bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating metabolites associated with brain MRI markers of Alzheimer’s disease
Authors: Wang Ruiqi , Satizabal Claudia L , Beiser Alexa S , Vasan Ramachandran S , DeCarli Charles , Gerszten Robert Edgardo , Yang Qiong , Seshadri Sudha 
Published: December 2020

AbstractBackgroundPrior research has identified metabolites associated with general cognitive function and Alzheimer’s Disease (AD). However, more research is needed to identify additional metabolites related to AD endophenotypes to better understand the earliest pathological processes. We aimed to identify metabolites associated with brain MRI markers of AD, including total brain volume, lateral ventricular volume, and hippocampal volume in the Framingham Heart Study.MethodAbout 2,145 participants from the Framingham Heart Study Offspring and Third‐Generation cohorts were used in this project. We used linear mixed effect models to assess the association between metabolites and MRI phenotypes. Brain MRI measures were introduced as the percentage of total intracranial volume to correct for head size. Our primary model was adjusted for age, sex, BMI, and use of lipid‐lowering medications. In secondary analyses, we ran the same model stratifying for APOE4 status subgroups (e4 carriers vs. non‐carriers). Multiple testing corrected significance levels was determined as P < 2.09 × 10‐4 after considering inter‐correlation of the metabolites. Finally metabolite set enrichment analysis (MSEA) was carried out to identify biologically meaningful patterns that are significantly enriched in the top associated metabolites.ResultWe found that higher levels of cotinine, fumarate‐malate‐valine and lactate were associated with lower total brain volumes (P < 8.13 × 10‐5). In subgroup analyses, we observed that higher levels of anthranilate were related to lower brain volumes in APOE‐e4 carriers. Further, only in APOE‐e4 non‐carriers, higher phosphatidylcholine (32:1) levels were related to lower brain volumes (P < 1.52 × 10‐4) and higher levels of urate were related to lower hippocampal volume (P < 1.11 × 10‐4). Valine, leucine and isoleucine biosynthesis, and aminoacyl‐tRNA biosynthesis are significantly overrepresented for hippocampal volume in APOE‐e4 non‐carriers.ConclusionSeveral metabolites were associated with total brain and hippocampal volumes. Remarkably, some of these have been previously related to cognitive function and AD, adding to the consistency of our findings and highlighting the power of endophenotype research. Expansion to include additional brain MRI markers and replication in other neuroCHARGE cohorts, a large international consortium, are currently underway.
Die Young as Late as Possible Project: Trajectory analysis of cognitive aging
Authors: Klinedinst Brandon S. , Obhi Hardeep K. , Pappas Colleen , Shirtcliff Elizabeth , Willette Auriel A. 
Published: December 2020

AbstractBackgroundPopulations are aging worldwide, average life expectancy in the U.S. has stagnated around 80 years old, and prevalence of Alzheimer’s disease and related dementias are increasing. The Hayflick limit predicts a maximum lifespan of about 120 years among humans, and the oldest observed living human, Jeanne Calment, died after her 122nd birthday. In other words, there appears to be a wide gap between actual and potential human lifespans. Furthermore, the onset age for most health conditions has not increased markedly in many decades. This suggest that increases in lifespan may stem from extensions in the duration of sickness prior to death. Preventing morbidity and increasing healthspan will require better understanding of the different ways individuals can age. Typically, brain aging is accompanied by volumetric changes that negatively impact most cognitive processes. Despite what happens to the majority, or what happens on average, there is a vast range of variation in neurocognitive development in late life. Charting the distinctiveness of developmental trajectories within a population will help identify meaningful subpopulations that could not be uncovered ex ante. In this study we investigated cognitive changes over time and developed typologies of different and unique ways people experienced brain aging.MethodFluid intelligence data among 17,016 UK Biobank subjects was sampled three times from 2006 until 2014. Growth curves were used to estimate everyone’s level and rate of change. With these trajectory values, a cluster analysis distinguished several cognitive aging trajectories.ResultWe identified up to seven distinguishable trajectories. Each trajectory component was significant at p<.001. Two trajectories exhibited learning and other cognitive improvements over time, three maintained their cognitive performance, and two experienced cognitive declines over the eight‐year period.ConclusionAmong longitudinal cohorts, cluster analysis applied to growth curves identified meaningful subpopulations without the need for expert diagnosticians. Including typological information in population models promises to reduce within‐group variance and allow testing for processes that are conditional rather than unanimous across a population. Future works should investigate how trajectories are related to one another and whether more diverse populations demonstrate similar trajectory typologies.
Exercise intervention and promoting physical activity to prevent and delay onset of dementia
Authors: Park Hyuntae , Park Kyung Won , Yang Jakyung , Thapa Ngeemasara , Park Hyejin , Son Haeun , Jang Minwoo , Lee Jihyeon , Kim Hansol 
Published: December 2020

AbstractBackgroundThis study aimed to investigate the effectiveness of a combined‐exercise intervention program on cognitive and physical functions.MethodIn a randomized controlled trial, we enrolled 167 individuals with mild cognitive impairment (MCI). The definition of MCI was based on medical evaluations through a clinical interview conducted by a dementia specialist. Cognitive assessments were performed by neuropsychologists according to standardized methods, including the MMSE and frontal cognitive function, both at baseline and at 6 months follow‐up. The program comprised physical activity and behavior modification, exercise (aerobic and resistance), and a cognitive and exercise combined intervention program.ResultAnalysis of the subjects for group‐time interactions revealed that the exercise group exhibited a significantly improved attention, working memory, and executive function. Total habitual physical activity levels during intervention were associated with improvements in cognitive function, gait performance and the SPPB score, and the associations were stronger for those who are 75 and older are more likely than for <75, and those who have prefrail than frail individuals.ConclusionThe 6‐month combined intervention improved cognitive function and physical function in patients with cognitive impairment relative to controls. Encouraging and motivating older adults, particularly old‐older adults and prefrail individual, to improve moderate physical activity under supervision, during ongoing intervention, may be more beneficial to prevent cognitive decline and improve exercise adherence.
Structural‐MRI‐based Alzheimer's disease dementia score using 3D convolutional neural networks to achieve accurate early disease prediction
Authors: Yee Evangeline , Popuri Karteek , Ma Da , Wang Lei , Beg Mirza Faisal 
Published: December 2020

AbstractBackgroundIn recent years, many convolutional neural networks (CNN) have been proposed for the classification of Alzheimer's Disease (AD). Due to memory constraints, many of the proposed CNNs work at a 2D slice‐level or 3D patch‐level. Other subject‐level 3D CNNs which take a whole brain 3D MRI image as input require a long training time.MethodHere, we propose a lightweight subject‐level 3D CNN featuring dilated convolutions which allow the receptive field to be increased efficiently through a small number of layers. To comprehensively evaluate the generalizability of our proposed network, we performed four independent tests which includes testing on images from other ADNI individuals at various stages of the dementia, images acquired from other databases/sites (AIBL), images acquired using different protocols (OASIS) and longitudinal images acquired over a short period of time (MIRIAD).ResultWe trained our network on the ADNI data, and we achieved a 5‐fold cross‐validated balanced accuracy of 88% in differentiating stable Dementia of the Alzheimer's type (sDAT) from stable normal controls (sNC). Our network showed 78.5% accuracy in classifying images of mild cognitive impairment (MCI) subjects acquired 2 years prior to conversion to DAT. We achieved an overall specificity of 79.5% and sensitivity 79.7% on the entire set of 7902 independent test imagesConclusionIn this study, we constructed a lightweight 3D CNN network that converts the subject‐level image into a single AD dementia score to represent the disease progression. For estimating the generalization ability of the network to unseen data, independent testing is essential but is often lacking in studies using CNN for DAT classification. This makes it difficult to compare the performances achieved using different architectures. The result of our study highlights the competitive performance of our network and potential promise for generalization.
Genome‐wide association study of tau‐PET: Association of variant near NTNG2 with resistance to tau deposition
Authors: Ramanan Vijay K. , Wang Xuewei K , Przybelski Scott A. , Pillai Sheela Kumari Raghavan , Kosel Matthew L. , Batzler Anthony K. , Knopman David S. , Radford Jonathan Graff , Lowe Val J. , Mielke Michelle M. , Jack Clifford R. , Petersen Ronald C. , Ross Owen A. , Vemuri Prashanthi 
Published: December 2020

AbstractBackgroundTau deposition is a key biological feature of Alzheimer’s disease (AD) that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau accumulation while others are more resistant. The recent availability of tau positron emission tomography (tau‐PET) provides an opportunity to test the hypothesis that genetic factors are associated with differential tau deposition.MethodsWe performed a genome‐wide association study (GWAS) of tau‐PET on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.4% cognitively unimpaired) from the population‐based Mayo Clinic Study of Aging. Following genotyping with the Illumina GSA array and standard quality control, 515,206 single nucleotide polymorphisms (SNPs) were tested for association with entorhinal cortex 18F‐flortaucipir tau‐PET burden using linear regression under an additive genetic model and covarying for age and sex.ResultA genome‐wide significant association was identified for rs75546066, an intergenic SNP on chromosome 9 between MED27 (mediator complex subunit 27) and NTNG2 (netrin G2), with the minor (A) allele associated with lower tau burden (p=2.85 x 10‐8, β=‐0.48). Linkage disequilibrium and public expression quantitative trait loci (eQTL) data suggested a functional relationship between rs75546066 and NTNG2, the latter of which is highly expressed in the brain. In addition to this novel finding, three SNPs within MAPT (microtubule‐associated protein tau) displayed nominal associations to tau‐PET burden, including rs3785883 (p=0.04, β=0.07) which was previously associated with higher cerebrospinal fluid tau in an independent cohort. No associations with tau‐PET burden were identified for the APOE (apolipoprotein E) ɛ4 or ɛ2 alleles or for genotyped SNPs previously associated with AD in large case‐control studies.ConclusionTo our knowledge, this study represents the first reported neuroimaging GWAS of tau pathology. Our findings confirm the association of MAPT with tau burden and nominate the rs75546066‐NTNG2 locus as a novel potential protective influence against tau pathology which warrants further functional characterization. Our data also supports the inference that tau accumulation may have a genetic architecture distinct from APOE and other known AD susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting models.
Detection of misfolded protein aggregated in HIV‐infected people
Authors: Calderon Olivia , Ruiz Nazaret Gamez , Moreno‐Gonzalez Ines , Gelman Benjamin B. , Rocha Natalia P. , Soto Claudio 
Published: December 2020

AbstractBackgroundMany people living with HIV (PLWH) develop dementia and cognitive dysfunction often referred as HIV‐associated neurocognitive disorder (HAND). The prevalence of HAND increases with age and considering that the number of PLWH aged 55 and older is increasing in the United States, it is expected that this number will also increase in the near future. The cellular and molecular mechanisms responsible for HAND are not well defined but evidence suggests many commonalities with Alzheimer’s disease and related neurodegenerative disorders.MethodIn the present study, we analyzed by histological analysis the presence of misfolded protein aggregates of amyloid‐β (Aβ) and Tau in the brain of 22 PLWH (67.41±1.48 y/o) and 15 controls (HIV negative, 73.87±2.93 y/o).ResultWe found a higher prevalence of Tau deposits in the brain of PLWH (N=9/22; 41%) in comparison with HIV‐negative controls (N=3/15; 20%). However, the co‐occurrence of Aβ and Tau pathology was more prevalent in controls (N=8/15; 53%) than in PLWH (N=7/22; 32%) samples.ConclusionThis result may be due to the fact that the control group was significant older than the HIV‐infected group. More analyses with age‐matched groups are needed to clarify this finding. Our preliminary results suggest some differentiation between the groups with a higher prevalence of Aβ‐independent Tau pathology in HIV.
External validation of a proprietary delirium superimposed on dementia risk score using claims data and predictive analytics
Authors: Rao Anitha , Miller Benjamin , Kulman Tanzila , Pinho Paulo , Aggarwal Neelum T 
Published: December 2020

AbstractBackgroundDelirium is an acute change in mental status, attention, and cognition that develops over a short period of time and can fluctuate in course. When delirium occurs in patients with underlying dementia, it is known as dementia superimposed on delirium (DSD). The prevalence of DSD is high in all care settings and patients with DSD have a 15‐fold increase in walking dependence, 5‐fold increase in nursing home placement, and 2‐fold increase in mortality according to published studies.MethodCognitive claims from long term care insurance (LTCI) were processed using proprietary predictive analytics from Neurocern Inc, a neuroinformatics and data analytics company. The insurance third party administrator (TPA) who processes claims was blinded to the results from the predictive analytics. Claims data including carrier approval and denial decisions were provided. A DSD risk score was given to cognitive claims that met clinical criteria for delirium. A third party neurology task force validated Neurocern’s proprietary analytics and DSD score.ResultA total of 67 claims (F=41, M=26) were assessed by the third party task force, the proprietary DSD score had a sensitivity of 94.7% and a specificity of 100%. Inter‐rater reliability was high. Females had a higher incidence of DSD than males. Delirium was missed on 28% of approved claims by both the insurance carrier and the TPA.ConclusionClaims flagged with a DSD score should be medically assessed before any severity of dementia or benefit eligibility workup is performed. The high number of delirium cases missed by the insurance carrier and TPA represent claims where the patient’s condition may have improved with appropriate medical management and support. DSD claims represent high cost and high mortality claims that require appropriate financial reserving from insurance carriers.
Gamma stimulation improves sleep in Alzheimer’s patients as assessed by continuous actigraphy recordings over six months
Authors: Cimenser Aylin , Hempel Evan , Travers Taylor , Williams Martin , Hajos Mihaly , Malchano Zach 
Published: December 2020

AbstractBackgroundPrevious work has shown that sleep abnormalities are associated with Alzheimer’s Disease (AD) in multiple ways, including the observation that sleep disruptions precede the onset of cognitive symptoms in AD subjects, and that there is a strong association between disrupted sleep and development and progression of AD (Ju et al, Nat Rev Neurol. 2014 Feb; 10(2): 115‐119, Lim et al, Neurodegener Dis Manag. 2014; 4(5):351‐362). These associations, along with the fact that sleep disturbances can have broad behavioral effects, have led to the suggestion that improving sleep is an important aspect of therapeutic strategies for subjects with AD. In the present study, the long‐term effects of non‐invasive gamma sensory stimulation (Cognito Therapeutics, Inc) on sleep were evaluated in mild to moderate AD patients.MethodActivity of mild to moderate AD patients was monitored continuously with a wrist worn actigraphy watch, and data was collected during a 6‐month period. Patients were randomized to receive either 40Hz non‐invasive audio‐visual stimulation or placebo treatment. The durations of rest periods during the night was estimated from the actigraphy data and the distributions of these durations were compared between the first 3 months of the treatment period and the second 3 months of the treatment period in both cohorts.ResultAnalysis of the actigraphy data revealed that sensory‐evoked gamma stimulation improved sleep as assessed by continuous actigraphy recordings. In the active treatment group, the distribution of rest‐durations was shifted towards longer durations in the second 3 months compared with the first 3 months. In the placebo group the reverse was observed: the distribution of rest periods was shifted to shorter durations compared in the second 3 months to the first 3 months. The overall total sleep‐time at night was unaltered in either group.ConclusionGamma stimulation therapy over six months demonstrated an improvement in sleep quality and increased night‐time restful periods as assessed by continuous actigraphy recordings.
Clioquinol reduces tau phosphorylation and oligomerization
Authors: Zhu Feiyan , Lin Gaoping , Hamano Tadanori , Kanaan Nicholas M. , Yen Shu‐Hui , Asano Rei , Shirafuji Norimichi , Sasaki Hirohito , Enomoto Soichi , Yamaguchi Tomohisa , Ueno Asako , Ikawa Masamichi , Yamamura Osamu , Nakamoto Yasunari 
Published: December 2020

AbstractBackgroundThe pathological features of AD are neurofibrillary tangles (NFTs) composed of highly phosphorylated tau and senile plaques (SPs) composed of amyloid β protein (Aβ). It was suggested that Cu2 + induced hyperphosphorylation of tau and Zn2 + deposits on SPs. Clioquinol (CQ) has a mild chelating effect on Zn2 + and Cu2 +. In addition, CQ has been shown to reduce Aβ aggregation by removing Zn2+ from SPs. However, the effect of CQ on tau aggregation is not fully understood. The purpose of our study is to examine the effect of CQ on tau metabolism by using a cell culture model of tauopathy.MethodsHuman neuroblastoma cell line M1C cells that express wild‐type tau protein (4R0N) via tetracycline (Tet) off induction was used. M1C cells were exposed to 0.1‐10 μM CQ on day 4 of Tet‐Off induction, and harvested at the end of Day 5. Total tau detected by Tau5, and phosphorylated tau detected by PS199/202, AT180, AT270, CP13, and PHF‐1 antibodies, were examined using Western blot analysis. Immunocytochemical studies, fractional analysis and immunoprecipitation of ubiquitinated tau were also performed. Tau kinases including c‐Jun N‐terminal kinase (JNK), and P38 MAPK and tau phosphatase, protein phosphatase 2A (PP2A) were also examined. C‐terminal truncated pathological tau was detected by using the antibody TauC3. In addition, autophagy and proteasome activity were also examined.ResultPhosphorylated tau levels were reduced by 1‐10 μM CQ treatment. Tau kinases, JNK and p38 MAPK were inactivated by CQ treatment. Interestingly, activation of the tau phosphatase PP2A was also observed with CQ treatment. Fractionation studies showed that CQ treatment reduced AT180 and AT270 positive high molecular weight tau in the Tris‐insoluble, sarkosyl‐soluble fraction. CQ also reduced tau oligomer specific antibody TOC1‐positive oligomeric tau. CQ reduced caspase‐cleaved tau detected by antibody TauC3. P62 levels were reduced by CQ treatment, suggesting that CQ activates autophagy. In addition, CQ slightly reduced high molecular weight ubiquitinated tau. This implies activation of the ubiquitin‐proteasome by CQ.ConclusionCQ could provide beneficial effects against pathogenic forms of tau via multiple mechanisms and may represent a viable therapeutic approach for AD and other tauopathies.
Comparison of sub‐tests in working memory index among posterior cortical atrophy, Alzheimer’s disease and age‐associated memory impairment
Authors: Sarutikriangkri Yuthachai , Chokesuwattanaskul Anthipa , Phanthumchinda Kammant , Likitjaroen Yuttachai 
Published: December 2020

AbstractBackgroundPosterior cortical atrophy (PCA) is a rare syndrome of Dementia. Typically, the main symptoms is visuoperceptual impairment. However, working memory impairment has also been reported. This study aimed reveal the pattern of working memory index impairment in PCA by comparing to Alzheimer’s disease patients (AD) and Age‐associated Memory Impairment subjects (AAMI).MethodPatients were recruited from Neurocognitive Clinic, King Chulalongkorn Memorial Hospital. Working Memory Index (WMI) in Wechsler Adult Intelligence Scale – Fourth Edition (WAIS‐IV) was used to assess working memory. WMI is composed of 2 subtests which are Digit Span (DS) and Arithmetic (AR). DS is divided into 3 tasks including Digit Span Forward (DSF), Digit Span Backward (DSB), and Digit Span Sequencing (DSS). The score of WMI and all subtests were converted to standard score by age‐matched group. Descriptive statistics, One‐way ANOVA, and Wilcoxon Sign Test were used to analyze.ResultThere were 7 PCA, 19 AD, and 22 AAMI. WMI score of PCA, AD, and AAMI were 65.86, 91.63, and 99.50 respectively. WMI score of PCA were significantly less than AD (p<0.001) and AAMI (p<0.001). For each subtest scaled score of WMI revealed PCA had DS and AR significantly less than AD (p=0.001) and AAMI (p<0.001). Regarding the scaled score of PCA patients, DS was 4.57 (DSF=7.86, DSB=5.29, and DSS=3.57) and AR was 3.57. DSB and DSS were significantly less than DSF (p≤0.05).ConclusionWorking memory in PCA patients was extremely low compared to AD and AAMI patients. PCA patients were more impaired in mental manipulation and calculation compared to attention. We should consider PCA as a differential diagnosis in dementia patients who score very low on WMI.