bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF1R inhibitor abrogates tau propagation exacerbated in APPNL‐G‐F knock‐in mice but enhances fibrillar beta‐amyloidosis and dystrophic neurite formation in the brain
Authors: Clayton Kevin , Delpech Jean Christophe , Herron Shawn , Saito Takashi , Ikezu Seiko , Saido Takaomi C. , Ikezu Tsuneya 
Published: December 2020

AbstractBackgroundMicroglia are the primary innate immune cells in the brain. They can phagocytose apoptotic neurons and dystrophic neurites containing aggregated and phosphorylated tau (p‐tau) in tauopathies, and possibly spread pathological tau via extracellular vesicles (EVs) release. Proteinopathic stress like amyloid plaque accumulation can transform microglia into a neurodegenerative phenotype (MGnD), possessing enhanced phagocytic and exocytotic functions. Thus, MGnD could exacerbate tau spreading throughout the brain. To determine the role of MGnD on tau propagation, we employed microglia depletion in adeno‐associated virus (AAV)‐mediated tau propagation mouse models.MethodC57BL/6 (WT) and APPNL‐G‐F mice were fed with a CSF1R inhibitor (PLX5622) or control chow for one month before and after stereotaxic injections of AAV2/6‐SYN1‐P301Ltau expressing P301L tau mutant into the medial entorhinal cortex (MEC) at 5 months of age. Propagation of tau to the dentate granular cells of the hippocampus, amyloid plaque formation, and association of microglia and p‐tau with plaques were assessed by immunohistochemistry after one month. MGnD and homeostatic microglia were separately isolated from APPNL‐G‐F mouse brains by FACS and evaluated for expression of EV marker molecules.ResultFACS data showed higher percentage of Clec7a (MGnD marker)‐positive microglia (20.8%) in APPNL‐G‐F compared to WT. Immunohistochemistry of APPNL‐G‐F mouse brains revealed strong positivity of Clec7a+ microglia surrounding both amyloid plaques and plaque‐associated p‐tau. APPNL‐G‐F mice exhibited approximately a 10‐fold increase in tau propagation compared to WT mice. Strikingly, PLX5622 treatment, which depleted ∼ 99% of microglia, showed 74 and 87% reduction of tau propagation in WT and APPNL‐G‐F groups, respectively. Contrarily, PLX5622 treatment increased intensity of plaque associated p‐tau along with increased size and number of amyloid plaques in the APPNL‐G‐F mice, suggesting their regulation by MGnD. Gene expression of EV markers, CD9 and CD63, was upregulated in Clec7a+ microglia compared to Clec7– microglia isolated from APPNL‐G‐F mice, suggesting enhanced microglial EV synthesis. This was further supported by the significant colocalization of Tsg101, an exosome marker, in Clec7a+ MGnD.ConclusionTau propagation may be influenced by engulfment of pathological tau seeds by microglia and secretion through EVs, which is exacerbated in MGnD in APPNL‐G‐F mice and mitigated by PLX5622 treatment.
Correlation between cerebrospinal fluid and blood neurofilament light protein: A systematic review and meta‐analysis
Authors: von Widekind Sophia , Alagaratnam Jasmini , de Francesco Davide , Underwood Jonathan , Winston Alan , Zetterberg Henrik , Fidler Sarah 
Published: December 2020

AbstractBackgroundCerebrospinal fluid (CSF) neurofilament light protein (NfL) is a sensitive biomarker of central nervous system neuro‐axonal injury. A novel assay measuring blood NfL has been developed, avoiding the need for CSF sampling. Several studies have published correlations between CSF and blood NfL, but the pooled correlation is unknown. This meta‐analysis aims to determine the pooled correlation coefficient estimate between CSF and blood NfL, and to stratify by correlation technique and blood NfL assay.MethodWe searched Medline, Embase and Web of Science for published manuscripts in English, from their inception to July 9, 2019, according to PRISMA guidelines. We included studies reporting the correlation between CSF and blood (plasma/serum) NfL. We then conducted a random‐effects meta‐analysis to calculate the pooled correlation coefficient estimate, accounting for correlation technique and assay used. Heterogeneity was assessed using the Cochran Q test. In sensitivity analyses, we calculated the pooled correlation coefficient estimate according to whether Spearman’s rank or Pearson’s correlation coefficient was reported (where unspecified, Pearson’s correlation was imputed), and according to blood NfL assay: single‐molecule array digital immunoassay (Simoa), electrochemiluminescence (ECL) or enzyme‐linked immunosorbent assay (ELISA).ResultData were extracted from 37 articles, including 3797 individuals. 23 studies reported Spearman’s rank and 10 studies reported Pearson’s correlation coefficient; correlation technique was unspecified in 4 studies. 29 studies used Simoa, 7 ECL and 1 ELISA. Results from the overall meta‐analysis demonstrated that the pooled correlation coefficient estimate for CSF and blood NfL was r=0.72, 95% confidence interval 0.56‐0.83, p<0.001 (Figure 1). Heterogeneity was significant: Q=206.2, p<0.0001. In sensitivity analyses, for studies quoting Spearman’s rank, the pooled estimate was r=0.66, p<0.001, while the pooled estimate was r=0.76, p<0.001 for studies quoting Pearson’s correlation. When stratified by blood NfL assay, the pooled correlation coefficient was similar for Simoa and ECL (r=0.70, p<0.001 and r=0.73, p<0.001, respectively), but weaker for ELISA (r=0.35, p=0.272).ConclusionStrong correlations are demonstrated between CSF and blood NfL, especially with Simoa and ECL blood NfL assays. Simoa is the preferred blood NfL assay due to its low detection limit, and this meta‐analysis supports blood NfL measured using Simoa, as a surrogate measure of CSF NfL.
Scalable diagnostic screening of mild cognitive impairment using AI dialogue agent
Authors: Tang Fengyi , Uchendu Ikechukwu , Wang Fei , Dodge Hiroko H , Zhou Jiayu 
Published: December 2020

AbstractBackgroundThe search for early biomarkers of mild cognitive impairment (MCI) has been central to Alzheimer's Disease (AD) and the dementia research community in recent years. While there exist in‐vivo biomarkers (e.g., beta‐amyloid and tau) that can serve as indicators of pathological progression toward AD, biomarker screenings are prohibitively expensive to scale if widely used among pre‐symptomatic individuals in the outpatient setting. Behavior and social markers such as language, speech, and conversational behaviors reflect cognitive changes that may precede physical changes and offer a much more cost‐effective option for preclinical MCI detection, especially if they can be extracted from a non‐clinical setting.MethodWe developed a prototype AI conversational agent that conducts screening conversations with participants. Specifically, this AI agent must learn to ask the right sequence of questions to distinguishing the conversational characteristics of the participants with MCI from those with normal cognition. Using transcribed data obtained from recorded conversational interactions between participants and trained interviewers generated in a recently completed clinical trial, and applying supervised learning models to these data, we developed a novel reinforcement learning (RL) pipeline and a dialogue simulation environment to train an efficient dialogue agent to explore a range of semi‐structured questions. We train and validate our AI dialogue agent based on transcribed data from a randomized controlled behavioral intervention study, where we use the transcribed data from 41 subjects (14 MCI, 27 NL). Each subject has an average of 35 turns of dialogue on average.ResultThe results show that while using only a few turns of conversation, our framework can significantly outperform state‐of‐the‐art supervised learning approaches used in a past study. An AI agent of 30 turns of dialogue achieves over 0.853 Area Under the Receiver Operating Characteristic Curves (AUC) and 0.809 AUC with 20 turns, as compared to 0.811 AUC with the full dialogue turns.ConclusionOur dialogue‐based AI agent presents a step toward using AI to extend clinical care beyond the classical hospital and clinical settings, where we find that AI‐generated dialogues produce more predictive linguistic markers.
The API Generation program: Umibecestat treatment and discontinuation effects on hippocampal and whole brain volumes in the overall population and amyloid‐negative APOE4 homozygotes
Authors: Reiman Eric M. , Tariot Pierre N. , Borowsky Beth , Liu Fonda , Riviere Marie‐Emmanuelle , Rouzade‐Dominguez Marie‐Laure , Cazorla Pilar , Quinn Matt , Ricart Javier , Langbaum Jessica B. , Viglietta Vissia , Sui Yihan , Caputo Angelika , Graf Ana , Seneca Nicholas , Neumann Ulf , Eichenlaub Udo , Chien Yuchen , Arkuszewski Michal , Piccard Hernan , Quarg Peter 
Published: December 2020

AbstractBackgroundIn addition to early mild non‐progressive cognitive worsening, BACE inhibitors have been associated with early non‐progressive reductions in hippocampal and whole brain volume in trial participants with elevated amyloid (A+, Egan et al, 2019). We have begun to evaluate the effects of umibecestat treatment and discontinuation on cognitively unimpaired amyloid‐positive (A+) and A‐ APOE4 homozygotes and A+ heterozygotes, testing the hypotheses that BACE inhibitor‐related hippocampal and whole brain shrinkage is apparent soon after treatment initiation, non‐progressive, limited to A+ participants, and reversible following discontinuation.MethodThe API Generation Program had begun to evaluate umibecestat in 1,623 cognitively unimpaired 60‐75 year‐old participants including 921 A+ APOE4 heterozygotes and 702 homozygotes (A+ or A‐).Following randomization, volumetric brain MRIs were scheduled at month 6, month 12 and then annually. After discontinuation of study medication, participants continued to be assessed under double‐blind conditions, and MRIs were acquired within 3 months after the last dose. We investigated 6‐month hippocampal and whole brain volume changes and their relationship to RBANS immediate, delayed and total memory score changes; and we plan to investigate the persistence or reversibility of these changes within 3 months of discontinuation after study completion in Q2 2020.ResultUmibecestat was associated with significant 6‐month hippocampal and whole brain shrinkage in the aggregate APOE4 homozygote and A+ heterozygote group, but not in the A‐ homozygotes. While an early non‐progressive worsening in RBANS immediate, delayed, and total memory scores (Graf et al, AAIC 2020 submitted) was seen in the overall population as well as in A‐ HMs, we failed to demonstrate any significant association between brain shrinkage and cognitive worsening in the overall group (R2 coefficient <0.1) in the active treatment group for any of the visits (on‐ and off‐ treatment).ConclusionBACE inhibitor‐related brain shrinkage appears to be early, non‐progressive, related to pre‐existing amyloid plaque burden, and unrelated to its cognitive worsening. Pending findings will help to clarify the extent to which it is also reversible. Together, our cognitive and MRI findings could help to assess potential benefits versus risks of BACE inhibitors in future prevention trials.
First‐in‐human studies of MW01‐6‐189WH, a brain‐penetrant, anti‐neuroinflammatory, small molecule drug candidate: Phase 1 safety, tolerability, pharmacokinetic, and pharmacodynamic studies in healthy adult volunteers
Authors: Van Eldik Linda J. , Roy Saktimayee M. , Guptill Jeffrey T. 
Published: December 2020

AbstractBackgroundAcute brain injuries, such as intracerebral hemorrhage (ICH) or traumatic brain injury (TBI), are major medical problems that cause considerable mortality and morbidity in older individuals. In addition to the initial injury, secondary neuroinflammatory events can further damage the brain and lead to increased risk of neurologic complications, including Alzheimer’s disease (AD) and related dementias (ADRD). A specific aspect of neuroinflammation, injury‐induced proinflammatory cytokine overproduction from abnormally activated glia, has been linked to subsequent neurological damage and cognitive deficits in both acute and chronic CNS disorders. Despite advances in our understanding of these molecular neuroinflammatory mechanisms, approved therapeutics that target this pathological process are lacking. To address this need, we developed a CNS‐penetrant, small molecule drug candidate, MW01‐6‐189WH (=MW189), that selectively attenuates stressor‐induced proinflammatory cytokine overproduction. MW189 is efficacious at low doses in animal models of AD, TBI and ICH. Based on promising drug‐like properties, preclinical efficacy, and excellent safety profile, an intravenous formulation of MW189 was developed and tested in phase 1 human studies.MethodsPhase 1 studies were done to evaluate safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending doses of MW189 in healthy adults. A pilot pharmacodynamic study administering low dose endotoxin to induce a systemic inflammatory response was done to evaluate effects of a single dose of MW189 on plasma cytokine levels.ResultsMW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. No clinically concerning changes were seen in vital signs, ECGs, physical or neurological examinations, or safety laboratory results. PK analysis showed dose‐proportional increases in MW189 plasma concentrations after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. In the pilot pharmacodynamic study, MW189 treatment resulted in lower plasma levels of the proinflammatory cytokine TNFα and higher levels of the anti‐inflammatory cytokine IL‐10 compared to placebo treatment, suggesting engagement of pharmacological mechanism.ConclusionOverall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute CNS injury, AD/ADRD, or other disorders involving dysregulated neuroinflammation as a driver of disease progression.
Let’s CHAT – Dementia: Primary care model of care to optimise detection and management of dementia in Aboriginal and Torres Strait Islander older people: Determination of the risk factor profile in this population
Authors: Hughson Jo‐Anne , Flicker Leon , Smith Kate , Bradley Kate , Belfrage Mary , Strivens Edward , Bessarab Dawn , Atkinson David , Radford Kylie , Russell Sarah G , Quigley Rachel , Allan Wendy , Malay Roslyn , Sullivan Kylie , Ducker Belinda , LoGiudice Dina 
Published: December 2020

AbstractBackgroundRates of dementia and cognitive impairment in Australian Aboriginal and Torres Strait Islander populations are 3‐5 times higher than in the overall population. In addition, under‐detection of these conditions has been consistently confirmed, particularly in primary care. A national co‐design project called the Let’s CHAT (Community Health Approach To) Dementia aims to optimise detection rates and management of dementia and cognitive impairment in Indigenous primary care contexts. This will occur through the co‐development of a model of care, and outcome measures include data profiling the dementia risk of older Indigenous persons and current management of patients with confirmed or suspected cognitive impairment or dementiaMethodSix‐monthly medical record audits of patients aged 50 and over recording: basic demographic information, presence of dementia risk factors, current care practices in relation to dementia and co‐morbid conditions of ageing.ResultAudits were conducted on patients (n=1675) in 12 primary health services across Australia. The mean age of patients was 60.3 (8.3). The top ten risk factors documented overall were: hypertension (50.9%), polypharmacy (46.7%), current smoking (43%), diabetes (42.9%), dyslipidaemia (41.1%), obesity (35%), depression (30%), mental health concerns (25.9%) cardiovascular disease (25.6.%) and low physical activity (19.1%), but there was some inter‐service variation in risk factor profiles. Documented evidence of health service assessment for, and investigation of, cognitive impairment was limited. Use and type of diagnostic tools varied widely between services (e.g. MMSE used with 0.6%‐45.9% of sample, KICA (culturally appropriate cognitive assessment tool) used with 0.0%‐5.0% of sample). Diagnoses of dementia and cognitive impairment (combined = 3.8%) are well below known prevalence rates in these populations (∼20%), although there is variation from service to service (range = 0.8% ‐8.9%).ConclusionThe audit data confirm low rates of detection and low levels of assessment activity for cognitive impairment and dementia in Indigenous primary care contexts, while the population displays a high risk for developing these conditions. These findings underscore the need for more focus on detection activities in primary health care, as well as reinforcing the importance of preventive health care strategies.
Visual rating and automated brain volumetry for medial temporal lobe atrophy in differential diagnosis and early detection of Alzheimer’s disease
Authors: Zhao Lei , Liu Wenyan , Luo Yishan , Kung Wing Kit , Xiong Li , Mok Vincent C.T. , Shi Lin 
Published: December 2020

AbstractBackgroundVisual rating of medial temporal lobe atrophy (MTA‐scale) has been well recognized as a biomarker for Alzheimer’s disease (AD), and automatic quantification of MTA (QMTA) based on the volume of hippocampus and inferior lateral ventricle (ILV) has been proposed. However, a comprehensive comparison of MTA‐scale, QMTA as well as the components of MTA (i.e. volume of hippocampus and ILV) is still lacking in differential diagnosis or early detection of AD. Also, it’s not clear about the difference of performance between the conventional MTA measures and the recently proposed AD resemblance atrophy index (AD‐RAI) that integrates multiple brain regions more than MTA.MethodWe included 132 AD, 132 normal control (NC) subjects, and 353 subjects with mild cognitive impairment (MCI) from ADNI. Among the MCI patients, 290 remained stable (MCIs) and 63 converted to AD (MCIc) in a two‐year follow‐up. The AD and NC subjects, and the MCIs and MCIc subjects were matched in age, gender and education, respectively (Table 1). MTA‐scale was visually rated by an experienced neuroradiologist. Baseline T1‐weighted images were processed with AccuBrain to quantify the volume of hippocampus and ILV as well as the AD‐RAI. Receiver operating characteristic (ROC) curve analyses were performed to compare these measured when differentiating AD from NC and MCIc from MCIs. Sub‐analyses were conducted by grouping the study cohort by age (>75 years or not) and gender. The optimal threshold was determined by Youden Index.ResultThe Spearmen correlation of QMTA and MTA‐scale was 0.805 (p<0.001). Regarding the ROC analyses, the AD‐RAI performed the best in differentiating AD from NC (AUC=0.860, Youden Index=59.1% for all individuals) and MCIc from MCIs (AUC=0.768, Youden Index=41.6% for all individuals), followed by the hippocampal fraction/volume, QMTA, MTA, and ILV fraction/volume (Table 2 and Table 3). For all the MRI‐based measures, the differentiation performance was better for those with age≤75 years in both classifications, and better for men in AD vs. NC and women for MCIc vs. MCIs.ConclusionMTA measures based on automated brain volumetry performed better than visual rating, and the superiority of AD‐RAI over MTA measures needs further validations in a larger population.
Antiviral therapy reduces the risk of dementia in patients with herpes zoster: A propensity score‐matched analysis
Authors: Bae Sungman , Yoon Woon , Choi Seong Won , Yun Sung‐Cheol , Kim Sung‐han , Kim Seong Yoon 
Published: December 2020

AbstractBackgroundSome epidemiological evidences show that the herpes zoster (HZ) may be associated with dementia. We investigated whether HZ was associated with the subsequent dementia in a nationwide population‐based (dynamic) cohort, and evaluated whether antiviral therapy might reduce the risk of subsequent dementia.MethodThe National Health Insurance Service‐National Sample Cohort (NHIS‐NSC) database was used for analysis. This randomized one million people cohort representing the entire population of South Korea was followed up from 2002 to 2013. New events of HZ and dementia were identified using the diagnostic codes of claim data. Dementia was defined as the presence of the diagnostic codes and prescription of anti‐dementia drugs for more than 30 days. Each HZ patient receiving antiviral therapy was 1:1 matched with an untreated HZ patient having the same propensity score in the relevant year.ResultA total of 229,594 individuals of ≥ 50 years were followed up for 11 years. The incidence of the first‐diagnosed HZ cases was 16.69 per 1000 person‐years, and that of the first‐diagnosed dementia was 4.67 per 1000 person‐years. The risk for dementia was higher in patients who had previous HZ episodes than in those who had never experienced HZ (incidence rate ratio [IRR] 1.94; 95% CI 1.83‐2.06 and adjusted hazard ratio [HR] 1.12; 95% CI 1.05‐1.19, respectively). Of the 34,505 patients who were diagnosed as the first‐ever HZ, 28,873 (84%) received antiviral treatment and 5,632 (16%) did not. The crude incidence rates of the subsequent dementia were 7.79 and 12.27 per 1000 person‐years for treated and untreated groups, respectively, giving IRR of 0.63 (95% CI, 0.56‐0.72) and the covariate‐adjusted HR of 0.79 (95% CI, 0.69‐0.90). The HZ patients who received antiviral therapy had a significantly lower risk of dementia than those who did not; HR after propensity score‐matching was 0.77 (95% CI, 0.64‐0.91). In addition, the patients treated with antiviral agents showed significantly lower mortality than untreated patients (HR 0.58; 95% CI 0.53‐0.64 by propensity‐score matched analysis).ConclusionHZ is associated with the subsequent dementia development, and the use of antiviral agents in patients with HZ significantly reduces the incidence of the subsequent dementia and the mortality.