bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimized extraction of the medial temporal lobe for postmortem MRI based on custom 3D printed molds
Authors: Lasserve Jade , Lim Sydney A. , Wisse Laura , Ittyerah Ranjit , Ravikumar Sadhana , Lavery Madigan , Robinson John L. , Schuck Theresa , Grossman Murray , Lee Eddie B. , Yushkevich Paul A. , Tisdall Dylan M. , Prabhakaran Karthik , Mizsei Gabor , Artacho‐Perula Emilio , Martin Maria Mercedes Iniguez de Onzono , Jimenez Maria del Mar Arroyo , Munoz Monica , Romero Francisco Javier Molina , Rabal Maria del Pilar Marcos , Irwin David J. , Trojanowski John Q. , Wolk David A. , Insausti Ricardo 
Published: December 2020

AbstractBackgroundStructural magnetic resonance imaging (MRI) biomarkers are important for early detection of Alzheimer’s Disease (AD). However, atrophy measures can be confounded by changes due to aging and comorbid non‐AD neurodegenerative pathologies. Linking postmortem MRI of the medial temporal lobe (MTL) to histopathology may identify focal patterns of change associated specifically with early AD. We implemented a pipeline of high‐resolution MRI of MTL specimens and serial histopathology imaging [REF]. However, the task of extracting the intact MTL specimen such that it fits into the MRI coil requires anatomical expertise and has proven error prone. Here we present an algorithm to automatically create 3D printed molds guiding MTL extraction.MethodINPUTS: 7T MRI scan of a formalin‐fixed hemisphere in which the hemisphere, MTL ROI and optional second ROI to be spared during cutting (e.g. frontal lobe) have been segmented using ITK‐SNAP semi‐automatic segmentation tools. OUTPUTS: Two 3D printed molds with slits that guide cutting. Mold 1 holds the whole hemisphere, guiding four cuts orthogonal to the midsagittal plane (Figure 1). Mold 2 holds the extracted tissue block, guiding three subsequent longitudinal cuts that trim the tissue to fit into a 50mm cylindrical holder (Figure 2). The positioning of the cuts can be specified interactively by the user using ITK‐SNAP (translating and rotating 3D images representing cutting planes) or automatically by optimizing (using Powell’s method) energy functions that minimize the volume of the final piece of tissue under multiple constraints (see Figures 3 and 4).ResultThe algorithm with interactively positioned cut planes was used in four hemispheres; the automated version in one (Figure 5). For each MRI scan, the MTL was intact. By contrast, retrospective review revealed cutting errors in 48% of manually cut specimens.ConclusionOur image‐guided approach reduces errors and dependence on anatomical expertise; allows more tissue to be spared from each brain donation; and enables postmortem imaging at a larger scale. It is not limited to the MTL and could be of interest to brain banks and AD research centers involved in postmortem imaging.
Effects of physical exercise in dual task performance and global cognition of elders with Alzheimer's disease
Authors: Ferreira Jose Vinicius , Silva Felipe de Oliveira , dos Santos Sacramento Plácido Jessica , Laks Jerson , Deslandes Andrea Camaz 
Published: December 2020

AbstractIntroductionThe increased prevalence of Alzheimer’s Disease (AD) has been generating a pursuit for different strategies that may help its treatment1. Physical exercise has been getting increasing attention, considering the low coast and benefits for physical and mental health2. To evaluate the effect of 12‐week multimodal training program in dual‐task performance, and on global cognitive function in elderly with AD.Methods24 elderly subjects diagnosed with AD were randomized and divided into two groups: exercise group (EG) n = 10, Age = 79.2 ± 10.04 and Mini Mental State Exam = 19.90 ± 4.88; and control group (CG), n = 14, Age = 75.7 ± 7.94 and Mini‐Mental State Exam = 21.42 ± 4.18. The evaluation of global cognition was measured through the Mini Mental State Exam, and the dual task through the 8 foot up and go test performance while naming as many animals as possible. In dual task condition we analyze the performance by mean velocity (m/s), DT cost (DTC) which was calculated by the formula (DTC = ([time of the test in a single task – time of the test in a dual task] / time of the test in a single task) × 100), and the number of the animals named per second during the performance. In order to compare groups before and after 12 weeks of intervention, a two‐way ANOVA of repeated measures and Cohen’s calculus of effect size (d) were applied.ResultsAfter 12 weeks, the EG showed clinical and significant improvement in the DT animals (ES=0.66) and clinical, but not significant, improvement in the variables DT (m/s) (ES=0.37), and DTC (ES=0.58). In regards to the Mini Mental State Exam, the EG showed conservation of global cognitive capacity, while the control group showed deterioration.
Effects of homotaurine on DLPFC disarray in MCI and the role of GABA
Authors: Bonomi Chiara Giuseppina , De Lucia Vincenzo , Motta Caterina , Koch Giacomo , Martorana Alessandro ,   Non Invasion Brain Stimulation Unit
Published: December 2020

AbstractBackgroundHomotaurine has been studied for its capacity to interact with amyloid‐beta monomers preventing their aggregation to oligomers, which carry a high degree of synaptic toxicity and are thought to play an upstream role in the pathogenesis of Alzheimer’s disease (AD)1. At once, this compound directly modulates excitatory neurotransmission via its high affinity with GABA‐A receptors. A recent study showed that homotaurine improves cholinergic transmission, likely by modulating inhibitory cortical activity2. Its anti‐amyloid properties combined with the GABAergic profile make homotaurine a new potential drug for the treatment of AD. Since pathological changes long precede cognitive decline in AD, Mild Cognitive Impairment (MCI) should be looked upon as a favoured stage for interventions aimed at stopping or slowing the progression of the disease. Several neurophysiological studies also highlighted that, from the earliest stages of AD, cortical plasticity at the dorso‐lateral Pre‐Frontal Cortex (dlPFC) is impaired, with lost of physiological beta‐gamma oscillatory response to TMS. We decided to test the effects of homotaurine on dlPFC functionality in patients with MCI.MethodWe used TMS‐EEG to non‐invasively stimulate the left and right dlPFC of 5 patients that accessed to our Memory Clinic for subjective amnestic impairment (mean MMSE 28). Registration was performed at baseline and after 15 days of treatment with Tramiprosate 100 mg/day.ResultAt baseline, the response on left dlPFC was weak in frequency, with an anomalous spot on lower alpha frequencies. Instead, the stimulation on right dlPFC originated a powerful response, yet aspecific in frequency, outlining a prominent inter‐hemispheric asymmetry. Post treatment results showed (1) a spectrum of oscillation frequency more coherent with physiological registrations and (2) interhemispheric symmetry in response.ConclusionThese data suggest that Homotaurine increases frequency of oscillation in dlPFC, and helps re‐establishing, at least partially, interhemispheric balance in terms of oscillation in patients with amnestic impairment. This rapid effect likely depends on Homotaurine‐mediated changes of cortical GABA transmission, meaning that GABA might be implicated in cortical disarray from the earliest stages of AD.
Generation of a comprehensive disease progression model across the Alzheimer’s disease continuum
Authors: Hanan Nathan J. , Sivakumaran Sudhir , Sinha Vikram , Haeberlein Samantha Budd , Gold Michael , Romero Klaus 
Published: December 2020

AbstractBackgroundAdequate assessment of trial design optimization is an important factor to inform clinical trial design for complex disorders such as Alzheimer’s disease (AD). Critical Path Institute’s Critical Path for Alzheimer’s Consortium (CPAD) has achieved EMA qualification and FDA Fit‐for‐Purpose endorsement of the first‐ever quantitative drug development tool (the clinical trial simulator for mild‐to‐moderate AD) and is in the process of developing a disease progression model spanning the entire disease continuum, to enable clinical trial design optimization. The objective of this work is to develop a structural model that characterizes disease progression in AD patients using the integrated CPAD database and optimize experimental design using clinical trial simulations.MethodA disease progression model characterizing the time course of clinically relevant measures (ADAS‐Cog, CDR‐SB, other clinical scales and biomarkers), will be developed using an integrated dataset comprised of multiple observational and clinical trial data sources. Covariates including demographics, time from and to diagnosis, genetic status (APOE4), co‐morbidities and medication use will be assessed using non‐linear mixed effects methods. Monte Carlo simulations will be performed to compare the statistical power by sample size in trials with and without enrichment using relevant covariates.ResultModel selection based on the log‐likelihood ratio and goodness‐of‐fit plots will be used to select the model structure that most adequately describes the integrated database. Covariate analyses will be performed to identify variables that constitute relevant predictors of baseline severity and disease progression rates. Trial simulations for a therapeutic effect using standard drug effect models for symptomatic and disease‐modifying effects will be conducted to estimate an optimal sample size when trials are enriched with a clinically relevant covariate.ConclusionThe simulation output from the disease progression model will enable a more efficient design of clinical studies with better informed inclusion criteria and enrichment strategies. The proposed quantitative methodology permits a comprehensive integration of relevant patient characteristics available for decision‐making.
Robots, the Alzheimer patient, and the GDPR: Policy and privacy considerations for the use of robots in care, treatment, and diagnosis
Authors: Pierce Robin 
Published: December 2020

AbstractBackgroundSeveral types of robots are currently being designed and introduced to address the needs of dementia patients at various stages of the disease progression. Robots hold the potential to fill some of the gap left by nursing and other staff shortages. In recent years, smaller, lighter, and less expensive robots have entered the market. Moreover, more sophisticated robots that combine functions of “companionship” with other care functions are becoming available. Increasingly, these robots contain sensors that serve a range of monitoring functions that can alert caregivers, neighbors, and clinical staff to phenomenon that may signal the need for attention or follow‐up. Robots that employ AI and thus, through the processing and refining of outputs, are able to “evolve” to better interact with the patient.MethodsA survey of therapeutic, social, and social care robots were assessed to identify functions, processes, and designed purpose. A legal and ethical analysis identified data protection and privacy issues that arise in the deployment of these robots. This analysis is performed within the context of queries about the appropriateness of certain types of task‐shifting to robotics in dementia care and treatment.ResultIn performing monitoring functions for clinical or safety purposes, as well as “intelligent” companionship, these robots necessarily collect a range of data. Given that ever‐increasing phenomena, including behavioral, physiological, verbal, emotional, are recognized as being informative of a dementia‐relevant event (e.g. diagnosis, progression), this processing of environmental and personal information can be helpful to clinical staff and enhance caregiving. Yet, this data‐driven technology invokes consideration of privacy concerns, particularly in view of the General Data Protection Regulation in the EU. Concerns about the collection of sensitive (health) data of the patients and others in a shared environment, e.g. a nursing home, must comport with legal and ethical requirements.ConclusionBeyond data protection concerns, the broader issue of privacy is triggered by these technologies, forcing questions about optimal and ethical care, monitoring of the Alzheimer’s patient, and challenges for “task‐shifting”. This paper explores privacy and data protection issues in the shifting of certain tasks, functions, and responsibilities to therapeutic robotics, and addresses related legal and ethical considerations.
Neutrophil adhesion in brain capillaries contributes to cerebral blood flow deficits in APP/PS1 mice and is dependent on oxidative stress pathways
Authors: Ruiz‐Uribe Nancy E. , Bracko Oliver , Swallow Madison , Ali Muhammad , Njiru Brendah N. , Falkenhain Kaja , Chang Hsin‐Yun , Iadecola Costantino , Park Laibaik , Nishimura Nozomi , Schaffer Chris B. 
Published: December 2020

AbstractBackgroundCerebral blood flow (CBF) is decreased by ∼30% in both human patients and animal models of Alzheimer’s disease (AD). Previously, we found that about 2% of cortical capillaries in the APP/PS1 mouse model of AD had stalled blood flow due to an adhered neutrophil, while only 0.4% of capillaries were stalled in wild type controls. Blocking neutrophil adhesion in the APP/PS1 mice released the adhered cells, leading to increased CBF and improved cognitive function. Here, we report on the upstream molecular mechanisms contributing to the increased neutrophil adhesion, focusing on oxidative stress pathways that have previously been implicated in endothelial dysfunction in AD, including the loss of neurovascular regulation.MethodWe inhibited NOX2‐containing NAPDH‐oxidase, a reactive oxygen species producing enzyme shown to be activated in AD, in 10‐11 month old APP/PS1 mice for two weeks.ResultWe found that, in APP/PS1 mice, the fraction of capillaries with stalled blood flow was decreased by 67%, CBF was increased by 29%, and performance on short‐term memory tasks was improved. Enzyme‐linked immunosorbent assays showed no significant changes in amyloid‐beta levels and the overall plaque load was not affected. A decrease in the brain levels of activated astrocytes was detected, suggesting that NOX2 inhibition reduces overall inflammation.ConclusionThis study implicates the NOX2 pathway as a molecular mechanism likely underlying the vascular inflammation that contributes to capillary stalling and CBF reductions in a mouse model of AD and could represent a molecular pathway with potential therapeutic targets for AD.
Herpes simplex virus and early neuroimaging markers of Alzheimer’s disease: Hippocampal volume and white matter integrity
Authors: Linard Morgane , Baillet Marion , Letenneur Luc , Garrigue Isabelle , Catheline Gwenaelle , Dartigues Jean‐François , Pérès Karine , Helmer Catherine 
Published: December 2020

AbstractBackgroundWhile previous studies suggest an implication of herpes simplex virus in the onset of Alzheimer’s disease (AD), no study has investigated its association with early neuroimaging markers of AD. Moreover, a genetic susceptibility factor, the APOE4 status, is suspected to intervene in the entry of the virus into neurons and could partly explain why, despite a high seroprevalence, some infected individuals remain healthy carriers, while others develop neurological consequences of the infection. The present study aims to evaluate the association between HSV status and early neuroimaging markers of AD according to APOE4 status.MethodIn the AMI cohort, a population‐based prospective study on aging, the associations between HSV seroprevalence and i) hippocampal volume (n=172) and ii) white matter integrity in the parahippocampal cingulum and fornix (n=117), which are the main afferent and efferent axonal bundles of the hippocampus, were assessed according to APOE4 status. Serologies were performed at inclusion and magnetic resonance imaging scans were performed at 4 years of follow‐up. Right and left hippocampal volumes were averaged and expressed as a percentage of the total intracranial volume. White matter integrity was assessed using diffusion tensor imaging parameters: fractional anisotropy (FA) and mean diffusivity (MD). High FA and low MD values reflect a well‐organized and undamaged axon fiber architecture.ResultAmong APOE4 carriers, infected subjects presented lower hippocampal volumes (p=0.04) and higher microstructural alterations of the cingulum (lower FA, p=0.04; higher MD, p<0.01) than noninfected subjects; similar nonsignificant trends were observed for the fornix. Among APOE4 noncarriers, no associations were observed.ConclusionWhile the underlying mechanism remains uncertain and may involve direct action of the virus and/or the immune response against it, our findings suggest an association between HSV infection and early signs of AD among subjects with a genetic susceptibility factor, reinforcing the need to investigate the infectious hypothesis of AD and the potential related treatments.
Fluorinated gamma‐carboline derivatives delay motor deficits in transgenic mouse model of neuronal proteinopathy
Authors: Ustyugov Aleksey , Nebogatikov Vladimir , Vikhareva Ekaterina , Aksinenko Alexey , Fedyaeva Lyudmila , Mazin Pavel , Buchman Vladimir , Bachurin Sergey 
Published: December 2020

AbstractBackgroundAggregation of specific proteins is a key molecular event in pathogenesis of neurodegenerative diseases known as proteinopathies. Various products of this pathological aggregation cause neuronal dysfunction and death by different mechanisms. Prevention of protein aggregation at initial stages of this multistep process is seen as an important mechanism of therapeutic intervention into pathogenesis of proteinopathies.MethodWe used FUS(1‐359) mouse model of proteinopathy that is characterized by the formation of neuronal inclusions similar in ALS patients to determine effects of oral administration of gamma‐carboline fluorinated derivatives. Chronic treatments started at the age of two month prior to first visible symptoms and continued for 60 days or until the first symptoms were registered.ResultA statistically significant increase in the mean lifespan was observed in experimental groups treated with tested compounds compared to the non‐treated control transgenic animals. Administration of fluorinated gamma‐carboline derivatives also statistically significantly delayed the debut of clinical symptoms manifestation of the neurodegenerative process in transgenic animals. Moreover, chronic treatments prevented overall weight loss which was a characteristic feature of the undertreated controls. The most effective fluorinated gamma‐carbolines improved the disease duration leading to significant increase in animal lifespan. We used Noldus Catwalk gate analysis system to study effect of compounds on the very first signs of motor dysfunction. We performed multi‐dimension scaling analysis analyzing data from transgenic mice to identify a set of parameters distinguishing between transgenic and wild type mice prior to neurological pathology symptoms become visible. More detailed characterization of the effect of fluorinated gamma‐carboline derivates on animal nervous system at presymptomatic stage is required for better understanding of the mechanism of the drug action.ConclusionOverall, our study suggests that chronic administration gamma‐carbolines significantly prolongs the presymptomatic stage of FUS‐proteinopathy delaying the symptoms and enhancing the lifespan of treated animals. This study was supported by RSF 19‐13‐00378 (synthesis of compounds) and by the Program of Russian Academy of Sciences #18 (biological studies). Animals were provided by the Bioresource Collection of the Centre for Collective Use IPAC RAS (No. 0090‐2017‐0016).
PLD3 is a neuronal lysosomal phospholipase D associated with β‐amyloid plaques and cognitive function in Alzheimer’s disease
Authors: Nackenoff Alex , Hohman Timothy J. , Neuner Sarah M. , Akers Carolyn , Weitzel Nicole , Shostak Alena , Ferguson Shawn M. , Bennett David A. , Schneider Julie A. , Jefferson Angela L. , Kaczorowski Catherine C. , Schrag Matthew S. 
Published: December 2020

AbstractBackgroundPhospholipase D3 (PLD3) is a protein of unclear function that structurally resembles other members of the phospholipase D superfamily. A coding variant in this gene confers increased risk for the development of Alzheimer’s disease (AD), although the magnitude of this effect has been controversial.MethodBecause of potential significance, we undertook a study to determine whether PLD3 is relevant to memory and cognition in sporadic AD, to observe its distribution in normal human brain and AD‐affected brain, to describe its subcellular localization, and to evaluate its molecular function.ResultPLD3 mRNA levels in the human pre‐frontal cortex inversely correlated with β‐amyloid pathology severity and rate of cognitive decline in the Religious Orders Study and Rush Memory and Aging Project. PLD3 levels across genetically diverse BXD mouse strains and strains crossed with 5xFAD mice correlated strongly with learning and memory performance in a fear conditioning task. In human neuropathological samples, PLD3 was primarily found within neurons and colocalized with lysosome markers. This colocalization was also present in AD brain with prominent enrichment on lysosomal accumulations within dystrophic neurites surrounding β‐amyloid plaques. This distribution was conserved in mouse brain in wild type and the 5xFAD mouse model of cerebral β‐amyloidosis. We discovered PLD3 has phospholipase D activity in lysosomes. The V232M coding variant significantly reduced enzymatic activity compared to wild‐type PLD3.ConclusionIn summary, this study identified a new functional mammalian phospholipase D isoform which is lysosomal and closely associated with β‐amyloid pathology, dystrophic neurites and memory in sporadic AD.
Amyloid burden assessed by three amyloid PET tracers in the elenbecestat MissionAD Phase 3 program
Authors: Roberts Claire , Kaplow June , Giroux Monique , Krause Stephen , Kanekiyo Michio 
Published: December 2020

AbstractBackgroundEisai’s elenbecestat MissionAD Phase 3 studies in early Alzheimer’s disease (AD) screened a large cohort of nearly 10,000 subjects for eligibility.MethodScreening was performed in 5 sequential tiers, of which amyloid status was determined at tier 5. Three amyloid PET tracers were used: florbetapir, florbetaben, flutemetamol. PET scans were centrally read by trained raters who determined visually if subjects were amyloid positive (Aß+) or negative (Aß‐). Quantitative analysis calculated a mean composite SUVr using whole cerebellum as a reference region and were converted to centiloid values (CL) to combine data across tracers (Klunk et al., 2015; http://www.gaain.org/centiloid‐project).Result3259 subjects had amyloid PET status and SUVr data available; 53% were Aß+, 86% were MCI and 12% mild AD dementia (2% missing), 52% were female, and 45% of were APOE ɛ4 positive. 2452, 542, and 265 subjects were scanned using, florbetaben, flutemetamol, or florbetapir, respectively, of which 50%, 59%, and 65% were determined visually to be Aß+. Centiloid conversion combining the data for the tracers calculated a mean of 1.6 CL for Aß‐ subjects (n=1532) and 83.0 CL for Aß+ (n=1725). No differences were evident between the tracers; mean of 1.2 – 3.1 CL for Aß‐ subjects and 77.3 ‐ 84.1 CL for Aß+ subjects. No impact of gender was evident. 77% of the APOE ɛ4 positive subjects were Aß+, which increased the mean CL value by 9. Mild AD dementia subjects had a higher Aß+ rate compared with MCI (69% vs 52%), which increased the mean CL value by 10.ConclusionAß+ status of subjects was approximately 50%, even when assessed at the end of a screening cascade. Although florbetaben was used in 75% of the subjects, the data was consistent between the tracers when converted to CL. Aß‐ and Aß+ subjects SUVr were normally distributed with an appreciable overlap in the 20‐40 CL range.