bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Europe‐wide randomized controlled trial of hearing and vision rehabilitation in dementia: Results from the SENSE‐Cog trial
Authors: Leroi Iracema , Camacho Elizabeth , Chaghil‐Boissier Nathalie , Charalambous Anna Pavlina , Conelly JP , Constantinidou Fofi , David Renaud , Elliott Rachel , Frison Eric , Hann Mark , Holden Alison , Kennelly Sean , Lawlor Brian , Longobardi Julie , Politis Antonis , Kontogianni Evangelia , Rao Vinay Sudhindra , Reeves David , Termote Monique , Thodi Chryssoula , Worthington Mark , Yeung Wai 
Published: December 2022

AbstractBackgroundHearing and vision impairments are highly prevalent in people with dementia (PwD) and may have a negative impact on quality of life and other dementia‐related outcomes. Intervening to optimize sensory function improve these outcomes. The SENSE‐cog Trial evaluated whether a home‐based multi‐part ‘sensory support’ intervention (SSI) is effective in improving quality of life and other key outcomes in PwD (including hearing and/or vision problems), and their care partners.MethodsThis was a pan‐European, multi‐centre, observer blind, randomized controlled trial (RCT), of PwD with hearing and/or vision impairment and their companions. We compared ‘care as usual’ (CAU) to a multi‐part complex intervention of hearing and vision rehabilitation (SSI) tailored to each participant dyad. The SSI included: assessment and correction of hearing and/or vision impairments; home‐based, therapist‐delivered sensory support (i.e., adherence with devices; improving the sensory environment, communication training, and signposting to other support agencies). Outcomes were collected at baseline, intervention end (18 weeks) and post‐intervention (36 weeks – the primary endpoint) and included: quality of life, sensory and cognitive functional ability, relationship satisfaction, neuropsychiatric symptoms, and mental well‐being. Health resource utilization was measured to estimate cost‐effectiveness of the intervention.ResultsAcross 7 European centers (UK, France, Cyprus, Greece), 252 participants with dementia (median age 80 years, 53% female, 59% hearing impairment only, 4% visual impairment only and 37% both impairments) were randomized from May 2018 to May 2021 to receive either CAU or SSI (10 visits over 18 weeks). Mitigating strategies to adapt study procedures to the COVID‐19 pandemic were implemented. Over 75% of participants completed the primary outcome, the DEM‐QoL scale, at 36 weeks. An initial feasibility study yielded positive results for this outcome revealing an average improvement in the DEM‐QoL of 4.9 points (> minimum important clinical change).ConclusionsHearing and vision support in PwD is a potentially important and cost‐effective means of improving the lived experience of dementia, representing a critical step in the diagnostic and care pathway. Main RCT results will be available in May 2022.
Trial registration: ISRCTN17056211
BCI‐838, an orally active mGluR2/3 antagonist pro‐drug, mimics the beneficial effects of physical exercise on neurogenesis, behavior and exercise‐related molecular pathways in an Alzheimer’s disease mouse model
Authors: Bicak Mesude , Perez‐Garcia Georgina E. , Buros Jacqueline , Haure‐Mirande Jean‐Vianney , Perez Gissel E. , Otero‐Pagan Alena , Gama‐Sosa Miguel E. , DeGasperi Rita E. , Sano Mary , Gage Fred H. , Barlow Carrolee , Dudley Joel , Glicksberg Benjamin S. , Wang Yanzhuang , Readhead Benjamin , Ehrlich Michelle E. , Elder Gregory A. , Gandy Sam 
Published: December 2022

AbstractBackgroundModulation of physical exercise (PE) represents an intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD). One mechanism proposed to underlie beneficial effects of PE involves the apparent stimulation of adult hippocampal neurogenesis (AHNG). BCI‐838 is a pro‐drug whose metabolite BCI‐632 is one of the most active proneurogenic agents known and is an antagonist at group II metabotropic receptors (mGluR2/3). The drug stimulates AHNG while enhancing learning behavior and exerting anxiolytic and antidepressant properties. We previously demonstrated that the administration of BCI‐838 to a mouse model of cerebral and cerebrovascular accumulation of oligomeric AbE22Q (APPE693Q = “Dutch”) reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Thy1.1‐Dutch APP mice (Kim et al., Mol Psych 2014). Herein, we sought to determine whether BCI‐838 might substitute for PE, and/or whether treatment with a BCI‐838+PE combination might demonstrate synergistic effects in a mouse model of amyloidosis (APPKM670/671NL/PSEN1Δexon9 = APP/PS1).Method3‐month‐old APP/PS1 mice were treated with either BCI‐838, PE (running wheels), or a combination of BCI‐838+PE for 1 month. We performed learning behavior tests (novel object recognition and Barnes maze), biochemical, and transcriptomic analyses on the hippocampal dentate gyrus (DG) of APP/PS1 mice. We performed gene set enrichment analysis, drug repurposing, and chemogenomic enrichment analyses to reveal molecular pathways of interest and investigated compounds with transcriptomically similar profiles as well as drug targets and side effects.ResultWe report that: (i) BCI‐838, PE, or BCI‐838+PE combination enhanced AHNG, (ii) BCI‐838 alone or associated with PE led to improvement in both spatial and recognition learning behaviors, (iii) BCI‐838 treatment increased mRNA levels of BDNF, metabotropic glutamate receptors, and PIK3C2A of the PI3K‐MTOR pathway, and decreased EIF5A of ketamine‐modulating mTOR activity in the hippocampal DG. qPCR results validated the statistical significance of the association between BCI‐838 treatment and increased levels of BDNF.ConclusionOur study points to BCI‐838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHNG, learning behavior, and anxiety in the APP/PS1 mouse model.
Investigating the protective contribution of PLCG2 P522R variant in microglia‐mediated immune pathways in Alzheimer’s Disease
Authors: Liang Xinyan 
Published: December 2022

AbstractBackgroundAs the main innate immune cell in central nervous system (CNS), microglia plays an indispensable roles in neuroinflammation and neurodegenerative diseases, such as Alzheimer’s Disease (AD). Large scale population studies have identified an AD‐associated rare coding variant in the Phospholipase C Gamma 2 (PLCG2) locus (rs72824905, P522R, P=5.38x10‐10, odds ratio = 0.68), which potentially offers protection against AD. This variant is associated with lower Aβ1‐42 and pTau181 levels in patients, as well as delays cognitive decline in mild cognitive impairment (MCI) progression. It has been reported that PLCG2 highly expresses in microglia in CNS and mainly involved in immune response, therefore, PLCG2 P522R variant may be a central player in the microglial‐mediated immune pathways during AD pathogenesis.MethodWe generated a PLCG2522R/R knock‐in mouse model carrying this human variant with CRISPR‐mediated gene editing. To explore the protective nature of PLCG2 P522R variant, we generated PLCG2522R/R; 5XFAD mouse model by crossing PLCG2522R/R knock‐in model with the 5XFAD mice, and accessed major AD phenotypes including Aβ load and microgliosis in vivo.ResultOur data showed that PLCG2522R/R;5XFAD mice exhibited attenuated AD pathologies compared with PLCG2522P/P;5XFAD mice, including less burden of Aβ in cortical and hippocampal regions, and less Aβ‐associated microglia clustering around Aβ plaques at early stage of AD.Conclusion
PLCG2 P522R variant can protect against AD pathology in PLCG2522R/R;5XFAD mice, which may likely link to its hypermorphic effect in immune pathways, so that PLCG2522R/R microglia potentially have improved phagocytotic function and restrict Aβ accumulation in brain. We believe that investigating the protective role of PLCG2 P522R mutation may help us better understand the neuroinflammation aspect of AD pathogenesis, and provide new strategies to developing clinical therapy in the future.
Subcortical atrophy imaging biomarker performance across the sporadic and genetic frontotemporal dementias
Authors: Gordon Elizabeth , Bocchetta Martina , Nicholas Jennifer M , Cash David M , Rohrer Jonathan D. 
Published: December 2022

AbstractBackgroundFrontotemporal dementia (FTD) is a common cause of young‐onset dementia, with promising disease‐modifying candidates. Cortical signatures are well established; however, comprehensive longitudinal investigations of subcortical atrophy are limited and sample size estimates to inform imaging biomarker choice are lacking. Therefore, the current study investigated the relative utility of automated subcortical atrophy measures to detect putative disease‐modifying treatment effects in clinical, genetic and pathologically‐confirmed FTD.MethodLongitudinal registration and segmentation algorithms were applied to a cohort of 262 people, 184 of whom were diagnosed with FTD, to measure atrophy in the amygdala, hippocampus, caudate and thalamus. Clinical diagnoses were behavioural variant FTD (n = 66) and primary progressive aphasia (PPA, n = 118), comprising semantic variant PPA (n = 45), non‐fluent variant PPA (n = 45), logopenic variant PPA (n = 21), and PPA‐not otherwise specified (n = 7). Fifty‐three patients had either a known pathogenic mutation (in the MAPT, C9orf72 or GRN genes) and/or underlying tau or TDP‐43 pathology confirmed at post‐mortem. Seventy‐eight cognitively normal controls were included for comparison. Sample size estimates were computed to explore the relative feasibility of subcortical atrophy measures to track disease progression and detect treatment‐related effects across the different subgroups.ResultRelatively distinct patterns of significantly increased atrophy across the amygdala, hippocampus, caudate and/or thalamus were detected (p < 0.001) for all sporadic, genetic, and pathology‐confirmed FTD subgroups, with a strong left‐dominant pattern evident for PPA‐NOS and GRN patients. The best performing marker (as determined by lowest sample size required to detect a treatment effect) varied by subgroup supporting the importance of informed regional biomarker choice based on the population enrolled. Measures of the caudate and thalamus performed particularly well across all the subgroups, producing estimates well below 100 patients per treatment arm. The left hippocampal BSI (boundary shift integral) measure produced the lowest estimate overall in PPA‐NOS, with 12 individuals required to detect a 30% reduction in atrophy.ConclusionThis work confirms the relative utility of subcortical atrophy measures across the FTD spectrum and provides valuable sample size information to inform non‐invasive biomarker choice for sporadic and genetic FTD trials.
The longitudinal relationship between fatigue, mobility, and cognitive function in older adults with chronic stroke: secondary analysis of a randomized controlled trial
Authors: Liu‐Ambrose Teresa , Noseworthy Matt W 
Published: December 2022

AbstractBackgroundFatigue is a common consequence of stroke. Cross‐sectional evidence suggests post‐stroke fatigue is negatively associated with both mobility and cognitive function. We aim to understand the longitudinal relationship between fatigue, mobility, and cognitive function in community‐dwelling adults with chronic stroke (defined as having a stroke = or > 12 months prior to study).MethodsA secondary analysis of data from a 6‐month randomized controlled trial with 120 adults with chronic stroke who were randomized to group‐based, supervised: 1) exercise training; 2) complex social and mental activities; and 2) stretch and balance exercises with general education sessions. We constructed linear regression models to assess the contribution of changes in fatigue to changes in usual gait speed (over 4 meters) and to changes in cognitive function. Cognitive function was measured by the Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog) Plus. Higher ADAS‐Cog Plus scores indicate greater cognitive impairment. Fatigue was assessed using: 1) Fatigue Severity Scale; and 2) Visual Analogue Scale. The Fatigue Severity Scale measures fatigue severity and its impact on daily activities global fatigue The Visual Analogue Scale asks individuals to rate their global fatigue. Higher Fatigue Severity Scale and Visual Analogue Scale scores indicate greater severity and degree of fatigue, respectively. In the regression models, we controlled for experimental group, age, and biological sex.ResultsReduced severity of fatigue over the 6 months was associated with improved gait speed (p = 0.02). Reduced global fatigue was associated with improved cognitive function (p = 0.04). Specifically, a reduction of 25 points on the Fatigue Severity Scale was associated with an increase of 0.1 m/s in gait speed (R‐square = 5%). For the Visual Analogue Scale, a reduction of 3.3 points in global fatigue was associated with a reduction of 1 point (i.e., improvement) in the ADAS‐Cog Plus (R‐square = 4%).ConclusionsGiven the prevalence and consequence of fatigue on function in chronic stroke, future work is needed to identify effective interventions.
Tasks and activities of an effective collaborative Dementia Care Management program in German Primary Care
Authors: Mühlichen Franka , Michalowsky Bernhard , Raedke Anika , Platen Moritz , Mohr Wiebke , Thyrian Jochen René , Hoffmann Wolfgang 
Published: December 2022

AbstractBackgroundRecent studies have demonstrated the efficiency of collaborative dementia care, which aim to improve post‐diagnostic support. However, tasks carried out of such models are currently unknown, hindering its implementation.ObjectivesTo describe the tasks of an efficient collaborative dementia care management and analyze the association of these tasks with patients’ characteristics.MethodsThe analysis was based on 183 persons screened positive for dementia (PwD), who received dementia care management conducted by nurses with a dementia‐specific qualification. A standardized computer‐assisted assessment, patients’ and caregivers’ unmet needs were identified, based on these, pre‐specified algorithms generated an individual list of intervention tasks for each PwD. Tasks performed to meet unmet needs were documented and categorized and descriptively analyzed. We used multivariate regression models to identify socio‐demographic and clinical factors that are associated with a specific subgroup of tasks or a higher number of tasks.ResultsOn average 22.7 tasks were carried out per dyad (PwD and caregiver). 38%, 19% and 13% of tasks could be categorized to cooperation with other healthcare providers, medical and nursing care, and social and legal support, respectively. A lower mental and physical health‐related quality of life, age of PwD, lower education, higher deficits in daily living activities, higher depressive symptoms, and a higher number of drugs taken of the PwD, as well as female sex of the caregiver were associated with a significantly higher number of tasks carried out.ConclusionsSocio‐demographic and clinical characteristics and the subjective perception of health determine the intensity of intervention needed to address unmet needs of PwDs. A variability of the intensity of collaborative care should be considered in the development of future intervention studies and in the implementation into routine care.
Memorability of Word‐Pairs: Developing a Method for Generation of Calibrated Stimulus Sets for Repeat, Remote, Automated Testing
Authors: Kaula Alexander J , Cormack Francesca K 
Published: December 2022

AbstractBackgroundVerbal‐Paired Associates (VPA) is widely used measure of memory. However, the memorability characteristics of the word‐pairs are not well‐understood, and the task currently suffers from ceiling effects (Uttl et al. 2002). Here we describe a data driven process for word‐pair selection, yielding precise estimates of memorability at the item and list level. This allows tuning of task difficulty to participant characteristics, and the development of many well‐calibrated parallel forms for longitudinal automated testing.MethodFor model development we recruited a total of 185 participants aged 18–40 years without psychiatric diagnoses, chronic medication, or historical head injury using the Prolific online testing platform. We used Cambridge Cognition’s NeuroVocalix software to automatically deliver and score Learning and Recall phases of VPA.In a series of experiments, we explored the contributions of item‐level, pair‐level, list‐level, and study‐level properties to the probability of subsequent recall. At the item‐level, we considered word‐concreteness and word‐frequency. To capture the semantic relatedness of word‐pairs, we trained the GloVe neural network model (Pennington et al, 2014) to predict the co‐occurrence of words from a corpus of transcribed English. This yields high‐dimensional vectors, from which we could calculate the semantic cosine distance between items in a word‐pair. At the list‐level we considered order effects (primacy and recency), and at the study level we considered practice effects.Data from these experiments was combined in a linear mixed effects logistic regression model to yield predicted memorability estimates for new sets of word‐pairs. These test sets were then deployed with a cohort of 43 older adults (aged 55 years and upwards) to evaluate this prediction.ResultModelling showed significant contributions of item‐level, pair‐level, list‐level, and study‐level factors to probability of recall. When applied to the new set of words and tested with our older cohort, we found that this model‐derived measure was a robust predictor of recall (r = .931, p < 10−6).ConclusionWe have a robust method of predicting, for a given word‐pair, what the likelihood of recall will be. This enables the generation of sets of word‐pairs with well‐understood memorability characteristics, for use in automated, repeat, remote assessment.
Innate immune cGAS/STING in HFD‐induced obesity, prediabetes, and cognitive impairment
Authors: Elzinga Sarah E , Henn Rosemary E , Mendelson Faye E , Hayes John , Feldman Eva L 
Published: December 2022

AbstractBackgroundIncreasing in parallel with the worldwide aging population are rates of cognitive impairment and dementia, including Alzheimer’s Disease and Alzheimer’s Disease Related‐Dementia. Understanding underlying mechanisms that promote cognitive impairment with aging is therefore critical. One factor that significantly increases the risk of cognitive impairment and is reaching pandemic levels is obesity and prediabetes/diabetes. Common mechanisms that could underly the relationship between obesity and prediabetes/diabetes with cognitive impairment are changes in immune system function, particularly microglial dependent changes. Specifically, the innate immune cGAS/STING pathway is implicated in both cognitive impairment and obesity and prediabetes/diabetes.Method1 yr old BL6 male mice were fed 60% HFD (high fat diet) or 10% SD (standard diet) for 13 weeks. Body weight and glucose tolerance were used to determine metabolic phenotype. Cognition was measured using social recognition and fear conditioning. Hippocampal inflammatory gene expression was determined using Nanostring nCounter and cGAS/STING specific protein expression using western blotting. Additionally, we induced a prediabetic phenotype in a human microglial cell line by treating microglia for 24 hr with either palmitate alone or a combination of insulin and palmitate. Cells were then assessed for cGAS/STING protein expression using western blotting.ResultHFD feeding resulted in increased weights and impaired glucose tolerance along with cognitive deficits. Hippocampal gene expression profiles showed changes in several genes, such as cGAS, STAT2, and IL‐6 and there were changes in hippocampal cGAS/STING proteins in HFD mice. In microglia, prediabetic conditions increased expression of multiple cGAS/STING proteins, along with the immunosenescence marker p21.ConclusionChanges in inflammatory profiles indicate that HFD dysregulates hippocampal inflammatory gene expression and cGAS/STING protein expression in obese prediabetic mice with cognitive impairment. Microglial cGAS/STING changes indicate that this cell type is particularly sensitive to prediabetic conditions and may promote premature immunosenescence. While more data are needed to fully understand cGAS/STING mediated microglial mechanisms of cognitive decline in obesity and prediabetes, these data support the hypothesis that inflammatory mechanisms are an important contributor and that the cGAS/STING pathway represents a potential target for future research.
Characterization of CDR® plus NACC FTLD at Phenoconversion from Asymptomatic to Mild Behavioral and/or Cognitive Impairment in Familial Frontotemporal Lobar Degeneration: Data from the ALLFTD Consortium
Authors: Miyagawa Toji , Brushaber Danielle , Syrjanen Jeremy A. , Kremers Walter K. , Fields Julie A. , Forsberg Leah K. , Heuer Hilary W. , Huey Edward D. , Knopman David S. , Kornak John , Boxer Adam L. , Rosen Howard J. , Boeve Bradley F. , Consortium ALLFTD 
Published: December 2022

AbstractBackgroundThe three most common genes responsible for the familial Frontotemporal Lobar Degeneration (f‐FTLD) are MAPT, GRN, and C9orf72, with the C9orf72 mutation being the most common cause of f‐FTLD. The ALLFTD Consortium targets to characterize f‐FTLD, including its preclinical stage, to prepare for clinical trials in FTLD. We sought to investigate the initial symptoms and clinical picture of f‐FTLD and compare them among the common pathogenic genes using longitudinal CDR® plus NACC FTLD.MethodWe longitudinally assessed the CDR® plus NACC FTLD among 292 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD caused by MAPT (n = 99), GRN (n = 67), or C9orf72 (n = 126) mutations, and described the detailed profiles of the CDR® plus NACC FTLD in the participants who developed Mild Behavioral and/or Cognitive Impairment (MBCI).ResultForty‐one participants (17 MAPT, 11 GRN, 13 C9orf72) developed MBCI during follow‐up visits . Age at the diagnosis of MBCI was 52.3±13.0 years (GRN 63.2±11.8, MAPT 43.5±8.6, C9orf72 54.7±10.7). Frequencies of abnormal rating on the eight CDR® plus NACC FTLD domains at the time of MBCI diagnosis were: “Memory” 44% (MAPT 47%, GRN 55%, C9orf72 31%); “Orientation” 7% (MAPT 6%, GRN 9%, C9orf72 8%); “Judgment and Problem Solving” 39% (MAPT 41%, GRN 55%, C9orf72 23%); “Community Affairs” 22% (MAPT 24%, GRN 18%, C9orf72 23%); “Home and Hobbies” 22% (MAPT 35%, GRN 0%, C9orf72 23%); “Personal Care” 0%; “Behavior/Comportment/Personality” 51% (MAPT 59%, GRN 55%, C9orf72 38%); “Language” 29% (MAPT 18%, GRN 55%, C9orf72 23%).ConclusionInitial symptoms and clinical picture of f‐FTLD in MBCI stage differ among responsible FTLD genes, which could be useful in detecting very early features of f‐FTLD in pathogenic mutation carriers.