% confidence interval [CI]=0.715‐0.821; validation set: AUC =0.747, 95%CI= 0.627‐0.867) and calibration efficacy (Hosmer‐Lemeshow test: p>0.05). Adding risk score to the predictive model yielded a better AUC of 0.779 (95%CI=0.712‐0.845) than the one with clinical variables alone (p=0.014). The model combining polygenic hazard score, lipid signature and clinical variables yielded the best improvement in prediction. Baseline lipid signatures consisting of all selected lipids independently predicted declined cognition and positively associated with baseline cognitive performance (p=0.007) and cerebrospinal tau protein changes (p‐tau, p=0.025; t‐tau, p=0.010). Longitudinal analyses showed lipid signatures had adverse impacts on cognitive performance and brain atrophy over 10 years, and predicted diverse diagnostic categories (case vs. control, stable mild cognitive impairment [MCI] vs. cognitively normal [CN], progressive MCI vs.CN, A+[positive β‐amyloid deposition] vs. A‐[negative β‐amyloid deposition] , A+T+ [positive tau pathology] vs. A‐T‐[negative tau pathology]) and a trend for progressive outcomes.ConclusionA comprehensive panel of peripheral lipids instead of individual lipid molecule could better diagnose and predict cognitive decline. Further, integrating genetic variations, proteins and other biological information in future may expand the fit of exited detect models.
Neuropsychiatric correlates of cerebral amyloid burden in a memory clinic sample
Authors: Kan Cheuk Ni , Zhang Liwen , Reilhac Anthonin , Hilal Saima , Gyanwali Bibek , Chen Christopher , Xu Xin 
Published: December 2020

AbstractBackgroundNeuropsychiatric symptoms (NPS) affect quality of life for both patients and caregivers, worsen cognitive and functional impairment in elderly, and are associated with the development of dementia. Manifestations of neurodegenerative and vascular pathologies including abnormal amyloid deposition and cerebrovascular disease (CeVD) often co‐exist in both cognitively normal and impaired elderly. However, the impact of co‐occurrence of amyloid and CeVD on major clinical outcomes, such as neurocognition and neuropsychiatric disorders, have not been extensively explored. Hence, the present study aimed to determine the neuropsychiatric correlates of cerebral amyloid burden amongst patients across a spectrum of cognitive impairment, adjusting for significant CeVD. We hypothesized that amyloid burden is independently associated with NPS severity.MethodParticipants with or without cognitive impairment from the memory clinic underwent [11C]PiB‐PET and MRI scans between April 2016 and September 2018. NPS were assessed using the 12‐item neuropsychiatric inventory. CeVD markers (cortical infarcts, stenosis, white matter hyperintensities, lacunes, and microbleeds) were graded and significant CeVD was defined following previously validated criteria. The association of NPS severity with global standardized uptake value ratio (SUVR) was analyzed using generalized linear models, controlling for demographics, diagnosis, cognitive function, depression status, and significant CeVD. Possible interactions between amyloid and CeVD were evaluated. The correlations between NPS subsyndromes and regional amyloid uptake were also explored. Holm‐Bonferroni correction was applied to adjust for multiple comparisons.ResultsData for 168 participants [age=75.6 (7.3); female=93 (55.4%); MMSE=22.3 (5.7)] were analyzed, including 24 cognitively normal, 89 MCI, and 55 with dementia. Global SUVR was associated with higher total NPS score [β (CI)=0.67 (0.15‐1.18), p=0.011], driven by hyperactivity subsyndrome [β (CI)=0.96 (0.15‐1.11), p=0.002] and apathy subsyndrome [β (CI)=0.90 (0.34‐1.45), p=0.002]. Apathy subsyndrome was positively correlated with amyloid uptake in the thalamus (r=0.25, p=0.002) and parietal region (r=0.224, p=0.002). There was no significant interaction between global SUVR and significant CeVD on NPS.ConclusionNeuropsychiatric manifestations reflect underlying neurodegenerative pathology independent of vascular burden, suggesting that amyloid and CeVD may exert their effects through different pathways. This finding contributes to the neuropathological understanding of neuropsychiatric disorders, thus informs future development of novel treatment and monitoring of disease progression.
Characteristics of behavioral and psychological symptoms of dementia in long‐term care facility residents: An item response theory approach
Authors: Arai Asuna , Katsumata Yuriko , Ozaki Takashi , Khaltar Amartuvshin 
Published: December 2020

AbstractBackgroundBehavioral and psychological symptoms of dementia (BPSD) are a well‐known risk factor for an increased burden of care for staff in long‐term care facilities and family caregivers. The factors that contribute to BPSD development are multifaceted, and it is difficult to establish universal solutions for the different types of BPSD in different individuals. This study investigated the characteristics of each symptom and people with dementia using latent trait of BPSD appearance by item response theory.MethodWe conducted a cross‐sectional survey of older residents with dementia in 2015 at 10 selected long‐term care facilities in Hokkaido, Japan. Data were collected with a questionnaire completed by care staff. The questionnaire included a brief questionnaire form of the Neuropsychiatric Inventory (NPI‐Q), a standardized scale to assess 12‐item BPSD. Of the participants (n=312), we excluded 11 who had severe disability in daily living or were almost bed‐ridden and 104 for whom no medical records on cause of dementia were available. The two‐parameter logistic model was used to estimate an item difficulty and item discrimination for each symptom. We examined the association between the person parameters, latent BPSD score, and sociodemographic characteristics of the participants using Welch’s t test or ANOVA.ResultOf the 197 residents with dementia (women: 81.7%, mean age: 86.4±7.7 years), agitation was the most prevalent symptom in BPSD, followed by irritability and apathy. The difficulty of symptoms was lower in agitation, irritability, aberrant motor behaviors, and disinhibition. This means that those having even lower latent BPSD scores could appear these symptoms. Conversely, hallucinations, euphoria, anxiety, and delusions, which showed higher difficulty, could be exhibited in those with higher latent BPSD scores. Apathy, night‐time disturbances, depression, and appetite disturbances showed too high difficulty and too low discrimination. The latent BPSD scores were not associated with sex, age, place of residence, cause of dementia, but with ADL and cognitive functions.ConclusionWe demonstrated that some of BPSD symptoms could be characterized by latent trait on BPSD appearance. The characteristics based on latent BPSD trait might be useful to consider the measures of addressing BPSD.
Acute phase markers in CSF reveal inflammatory changes in Alzheimer’s disease that are impacted by APOE ε4, sex and age but not pathology
Authors: Ayton Scott , Janelidze Shorena , Roberts Blaine R. , Palmqvist Sebastian , Kalinowski Pawel , Diouf Ibrahima , Belaidi Abdel Ali , Stomrud Erik , Bush Ashley I , Hansson Oskar 
Published: December 2020

AbstractBackgroundNeuroinflammation may accelerate Alzheimer’s disease (AD) progression. We profiled acute phase response (APR) proteins (stimulated by IL‐6 released from pro‐inflammatory glia) in CSF of people along the clinical and pathology (CSF t‐tau/Aβ42) spectrum of AD to investigate the association between disease outcomes and inflammatory changes.MethodsAPR proteins in CSF from 920 subjects in the Swedish BioFINDER study were quantitively analyzed using multiple reaction modelling mass spectrometry: α1‐antitrypsin, α1‐antichymotrypsin, ceruloplasmin, complement C3, α‐fibrinogen, β‐fibrinogen, γ‐fibrinogen, haptoglobin, and hemopexin. Ferritin was measured using multiplex ELISA. CSF t‐tau and Aβ42 was measured using Euroimmun ELISA and the cohort was dichotomized for AD pathology using the t‐tau/Aβ42 ratio. Subjects were also stratified by the following clinical diagnoses: cognitively normal (CN); subjective cognitive decline (SCD); mild cognitive impairment (MCI); and AD dementia. N per group was: CN t‐tau/Aβ42‐ve=335; CN t‐tau/Aβ42+ve=104; SCD t‐tau/Aβ42‐ve=105; CN t‐tau/Aβ42+ve=44; MCI t‐tau/Aβ42‐ve=78; MCI t‐tau/Aβ42+ve=133; AD t‐tau/Aβ42+ve=121.ResultsIn separate multiple regressions (adjusting for diagnosis, age, sex, APOE‐ε4), CSF t‐tau/Aβ42 status did not affect APR protein levels in CN and SCD subjects (Figure 1). Rather, the APR elevated with symptomatic progression: MCI t‐tau/Aβ42+ve subjects had 4/10 proteins elevated compared to CN tau/Aβ42‐ve subjects (α1 antichymotrypsin, ferritin, α‐fibrinogen, β‐fibrinogen; 0.001<P<0.027), and all 10 proteins were elevated in AD (1.6x10‐8<P<0.017). Surprisingly, the APR was more robustly activated in people with cognitive changes but with low t‐tau/Aβ42 levels (7/10 and 5/10 proteins elevated in SCD and MCI respectively). APOE ε4 status did not affect levels of any APR proteins in CSF, while these were elevated in females and with increased age. The performance of the APR in predicting clinical diagnosis was greater in females, in younger subjects, and those without APOE ε4 (Figure 2).ConclusionsThe APR in CSF reveals inflammatory changes that occur with clinical and not pathological dimensions of AD. The APR has a complex interaction with clinical variables: the extent of the APR is affected by sex and age, not APOE ε4, yet the APR has more influence in non‐ε4 carriers, younger people and females (Figure 3). These data provide new insight into neuroinflammation in AD and how this varies according to demographics.
Lipid peroxidation status in cerebrospinal fluid samples from Alzheimer disease
Authors: Peña‐Bautista Carmen , Álvarez Lourdes , Baquero Miguel , López‐Nogueroles Marina , Hervás‐Marín David , Cháfer‐Pericás Consuelo 
Published: December 2020

AbstractBackgroundOxidative stress has been postulated as one of the mechanisms implied in Alzheimer Disease (AD). Brain lipids are especially vulnerable against reactive species due to the high metabolic activity in the brain. Our previous studies reported the utility of lipid peroxidation biomarkers in plasma as potential AD diagnosis biomarkers. The aim of this work is to study the brain specificity for these biomarkers.MethodLipid peroxidation products (isoprostanes, isofurans, neuroprostanes, neurofurans) were determined in cerebrospinal fluid (CSF) and plasma samples from AD patients (n= 42) and non‐AD participants (n= 34). For this, an analytical method based on liquid chromatography coupled to mass spectrometry was used. Participants’ classification was carried out following the NIA‐AA criteria based on standard CSF biomarkers, structural neuroimaging and neuropsychological evaluation. Correlations between both biofluids were evaluated by means of Pearson Correlation.ResultMost of the determined analytes did not show correlation between plasma and CSF levels. Only the compound 17(RS)‐10‐epi‐SC‐Δ15‐11‐dihomo‐IsoF showed a slight correlation between both matrices. However, CSF lipid peroxidation levels showed correlation with CSF amyloid beta or tau levels.ConclusionCSF lipid peroxidation biomarkers levels could reflect amyloid pathology and cognitive impairment associated to AD. However, these levels are not directly correlated with the corresponding plasma concentrations, probably due to transport alterations through the blood brain barrier.
Association of odor identification capacity with amyloid‐β and tau burden in older adults: A systematic review and meta‐analysis
Authors: Tu Lihui , Lv Xiaozhen , Fan Zili , Zhang Ming , Yu Xin , Wang Huali 
Published: December 2020

AbstractBackgroundPrevious studies have shown that smell identification test might predict cognitive decline in older adults. However, whether the odor identification capacity correlates to the pathological change of Alzheimer’s disease (AD) has not been fully investigated. The systematic review aimed to examine the association between odor identification capacity and the amyloid‐β (Aβ) and tau burden in older adults.MethodElectronic databases (MEDLINE, PsycINFO, Google Scholar) were searched up to June 2019 to identify studies that reported the correlation coefficients or regression coefficients between odor identification test scores and Aβ or tau levels in cerebrospinal fluid (CSF) or Aβ burden detected by 11C‐Pittsburgh compound B (PiB) positron emission tomography (PET). The protocol was pre‐specified (PROSPERO CRD42019138642).Result660 abstracts were retrieved, and 30 full‐text articles further explored, from which 24 were excluded. In the final sample, we identified four studies (468 participants) regarding Aβ PiB PET and two studies (223 participants) about Aβ or tau levels in CSF. There was a significant inverse linear relationship between odor identification test scores and global PiB binding (pooled correlation coefficient = ‐0.35, 95% confidence interval (CI)= ‐0.54∼‐0.13, p=0.002). There was no significant association between CSF Aβ1‐42 levels and odor identification test score (pooled correlation coefficient = 0.22, 95% CI= ‐0.04∼0.45, p=0.097). Due to lack of data, no pooled correlation coefficients could be computed on the association between odor identification test score and CSF tau level or the ratio of the Aβ1‐42 and tau.ConclusionThere was an inverse association between odor identification capacity and global cerebral Aβ burden in older adults. It suggests that odor identification capacity might be a proxy marker of preclinical Alzheimer’s disease.
Functional interpretation of genetic risk loci for dementia using a protein quantitative trait loci (pQTLs) approach in cerebrospinal fluid
Authors: Reus Lianne M. , Jansen Iris E. , Tijms Betty M. , Visser Pieter Jelle , Lemstra Afina W. , Pijnenburg Yolande A.L. , van Der Flier Wiesje , Teunissen Charlotte E. , Campo Marta Del 
Published: December 2020

AbstractBackgroundGenome‐wide association studies have successfully identified genetic risk loci for dementia,but through which biological mechanisms these factors contribute to dementia remains elusive. Cerebrospinal fluid (CSF) protein levels reflect ongoing biological processes that take place in the brain. Studying which CSF proteins associate with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of disease.We aimed to identify protein quantitative trait loci (pQTLs) in ante‐mortem CSF in different types of dementia, including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD).MethodWe included 513 subjects (144 non‐demented controls, 211 AD, 56 DLB, 102 FTD, age 64 ± 9 years, 36%female) from the Amsterdam Dementia Cohort and European Medical Information Framework for AD (EMIF‐AD) PreclinAD cohort who had genetic and CSF proteomic data available. Genetic data was generated using the Illumina Genome Screening Array(GSA). CSF proteins (n = 665) were measured using an antibody‐based proteomic array (Olink). We included 43 genetic risk loci for AD, 7 for DLB and 9 for FTD. Association signals between SNPs and CSF protein levels were determined using linear regression, adjusted for principal components, age and sex, stratified for diagnosis (i.e., non‐demented controls and diagnostic group combined). Results were corrected for multiple comparisons with the Bonferroni method.ResultVariants in three AD (CR1, ZCWPW1, HESX1) and one DLB (GBA) risk loci were associated with levels of seven CSF proteins (Figure 1). The CR1 risk locus (rs4844610) was associated with higher CR2 CSF levels (P = 5.47 × 10−7), ZCWPW1 (rs2906657) with lower PILRB (P = 2.28 × 10−32) and HESX1 (rs186108507) with higher RETN (P = 6.00 × 10−8). Within DLB, GBA (rs12742181) was associated with higher CSF protein levels of ANG, CD798, CXCL13 and TNFRS13B (P = 7.79 × 10−7, P = 8.83 × 10−8, P = 4.87 × 10−6, P = 4.47 × 10−8 respectively). No significant associations were identified between FTD risk loci and CSF protein levels.ConclusionWe identified four pQTLs in ante‐mortem CSF, providing a neurobiological link by which genetic risk loci potentially contribute to the development of AD and DLB. Dissecting the contribution of risk loci to neurobiological processes aids in understanding the complex disease mechanisms underlying different types of dementia. Our efforts are currently being extended to functional validation and genetic replication in independent cohorts.