bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual connectome priors improve neuroimaging‐based Alzheimer’s progression modeling
Authors: Kurmukov Anvar , Zhao Yuji , Gutman Boris A 
Published: December 2020

AbstractBackgroundDisease progression models (DPM) of Alzheimer’s disease (AD) based on non‐invasive biomarkers have received significant attention in recent years. Crucially for drug development, DPM promises to identify pre‐clinical stages of AD. However, traditional DPMs consider only a single canonical sequence of neurodegeneration, which may ignore important population clusters and individual variation. Addressing this, we propose a method to use individual dMRI‐based connectomes as an informative prior in AD DPM.MethodWe extracted regional cortical thickness measures and tractography‐based connectomes from T1 and diffusion MRI of 32 AD patients and 52 controls. We build a DPM using the event‐based (EBM) approach. EBM models AD staging discreetly. Every stage is identified with a neurodegenerative event, e.g. a regional thickness falling below some threshold. Disease stage is then defined by the last abnormal biomarker based on a canonical event order. The goal of the model is to find an event order specific to AD in a Baeysian setting. We replace the uninformative prior on the order with one based on the subject connectomes. Every regional biomarker pair is assigned a probability that one region degenerates following the other based on the shortest connectome path length between the regions. The idea follows closely the amyloid network diffusion hypothesis. We test the original EBM and our models on cross‐sectional data and test them on 12‐ and 24‐month follow‐up scans. Predicted patient stage and visit order are ordinally correlated to assess model performance.ResultOur model outperforms the original EBM (Kendall tau=0.34 vs 0.49). Our model systematically assigns higher progression scores for AD subjects (Fig.1). We also compare DPM performance using predicted stage in disease classification. Our model again outperforms traditional EBM, achieving ROC AUC=0.88 (std=0.046) vs 0.816 (std=0.008).ConclusionWe have developed an individualized neuroimaging disease progression model of AD based on the widely used EBM. Individual connectome variation allows the computational model to more finely pin‐point an individual’s specific stage of disease progression based on the observed pattern of neurodegeneration. The connectome‐based EBM shows significant improvement over standard EBM.
Machine learning analysis of speech and eye tracking data to distinguish Alzheimer's clinic patients from healthy controls
Authors: Field Thalia S. , Newton‐Mason Sally May , Shajan Sheetal , Barral Oswald , Jang Hyeju , Soroski Thomas , O'Neill Zoe , Conati Cristina , Carenini Giuseppe 
Published: December 2020

AbstractBackgroundClinical trials of disease‐modifying therapies for Alzheimer’s disease (AD) are increasingly focused on recruiting individuals with preclinical or early‐stage disease. Artificial intelligence may help in enriching clinical trial populations with high‐risk individuals. We analyzed prospectively‐collected speech and eye‐tracking data to distinguish individuals with mild‐moderate AD, mild cognitive impairment (MCI), and subjective memory complaints (SMC) from age and sex‐matched healthy volunteers.MethodIndividuals with known clinical diagnoses of AD, MCI, and SMC from a specialty clinic, and healthy controls from the community, were prospectively recruited. Participants described the “Cookie Theft Picture” from the Boston Aphasia Battery. Their speech was recorded and manually transcribed and eye movements were assessed using an infrared eye‐tracker. Data underwent feature extraction for language‐related features including lexical and acoustic parameters (from transcripts and speech), and fixation and saccades (from eye‐tracking). Additionally, for language and eye‐tracking, features capturing spatial neglect are explored following the approach in [1]. Separate predictive models were examined using logistic regression (LR), K‐Nearest Neighbours (KNN), and random forests (RF).ResultRecruitment and analysis are ongoing. Data from 34 clinic patients (9% SMC, 35% MCI, 56% mild‐moderate AD, mean age 7310, 44% female) and 39 controls (mean age 6811, 79% female) is reported. Best speech‐based models distinguished patients from controls with an Area Under the ROC Curve (AUC) of 79% (95% CI 0.70‐0.87). Eye‐tracking‐based models reached distinguished patients from controls with an AUC of 71% (95% CI 0.59‐0.82).ConclusionMachine‐learning mediated analysis of speech and eye‐tracking data achieved promising classification performance with the current cohort. Both increasing the size of the corpus with ongoing recruitment, and combining demographic and clinical data alongside multimodal feature fusion, may help to improve classification.
Sex differences in the association of APOE E4 allele and cognitive decline in a biracial population sample
Authors: Aggarwal Neelum T. , Barnes Lisa L. , Wilson Robert S. , Weuve Jennifer , McAninch Elizabeth A. , Evans Denis A. , Rajan Kumar B. 
Published: December 2020

AbstractBackgroundPrior studies of sex differences on the association of Apolipoprotein E4 allele and cognitive decline have reported conflicting results and have been done in predominantly White populations. In this study, we tested whether the association of the APOE E4 allele and cognitive decline differs between men and women in a biracial population‐based sample of older adults.MethodParticipants (N = 5,807, 63% females and 60% Black) underwent brief cognitive assessments at 3‐year intervals from 1993 to 2012. Using linear mixed effects models, adjusted for age, education and race, we examined the rate of cognitive decline among women and men with and without the APOE E4 allele.ResultThe presence of the APOE E4 allele did not vary between women and men (32% vs. 34%). Among participants without the APOE E4 allele, the rate of annual decline in global cognition was higher in women compared to men (0.048 standard deviation units [SDU] vs. 0.033 SDU per year, p = 0.0002). Among participants with APOE E4 allele, the rate of decline in global cognitive function and episodic memory was about twice as high among White women compared to white men (0.097 SDU vs. 0.057 SDU per year, p < 0.0001; 0.077 SDU vs. 0.031 SDU per year, p < 0.0001) respectively. Black men and women with APOE E4 did not differ in rates of global cognitive decline (0.078 vs. 0.073 per year, p = 0.58), or in any domains.ConclusionThe rates of global cognitive decline, especially in APOE E4 carriers differed significantly between White women and men, but was similar between Black women and men. Additionally, the APOE E4 genotype was associated with a faster rate of decline in global cognitive function and episodic memory in women compared to men. The reason for sex differences among Black and White participants and especially among White women needs further attention.
In preclinical AD, impaired amyloid clearance and mitochondrial function underlie associations between white matter integrity and glucose regulation deficits
Authors: Pappas Colleen , Wang Qian , Klinedinst Brandon S , Le Scott T. , Larsen Brittany , Pollpeter Amy , Willette Auriel A. 
Published: December 2020

AbstractBackgroundWhite matter tract integrity is an early marker for Alzheimer’s disease (AD) risk. Adults with AD genetic risk factors, such as Apolipoprotein E ε4 (APOE4) carriage or AD parental family history (AD FH), typically show less white matter integrity in AD‐sensitive tracts. Similar loss is seen in adults with glucose regulation problems, such as type 2 diabetes (“diabetes”), and is more pronounced with APOE4 or AD FH present. By 2050, due to the obesity epidemic, over 70% of aging adults will have some form of glucose regulation deficit. The mechanisms underlying this synergistic loss in tract integrity are unknown. Impaired glucose regulation lead to mitochondrial damage and amyloid clearance, where such markers may explain how genetic and metabolic factors interact in mid‐ vs. late‐life (Figure 1).MethodLongitudinal data were downloaded for 12,740 unimpaired UK Biobank participants (47‐81yo). Diffusion Tensor Imaging (DTI) quantified overall tract, axon, and myelin integrity. Neurite Orientation and Dispersion Density Imaging (DTI‐NODDI) quantified tract complexity, neurite density, and water diffusion. Tracts included the cingulum, uncinate fasciculus, superior longitudinal fasciculus, fornix, and corpus callosum. Linear mixed models tested the main effects of glucose‐determined diabetes status and serum insulin‐like growth factor 1 (IGF‐1), a marker of intact glucose regulation. Interactions were tested with AD genetic risk factors and age. Preacher‐Hayes moderation‐mediation analyses tested if markers of amyloid clearance and mitochondrial function, respectively cystatin c and AST:ALT ratio, drove these associations.ResultAmong all tracts, diabetes status and decreased IGF‐1 over 6 years were related to less tract and neurite density, but more tract complexity (p<.05 to .001). For APOE4 or AD FH (Figure 2), interactions indicated that among adults with genetic risk, higher IGF‐1 was related to more tract integrity in mid‐life, but much less integrity in late‐life. These interactions were fully moderated by cystatin C (indirect effect: 49.5%, p<.05) and AST:ALT (indirect effect: 51.5%, p<.05).ConclusionIn adults with APOE4 or AD FH, excess glucose in mid‐life may temporarily increase tract density because of excess ATP conversion. This process leads to mitochondrial damage and amyloid accumulation, however, and eventually becomes neurotoxic and degrades white matter.
Tau hyperphosphorylation in the retinal ganglion cells is attenuated upon silencing of SHP2 phosphatase
Authors: Gupta Vivek K. , Chitranshi Nitin , Thananthirige Kanshika Pushpitha Maha , Rajput Rashi , Gupta Veer Bala , Mirzaei Mehdi , Basavarajappa Devaraj , Graham Stuart 
Published: December 2020

AbstractBackgroundHuman and animal studies demonstrate that both amyloid precursor protein and phosphorylated Tau which are hallmark proteins associated with Alzheimer’s disease (AD) pathology are perturbed in the retinal tissues. The accumulation of pTau in the retina in addition to the brain tissue suggests eye as a valuable structure for disease diagnosis and to study the disease mechanisms in neurodegenerative disease. Recent studies in human tissues and animal models have established a molecular overlap of AD with glaucoma in the eyes and both the diseases demonstrate altered amyloid beta and Tau phosphorylation profile. We show that Shp2 interacts with Tau protein in retina and silencing this phosphatase in the retinal ganglion cells using AAV2 mediated gene therapy can protect the retina.MethodAnimal model of ocular hypertension was generated by repeat administration of polystyrene beads into the anterior chamber of rat eyes for 8 weeks resulting in sustained elevation of intraocular pressure (20.84±1.65 mmHg). Tau expression changes were investigated both in the animal model and human tissues obtained from the Sydney Eye bank (n=3) using immunohistochemical and WB. Silencing of Shp2 expression in the inner retina was achieved using intravitreal administration of AAV2 constructs under the control of CAG hybrid promoter. The animals were monitored for 2 months after Shp2 silencing and effects on Tau protein expression studied (n=48).ResultIncreased Tau Ser404 phosphorylation was observed in both human glaucoma retinas (p<0.02; student t‐test) and in the animal model of glaucoma (p<0.05) in the WB and immunohistochemical analysis. Shp2 silencing (82±4%) was achieved using AAV2 administration and transduction was monitored using GFP staining. A 7.5±3‐fold downregulation Shp2 expression was achieved using shRNAmir that resulted in significant reduction of pTau Ser404 levels in the inner retina (p<0.028, Bornferroni post‐hoc test) indicating a regulatory effect of the phosphatase on the pTau levels.ConclusionThis study demonstrates that TauSer404 phosphorylation in the retina in vivo is regulated by Shp2 phosphatase. Targeted gene therapy approaches to modulate Shp2 expression can be used as a novel strategy to reduce Tau pathology in the neural tissues in various neurodegenerative disorders.
Biomarkers and trial‐ready cohorts for Alzheimer’s disease clinical trials in the Down syndrome population
Authors: Fortea Juan 
Published: December 2020

AbstractBackgroundOver the past few years, substantial progress has been made in elucidating the natural history of AD in people with DS using standard AD biomarkers such as amyloid, tau and FDG PET, volumetric MRI as well as biofluid markers in CSF and plasma. Indeed, several research groups from around the world have shown that there exist remarkable similarities between AD biomarkers in DS and the sporadic and autosomal dominant forms of AD (Fortea et al, 2020; Rafii et al, 2015; Strydom et al, 2017; Fortea et al, 2018).MethodsWe will review recent advancements in blood biomarkers,. We will discus with the recruitment of trial ready cohorts in the US and Europe will facilitate and accelerate the conduction of Alzheimer’s disease Clinical Trials in the Down Syndrome Population.ResultsPlasma amyloid, p‐tau and neurofilament light in plasma which are emerging as key AD diagnostic, prognostic and theragnostic biomarkers. There have been enormous advancements in the recruitment of trial ready cohorts. Specifically, the NIH‐funded Alzheimer’s Clinical Trial Consortium for Down Syndrome (ACTC‐DS) utilizes the existing depth and breadth of expertise of the Alzheimer’s Clinical Trial Consortium (ACTC) to conduct AD clinical trials in adults with DS across international performance sites with unparalleled expertise. The project leverages the infrastructure of the ACTC as well as the Alzheimer’s Biomarker Consortium for Down Syndrome (ABC‐DS) and Horizon21 networks.ConclusionGiven the very high risk for AD, the potential impact of this approach on improving the lives of adults with DS cannot be overstated.
EURO‐FINGERS/UK FINGERS (Europe)
Authors: Solomon Alina , Kivipelto Miia , Ngandu Tiia , Mangialasche Francesca , Hartmann Tobias , Scheltens Philip , Molinuevo Jose Luis , Georges Jean , Middleton Lefkos T 
Published: December 2020

AbstractBackgroundLarge European pioneer trials (e.g. FINGER, MAPT, preDIVA) testing multidomain lifestyle‐based interventions for preventing cognitive impairment / dementia have highlighted the crucial need for better‐defined at‐risk groups for achieving intervention response. Although the long time between at‐risk or preclinical disease stages and dementia creates a window of opportunity for prevention, this window is still poorly defined due to the complex multifactorial nature of Alzheimer's disease (AD), and high inter‐ and intra‐individual variability in risk and prevention potential.MethodMIND‐ADmini is a multinational 6‐month pilot trial with an optional 6‐month extension testing the feasibility of the FINGER multidomain lifestyle intervention in people with prodromal AD and vascular/lifestyle‐related risk factors. Participants are randomized into 3 groups: multidomain lifestyle intervention; multidomain lifestyle intervention + medical food; and standard care. MIND‐ADmini also provides a first template for feasibility of future combinations of lifestyle + potential disease‐modifying drugs. The recently started EURO‐FINGERS project, based on a precision prevention and early detection model adapted from cancer research, will take the first steps towards an updated FINGER 2.0 intervention model aiming to bridge the gap between pharmacological and non‐pharmacological interventions. The 2‐year MET‐FINGER‐APOE trial plans to start with a drug repurposing approach, i.e. multimodal lifestyle+metformin intervention in an APOE4 enriched (min 50%) at‐risk population.ResultThe MIND‐ADmini pilot trial was completed in December 2019. Preliminary findings will be summarized based on ongoing data analysis. MET‐FINGER‐APOE trial protocol is currently under development, and a synopsis of the study design will be shown.ConclusionEURO‐FINGERS aims to provide a common framework for European multimodal dementia prevention studies, with a particular focus on precision medicine approaches, and accommodating combinations of lifestyle interventions with potential disease‐modifying drugs.
CAN‐Thumbs UP (Canada)
Authors: Nygaard Haakon B. , Chertkow Howard , Feldman Howard H. , Belleville Sylvie , Montero‐Odasso Manuel 
Published: December 2020

AbstractBackgroundThe Canadian Consortium on Neurodegeneration in Aging (CCNA) was founded in 2014 to bring together Canada's dementia research community to work together in a more synergistic manner to catalyze new important progress in dementia research in Canada. Teams are funded to work on questions and themes from basic science to clinical work. An important new initiative in Phase 2 of CCNA (2019‐24) is to set up a national study on dementia prevention. CCNA's "Canadian Therapeutic Platform Trial for Multidomain Interventions to Prevent Dementia "(CAN‐Thumbs UP or CTU) has begun with funding from the CIHR (national Canadian research fund) and the Alzheimer Society of Canada. It's building a research program that includes the recruitment of a Trial Ready Cohort (TRC) of over 2,000 non‐demented older individuals at high risk for dementia. These individuals will undergo detailed assessment focusing on cognitive level and risk factors, and be monitored and followed closely over 12 months using instrumentation such as actigraphy and activity monitoring as well as burst cognitive testing. They will also be offered a Brain Health Support Program (BHSP). The BHSP will offer internet‐based weekly modules to encourage lifestyles modification and awareness of dementia risk factors such as hearing loss and diabetes. The BHSP will become the "baseline" of best information on prevention of dementia that should be made available to the population. The initial program will focus on optimizing compliance, and fidelity of the interventions to allow that they reach the broad public with the most opportunity for effective uptake. At the same time, we will be designing a Master Trials Protocol (including a single uniform master protocol, uniform inclusion and exclusion criteria and common outcome measures) which will later be used to carry out combinations of multidomain interventions ‐ both lifestyle and pharmacological ‐ on subset populations of this Trial Ready Cohort. In these intervention trials, we plan to tailor interventions to individuals with specific risk factors (e.g., sleep interventions for those showing fragmented sleep). CAN‐Thumbs UP is still in its early stages, and is being built in conversation with scientists from WW Finger.
J‐MINT (Japan)
Authors: Arai Hidenori , Sakurai Takashi , Sugimoto Taiki 
Published: December 2020

AbstractBackgroundApproximately 5 million people are living with dementia in Japan. Appropriate countermeasures should be established to reduce the incidence of dementia. The purpose of the Japan‐multimodal intervention Trial for prevention of dementia (J‐MINT) was to address the effect of a multimodal intervention in subjects with cognitive impairment.MethodJ‐MINT is a RCT that will recruit 440 older people (65 to 85 years old) with high risk of dementia, defined as decreased cognitive performance in at least one of the four cognitive functional domains of memory, attention, executive function, and processing speed. Subjects will be randomized to either a group that receives usual care or a group that participates in an 18‐months multidomain intervention, consisting of exercise, nutritional counseling (visits and telephone follow‐ups by health consultants with expertise in nutrition), and cognitive training using the "Brain HQ” program. In the exercise program, the intervention group participates in activities described as “cognicise”, from the combination of the words "cognition" and "exercise," (a program developed at the National Center for Geriatrics and Gerontology, NCGG in Japan) which combines physical exercise and cognitive tasks. Additionally, diabetes, hypertension and dyslipidemia are treated in accordance with the Japanese guidelines for older patients. The primary outcome of J‐MINT is cognition, while secondary outcomes include functional status, blood‐based biomarkers reflecting β‐amyloid accumulation in the brain, omics analysis and neuroimaging (MRI).ResultWe are now recruiting the participants and this study will be completed at the end of 2021. Evidence from this research is expected to inform a large‐scale, national implementation of multimodal intervention programs for older people at high‐risk of dementia.ConclusionN/A. This study is supported by Japan Agency for Medical Research and Development.
Imaging misfolded tau in the retina
Authors: Kayabasi Umur A 
Published: December 2020

AbstractBackgroundRecent research suggests that Tau is the culprit lesion along with neuroinflammation in the etiology of Alzheimer' s Disease (AD). Retina is the extention of the brain and is the most easily approachable part of the central nervous system. Detection of thepathological protein accumulations may be possible by using spectral domain optical coherescent tomography (SD‐OCT) and fundus autofluorescein (FAF). There is evidence showing that retinal plaques start accumulating even earlier than the ones in the brain. Most recent Tau protein images in thebrain consist of normal or reverse C‐shaped paired hellical filaments.Method20 patients with PET proven AD were examined by SD‐OCT and FAF. Mean agewas 72. Hypo or hyperfluorescent retinal lesions were scanned by SDOCT and Neurofibrillary Tangles (NFT) in a masked fashion. The researchers agreed on the shape of the lesions. Both C‐shaped (normal or reverse) NFTsand thinner fibrillary structures were taken into consideration.ResultIn all the patients, NFTs that exactly corresponded with the histopathologic and cryo‐EM images of Tau (Figure 1) in terms of shape and dimension were detected along with thin fibrils and lesions similar to amyloid beta. The number of the retinal filaments and other abnormal proteins was in concordance with the severity of the disease process. The advanced retinal lesions had normal or reverse paired C shapes (Figure 2) and thin fibrils had the shape of histopathologic images seen in early developmental stages of the disease.ConclusionRetinal images of Tau were disclosed for the first time in live AD patients. Retinal neuroimaging is a trustable biomarker and tool for monitoring the disease.