bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic profiling of diverse mouse strains identifies sex‐specific Alzheimer's‐related pathway modifications
Authors: Olayan Rawan , Uyar Asli , Onos Kristen , Howell Gareth , Carter Gregory W. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a heterogenous disease that is associated with complex brain changes and major alterations in gene expression. The analysis of correlated transcriptomic variation can help in understanding the biological mechanisms underlying the disease. Having a comprehensive atlas of changes in human brain transcriptome, as in the Accelerating Medicine’s Partnership for AD (AMP‐AD), enables the use of animal models to validate, assess, and compare such changes. Identifying the optimal animal model can further advance the discovery of the early disease characteristics and development of potential drugs.MethodWe performed comprehensive transcriptome profiling of brains from a panel of early‐onset AD mouse models at 8 months of age, including six distinct genetic backgrounds carrying the same APP/PS1 transgenic construct. We identified co‐expression modules in female and male mice, separately. Then, we associated strains that drive each module. Moreover, we determined which mouse modules overlapped with modules derived from the AMP‐AD transcriptome studies. Finally, we identified the altered pathways in which the mouse strain effects mimic disease effects in human modules.ResultThe majority of mouse modules are driven by strain (independent of APP/PS1 genotype). These modules are significantly overlapped with multiple AD‐related processes in AMP‐AD modules including inflammation, microglia, and neuronal systems. Our results suggested that the altered pathways in mice are sex‐specific, where female mouse strain effects are associated more with immune systems and less with neuronal system than male mouse strain effects.ConclusionWe identified the potential mouse strain effects, in each sex, with the potential AD‐related genes that have similar genetic characteristics to human modules. We believe that using diverse mouse strains to model AD in human can facilitate the discovery of progression pattern of AD.
Evaluating technology‐based reminiscence for engagement and socialization in aged care: Time travelling with technology
Authors: Radnan Madeleine J , Stevens Catherine J , Jones Caroline , Leahy Andrew , Parker Deborah 
Published: December 2020

AbstractBackgroundTechnology offers promise of increased engagement with individuals in aged care. Reminiscence therapy (RT) stimulates discussion of past events and experiences (Woods, et al., 2018). Google Earth and Street View on a large display is readily available technology to support reminiscence. In this study, technology‐enhanced RT is operationalized as dynamic images panning the environment (High‐Tech condition), compared with static images (Low‐Tech/control condition). Behaviour and cognition were appraised pre and post the 6‐week intervention (called Time Travelling with Technology) using the NPI‐NH and discourse interviews to measure communication. If technology‐enhanced RT supports engagement, then NPI and communication scores will not worsen when pre and post intervention scores are compared.MethodParticipants were nine clients (8 female, mean age: 79, range: 72‐90, SD: 6.892) at an aged care day respite facility in Sydney, Australia, with comparable MMSE scores. Using a repeated measures and counterbalanced design, the High‐Tech and Low‐Tech condition each ran for 6 weeks, separated by a 3‐week break. The weekly sessions consisted of groups of 2‐4 clients for approximately 30 minutes. Each session displayed locations of significance to the clients on a flat screen television. Before and after the intervention, NPI‐NH and discourse interviews (Chapman, et al., 2004) were administered.ResultAttendance was consistently high across the program (79%). Comparing pre‐ to post‐intervention, NPI‐NH scores did not worsen in either Low‐Tech (p=0.92) or High‐Tech (p=0.74) conditions. There was no significant effect of intervention or technology on communication scores, ps>0.25. Inter‐rater reliability in scoring discourse interviews was positive and strong, r(7) = 0.95, p < 0.0001.ConclusionThe attendance rate highlights the feasibility and enjoyment of the Time Travelling with Technology program. No deterioration in NPI‐NH or communication across the program supported the hypothesis. While cautious interpretation is needed, these data are encouraging. Data collection from a larger sample for greater statistical power is underway. Further measures of engagement such as facial expressions and language change over time will also be reported.
Peripheral nerve conduction study in early cognitive impairment of Alzheimer's disease
Authors: Qian Xinyi , Xiao Shifu 
Published: December 2020

AbstractBackgroundMild cognitive impairment (MCI) individuals are at a higher risk to develop dementia, especially due to Alzheimer’s disease (AD). Dyskinesia, such as facial expressions, gait and postural changes, retardation and tremor, occurs even before significant clinical symptoms of AD. Besides, elders with central nervous degenerative diseases are more likely to have peripheral neuropathy. However, few studies have been devoted to exploring the relationship between peripheral nerve function and early cognitive impairment. The aim of this study was to compare MCI individuals with the normal population for peripheral nerve conduction, and to assess its relationship with cognitive function in elderly population living in Shanghai.Method74 MCI and 82 healthy controls (HC) underwent a peripheral nerve conduction examination and a neuropsychological evaluation. In order to minimized the effect of somatic diseases on peripheral nerve function, all the participants had no diabetes, thyroid dysfunction, Parkinson's disease and peripheral neuropathy. Nicolet EDX was used to assess peripheral nerve conduction of upper and lower limb, including median and sural sensory and median and peroneal motor nerve action potential amplitudes and velocities. Then we compared the peripheral nerve conduction results between two different cognitive groups. Furthermore, we also investigated the relationship between the peripheral nerve conduction and cognitive function.ResultBetween the two groups, MCI was older than HC (70.36±7.38 vs 68.04±6.27, p=0.07) although there was no significant difference. MCI group had less years of education (10.05±3.58 vs 11.45±2.57, p=0.009) and more depressive symptoms (3.65±4.37 vs 2.70±4.17, p=0.044), but no difference was found in gender. Median and peroneal motor nerve velocities were found slower in MCI group compared to HC group (54.51±4.18 vs 47.13±5.90, p=0.011; 56.36±4.72 vs 49.29±5.65, p=0.023). Both median (p=0.005) and peroneal (p=0.003) motor nerve velocities were correlated with MoCA. Furthermore, linear regression revealed that, after taking age, gender, education, depression and body mass index (BMI) into account as covariates, median motor nerve velocity was associated with MoCA (p=0.019).ConclusionOur study found that peripheral motor nerve velocity may be correlated with early cognitive impairment of AD, suggesting a new, possible research direction of early identification markers for AD.
Research‐based evaluation of a dementia support program: An analysis of input from 1164 participants
Authors: Tam Mallorie T , Robillard Julie 
Published: December 2020

AbstractBackgroundCommunity support programs can improve quality of life for people living with dementia and their caregivers. Support programs act as a gateway to autonomy, empowering people living with dementia to be more involved with their own care and decreasing the burden of caregivers. Important to the successful implementation of such programs is an evaluation process that allows for ongoing improvements to meet the needs of users. The goals of this study were to conduct a research‐based program evaluation of the First Link® dementia support program provided by the Alzheimer Society of British Columbia (the Society) to identify strengths and areas for improvement to better serve B.C. and to develop a methodological blueprint for the evaluation of similar programs around the world.MethodPeople living with dementia, caregivers, and healthcare providers (HCPs) who access and do not access the First Link® dementia support services were recruited from the Society, community venues, and through social media. Participants completed an online survey about their experience with the First Link® program.ResultA total of 1164 participants completed the survey (889 caregiver, 198 HCPs, 77 people living with dementia). The overall experience of the program was positive for people living with dementia and caregivers (78%). Possible areas for improvement included promoting social interactions (70%), supporting physical health (72%), and reducing stress for persons living dementia (58%) and overall burden for caregivers (57%).Healthcare providers were overall satisfied with the program (91%): many found the referral process easy (98%) and were able to access information about the program to share with their clients (94%).Strengths of the survey included its broad reach, the ability to quantify the impact of the program and the identification of specific areas for improvement. Limitations included challenges in interpreting the data in relation to the services offered, and lack of depth. A second phase of the program evaluation will harness qualitative interviews to address these limitations.ConclusionThis study will inform future research on their methodologies in program evaluations as well as improve the existing services to support people living with and impacted by dementia.
Machine‐learning‐based Alzheimer's disease dementia score using structural MRI neurodegeneration patterns: Independent validation on ADNI, AIBL, OASIS and MIRIAD
Authors: Popuri Karteek , Ma Da , Wang Lei , Beg Mirza Faisal 
Published: December 2020

AbstractBackgroundBiomarkers for dementia of Alzheimer's type (DAT) are sought to facilitate accurate prediction of the disease onset, ideally predating the onset of cognitive deterioration. T1‐weighted magnetic resonance imaging (MRI) is a commonly used neuroimaging modality for measuring brain structure in‐vivo, potentially providing information enabling the design of biomarkers for DAT.MethodWe propose a novel biomarker using structural MRI volume‐based features to compute a similarity score for the individual's structural patterns relative to those observed in the DAT group. We employed ensemble learning framework that combines structural features in most discriminative ROIs to create an aggregate measure of neurodegeneration in the brain. This classifier is trained on 423 stable normal control (NC) and 330 DAT subjects, where clinical diagnosis is likely to have the highest certainty, and then validated on several independent datasets for subjects at various stages along the longitudinal trajectory from NC to DAT.ResultIndependent validation on 8834 un‐seen images from ADNI, AIBL, OASIS, MIRIAD Alzheimer's disease (AD) databases showed promising potential to predict the development of DAT depending on the time‐to‐conversion (TTC). Classification performance on stable versus progressive mild cognitive impairment (MCI) groups achieved an AUC of 0.81 for TTC of 6 months, and 0.73 for TTC of up to 7 years, achieving the state‐of‐the‐art results.ConclusionWe propose and validate a novel ensemble‐learning based biomarker score based on 3D topographic patterns of MRI‐observed structural volumetric features. The output score, indicating similarity to patterns seen in DAT, provides an intuitive measure of how closely the individual's brain features resemble the DAT group. This score can be used for assessing the presence of AD structural atrophy patterns in normal aging and MCI stages, as well as monitoring the progression of the individual's brain along the disease course.
Associations between lower systolic blood pressure threshold, Alzheimer’s disease and vascular dementia among very old adults
Authors: Park Christina , Hajat Anjum , Leary Cindy S , Adam Claire , Semmens Erin O , Kaufman Joel D , Fitzpatrick Annette L 
Published: December 2020

AbstractBackgroundIncreasing evidence supports the contribution of hypertension to the risk of Alzheimer’s disease (AD) and vascular dementia (VaD). The objective of this paper is to examine whether the risk of AD and VaD is associated with a lower threshold of systolic blood pressure (SBP) than the traditional level of ≥140 mmHg.MethodsUsing data from the Ginkgo Evaluation of Memory Study (GEMS), we obtained baseline SBP measurements from 3,068 participants who were dementia‐free at enrollment. Cognition was evaluated every 6 months over 8 years; dementia and its subtypes were adjudicated by a panel of neurologists. Cutoff values for continuous SBP were estimated by the maximum Youden index (sensitivity + specificity ‐ 1) for AD (without VaD) and VaD (with or without AD). The performance of the estimated SBP cutoff values was compared with the traditional SBP threshold of 140 mmHg using the area under the receiver operating characteristic curve (AUC). Based on the estimated cutoffs, we dichotomized SBP, created Kaplan‐Meier survival curves, and calculated hazard ratios (HRs) for AD and VaD incidence using Cox proportional hazards models, adjusted for age, gender, race, education and baseline depression.ResultsThe mean (± SD) age of participants was 78.6 (± 3.3) years and 46% were female. According to the Youden index, the optimal SBP cutoff values for capturing AD and VaD were 122 (sensitivity: 74.2%; specificity: 27.6%) and 131 mmHg (sensitivity: 67.3%; specificity: 47.6%), respectively. Although these estimates for SBP cutoffs were not significantly different from AUC estimates for the traditional cutoff, a greater risk of VaD at the optimized threshold (131 mmHg) was found (Figure 1, Kaplan‐Meier analysis and log‐rank test P <0.001). Using Cox models, we found that SBP ≥131 mmHg was associated with a 70% increased risk of VaD (HR:1.71, 95% CI:1.21, 2.43; P = 0.002). We did not observe an association between SBP cutoff of 122 and AD incidence.ConclusionA lower SBP threshold was identified in relation to risk of VaD while associations with AD were inconclusive. Further study is needed to evaluate the accuracy of lower SBP cutoff values in identifying AD and VaD in other populations.
Tauopathy in autosomal dominant and late‐onset Alzheimer disease
Authors: Chen Charles , Holden Timothy R. , Gordon Brian A. , Franklin Erin E. , Perrin Richard J. , Morris John C. , Bateman Randall J. , Benzinger Tammie L.S. , Cairns Nigel J. ,   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2020

AbstractBackgroundTau PET imaging suggests greater tau pathology in autosomal dominant (ADAD) versus late‐onset Alzheimer disease (LOAD). However, this has not been validated with neuropathology. We studied how ADAD and LOAD differ in neurofibrillary tangle (NFT), neuropil thread (NT), and neuritic plaque (NP) distribution, and compared with 18F‐flortaucipir imaging.MethodIndividuals enrolled at the Knight Alzheimer Disease Research Center (n=10) and the Dominantly Inherited Alzheimer Network (DIAN, n=7) came to autopsy (Table 1). Histology was performed by DIAN Neuropathology Core protocols (Cairns et al., 2015). The burden of tauopathy (NFT, NP, and NT) was determined with PHF‐1 immunostaining from frontal (FL), temporal (TL), parietal (PL), and occipital lobes (OL), parahippocampal gyrus (PHG), and CA1 hippocampal subfield, assessed stereologically using the Area Fraction Fractionator (MBF Bioscience). 18F‐flortaucipir imaging was performed in the same cohorts, but different individuals (LOAD, n=35, ADAD, n=14), and regional SUVRs were calculated by in‐house pipelines (Su et al., 2013).ResultNFT burden and regional SUVRs vary significantly both within and across cohorts. NFT burden was significantly elevated in ADAD versus LOAD in non‐temporal regions (FL/PL/OL); regional SUVRs mostly recapitulate this pattern (Figure 1). Within cohort, NFT burden and regional SUVRs follow similar rank order, except medial temporal lobe regions (CA1/PHG). NP burden did not vary significantly within or across cohorts (Figure 2). NT burden did not vary significantly within cohort, but was significantly elevated across most regions (FL/TL/PL/OL/PHG). Mean NP/NT burden show greater magnitude differences across cohorts than NFT burden and regional SUVRs (Figure 3).ConclusionOverall, there was concordance between NFT burden and 18F‐flortaucipir imaging of elevated tauopathy in ADAD versus LOAD. Exceptions involved hippocampal regions; likely due to confounds from off‐target binding in imaging. NT burden was significantly elevated across most regions and on average showed the greatest magnitude differences across cohorts, suggesting significant, previously underappreciated differences between ADAD and LOAD not captured by neuropathologic NFT burden and tau PET imaging. These differences could arise from differing causes of disease between sporadic versus mutation, age of onset, or both, and quantifying subtypes of tauopathy progression in both cohorts presents an interesting future direction.
Human MAPT knock‐in mice that harbor familial tauopathy‐causing mutations
Authors: Watamura Naoto 
Published: December 2020

AbstractBackgroundTauopathy is characterized by the accumulation of pathological tau in brain. In order to clarify the disease mechanisms, we aimed to develop mouse models that reproducibly display specific tau pathology without artifacts because the current tauopathy models depend on the overexpression paradigm. The purpose of this study is to develop new tauopathy mouse models by knock‐in strategy.MethodPreviously we generated human MAPT knock‐in (hTau‐KI) mice, in which the entire Mapt gene was humanized. The hTau‐KI mice express all six isoforms (Hashimoto et al., 2019; Saito et al., 2019). In this study, several tauopathy‐causing mutations were introduced into hTau‐KI mice by Base Editor, a novel CRISPR/Cas9‐based genome editing technology.ResultWe obtained several tauopathy mouse models (hTau‐KIP301L, hTau‐KIP301S, hTau‐KIP301V, hTau‐KIIntron10+3 G>A, hTau‐KIP301L; Intron10+3 G>A, hTau‐KIP301S; Intron10+3 G>A, hTau‐KIS305N; Intron10+3 G>A). Immunohistchmical analysis showed phospho‐tau positive signals in the entorhinal cortex in some of these lines. In addition, Biochemical analysis demonstrated that the Intronic mutation altered the expression patterns of 3‐ and 4‐ repeat tau.ConclusionWe successfully introduced tauopathy‐causing mutations in hTau‐KI mice. Also, we detected the effect of mutations on MAPT gene in hTau‐KI mice. We expect these models to contribute to elucidating the mechanism of tauopathies and plan to make them available to the research community worldwide.
The clinical characteristics of cognitive impairment in patients with vascular mild cognitive impairment
Authors: Yuan Junliang 
Published: December 2020

AbstractBackgroundTo investigate the characteristics of the cognitive impairment in patients with vascular mild cognitive impairment (VaMCI).MethodSeventy‐five patients with VaMCI and 38 age, gender‐matched healthy subjects were recruited from the department of Neurology, Beijing Chaoyang Hospital, Capital Medical University. All the participant underwent the neuropsychological tests. The Fazekas scale was used to assess the severity of white matter lesions, and the medial temporal lobe atrophy (MTA) to evaluate the atrophic severity of medial temporal lobe.ResultThe results of our study showed that patients with VaMCI were associated with comprehensive cognitive function deficits, including MMSE (25.7±2.3 vs 28.4±2.0) MoCA (22.8±3.9 vs 26.3±3.7), AVLD‐I (5.1±1.0 vs 8.9±1.9), AVLT‐D (3.7±1.0 vs 9.8±1.5) and AVLT‐R (7.6±1.9 vs 12±1.5) (P<0.05). Correlation analysis showed that the scale of medial temporal lobe atrophy had a negative relationship with the performance of MoCA (r=‐0.434, P=0.002).ConclusionOur findings demonstrate patients with VaMCI were closely correlated to cognitive impairment, especially with memory decline, which may be attributed to white matter lesions and the atrophy of medial temporal lobe.
Blood‐based cardiac biomarkers and the risk of cognitive decline, vascular events and mortality
Authors: Gyanwali Bibek , Liu Benedict , Lai Mitchell KP , Richards Arthur Mark , Chen Christopher , Hilal Saima 
Published: December 2020

AbstractBackgroundVascular pathology plays an important role in the development of cognitive decline, stroke and mortality. In this context, amino terminal pro‐brain natriuretic peptide (NTpro‐BNP), high sensitivity cardiac troponin T (hs‐cTnT) and growth differentiation factor‐15 (GDF‐15) have been proposed as important biomarkers of early vascular pathology due to their up‐regulation in inflammatory and trophic responses during tissue injury. However, little is known on the longitudinal effects of these cardiac biomarkers and their potential clinical implications. We examine the association of blood‐based cardiac biomarkers (NTpro‐BNP, hs‐cTnT and GDF‐15) with cognitive decline and risk of vascular events and mortality in a memory clinic study.MethodA total of 414 (mean age:72.7± 9.1years, 56% women) patients with blood samples, neuropsychological assessment (baseline and at least two neuropsychological assessments obtained a minimum of one year apart), 3T neuroimaging and detailed clinical assessment were recruited. NTpro‐BNP and hs‐cTnT concentrations were measured by electrochemiluminescence immunoassay and GDF‐15 by quantitative sandwich immunoassay technique. Data on incident clinical outcomes and mortality were obtained until June 2018.ResultPatients with higher levels of NTpro‐BNP, hs‐cTnT and GDF‐15 showed a greater decline in memory domain per year with a stronger decline observed for hs‐cTnT (p for interaction, <0.001) followed by NTpro‐BNP (p for interaction, 0.001) and GDF‐15 (p for interaction, 0.006). Additionally, hs‐cTnT was associated with accelerated decline in global cognition, executive function and visuomotor speed. During a mean follow‐up of 3 years, 26 (6.2%) patients died and 43 (10.4%) developed vascular events (heart disease and stroke). Patients with higher levels of NTpro‐BNP and hs‐cTnT were at increased risk of vascular events (OR for NTpro‐BNP:2.40, 95%CI: 1.15‐4.98 and OR for hs‐cTnT:5.59, 95%CI: 1.38‐22.72) whereas those with higher levels of NTpro‐BNP and GDF‐15 were at risk of mortality (OR for NTpro‐BNP: 4.48, 95%CI:1.59‐12.58 and OR for GDF‐15: 44.27, 95%CI:5.36‐363.46).ConclusionWe showed that the higher levels of blood‐based cardiac biomarkers were associated with worse decline in memory. This suggests that cardiac biomarkers may be useful indicators of vascular brain damage and to identify patients at risk of adverse vascular events and death and could warrant consideration of treatment trials.