bluuebunny/crossref_metadata_2025_split huggingface dataset:
TMS‐measures of cortical excitability are abnormal in amyloid‐positive MCI, relate to amyloid burden, and predict faster cognitive decline
Authors: Buss Stephanie S. , Macone Joanna , Li Gongri , McDonald Katherin , Shafi Mouhsin , Donohoe Kevin , Press Daniel Z. , Pascual‐Leone Alvaro , Fried Peter J. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is associated with increased cortical excitability, including a risk of seizures and epileptiform discharges. Transcranial magnetic stimulation (TMS) can be used to index cortical excitability non‐invasively, and previous studies have revealed increased TMS excitability measures in AD. However, it is not yet known if TMS shows increased cortical excitability in amyloid‐β positive mild cognitive impairment (Aβ+ MCI), how TMS excitability relates to other AD biomarkers, or the extent to which cortical excitability may predict disease progression.MethodTMS was applied to left motor cortex in 18 participants with Aβ+ MCI (aged 70±8.9, 9 females). Resting motor threshold (RMT) was measured as the minimum TMS intensity required to elicit a motor evoked potential on 5/10 trials. The primary analyses tested if RMT differed between Aβ+ MCI participants and a cohort of 36 older healthy controls (OHC; aged 63±9.7, 17 females). Separate linear models in Aβ+ MCI tested the relationship of RMT with hippocampal volume, Aβ burden on [18F]Florbetapir PET, and the Clinical Dementia Rating – Sum of Boxes (CDR‐SB). CDR‐SB was reassessed after 1‐2 years follow‐up, and a CDR‐SB Change Score was calculated to measure cognitive decline. The relationship with RMT and CDR‐SB Change Score was tested using a simple linear regression.ResultThe primary linear model controlling for age, gender, and scalp‐to‐cortex distance (SCD) showed a between‐group difference in RMT (B=3.62, p=0.023, Figure 1), with Aβ+ MCI showing lower RMT reflecting higher levels of cortical excitability. The covariate of SCD (B=1.92, p<0.001) was also significant. Secondary models with the same covariates showed that lower RMT was related to greater Aβ burden (B=‐0.43, p=0.016), but not hippocampal volume or CDR‐SB. In the subgroup of 10 Aβ+ MCI participants with longitudinal follow‐up, lower RMT predicted of worsening cognition on CDR‐SB Change Score (R=0.74, p=0.015, Figure 2).ConclusionIncreased cortical excitability is found in Aβ+ MCI, is related to amyloid burden, and appears to predict greater longitudinal cognitive decline. TMS measures of cortical excitability may be useful as measures of target engagement for future therapies aimed at delaying disease progression in the early symptomatic stages of AD.
Augmenting cognitive assessment with instruction‐less eye‐tracking tests: A machine learning approach for detecting abnormal oculomotor biomarkers
Authors: Mengoudi Kyriaki , Ravi Daniele , Yong Keir XX , Primativo Silvia , Pavisic Ivanna M , Brotherhood Emilie V , Lu Kirsty , Schott Jonathan M , Crutch Sebastian J , Alexander Daniel C. 
Published: December 2020

AbstractBackgroundEye‐tracking technology is an innovative tool that holds promise for enhanced dementia screening, offering the potential of brief and quantitative assessment of cognitive functions. Critically, instruction‐less eye‐tracking tests may ameliorate some of the issues with complex test instructions and linguistic variations associated with traditional cognitive tests, and capture additional sensitive metrics of task performance. However, the extraction of relevant biomarkers from large, complex eye‐tracking datasets is non‐trivial. In this work, we introduce a novel automated way of extracting abnormal oculomotor biomarkers using machine learning from raw eye‐tracking data acquired during an instruction‐less cognitive test.MethodA free‐viewing instruction‐less cognitive battery (5 minutes) was administered to healthy controls (N=553) and patients with a range of dementias (N = 30) [Figure 1]. Our method is based on self‐supervised representation learning: a deep neural network is initially trained to solve a pretext task that has well‐defined available labels. Here the pretext task is to identify distinct tasks ‐ scene perception, reading, episodic memory for scenes ‐ in healthy individuals from eye‐tracking patterns. Figure 2 visualises some features of eye‐tracking patterns that correspond to particular tasks. Once trained, this network encodes high‐level semantic information which is useful for solving other problems of interests (e.g. dementia classification) [Figure 3]. The extent to which eye‐tracking features of patients with dementia deviate from healthy behaviour is then explored, followed by a comparison between self‐supervised and handcrafted representations on discriminating between controls and patients.ResultBased on the results of the handcrafted features, patients with dementia had significantly lower scanpath lengths than controls (z = ‐276.56, SE = 97.09, p =0.00439), consistent with less extensive and efficient scanning of the presented stimuli. The self‐supervised learning features showed higher performance in discriminating dementia patients from controls (F1 score (95% CI: [0.78, 0.82]) vs standard handcrafted features [0.62, 0.67]).ConclusionThese results suggest that instruction‐less eye‐tracking tests can detect dementia status, even in the absence of explicit task instructions. We reveal novel self‐supervised learning features that are more sensitive than handcrafted features in detecting performance differences between participants with and without dementia across a variety of eye‐tracking‐based cognitive tasks.
Activity and TREM2‐dependent phagocytic cup formation by microglia in the mouse cortex
Authors: Martin‐Avila Alejandro , Tiberi Alexia , Zhao Ruohe , Weinhard Laetitia , Cheng Zongyue , Gan Wen‐Biao 
Published: December 2020

AbstractBackgroundMicroglia are the main innate immune cells capable of engulfing dead cells and cellular debris in the brain. Trem2 receptor is expressed in microglia and plays an important role in phagocytosis. This receptor has been linked to Alzheimer’s disease and involved in the uptake of amyloid plaques by microglia. However, how microglia engulf dead cells and the role of Trem2 in this process remain unclear.MethodWe used two‐photon microscopy to image microglia engulfing of dead cells in the primary motor cortex of Cx3cr1
gfp/+ mice, Cx3cr1gfp/+:Trem2‐/‐ mice, Cx3cr1gfp/+:Trem2R47H/+ mice, and ThyGCaMP6 mice. These mice were placed on a custom made, free‐floating treadmill and subjected to five motor‐running sessions over one hour. Electron microscopy was used to determine the ultrastructure of microglial phagocytic cups engulfing dead cells. We manipulated neuronal activity by using AAV viral infection to express ChR2 in thalamic neurons or by administrating MK‐801 or muscimol in the motor cortex.ResultOur time‐lapse imaging data show that microglial processes form phagocytic cups to engulf dead cells within tens of minutes in the motor cortex during running. Ultrastructural examination of phagocytic cups confirmed the engulfment of dead cell body by microglial processes as revealed by live imaging. Pharmacological inhibition of neuronal activity was sufficient to prevent running‐dependent phagocytic cup formation. On the other hand, optogenetic stimulation of thalamocortical projections induced the formation of microglial phagocytic cups. In Trem2‐deficient mice and Trem2 R47H mice, running‐dependent phagocytic cup formation was reduced as compared to wild type controls. There was an increase of propidium iodide (PI)‐positive cell bodies in Trem2 deficient/haplodeficient mice comparted to the control mice.ConclusionThese findings reveal that the formation of phagocytic cups by microglia is dependent on neuronal activity and the Trem2 receptor in the mouse cortex. They also suggest that the lack of dead‐cell clearance mediated by microglia might play a role in the pathogenesis of Alzheimer’s disease.
Partial mitochondrial complex I inhibitors as disease‐modifying therapeutics for Alzheimer’s disease
Authors: Trushin Sergey , Stojakovic Andrea , Chang Su‐Youne , Trushina Eugenia 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) has no effective treatments, and recent clinical trials focused on prevention of amyloid beta (Ab) production have consistently failed. Alternative approaches are urgently needed. We developed small molecules partial mitochondrial complex I (MCI) inhibitors and demonstrated that their application prevents the development of cognitive and behavior phenotype, improves LTP, reduces oxidative stress and inflammation, and restores glucose uptake and utilization in the brain in mouse models of familial AD. Efficacy could be monitored in vivo using translational biomarkers FDG‐PET, 31P NMR and blood biomarkers.MethodWe conducted extensive structure‐activity relationship (SAR) studies to characterize novel classes of compounds partial MCI inhibitors including a new lead compound C458. Target engagement, selectivity and specificity of new compounds were established using multiple in vitro and cellular assays including SPR, competitive and direct binding, proteomics and pull down experiments.ResultWe demonstrated that the lead C458 directly binds and competes with the FMN for binding to complex I. In primary neurons and mouse brain tissue, single dose administration of C458 activates AMPK‐a, autophagy, Sirtuins 1 and 3, and upregulate PGC‐1a leading to enhanced mitochondrial biogenesis. In vivo, chronic administration of C458 had no detectable toxicity at therapeutic doses. C458 has excellent oral bioavailability and blood–brain‐barrier penetration. C458 was remarkably clean in 250 kinase panel. Finally, in pre‐symptomatic APP/PS1 mice, treatment with C458 resulted in cognitive protection and improved long‐term potentiation after 6 months of chronic oral administration (25 mg/kg/day), decreased oxidative stress and inflammation. Furthermore, APP/PS1 mice treated with C458 showed a significant increase in metabolic rates and glucose brain uptake and utilization detected with translational FDG‐PET imaging as well as an enhancement of ATP production in the brain measured in vivo with 31P NMR.ConclusionMechanistic studies demonstrate that MCI inhibitors induce protective stress response increasing mitochondrial biogenesis and turnover, augmenting cellular energetics and the protection against oxidative stress, and engage other mechanisms that intersect with the pathways involved in longevity and health extension. Our studies demonstrate that modulation of MCI activity using novel FMN MCI inhibitors improves bioenergetics in the brain and averts cognitive decline in Alzheimer’s Disease representing novel therapeutic approach.
The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND): A longitudinal public health research program targeting dementia risk reduction
Authors: Bartlett Larissa , Doherty Kathleen , Farrow Maree , Bindoff Aidan , Kim Sarang , Eccleston Claire , Hill Edward , Alty Jane , King Anna E , Vickers James C 
Published: December 2020

AbstractBackgroundA substantial proportion of risk for age‐related dementia may be attributable to modifiable factors. The ISLAND Project responds to international calls (Lancet Commission, World Health Organisation) to investigate the effectiveness of public health strategies for reducing dementia risk. This large longitudinal and interventional cohort study will evaluate a sustained public health campaign to mitigate behaviours associated with dementia risk. The Tasmanian population comprises approximately 500,000 urban, rural and remote residents and has a prevalence of factors associated with dementia risk that is higher than Australian norms. This contained island population offers a unique opportunity for recruitment, cohort maintenance and tracking changes in participants’ dementia risk profile over time.MethodThe ISLAND Project aims to recruit 10% of Tasmanians aged 50 and over (target n=20,000). Participants will be offered a series of educational and community‐based interventions to build self‐efficacy in dementia risk management. Engagement with these interventions will be evaluated. Self‐report, online surveys administered annually will track changes in participants’ physical and mental health, social functioning, dementia risk literacy and risk‐related behaviours. Cognitive screening and biomarkers (e.g. blood) will be collected biennially. The Dementia Risk Profile (DRP) will support and track behaviour change. The DRP provides a traffic‐light indicator of personal risk and recommended actions, based on WHO risk reduction guidelines. The DRP can be updated every six months and printed to support health consultations.ResultThe ISLAND Project launched in June 2019. Preliminary data collected between October and December 2019 indicate the ambitious recruitment target is feasible, with 10,729 registering interest in the study, of whom 4,937 have provided research consent (73% female, median age 62 years). Participants’ postcodes signify reasonably representative geographical distribution (urban 77%, rural 22%; Figure 1) and current baseline data include: background and health (n=4270), knowledge (n=3781) and attitudes about dementia risk (n=3588), depression (n=3541) and the DRP (n=3269).ConclusionThe ISLAND Project aims to translate, into a public health setting, research evidence that reducing dementia risk can be achieved through modifying behaviours. Findings from this population‐based approach to dementia risk reduction will be used to inform future public health policy and practice.
Linking central auditory deficits to cognitive decline in mice with amyloid deposition
Authors: Wang Aaron , Lawlor Jennifer , Fogelson Kelly , Kuchibhotla Kishore 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a form of dementia that is characterized by the progressive loss of cognitive capacity, including the loss of executive functions and memory. There is growing evidence suggesting that hearing loss and dementia are tightly linked, with recent studies showing that hearing loss is independently associated with accelerated cognitive decline. However, the neural mechanisms linking hearing loss to AD‐related pathologies and subsequent cognitive decline remain unknown.MethodWe will test the hypothesis that amyloid pathology impacts feedforward sensory processing in primary auditory cortex (A1). We performed in vivo two‐photon calcium imaging in awake, head‐fixed APPswe/PS1dE9 (APP/PS1) mice to investigate how AD pathology impacts central auditory processing. APP/PS1 mice express chimeric mouse/human amyloid precursor protein (APP) and mutant presinilin‐1 (PS1). These transgenes target neurons of the central nervous system and lead to the rapid accumulation of soluble amyloid beta and subsequent plaque deposition in cortical and hippocampal areas. Our study uses the fine‐scale tonotopic arrangement of excitatory neurons in A1 as an assay for feedforward sensory integration. With two‐photon calcium imaging, we have the spatial and temporal resolution to monitor the activity of hundreds of neurons simultaneously with single‐cell resolution.ResultPreliminary data collected from 11 mice (7 APP+, 4 WT) suggests clear differences in the processing of feedforward sensory information, namely differences in the tonotopic arrangement of neurons in A1 between WT and APP/PS1 mice.ConclusionFuture work will investigate how AD pathology affects sensorimotor learning. Learning rates will be monitored in APP/PS1 mice trained on a go/no‐go stimulus recognition task. To probe the neural computations that are critical for the selection of auditory cues during behavior, excitatory networks in A1 will be monitored using two‐photon calcium imaging while animals perform the task. This study hopes to elucidate neural mechanisms of how amyloid beta pathology impacts central auditory processing, and thus, mechanistically link hearing loss, AD‐related pathologies and cognitive impairments.
Impact of unreliability on intraclass correlation coefficient and its implications for studies with clustered data
Authors: Ma Yue , Jonaitis Erin M , Hulle Carol A , Koscik Rebecca L , Jones Richard N , Carlsson Cynthia M. 
Published: December 2020

AbstractBackgroundStudies using cerebrospinal fluid (CSF) biomarkers often combine CSF samples collected at different centers or assayed in different laboratories or batches, creating a clustered data structure. Such clustering needs to be controlled in the analysis of the combined data. Intraclass correlation coefficient (ICC), i.e., the ratio of the between‐cluster variance over the total variance, is used to quantify the magnitude of the clustering. The between‐cluster variance is a mix of (a) difference in CSF samples and (b) variation in measurement (i.e., unreliability). Thus the observed ICC (under unreliability) would deviate from the true ICC (under perfect reliability). We studied (1) how the observed ICC would deviate and (2) the statistical performance in its estimation.MethodAim (1) was achieved through mathematical derivations based on Classical Test Theory. Aim (2) was achieved using a simulation study to evaluate the relative bias, empirical standard error (se), and root mean square error (RMSE) in the sample estimates of the observed ICC, under three reliability levels (0.7, 0.8, 0.9), three true ICC values (0.1, 0.3, 0.5), and two cluster sizes (10, 50), with 10,000 replications for each condition.ResultAim (1): The observed ICC is greater than the true ICC. The inflation, represented as their ratio, is a function of reliability, true ICC, and cluster size (Figure 1). It decreases with increased reliability or true ICC, or decreased cluster size (Figures 2, 3). Aim (2): The sample estimates had very small negative bias (within 3%), which generally decreased with increased cluster size or true ICC, or reduced reliability. The empirical se and RMSE decreased with increased cluster size, but their relations with reliability or true ICC varied across conditions (Table 1).ConclusionThe observed ICC is deviated (inflated), but unbiased. Using reliable measure is crucial when CSF samples have low variation between clusters to avoid substantial inflation in ICC. Increasing cluster size would exacerbate the inflation, yet would also increase estimation accuracy and efficiency. Such tradeoffs should be considered with planning CSF sample collection and assay. These findings can be applied to clustered data of other outcomes such as imaging and cognition.
Retinal capillary perfusion in autosomal dominant Alzheimer’s disease
Authors: Singer Maxwell , Ringman John M , Laughlin Alice , Chu Zhongi , Wang Ruikang , Kashani Amir H 
Published: December 2020

AbstractBackgroundAlterations of perfusion in small blood vessels may be early events during Alzheimer’s disease (AD) development and such differences may be visible in the retina. The purpose of the current study is to quantify retinal capillary density and blood flow in subjects with autosomal dominant Alzheimer’s Disease (ADAD)‐causing mutations during the preclinical and clinical disease stages using optical coherence tomography angiography (OCTA).MethodThis is a cross‐sectional study of subjects with PSEN1 or APP mutations (n = 12) and age‐matched controls (n = 21). Mutation carriers were split into early‐stage (ES) and late‐stage (LS) groups based on an age‐adjusted cutoff of ‐4 (four years before predicted age of dementia onset based on mutation variant). Each subject underwent OCTA imaging of the central 3x3mm macula. Capillary density was measured using previously validated custom software and quantified as vessel skeleton density or VSD. Capillary blood flow was measured using a novel metric called flux which is derived from non‐binarized OCTA images and represents total number of red blood cells passing through the voxel per unit time. Statistical analysis was performed using generalized estimating equations adjusting for gender and correlation of two eyes from the same subject.ResultES carriers (n = 4, 3 w/CDR = 1, 1 w/CDR = 0.5) had a significantly greater flux (0.161 ± 0.006) than controls (n = 21, 0.144 ± 0.01, p = 0.02) and LS carriers (n = 12, CDR scores 0.5 – 3, 0.144 ± 0.008, p<0.0001, Figure 1). In contrast, there was no difference between flux of LS carriers and controls. ES carriers also had significantly greater capillary density (VSD) than controls (0.157 ± 0.006 vs 0.153 ± 0.005; p = 0.017).ConclusionES carriers of PSEN1 or APP mutations demonstrate increased retinal capillary blood flow when compared to controls that was not present in LS carriers. Our data suggests that there is increased retinal perfusion in ES carriers, possibly resulting from increased blood flow in perfused capillary segments and recruitment of dormant capillary segments. These findings are consistent with studies showing cerebral hyperperfusion in pre‐symptomatic individuals with ADAD and indicate this may extend to the retina.
Cornel iridoid glycoside ameliorates cognitive deficits in APP/PS1/tau triple transgenic mice by attenuating amyloid‐beta, tau, and neurotrophic dysfunction
Authors: Yang Cuicui , Zhang Lan 
Published: December 2020

AbstractBackgroundTargeting proteinopathies is involved in the protective effects of pharmacologic agents to treat Alzheimer’s disease (AD). Cornel iridoid glycoside (CIG) are the effective component from Cornus officinalis. The aim of the present research was to explore the potential effects of CIG on β‐amyloid (Aβ) and tau pathology and its underlying mechanisms in APP/PS1/Tau triple transgenic (3×Tg) mice.MethodWe intragastrically administered 16‐month‐old 3×Tg mice with CIG (100 and 200 mg/kg) for 2 months. Morris water maze and object recognition tests were used to detect learning and memory abilities. Thioflavin‐S staining and immunohistochemistry were used to detect amyloid plaques and Aβ40/42. Western blotting assay was performed to determine the expression of related proteins in the cerebral cortex and hippocampus of mice.ResultThe results showed that CIG treatment improved learning and memory impairment in 3×Tg mice. CIG decreased amyloid plaque deposition, Aβ40/42 and the expression of full‐length amyloid precursor protein; and increased the levels of ADAM‐10 (a‐secretase), neprilysin (NEP) and insulin degrading enzyme (IDE) in the brain of 3×Tg mice. Moreover, CIG reduced tau hyperphosphorylation, and elevated phosphorylation level of GSK‐3β at Ser9 and methylation of PP2A catalytic subunit C in the model mice. CIG increased the expression of nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF) and phosphorylated cAMP‐responsive element binding protein (p‐CREB) in the brain of 3×Tg mice.ConclusionCIG ameliorated learning and memory deficit via reducing Aβ content and, tau hyperphosphorylation and increasing neurotrophic factors in the brain of 3×Tg mice. These results suggest that CIG may be beneficial for AD therapy.