bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensitivity and specificity of EEG biomarkers of AD at the preclinical stage
Authors: Noce Giuseppe , Babiloni Claudio , Lopez Susanna , Percio Claudio Del , Pascarelli Maria Teresa , Lizio Roberta , Teipel Stefan J. , González‐Escamilla Gabriel , Bakardjian Hovagim , George Nathalie , Cavedo Enrica , Lista Simone , Chiesa Patrizia Andrea , Vergallo Andrea , Lemercier Pablo , Spinelli Giuseppe , Grothe Michel , Potier Marie‐Claude , Stocchi Fabrizio , Ferri Raffaele , Habert Marie‐Odile , Fraga Francisco J. , Dubois Bruno , Hampel Harald ,   INSIGHT‐preAD study group
Published: December 2020

AbstractBackgroundCognitive reserve (CR) is present in Alzheimer’s disease (AD) seniors with high education attainment making them clinically resilient to extended brain neuropathology and neurodegeneration. Here we tested whether subjective memory complaint (SMC) seniors with AD neuropathology and high education attainment may present abnormal eyes‐closed resting state posterior electroencephalographic (rsEEG) rhythms around individual alpha frequency peak (IAFp), typically altered in AD patients with mild cognitive impairment and dementia.MethodWe selected all individual baseline data of the prospective INSIGHT‐preAD cohort (Paris) including mini mental state examination score ≥ 28, artifact‐free markers of 18F‐florbetapir positron emission tomography (amyPET), structural magnetic resonance imaging, and rsEEG rhythms (e.g., 172 SMC seniors). Delta, theta, alpha1, alpha2, and alpha3 bands were determined on individual basis based on IAFp, while beta1 (14‐20 Hz), beta2 (20‐30 Hz), and gamma (30‐40 Hz) were standard fixed bands.ResultThe SMC participants negative to amyPET AD markers (SMCneg) with high (over low‐moderate) education level showed higher posterior alpha 2 power density (possibly “neuroprotective”). Furthermore, amyPET‐positive SMC (SMCpos) participants with high (over low‐moderate) education level showed higher temporal alpha 3 power density (possibly “neuroprotective”) and lower posterior alpha 2 power density (possibly “compensatory”; Figure 1). This effect may reflect CR as no differences in brain gray‐white matter and cognitive functions were observed between these SMCpos/SMCneg sub‐groups.ConclusionPreclinical Alzheimer’s neuropathology may interact with education attainment and neurophysiological mechanisms generating cortical alpha rhythms around IAFp (i.e., alpha 2 and 3) in quiet wakefulness.
Targeting SHIP1 for therapeutic intervention in Alzheimer’s disease
Authors: Obst Juliane , Bradshaw William , Roberts Hazel Hall , Priestley Richard , Jimenez‐Antunez Carmen , Cowley Sally A. , Gileadi Opher , Mead Emma , Daniel Elena Di , Davis John B. 
Published: December 2020

AbstractBackgroundGenome wide association studies (GWAS) and systems biology approaches have identified several Alzheimer’s disease (AD) risk associated genes expressed in microglia. SHIP1, an inositol phosphatase, has been identified as a regulator of TREM2 signalling, inhibiting the cascade by opposing SYK and PI3K phosphorylation. A SHIP1 variant (rs39349669) confers AD risk by increasing SHIP1 expression, thereby inhibiting TREM2 signalling and reducing beneficial microglial phenotypes including phagocytosis. We hypothesise that SHIP1 inhibition may restore the protective signalling pathway associated with TREM2.MethodUtilising human iPSC macrophages, we aim to understand the role of SHIP1 in regulating TREM2 signalling. We are able to stimulate TREM2 signalling using an activating antibody, and we have measured SYK phosphorylation and Ca2+ flux in the presence of SHIP1 modulators. As development of small‐molecule inhibitors of phosphatases is challenging due to polar active sites, we hope to identify allosteric binding sites on SHIP1. We have determined the structure of SHIP1 and aim to use crystallography to promote the development of potent modulators. We have performed a crystallographic fragment screen of 597 compounds to identify SHIP1 binders, which will be used as starting points for medicinal chemistry.ResultThe SHIP1 inhibitor 3AC increases SYK phosphorylation and intracellular Ca2+ flux following TREM2 stimulation. We are now working with an isogenic SHIP1 KO iPSC line to validate these findings. We have determined the structure of the phosphatase and C2 domains of SHIP1, both in the apo form and with a phosphate and a magnesium ion bound to the active site. We are working towards further structures. The fragment screen revealed more than 100 binding events. These identify new potential binding pockets outside of the active site and work is ongoing to perform SAR.ConclusionWe have demonstrated that SHIP1 regulates TREM2 signalling and is a druggable target. Furthermore, we are working towards identifying inhibitors that will increase TREM2 mediated protective signalling in microglia. We have improved understanding of the structural basis of the reaction catalysed by SHIP1, which will inform the development of novel and selective compounds. Targeting SHIP1 could represent a novel therapeutic strategy for the treatment of AD.
Preclinical features of familial FTD
Authors: Jiskoot Lize C. 
Published: December 2020

AbstractBackgroundUp to 40% of frontotemporal dementia (FTD) cases carry an autosomal dominant mutation, the majority in the progranulin (GRN), microtubule‐associated protein tau (MAPT) or chromosome 9 open reading frame 72 (C9orf72) genes. Familial FTD offers a unique window for observing the earliest disease‐related changes, as mutation carriers can be identified in their presymptomatic stages.MethodWe performed a systematic review of discoveries from major European prospective longitudinal cohorts of presymptomatic mutation carriers, particularly the Rotterdam FTD Risk Cohort (FTD‐RisC) and the GENetic Frontotemporal dementia Initiative (GENFI).ResultIn the last 10 years, biomarker changes that begin many years before symptom onset have been identified. Presymptomatic neuropsychological assessment have demonstrated executive dysfunction as a common feature of all the genetic groups, as well as mutation‐specific patterns in GRN (memory), MAPT (language) and C9orf72 (attention). Grey matter atrophy and hypometabolism appear around 10 years prior to symptom onset. White matter tract abnormalities signify the first disease‐related changes, seen as early as three decades before symptom onset, again with mutation‐specific patterns in GRN (internal capsule), MAPT (uncinate fasciculus) and C9orf72 (posterior tracts). Several fluid biomarker candidates have been identified. Neurofilament light chain provides a reliable measure of disease staging, progression and survival, with levels being highest in C9orf72‐associated ALS and lowest in MAPT mutation carriers. Two of the biggest challenges are identifying and conceptualizing the transitional (conversion) stage between presymptomatic and overt disease, similar to mild cognitive impairment in the evolution to Alzheimer’s Disease dementia, and the use of estimated years to symptom onset as a proxy for actual symptom onset—which varies widely between and within families and across mutations. Conversion seems to be a relatively rapid process, and there are no clinical tools to capture this transition. There is also a lack of reliable disease‐staging markers.ConclusionThe pathological heterogeneity in FTD warrants a multimodal approach, and future challenges lie in finding sensitive clinical markers that are able to identify the earliest cognitive and behavioural features, as well as neuroimaging and fluid biomarkers that can reliably differentiate between clinical and pathological FTD subtypes.
Latent disease models estimate symptom onset in familial frontotemporal lobar degeneration and enable novel designs for early‐stage clinical trials
Authors: Staffaroni Adam M. , Quintana Melanie , Wendelberger Barbara , Heuer Hilary W. , Rojas Julio C. , Cobigo Yann , Goh Sheng‐Yang Matthew , Wolf Amy , Onyike Chiadi U. , Boeve Bradley F. , Rosen Howard J. , Boxer Adam L. 
Published: December 2020

AbstractBackgroundMeasuring changes in the earliest phases of familial frontotemporal lobar degeneration (f‐FTLD) and estimating symptom onset has important implications for clinical care. Early stage clinical trials have begun for f‐FTD, but the low prevalence of f‐FTLD mutation carriers and heterogeneous symptomology challenges trial design. Bayesian disease progression models (DPM) incorporate clinical data, neuroimaging metrics, and fluid biomarker concentrations to estimate latent disease age, providing estimates of symptom onset and progression status. Such models may facilitate enrollment in studies (i.e., inclusion of presymptomatic individuals) and provide more powerful analysis methods for trials.MethodA Bayesian latent variable repeated measures model was used to estimate disease progression, conditional on latent disease age (proximity to symptom onset), in 275 participants with mutations in GRN (n=68), MAPT (n=80) and C9orf72 (n=127). Median follow‐up was one year (range: 0‐4). Jointly modeled longitudinal variables included neuropsychological scores, CDR®+NACC‐FTLD box score, 3T MRI frontotemporal brain volumes, and plasma levels of neurofilament light chain (NfL). Sample size estimates for detecting treatment effects were generated by varying thresholds of estimated proximity to symptom onset.ResultThe Bayesian DPM provided a clear picture of clinical and neurological progression within each mutation group. Neuroimaging and NfL captured early progression rates (1 SD from controls) 5‐10 years before symptom onset. After symptom onset, CDR®+NACC‐FTLD box score was the most sensitive measure of disease progression. GRN mutation carriers had the largest annual progression rates (and lowest variability) compared to MAPT and C9orf72. Between 5 years pre‐ and 10 years post‐onset, CDR®+NACC‐FTLD box score progressed by 2 units/year (SD=2.7) in GRN mutation carriers ‐ almost twice the rate of progression in MAPT (M=1.2;SD=2.5) and C9orf72 (M=1.1;SD=2.2) mutation carriers. Compared to a trial enrolling only early symptomatic cases (CDR®+NACC‐FTLD=0.5 or 1), utilizing latent disease age would facilitate enrollment of asymptomatic cases with the same power.ConclusionBased on an estimation of symptom onset, Bayesian DPMs suggest clinical trials in GRN mutation carriers would require the smallest sample sizes. Furthermore, leveraging these DPMs would allow novel, powerful trial designs that may facilitate greater participant enrollment.
Elevated systolic blood pressure is associated with episodic memory decline in healthy aging
Authors: Solé‐Padullés Cristina , Vaqué‐Alcázar Lídia , Abellaneda‐Pérez Kilian , Ros Emilio , Bartres‐Faz David 
Published: December 2020

AbstractBackgroundElevated blood pressure (BP) is associated with poorer cognitive performance in ageing but not in the very old (Obisesan et al., 2008). Likewise, hypertension causes vascular dysregulation and eventually decreased blood flow in several regions including the hippocampus (Glodzik et al., 2019) and is associated with faster cognitive decline in Mild Cognitive Impairment (MCI) patients (Goldstein et al., 2013). However, the association between BP and memory performance remains controversial with studies finding different results (reviewed in Forte et al., 2020). Longitudinal examinations are also non‐conclusive. One study showed association between poorer memory performance and higher systolic BP (SBP) at baseline, but not at follow‐up examination (Waldstein et al., 2005); and a previous one found that elevated SBP predicted greater number of errors in a memory task over time (Glynn eta l., 1999). We aim to explore the association between baseline SBP and memory change in healthy aging.Method77 healthy elders (age range 65‐78) were selected from the Institute of Aging (Barcelona). Rey Auditory verbal learning Task (RAVLT) was administered at baseline and follow‐up examination (mean interval period was 4.15 years, SD=0.44). Partial correlations were conducted between SBP and percent of change in RAVLT total learning and delayed scores. Control variables included age at baseline, interval period between assessments, medication for hypertension (medicated versus unmedicated) and years of education. All individuals presented normal global cognitive function (Mini Mental state Examination ≥ 25) and RAVLT delayed scores ≥ 5, to exclude possible MCI cases.ResultA significant negative correlation was found between SBP at baseline and percent of change in delayed episodic memory (r=‐0.338, p=0.003, Bonferroni corrected p=0.021). Interestingly, no significant associations were found between SBP and cross‐sectional measures of delayed RAVLT.ConclusionElevated SBP was associated with increased decline in delayed verbal memory in healthy aging. Delayed episodic memory is a key factor for characterizing subjects at risk of dementia and therefore, targeting measures to maintain optimal levels of BP should be a priority for primary care medicine.
Genome‐wide DNA methylation signatures of tau and amyloid neuropathology
Authors: Castanho Isabel , Murray Tracey K. , Leung Szi Kay , Hannon Eilis , Jeffries Aaron , Lunnon Katie , Ahmed Zeshan , Mill Jonathan 
Published: December 2020

AbstractBackgroundThe onset and progression of Alzheimer’s disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and the accumulation of β‐amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD, the regulatory genomic mechanisms involved in disease progression are not fully understood. DNA methylation (DNAm) is the most widely studied epigenetic modification in human disease, with recent work by our group robustly linking methylomic variation to AD and other neurodegenerative disorders. To date, no study has systematically profiled DNAm in mouse models of AD. This study aimed to relate progressive changes in DNAm to AD neuropathology in the cortex, using transgenic models of amyloid and tau pathology.MethodWe used transgenic mice harboring human microtubule‐associated protein tau (MAPT, rTg4510) and amyloid precursor protein (APP, J20) mutations to investigate epigenomic and transcriptional changes associated with the development of tau and amyloid pathology. Using sequencing‐based approaches, we quantified changes in DNAm and gene expression identifying genomic signatures paralleling the progression of tau and amyloid across multiple brain regions. Methylomic and transcriptomic changes associated with amyloid and tau pathology were compared to similar data generated from human AD brain.ResultWe identified progressive changes in gene regulation associated with the development of AD neuropathology, including changes in DNA methylation and gene expression at loci previously identified in previous and ongoing human AD studies (Ank1, Hoxa, Abca7, Bin1). Of note, significantly upregulated genes were strikingly enriched for genes involved in immune regulation, and significantly downregulated genes were enriched for synaptic function pathways related to AD. This study represents the most systematic analysis of progressive changes in gene expression and DNA modifications in mouse models of AD pathology and the first to focus specifically on the entorhinal cortex, a key region affected early in human AD.ConclusionOur data provide further evidence for an immune‐response to the accumulation of tau and Aβ, and reveal novel genomic pathways associated with the progression of AD neuropathology.
Stroke, genetic risk and incidence of dementia
Authors: Ranson Janice M , Lourida Ilianna , Hannon Eilis , Littlejohns Thomas J , Ballard Clive , Langa Kenneth M , Hyppönen Elina , Kuzma Elzbieta , Llewellyn David J 
Published: December 2020

AbstractBackgroundStroke is a strong, independent and modifiable risk factor for all‐cause dementia. However, the extent to which stroke adds to or moderates genetic risk is unknown.MethodIn this cohort study, we used data from UK Biobank including adults aged 60 years and older of European ancestry without cognitive impairment or dementia at baseline. Participants joined the study between 2006 and 2010 and were followed until 2016 or 2017. Genetic risk was estimated using a polygenic score for dementia incorporating 249,273 single‐nucleotide polymorphisms with low (lowest quintile), intermediate (quintiles 2‐4), and high (highest quintile) categories. Stroke was a binary variable based upon history of stroke occurring before dementia diagnosis or end of follow‐up in participants who remained dementia‐free. The outcome was incident all‐cause dementia, ascertained through hospital inpatient and death records.Result196,383 individuals (mean [SD] age, 64.1 [2.9] years; 52.7% were women) were followed up for 1,545,433 person‐years (median [interquartile range] follow‐up, 8.0 [7.4‐8.6] years). Overall, 3.8% of participants had a history of stroke. 20.0% had high polygenic risk scores, 60.0% had intermediate risk scores, and 20.0% had low risk scores. Of the participants with high genetic risk, 1.2% developed dementia compared with 0.63% of the participants with low genetic risk (adjusted hazard ratio, 1.94 [95% CI, 1.66‐2.27]). Of the participants with stroke, 2.7% developed dementia compared with 0.8% of participants without a stroke (adjusted hazard ratio, 2.73 [95% CI, 2.35‐3.17]). Of the participants with a high genetic risk and stroke, 3.4% developed dementia compared with 0.57% of participants with low genetic risk and no stroke (adjusted hazard ratio, 5.02 [95% CI, 3.67‐6.86]). There was no significant interaction between genetic risk and stroke (P = 0.633). Among participants with high genetic risk, 1.2% of those without stroke developed dementia compared with 3.4% of those with stroke (hazard ratio, 0.40 [95% CI, 0.29‐0.53]).ConclusionAmong older adults without cognitive impairment or dementia, both stroke and high genetic risk were significantly associated with higher dementia risk. Stroke prevention should be a key element of risk reduction strategies for the prevention of dementia, particularly amongst those with a high genetic risk.
Impact of psychosis on quality of life and well‐being in dementia
Authors: Choi Aaron , Ballard Clive , Martyr Anthony , Collins Rachel , Morris Robin G. , Clare Linda 
Published: December 2020

AbstractBackgroundThis study aimed to: 1) Examine the impact of psychotic symptoms on the quality of life, wellbeing and satisfaction of life in people with dementia(PwD) living in the community, and 2) determine whether other symptoms known to affect quality of life in PwD would confound any effect detected.MethodThe Neuropsychiatric Inventory Questionnaire was completed by informant interview. Mean differences between the absence and presence of each psychotic symptom (delusions, auditory hallucinations) were then compared for each of three validated measures of living well and quality of life: Quality of Life in Alzheimer’s scale, World Health Organization‐Five Well‐being Index and Satisfaction with Life Scale. Analysis of co‐variance was used to determine the confounding contributions of cognition via Mini‐Mental State Examination, depression via Geriatric Depression Scale‐10, carer stress via Relative Stress Scale and antipsychotic usage.ResultPresence of delusions was not associated with quality of life, wellbeing or satisfaction with life. Presence of auditory hallucinations was associated with lower scores for QoL [p<0.001, η2=0.013], wellbeing [p<0.001, η2=0.016] and satisfaction with life [p<0.001, η2=0.010]. After controlling for confounding factors, the relationship between auditory hallucinations and Qol [p=0.003, pη2= 0.011] and wellbeing p <0.001, pη2= 0.018] remained significant, but there was no significant association with satisfaction with life.ConclusionPresence of auditory hallucinations but not delusions is associated with lower quality of life and wellbeing in people with dementia living in the community.
Application of two‐graph receiver operating characteristics for defining intermediate amyloid‐beta CSF cutoffs
Authors: Brum Wagner Scheeren , De Bastiani Marco Antônio , Souza João Pedro Ferrari , Bieger Andrei , Therriault Joseph , Benedet Andréa Lessa , Pascoal Tharick A. , Povala Guilherme , Ferreira Pamela C.L. , Souza Diogo O. , Rosa‐Neto Pedro , Zimmer Eduardo R. 
Published: December 2020

AbstractBackgroundThe NIA‐AA 2018 Research Framework envisioned Alzheimer's disease (AD) as a biological construct, dichotomizing individuals into normal and abnormal for each biomarker category. Furthermore, it suggests that developing intermediate‐range cutoffs would aid in advancing AD research. However, few statistical methodologies have been proposed to define what would constitute an intermediate range for an AD biomarker. Here, we apply a three‐range method for defining cutoff in amyloid‐β (Aβ) cerebrospinal fluid (CSF) measurements to assess intermediate range's predictive value over clinical progression. Considering it is expected that a biomarker loses its predictive value in the perithreshold zone, we hypothesized that Aβ‐intermediate (AbInt) status of cognitively unimpaired (CU) would not be able to predict progression to symptomatic stages of AD.MethodFor defining intermediate‐range cutoffs with two‐graph receiver operating characteristics (TG‐ROC) method, 807 individuals with baseline [18F]AV45 Aβ‐PET and CSF Aβ1‐42 Elecsys® biomarkers were selected from the ADNI. Mean standardized uptake value ratio cutoff of 1.11 for [18F]AV45 was employed to stratify individuals into true‐positive (n=433) and true‐negative (n=374). Based on TG‐ROC cutoffs, 336 CU individuals with baseline CSF Aβ1‐42 Elecsys® were divided into Aβ‐, Aβint and Aβ+ and followed‐up for 6 years. Predictive values of baseline biomarker status for clinical progression were assessed using Cox proportional hazards models adjusted for age, gender, APOE and baseline MMSE.ResultTG‐ROC analysis yielded cutoffs for Aβ‐ (>1131 pg/mL; n=199), AβInt (820.1<Intermediate<1131 pg/mL; n=55) and Aβ+ (<820.1 pg/mL; n=82), as shown in Figure 1. A total of 52 individuals progressed clinically to mild cognitive impairment (n=50) or to dementia (n=2). Adjusted hazard ratios (HR) for progression, compared to the Aβ‐ group, were, as expected, significantly elevated for Aβ+ individuals (HR=2.428; 95% CI 1.299‐4.537; p=0.005), whereas non‐significant for AβInt (HR=‐0.375; 95% CI 0.259‐1.826; p=0.452). Kaplan‐Meier survival curves illustrate these trajectories (Figure 2).ConclusionOur findings support the notion that biomarker measurements lose their ability to significantly predict cognitive decline within the perithreshold zone, emphasizing the need for further investigation of these individuals. As an alternative for operationalizing this matter of pivotal importance, we propose further investigation about the clinical utility of TG‐ROC, a well‐established method for defining three‐range cutoffs.