bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individualized subtypes prognosis of MCI using deep‐learning based jointly optimized clustering‐classification method
Authors: Kang Sohyun , Seong Joon‐Kyung , Kim Sung‐Woo 
Published: December 2021

AbstractBackgroundThe heterogeneity of Alzheimer’s disease is important theme for studying the epidemiology of the disease. Practically, understanding disease phenotypes helps deciding treatment before proceeding to dementia. Generally, it is known that AD’s subtype can be divided into three.MethodWe used 660 mild cognitive impairment (MCI) patients’ T1‐weighted magnetic resonance images (MRI) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). Inputs are atrophy vectors which mean excluding the positive part and resigned W‐scores calculated from 81,924 vertex‐level cortical‐thicknesses extracted from T1. Unlike existing clustering‐only or separated clustering‐classification models, we used a model which is jointly optimized with respect to both clustering and classification. The model is comprised of three parts: 1) feature extractor, 2) clustering module, and 3) classifier. In first part, we extract important features using simple neural network. Then, we do clustering using the deep‐features and obtain pseudo‐labels in latent space. Finally, we implement classification at last layer with the answers which are assigned from clustering module. It is end‐to‐end training being able to find the solution of combined objective function.ResultsResults were represented from 10 fold cross‐validation. Average log‐likelihood of Gaussian mixture and normalized mutual information of labels between adjacent iterations are used as clustering performance metric, cross‐entropy loss and accuracy as classification. It is difficult for such models to converge according to referenced studies. But, in this study, all the metrics were well‐converged. Atrophy maps show group comparison results of cortical thicknesses between each subtype and cognitive normal (CN) patient with FDR correction and W‐score averaged in each subtype. The demographic table about Aβ positivity and dementia conversion percentages without missing information and neuropsychological test scores table of each subtypes showed that subtype‐I has highest degree of disease severity, then subtype‐II and finally III. External validation with 662 aMCI patients’ data from Samsung Medical Center (SMC) used in similar study represented bigger gap of dementia conversion percentages between subtype‐I and II.ConclusionsIn this study, we made clustering‐classification model for individualized subtype prediction. It is end‐to‐end training method optimizing clustering and classification loss simultaneously. The results showed our model exceeds existing subtype clustering model.
High education, but not occupation or work experience, is related to a lower risk of dementia in the oldest‐old: The 90+ Study
Authors: Melikyan Zarui A , Phelan Michael J , Kawas Claudia H , Corrada Maria M 
Published: December 2021

AbstractBackgroundMost studies find that high education, work experience, and cognitively demanding occupations are independently associated with a lower dementia risk, and that the association may be strongest for occupation. It is hypothesized that these three factors provide cognitive reserve. Here we examine the risk of dementia in relation to education, work experience, and occupation in the oldest‐old (age 90+), an age group with the highest dementia risk.MethodWe analyzed data on 598 participants of The 90+ Study, a longitudinal study of aging and dementia, who were previously part of the population‐based Leisure World Cohort study, had no dementia at entry into The 90+ Study, had additional follow‐up, and reported their education and occupation. Education was categorized as <high school, vocational school or some college, and >college. Occupation categories were assigned based on 1970 US Census and grouped according to cognitive demand: more (managers/administrators and professionals) and less (all other occupations). Participants who never worked/ housewives were a separate group. We estimated risk of dementia in relation to education, occupation, and having worked vs. never worked using Cox regression.ResultAt baseline, the average age was 93 years, 42% had ≥college education, and 52% had more cognitively demanding occupations (Tables 1, 2). Over an average of 3 years of follow‐up, 48% of participants developed dementia. Compared to participants with <high school education, those with >college education had a 32% lower risk of dementia (HR=0.68) in the unadjusted model and 35% lower risk when adjusted for occupation (HR=0.65). Adjustment for sex or for sex and occupation did not change the results (Table 3). Occupation (men and women) (Table 4), or having worked (women only) (Table 5), were not related to dementia risk.ConclusionIn this oldest‐old group, education, an early life experience, remains strongly associated with dementia risk. This is in contrast to other life‐long dementia risk factors, such as APOEe4, which are no longer associated with dementia risk at very advanced ages. These results suggest that education determines cognitive reserve and life‐long lifestyle factors that protect against dementia, whereas occupation or work experience do not contribute to cognitive reserve.
Systemic inflammation is associated with dementia status in the health and retirement study
Authors: Higgins Cesar , Ware Erin B , Hicken Margaret , Zawistowski Matthew , Bakulski Kelly M 
Published: December 2021

AbstractBackgroundThe prevalence of dementia is expected to increase in the coming decades. The highest burden of this chronic condition will likely be borne by racial/ethnic minorities. Systemic inflammation is associated with dementia. This effect may be modified by race/ethnicity, since racial minorities are more likely to have elevated levels of systemic inflammation due to the accumulation of compounded negative experiences (e.g., discrimination, racism, and marginalization). Our goal was to test baseline systemic inflammation in relation to cognitive function in a racially/ethnically representative cohort of US adults.MethodsIn a cross‐sectional analysis of the Health and Retirement Study (2006 and 2008 waves, n=9,983), highly sensitive C‐reactive protein (hsCRP) was measured in dried blood spots. Cognitive status (dementia, cognitive impairment non‐dementia (CIND), and normal cognition) was measured and categorized using the Langa‐Weir classification of a modified telephone interview for cognition scale. We estimated the adjusted associations between hsCRP and cognitive status, using multivariable logistic regression. We stratified models by race/ethnicity to explore race‐dependent associations.ResultsOur study prevalence of dementia and CIND is 3.5% and 15.8%, respectively. Similarly, 26.7% of dementia and 30.1% of CIND cases occurred among participants with circulating hsCRP levels above the 75th quartile. We observed a racial and gender gradient in the levels of hsCRP in our cohort. For example, Black females had the highest average concentration of hsCRP (7.53 mg/L, SD =15.1) and Whites males the lowest (3.95 mg/L, SD = 7.42). Among participants with hsCRP >75th we observed higher odds of CIND (OR = 1.45; 95%CI: 1.22, 1.72) with respect to those in the . Similarly, elevated hsCRP >75th was associated with dementia (OR= 1.21; 95%CI: 0.86, 1.69), in comparison to the reference lower quartile. We did not observe a race‐dependent relationship between hsCRP and cognitive status.ConclusionsSystemic inflammation, as represented by high levels of hsCRP, was associated with concurrent cognitive status. Despite racial minorities exhibiting higher levels of hsCRP; in our study, the association between inflammation on cognition did not differ by race. Further studies should explore whether the established relationship is causal, seek larger sample sizes in diverse populations, and examine longitudinal relationships
Cortical thinning and white matter abnormalities relate to longitudinal neuropsychiatric symptoms differentially in predementia and dementia stages
Authors: Ji Fang , Xu Xin , Ong Marcus Qin Wen , Kan Cheuk Ni , Tan Boon Yeow , Venketasubramanian Narayanaswamy , Pasternak Ofer , Chen Christopher , Zhou Juan Helen 
Published: December 2021

AbstractBackgroundSubjects with cognitive impairment and dementia often suffer from neuropsychiatric symptoms (NPS). Recent studies reported the association between brain structural damages and NPS. However, little is known about how domains of NPS map to region‐specific multimodal macro‐ and micro‐structural brain changes and whether the patterns vary across different cognitive stages. Importantly, most existing evidence is cross‐sectional. Here, we sought to investigate how baseline cortical thickness (CTh) and white matter (WM) microstructure influenced longitudinal progression of NPS in predementia and dementia.MethodLongitudinal neuropsychiatric inventory (NPI) total severity and subsyndrome scores (Hyperactivity, Psychosis, Affective, Apathy) over 5 years were reported in 334 memory‐clinic patients (187 cognitive impairment no dementia (CIND) and 147 dementia). All participants underwent T1‐weighted structural and diffusion MRI at baseline. A free‐water (FW) imaging method was applied to derive individual‐level WM‐FW and tissue‐compartment maps from diffusion‐MRI. The grey matter (GM) CTh was derived using Freesurfer. We examined the association of baseline WM‐FW, WM‐tissue or GM‐CTh with baseline/longitudinal NPI (total severity and sub‐syndrome) using general linear models.ResultIn CIND, higher total NPI severity was associated with widespread WM‐FW increases (fronto‐parietal projection, temporal and callosal fibres) and more focal tissue fractional‐anisotropy (FAt) reductions (fronto‐parietal/callosal fibres) cross‐sectionally (Fig‐1). Specifically, such WM‐measures were associated with affective and hyperactive sub‐syndromes, but not with psychosis and apathy. No NPI‐cortical thickness association was detected in CIND. By contrast, in dementia, GM‐CTh in frontal executive and default mode and central sensory networks, but not WM‐alteration, was related to higher total NPI severity (Fig‐2). Also, GM‐CTh was associated with apathy and psychosis, but not with affective and hyperactive sub‐syndromes.Furthermore, baseline WM‐measures were associated with longitudinal changes in total NPI severity (Fig‐3) and affective and hyperactive in CIND. By contrast, no association was found between GM‐CTh and longitudinal NPI (total and subsyndromes) in dementia.ConclusionThis study demonstrated that WM‐abnormalities, which were early marker of disease, were related to NPS in CIND, while GM‐CTh was associated with NPS in dementia. Early identification and interventions should be developed for timely management of affective and hyperactive disorders, followed up by close monitoring of the progression of cerebral structural disruptions.
Quantitative systems pharmacology model of amyloid and tau to explore efficacy of therapy targeting modified forms of amyloid
Authors: Karelina Tatiana , Lerner Stepan 
Published: December 2021

AbstractBackgroundAmyloid targeting therapy in different variations is still under development. One of the potential targets is modified forms of amyloid, Ab3p. They are very specific marker found in plaques of AD subjects, and demonstrate higher toxicity to neurons. Its correlation with tau load and AD severity is stronger than for non‐modified forms. Specific therapy targeting modified Ab may be more effective and less toxic due to lower required concentration of antibodies. Glutaminyl cyclase (QC) inhibitors have considerable BBB penetration and concomitant anti‐inflammatory activities. Monoclonal antibodies to specific to pGlu3‐Ab successfully reduce cognitive impairment in preclinical settings. Quantitative systems pharmacology QSP model is a good tool to study contribution of protein modification to disease progression and investigating sensitivity of overall system to specific targeting.MethodQSP model was developed to describing amyloid production and distribution, hetero‐oligomerization of Ab1‐40, Ab1‐42 and pGlu3‐Ab. It has been combined with description of tau pathology and neuron homeostasis (NH) model. NH model describes processes regulating protein degradation and transport. Modified amyloid polymerizes with higher rate and resistant to degradation. Rate of amyloid modification was assumed to be one of the drivers, depending on age (we assumed it can be related to the calcium EPR stress in neurons and microglia activation due to inflammatory stimuli). Amyloid and tau during accumulation disrupt transport, proteasomal and autolysosome system. The model was calibrated on multiple in vitro and in vivo data, as well as preclinical and clinical data for treatments by immunotherapies.ResultIntegrated model describes accumulation of amyloid and tau according to Braak stages. It captures the role of intraneuronal processes on tau and amyloid metabolism. Model describes influence of amyloid modification on total accumulation of amyloid. Both QC inhibition and targeting by antibodies attenuate accumulation of amyloid in brain. Tau pathology progression is reduced, assuming that binding of antibody prevents toxicity of pGlu3‐Ab on tau kinase activation and calcium influx.ConclusionModel can be used to analyze contribution of different amyloid forms to pathology and efficacy of specific therapies on multiple biomarkers. It can be used for explorations of different combinations and regimens.
Efficacy of a vectorized anti‐tau antibody using systemic dosing of a blood brain barrier penetrant AAV capsid in mouse models of tauopathies
Authors: Liu Wencheng , Holth Jerrah , Paranjpe Maneesha , Ren Xiao‐Qin , Shu Yanqun , Murlidharan Giridhar , Chung Charlotte , Powers Alex , Peterson Emalee , Ecker Abigail , Hameedi Usman , Grant Kyle , Kurella Vinodh , Kavanagh Dillon , Khwaja Omar , Hou Jay , Paul Steven M. , Bales Kelly R. , Carter Todd 
Published: December 2021

AbstractBackgroundAnti‐tau immunotherapy is a promising therapy for tauopathies, including Alzheimer's disease (AD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). While passive immunization with anti‐tau monoclonal antibodies has been shown by several laboratories to reduce age‐dependent tau pathology and neurodegeneration in mouse tauopathy models, these studies have typically used repeated high weekly doses of antibody and reported only moderate reduction of tau pathology. To circumvent these limitations, using an adeno‐associated virus (AAV) vector to deliver a tau monoclonal antibody into hippocampus by direct injection to the location have been described. High levels of antibody and marked reduction of tau pathology is achieved by this approach. To further optimize this approach with a lesser invasive administration route, we have previously demonstrated broad distribution and expression of a vectorized anti‐tau antibody in the mouse brain using a blood‐brain barrier (BBB) penetrant AAV capsid administered intravenously (IV). This gene therapy‐based approach has potential advantages, including continuous expression of antibody in the central nervous system (CNS) after a single administration of vector, increased CNS levels of tau antibody relative to passive immunotherapy, and the potential to target intracellular tau aggregates. Here we describe studies characterizing the onset of transduction following dosing with a vectorized tau antibody and its efficacy in mouse models of tauopathy.MethodAAV vectors comprising the BBB‐penetrant AAV capsid and a transgene encoding an anti‐tau monoclonal antibody were administered by IV bolus to mouse models of tauopathy. Biodistribution and cellular tropism in the CNS were evaluated by ELISA and (or) immunostaining. Tau pathology was measured by AT100 immunohistochemistry and AT8 ELISA.ResultWe then investigated efficacy in reduction of tau pathology in mouse tauopathy models. Treatment with our vectorized antibody resulted in durable antibody expression in the CNS and a corresponding reduction in CNS insoluble pathological tau and neurofibrillary tangles.ConclusionOur results indicate that systemic dosing of a vectorized anti‐tau antibody using a BBB‐penetrant AAV capsid results in reduced tau pathology and may represent a new single‐dose therapeutic strategy for treating various tauopathies.
High precision plasma Aβ42/Aβ40 ratio detects early amyloid deposition in non‐demented elderly adults
Authors: Shi Dai , Zhang Lei , Guo Tengfei ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2021

AbstractBackgroundPlasma Aβ42/Aβ40 ratio measured by an immunoprecipitation and liquid chromatography–mass spectrometry assay showed high accordance with amyloid PET. However, it is still unclear about the risk factors related to plasma Aβ42/Aβ40, whether it can detect Aβ pathology earlier than Aβ PET, and how it relates to tau deposition, neurodegeneration and cognitive decline. In this study, we aim to investigate: 1) the risk factors related to plasma Aβ42/Aβ40; 2) the concordance and discordance of plasma Aβ42/Aβ40 and Aβ PET, and their associations with tau deposition at follow‐up and perspective changes of Aβ PET, neurodegeneration and cognition in cognitively unimpaired (CU) and mild cognitive impairment (MCI) elderly adults.MethodWe analyzed 181 (97 CU, 85 MCI) ADNI participants with plasma Aβ42/Aβ40, Aβ PET, white matter hyperintensities (WMH), vascular factors, adjusted hippocampal volume (aHCV) measured by structural MRI, 18F‐fluorodeoxyglucose (FDG) PET and memory score obtained within one year. The associations of plasma Aβ42/Aβ40 with age, sex, APOE‐ε4 status, vascular risk factors were tested using Pearson’s correlation or Mann‐Whitney U test. Participants were classified into Plasma±/PET± groups according to the thresholds of plasma Aβ42/Aβ40 and Aβ PET (Fig.2A). Longitudinal changes of Aβ accumulation, aHCV, FDG PET and cognition, and tau PET measured at a mean of 5.32±1.24 years later were compared among different Plasma±/PET± groups.ResultWe found older age, APOE‐ε4 carrier and greater WMH burden (Fig.1) were significantly related to reduced plasma Aβ42/Aβ40. Plasma Aβ42/Aβ40 may become abnormal earlier than Aβ PET. Plasma+/PET‐ individuals were accumulating Aβ burden in early‐affected brain regions (Fig. 2), had no evidence of tau deposition, neurodegeneration and cognitive decline at follow‐up (Fig. 3), suggesting Plasma+/PET‐ individuals are very likely in the very early stage of Alzheimer’s disease (AD).ConclusionIn summary, our results suggest that age, APOE4 carrier and white matter lesion may be related to lower plasma Aβ42/Aβ40. Individuals with abnormal plasma Aβ42/Aβ40 but normal Aβ PET may be at early stage of Aβ pathology, are significantly accumulating Aβ in AD typical cortical regions. These findings may provide useful reference for screening Aβ+ participants by using plasma Aβ42/Aβ40.
Examining the relationship between mild traumatic brain injury, later‐life brain health and cardiorespiratory fitness in a community‐dwelling sample of older adults
Authors: Markovic Shaun J , Fitzgerald Melinda , Peiffer Jeremiah J , Scott Brendan R , Brown Belinda M 
Published: December 2021

AbstractBackgroundTraumatic brain injury (TBI) has been recognised as an important global health priority. Mild traumatic brain injury (mTBI), also known as concussion, accounts for up to 90% of all TBI diagnoses. Accumulating evidence also suggests that mTBI may be a risk factor for later‐life cognitive decline and neurodegeneration, including Alzheimer’s disease and other forms of dementia. Physical activity and exercise have received increasing attention as a potentially cost‐effective mechanism to attenuate age‐related declines to cognitive functioning and brain volume. However, little is known about the interaction between maintaining a higher level of physical fitness later in life and its impact on markers of brain health in individuals with a history of mTBI in the general population.Method79 community‐dwelling older adults (mean age 68.72 ± 4.28 years, 54.4% female) underwent a comprehensive cardiorespiratory fitness assessment and magnetic resonance imaging. Participants also completed a retrospective mTBI history questionnaire.Result25 (32%) of the study participants reported sustaining at least one lifetime mTBI. No differences in total hippocampal or white matter volumes were found between participants who had a history of mTBI and those who did not. However, participants with a history of mTBI had, on average, a significantly higher total grey matter volume (581.16 ± 19.44) in comparison to controls with no mTBI history (570.05 ± 17.22), p = 0.005. Subsequent analyses found that cardiorespiratory fitness did not moderate the relationship between mTBI history and any of the MRI metrics examined.ConclusionThe results of this study suggest that later‐life cardiorespiratory fitness, in isolation, does not protect the brain from mTBI‐induced global or regional volumetric changes. Tracking longitudinal post‐mTBI physical activity habits will be critical to elucidating whether longer‐term cardiorespiratory fitness patterns are more influential in determining later‐life neurocognitive outcomes.
The impact of the COVID‐19 pandemic on nutritional status in Alzheimer's disease
Authors: Castagna Alberto , martis Ilaria , Ruberto Carmen , Fabbo Andrea 
Published: December 2021

AbstractBackgroundIn March 2020, the WHO declared a global pandemic due to the novel coronavirus SARS‐CoV‐2 and several governments planned a national quarantine in order to control the virus spread. Acute psychological effects of quarantine in frail elderly subjects with special needs, such as patients with dementia, have been poorly investigated. The aim of this study was to assess modifications of nutritional status during quarantine in patients with Alzheimer’s Disease (AD).MethodsParticipants were recruited from patients referring to Center for Cognitive Disorders and Dementia in Italy. A total of 205 patients were included. A structured telephone interview was delivered to family caregivers of patients with diagnosis of Alzheimer disease (AD). At baseline (T0) and month 6 (T1) since quarantine declaration, nutritional risk assessment were assessed by Self.Mini Nutrition Assessment (Self MNA).ResultsA total of 205 subjects (79,6 ± 6,4 years old, M=42%) were enrolled. A baseline according with the Self‐MNA test score, 32,7% were classified as malnourished, whereas 42% of were at risk of malnutrition. A T1 according with the Self‐MNA test score, 37,1% were classified as malnourished, whereas 46,3% of were at risk of malnutrition.ConclusionQuarantine induces a rapid increase malnourished and risk of malnutrition an AD. Health services need to plan a post‐pandemic strategy in order to address these emerging needs.