bluuebunny/crossref_metadata_2025_split huggingface dataset:
Liquid biopsy shows differences in cfDNA fragmentation pattern between AD patients and controls
Authors: Santamaria Blanca Acha , Luquin Idoia Blanco , Corroza Jon , Miguel Mikel San , Roldan Miren , Zueco Sara , Beiras Itsaso Elizalde , Cabello Carolina , Agudo Maria Ángeles Garde , Jericó Ivonne , Erro Elena , Mendioroz Maite 
Published: December 2020

AbstractBackgroundIn the field of precision medicine, liquid biopsy has been developed as a non‐invasive blood test to isolate circulating cell‐free DNA (cfDNA). Although liquid biopsy has gained much attention in oncology as a diagnostic tool, the role of liquid biopsy to aid diagnosis in neurodegenerative diseases remains unclear. Here, we investigated characteristics of plasma cfDNA in AD patients and controls.MethodPlasma cfDNA was isolated from 2 mL of plasma by using QIAmp Circulating Nucleic Acid Kit (QIAGEN) in a set of 95 subjects (43 Probable AD patients based on the NIA‐AA criteria and 52 controls). Fragment Analyzer system (Agilent formerly Advanced Analytical) was used to (1) check cfDNA purity, (2) measure concentration and (3) assess the fragmentation pattern including cfDNA length and concentration of the “classical” three cfDNA peaks. Statistical significance for intergroup differences was evaluated by Mann‐Whitney test with a significance level of 0.05.ResultThe distribution of age and gender was similar between AD patients and controls. No genomic contamination was identified in cfDNA samples. Global plasma concentration of cfDNA was similar in both groups [median (IQR) 17.8 (31) in AD vs. 13.4 (10) in controls, p‐value=0.129]. However, differences were found in the concentration of the first cfDNA peak (size 166 bp) [0.019 (0.025) in AD vs. 0.033 (0.031) in controls; p‐value< 0.05] and in the concentration of the third cfDNA peak (size 534 bp) [0.099 (0.079) in AD vs. 0.193 (0.196) in controls; p‐value< 0.05]. No significant differences in cfDNA fragment length were detected between AD patients and controls.ConclusionThis exploratory study provides evidence of significant differences in the fragmentation pattern of cfDNA in AD patients compared to controls. These results suggest that liquid biopsy is a diagnostic tool worthy to be explored in larger AD cohorts.
lncRNAs as a novel source of diagnostic applications for early Alzheimer’s disease and other dementia types
Authors: Firat Hüseyin , Nazi Sami Ait Abbi , Bier Jean‐Christophe , Blanc Frédéric , Boutillier Stéphanie , Danilin Sabrina , David Renaud , Démonet Jean‐François , Dubois Bruno , Frisoni Giovanni B , Gabelle Audrey , Gurvit Hakan , Ivanoiu Adrian , Magnin Eloi , Marizzoni Moira , Moussaoui Saliha , Mutter Catherine , Pasquier Florence , Schordan Eric , Sellal François ,   ADDIA Consortium,   ADKIT Consortium
Published: December 2020

AbstractBackgroundThere is an unmet need for an accurate, non‐invasive biomarker test for the diagnosis of early Alzheimer’s disease (AD). To identify new biomarkers, we focused on long non‐coding RNAs (lncRNAs) as they are tissue‐ specific to identify lncRNA panel candidates for diagnostic of early Alzheimer’s disease (AD) and other dementia types.MethodWe performed a screening using NGS RNA‐Sequencing to quantify over 127000 lncRNAs in human postmortem brain tissue and blood samples including whole blood, PBMCs and, plasma samples collected in prospective clinical studies that recruited patients with early AD, patients with late AD, patients with one of the other 5 dementia types and healthy controls.ResultWe identified for the first time several panels (i) a panel of brain‐enriched lncRNAs never described before, (ii) panels of brain‐enriched lncRNAs that are either expressed in whole blood or circulating in plasma. (iii) Interestingly, out of these, we also identified panels of lncRNAs that are differentially expressed in the blood of patients with AD or with other dementia types as compared to healthy control subjects. The most accurate lncRNA panel to detect early AD is selected for use as Research‐Use‐Only test and is being further validated to compile the data dossier for submission to regulatory agencies for approval as an in‐vitro diagnostic (IVD) tool diagnostic of AD. Additional clinical applications are for prognostic or theragnostic purposes.ConclusionOur results from studies combining the use of high‐quality samples from well‐designed prospective clinical studies, cutting edge technologies and scientific knowhow enabled to translate novel brain specific lncRNA panels measurable in blood as new non‐invasive and accurate diagnostic approaches using highly specific and low represented sequences specific to neurodegenerative diseases. This project is funded by the Alzheimer's Drug Discovery Foundation (ADDF) Diagnostics Accelerator, a fund set up in collaboration with Bill Gates and other philanthropic partners, By H2020 SMEINST (GA#674474) and by EuroTransBio (ETB‐2014‐63 supported by Region Grand Est).
Combined training of aerobic exercise and 3D video game to improve hippocampal and memory functions in older adults: An RCT trial
Authors: Cui Xiaoyu , Gui Wenjun , Li Juan 
Published: December 2020

AbstractBackgroundWith the proportion of older adults rising, the progressive cognitive decline and dementia have become one of the most serious public health issues worldwide. As a result, there is a pressing need for developing effective non‐pharmaceutical intervention programs to counteract age‐related cognitive decline. Animal models robustly support that aerobic exercise can effectively improve neurogenesis and memory, whereas most of the current findings from human studies are in contrast. We speculated that two reasons may contribute to these inconsistent findings in human research. One is that hippocampal neurogenesis induced by the aerobic exercise is more likely to survive when simultaneously accompanied by cognitive stimulations, particularly when the cognitive goals are challenging. Another is that the beneficial effects from aerobic exercise are specific to hippocampal dependent memory tasks. Therefore, we designed a training program by combining aerobic cycling with 3D video game.MethodWe conducted a randomized controlled trial with healthy older adults randomly assigned to combined aerobic cycling and 3D video game training group (n=22), aerobic cycling group (n=23), 3D video games group (n=25), or control group (n=28). The effects of combined training on neuroplasticity (including plasma brain‐derived neurotrophic growth factor, hippocampal gray matter volume, and hippocampal‐cortical functional connectivity) and cognitive plasticity (focusing on hippocampal‐dependent memory, tested via Mnemonic Similarity Task) were examined compared with all three other groups. The training lasted four months with a frequency of twice per week, 1hour per session.ResultThe combined and video game training groups reported equivalent game experiences and reached similar game levels. The average and maximum heart rates were being monitored to ensure a medium exercise intensity in both combined and cycling groups. In addition self‐reported fatigue levels were equivalent in these two groups. The preliminary behavioral data analysis revealed that combined group performed better on immediate and delayed memory recall. More importantly, there was a larger effect size in pattern separation task in combined group (Cohen’s d =1.12) than in cycling (Cohen’s d =0.49) and video game (Cohen’s d =0.55) groups.ConclusionCombined aerobic exercise ‐ video game training could improve hippocampal‐dependent memory functions, which waits the MRI data analysis to further prove.
Clinical course of early and late mild cognitive impairment
Authors: Lin Szu‐Ying , Lin Po‐Chen , Lin Yi‐Cheng , Lee Yi‐Jung , Wang Pei‐Ning 
Published: December 2020

AbstractBackgroundAmnestic mild cognitive impairment can be sorted to early mild cognitive impairment (EMCI) or late mild cognitive impairment (LMCI) according to severity of memory impairment. The aim of present study is to compare the prognosis and clinical course between EMCI and LMCI.MethodFrom January 2009 to December, 2017, we recruited 640 participants from memory and dementia clinic at the Neurology Department of Taipei Veteran General Hospital. All patients receive at least two series neuropsychological evaluation annually and were categorized to EMCI or LMCI according to ADNI‐2 criteria.ResultTotal 186 patients with EMCI and 277 patients with LMCI were included. 177 cognitive normal participants were also included as normal control. The mean follow‐up duration was 2.85 ± 2.02 years (minimal: 1, maximum: 9 years). At the secondary year, 58 (31.2%) EMCI and 9 (3.2%) LMCI reversed to normal cognitive status. Annual dementia conversion rates were 1.61, 4.41, 21.98 per person year in NC, EMCI and LMCI groups, respectively. EMCI and LMCI had higher rate of progression to dementia (Log rank test, p<0.001) than normal subjects. Both MCI groups showed significant decline in global function (MMSE) and executive function (digital forward, Trail making test A (time), Trail making test B (line) and verbal fluency) than those in normal subjects. No significant different was found in episodic memory and language function between converters and non‐convertersConclusionBoth early and late MCI showed higher risk of dementia. Although MCI showed wide variation in neuropsychological tasks and clinical diagnosis during follow‐up periods, there was higher global and executive functional decline.
Restoring dysfunctional regulatory T cells through ex vivo expansion in Alzheimer disease
Authors: Faridar Alireza , Thome Aaron , Zhao Weihua , Thonhoff Jason R , Beers David , Pascual Belen , Masdeu Joseph C. , Appel Stanley 
Published: December 2020

AbstractBackgroundInflammation is a significant component of Alzheimer disease (AD) pathology. Chronically activated microglia release proinflammatory cytokines, mediate synaptic loss and exacerbate tau propagation. Regulatory T cells (Tregs) have been shown to suppress microglia‐mediated inflammation. We have previously found a failure in suppressive activity of Tregs at the clinical Alzheimer dementia stage. In this study we evaluate the potential of ex vivo expansion of AD Tregs to modify their immunophenotype and restore their function.Method10 patients with Alzheimer disease, 10 with mild cognitive impairment and 10 healthy controls were studied. Tregs were co‐cultured with responder T cells and proliferation was determined by 3H‐thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell‐derived pro‐inflammatory macrophages and changes in IL‐6/TNF‐a transcripts and protein levels were measured. Freshly isolated regulatory T cells were also expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin‐2 (IL‐2) and rapamycin to promote their suppressive function. The immunophenotype of baseline and ex vivo expanded regulatory T cells from were also assessedResultThe suppressive function of regulatory T cells on responder T cell proliferation was compromised at the Alzheimer disease stage, compared with mild cognitive impairment and healthy controls. Tregs did not suppress proinflammatory macrophages at baseline. However, following ex vivo expansion, Treg suppression of responder T cell proliferation and pro‐inflammatory macrophage activation increased in both patients and controls. Ex vivo expanded Tregs expressed higher levels of immunoregulatory markers including CD25, FoxP3, Granzyme B and PD1. In further evaluation of underlying mechanism, these cells exerted their suppressive function on pro‐inflammatory macrophages through a contact‐mediated mode of action.ConclusionOur data demonstrates that the ex vivo expansion of dysfunctional Tregs alters their immunophenotype and enhance their suppressive function at the Alzheimer disease stage. Restoration of regulatory T cell function could be explored as a means to modulate the inflammatory status of Alzheimer disease.
Hippocampal subfield deformation shows unique patterns associated with amyloid‐beta, TDP‐43, and PHF‐tau burden
Authors: Heywood Ashley , Schneider Julie A , Bennett David A , Arfanakis Konstantinos , Beg Faisal , Wang Lei 
Published: December 2020

AbstractBackgroundAlzheimer's dementia (AD) is the most common form of dementia in adults over the age of 65, however, current diagnostic tools need to be improved. The relationships between clinical syndromes and pathological causes are complex, which makes accurate diagnosis difficult. The goals are to develop an in vivo hippocampal surface atlas from structural MRI that is predictive of postmortem β‐amyloid, paired helical filament (PHF‐tau) neurofibrillary tangles (NFTs) and transactive response DNA‐binding protein‐43 (TDP‐43) neuropathologies.MethodUsing a sample of 101 older adults from two longitudinal cohort studies conducted by the Rush Alzheimer’s Disease Center, we utilized hippocampal shape analysis of ante‐mortem T1‐weighted sMRI to generate surfaces for the whole hippocampus and zones approximating the underlying subfields using a previously developed automated image‐segmentation pipeline (Freesurfer‐Initiated Large Deformation Diffeomorphic Metric Mapping; FSLDDMM). Multivariate linear regression models were constructed to examine the relationship between shape and pathology measures while accounting for covariates which include co‐existing pathologies and other neuropathological variables (hippocampal sclerosis, Lewy bodies, gross infarcts, atherosclerosis, arteriosclerosis, and cerebral amyloid angiopathy). These relationships were mapped onto hippocampal surface locations. In a previous sample of 42 subjects from the same cohort, univariate models were not able to be examined due to low power.ResultA significant and unique pattern of deformation for each neuropathology when accounting for covariates were seen. Specifically, β‐amyloid was associated with a significant inward deformation in zones approximating the subiculum, where PHF‐tau NFTs were associated with a significant inward deformation along the left hippocampal tail within the subiculum. TDP‐43 inclusions were associated with a significant inward deformation in the body of the hippocampus along the CA1/subiculum border. Results were corrected for multiple comparisons using the random field theory (RFT) with a family‐wise error rate (FWER) < 0.05.ConclusionThese results indicate a unique pattern of deformation due to individual neuropathology, after accounting for covariates. With the presented increased sample size, a significant TDP‐43 signature arose. Results indicate that hippocampal deformation may be used to represent a biomarker of individual post mortem disease which could allow for the early and accurate diagnosis of disease and aid in the selection for clinical trials.
Dementia in care homes: Using an intergenerational programme to support engagement, community inclusion and positive care environments
Authors: Chandler Rebecca , Gillin Nicola 
Published: December 2020

AbstractBackgroundTherapeutic interventions and activities are often used in care homes (CH) to improve the quality of life for residents with dementia. Intergenerational programmes (IPGs) are one form of intervention which may offer benefits to the CH environment and its residents by engaging people with dementia in new relationships and activities with younger people. This study explored the use of an IGP called Up which brings together school children and CH residents for weekly visits.AimsTo explore the perceived benefits of intergenerational interactions for older adults with dementia living in a CH, and the CH workforce and environment. To explore perceived benefits to school children, and community inclusion and understandings of dementia.Method16 semi‐structured interviews and 2 focus groups (relatives of CH residents, CH staff, school teachers, & school children) were analysed using Thematic Analysis. Emergent themes most relating to older adults with dementia are presented.ResultsMeta‐theme 1, Opportunities to Shine, explores how the intergenerational interactions provided unique and new opportunities for residents to demonstrate their individual personalities and skills, irrelevant of their disabilities or illness. Seeing residents in this way transformed how they were seen by CH staff, relatives and others, allowing them to be re‐humanised and recognised beyond their sometimes dependent states. Meta‐theme 2, Evolving Environments, refers to how intergenerational interactions were perceived to bring new life into the CH environment, uplifting residents and challenging monotony and the care home stereotypes of silence. The positive atmosphere created spilled over into the work environment and staffs approach to their work and the residents. Within the evolving environment and changing perspectives, residents with dementia could be seen as ‘normal’ and integrated members of the wider community, a community now felt more understanding of dementia through the presence of younger generations within the CH.ConclusionThese findings provide insight into how IGPs can be used to positively impact the lives of people with dementia living in CH. They too suggest that IGPs can provide the opportunity for environments, both within and outside the CH communally, which are more conducive to caring and understanding approaches to people with dementia.
The flexibility and reversibility of cognitive frailty
Authors: Lin Yicheng 
Published: December 2020

AbstractBackgroundDeclining physical and cognitive functioning play critical roles in ageing. Cognitive frailty is a concurrent physical and cognitive decline condition. We defined cognitive frailty as dynapenia concomitant with impairment in any cognitive domain, but without dementia. This definition not only includes a larger population at earlier stages of both physical and cognitive impairments but also highlights the potential reversibility of cognitive frailty. In this study, we tried to validate the flexibility and reversibility of cognitive frailty.MethodThe I‐Lan Longitudinal Aging Study (ILAS) is a population‐based cohort study. There were 551 community‐dwelling people aged beyond fifty years old had received second wave evaluation. The mean follow‐up duration was 2.5 years (2.50 ± 0.38 years). We divided all participants to four groups based on the physical and cognitive evaluations: normal, physical frailty only, cognitive impairment only and cognitive frailty in the first visit and follow‐up after 2.5 years. We aim to investigate the transformation of 4 different groups at two different evaluation time.ResultMore than half (62.7%) of cognitive frailty subjects remained in cognitive frailty condition at the 2nd wave evaluation. The incidences for baseline cognitive frailty group transforming to normal, physical frailty only, and cognitive impairment only were 6.5%, 19.6%, and 11.1%, respectively. The cognitive impairment only group had higher rate of transforming to cognitive frailty than the frailty only group (37.5 % vs. 27.0%). There were 26.2% physical frailty only subjects returned to no frailty state and 29.9% cognitive impairment only subjects returned to no cognitive impairment condition. The incidences of normal group transforming to physical frailty only, cognitive impairment only and cognitive frailty group were 32.7%, 14.5% and 15.7%, respectively.ConclusionThe clinical transformation of cognitive frailty points out the reversibility of the disease, which indicate that controlling the risk of frailty and physical, cognitive training, and exercise may be therapeutic for cognitive frailty.
Risk factors for dementia progression among community‐dwelling older adults in a longitudinal national survey
Authors: Allen Samuel C. , Pajewski Nicholas M. , Yang Mia 
Published: December 2020

AbstractBackgroundThe sociodemographic factors that influence the progression to dementia are poorly understood.MethodTo examine dementia progression, we used Rounds 1‐4 (2011‐2014) of the NHATS weighted sample survey of in‐person interviews with adults age 65 and over (N=12,409). We used the NHATS definitions for dementia, possible dementia (MCI), and probable dementia which utilized AD8 Dementia Screening Interviews, self‐reports, and additional cognitive tests to assess dementia categorization for each round. Progression to dementia was defined as either transition from no dementia to possible dementia or possible dementia to probable dementia on consecutive rounds without regression in the opposite direction. We used a cox proportional hazard regression (SAS v. 9.4) to assess how each sociodemographic factor impacts dementia progression.ResultThe average age at the beginning of the study was 77.8 years old, 59% were female, and the largest racial group was White (41.8%). Advancing age (p<0.0001; HR = 1.049) and Hispanic race (p<0.0001; HR = 2.105) increase the chances of dementia progression. Moreover, a participant having one or no people in their social network (a proxy for social isolation) also increases the likelihood of dementia progression (p=0.0378; HR=1.346) as does refusing to answer how many people are in the participant’s social network (p=0.0007; HR=2.686). Using a cane or walker in the past month (a measure of mobility impairment) is also associated with increased dementia progression (p=0.0016; HR=1.525). The protective effect of exercise was not statistically significant (p=0.3523; HR=0.863). Other factors which do not predict dementia progression to a statistically significant degree include: gender, educational status, living alone, depression, hearing/vision impairment, and multimorbidity (≥3 comorbidities).ConclusionAdvanced age, Hispanic race, social isolation, and using a cane or walker in the past month are all associated with an increased risk of dementia progression. The modifiable risk factors—mobility and social isolation—may be of particular clinical significance for at‐risk populations such as elderly patients with MCI. Further research is needed to determine whether altering these risk factors leads to a decrease in dementia progression.