bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of traumatic brain injury with late life neuropathological outcomes in a community‐based cohort
Authors: Gibbons Laura E , Power Melinda C , Walker Rod L , Kumar Raj G , Murphy Alia , Latimer Caitlin S , Melief Erica J , Beller Allison E , Keene C Dirk , Larson Eric B , Crane Paul K , Dams‐O'Connor Kristen 
Published: December 2020

AbstractBackgroundDespite extensive interest in risk for dementia following traumatic brain injury (TBI), there is scant research on neuropathological outcomes among community‐dwelling elders with TBI exposure. We previously reported an association of TBI resulting in loss of consciousness (LOC) with microinfarcts and Lewy body pathology, but TBI exposure data were limited to a single self‐report question. With expanded ascertainment data from medical records and structured interview on lifetime TBI exposure, we conducted a comprehensive investigation of neuropathological associations of TBI in a large autopsy cohort.Method780 older adults from the Adult Changes in Thought (ACT) study underwent brain autopsy (Table 1). Participants were members of Kaiser Permanente Washington who completed biennial clinic visits including self‐reported head trauma with LOC exposure. These data were supplemented with medical record abstraction, and, for 244 people, with structured interviews, increasing the sensitivity for TBI‐LOC in that sample from 16% to 20% (see Figure 1). Neuropathology outcomes included neurofibrillary tangle distribution (Braak), neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral cortical atrophy. Exposures of interest included TBI with or without LOC. We used Poisson regressions with robust standard errors adjusted for age, sex, education, and APOε4 genotype, weighted back to the full cohort (n=5546; Table 2) in a bootstrapping procedure accounting for errors in estimating weights.ResultTBI with LOC was associated with increased cortical atrophy (Table 3). In those with the structured interview (including TBI without LOC), the neuropathological associations of TBI were attenuated; no outcomes were statistically significant (Table 4). These findings apply to the full ACT cohort, not just people with TBI data in the autopsy sample.ConclusionCerebral cortical atrophy results from chronic brain parenchymal injury, potentially including vascular brain injury and tauopathy. Understanding mechanisms underlying associations of TBI with microvascular brain injury and pathological tau are poorly understood; future studies deploying new techniques to better quantify these lesions and differentiate between TBI‐related, age‐related, and ADRD‐related pathways are needed.
Potential for primary prevention of dementia in low‐ and middle‐income countries: A cross‐sectional analysis of population attributable risk of dementia using twelve modifiable factors in population surveys of aging
Authors: de Langavant Laurent Cleret , Bayen Eleonore , Bachoud‐Levi Anne‐Catherine , Yaffe Kristine 
Published: December 2020

AbstractBackgroundThe World Health Organization recently assessed twelve modifiable risk factors that could be targeted to prevent future dementia but did not find sufficient evidence for recommending prevention programs for each of them. Several groups estimated the population attributable risk of dementia for seven to nine of these risk factors and suggested that one third of dementia cases could be prevented worldwide (Barnes & Yaffe, 2011; Norton, 2013). This proportion of avoidable dementias might be even higher in low‐ and middle‐income countries (LMIC) based on 10/66 data surveys (Mukadam, 2019). Our goal is to expand this research in ten population‐based surveys of aging on four continents using twelve modifiable risk factors.MethodWe previously identified probable dementia cases based on unsupervised machine learning (Cleret de Langavant, 2018, AAIC 2019, and submitted) in the following studies from LMIC: MHAS (Mexico, 2015), ELSI (Brazil, 2016), CHARLS (China, 2015), IFLS (Indonesia, 2015), LASI (India, 2016), SAGE‐Ghana wave 1 (2007), SAGE‐South Africa (2007), SAGE‐Russia (2007) and from high income countries (HIC): HRS (USA, 2014) and SHARE (Europe and Israel, 2015). In the different cohorts, we first estimate the communality between twelve risk factors (when available): hypertension, diabetes, dyslipidemia, low education, low physical activity, social isolation, depression, poor diet, smoking, alcohol abuse, unhealthy weight gain and hearing loss. We calculate the overall weighted population attributable risk of dementia to estimate avoidable dementia proportion in each cohort. We then compute the individual weighted population attributable risk of dementia for each factor in each cohort to identify the most important targets for dementia prevention.ResultOur preliminary results suggest that the population attributable risk of dementia vary according to the country of origin of the cohort. According to our approach, the proportion of avoidable dementias might be higher than expected in HIC, and much higher in LMIC compared to HIC. We will present an overview of the most important risk factors of dementia in each cohort.ConclusionOur investigation confirms a huge potential for primary prevention of dementia in both HIC and LMIC. Health policy makers should adapt their prevention efforts according to country specificities.
PIN1 is an indicator of age‐ and sex‐associated risk of mild cognitive impairment and subsequent Alzheimer’s disease
Authors: Mastroeni Diego F. 
Published: December 2020

AbstractBackgroundWomen have a higher incidence of Alzheimer’s disease (AD) than men, even after correction for the greater longevity of women. It is also known that AD on the maternal side increases risk for offspring more than does AD on the paternal side. Considerations such as these have led to intense interest in potential molecular differences between the male and female brain, with special emphasis on aging in many studies. Thus, there is an urgent need to identify molecules that identify gender risk early in disease. Excessive post‐translational modifications (e.g. phosphorylation) are known early events in AD. Phosphorylation events are critical intermediates of “normal” protein function, but excessive phosphorylation (e.g. hyperphosphorylation) is unfavorable. Hyperphosphorylation of tau and amyloid triggers the formation of neurofibrillary tangles (NFTs) and toxic Aβ aggregates, both of which have been descried as classical hallmarks of AD. Recent efforts have identified the peptidyl‐prolyl cis/transisomerase (Pin1) as a key regulator of the phosphorylation signaling pathway.MethodHere, we demonstrate using Laser Capture micro‐dissection, Affy‐Microarray, RNA sequencing and 450K methylation array that Pin1 is significantly down‐regulated as a function of age (22yrs‐99yrs) and AD, and up‐regulated in MCI limbic and neocortical brain regions.ResultsAnalysis revealed a significant sex and aging effect. In order to confirm, further analysis in a larger AD and matched control cohort (630 patients) from the Religious Orders Study and Memory and Aging Project (ROSMAP) study revealed that the significant decreases in Pin1 levels in AD are wholly driven by female subjects.ConclusionThese results set the stage for the development of therapeutic strategies to target Pin1 in females in preclinical AD as a method of preventing, and monitoring the progression of healthy aging to AD.
Impact of video decision aids for caregivers of people with young‐onset dementia
Authors: Brandt Katie , Quimby Megan , Quintiliani Lisa M , Wong Bonnie , Paasche‐Orlow Michael K , Krahn Erin , Krivensky Samantha , O’Chander Raseeka , Volandes Angelo , Dickerson Brad C 
Published: December 2020

AbstractBackgroundYoung‐onset (age < 65) dementias, especially the Frontotemporal Dementia spectrum of diseases and young‐onset Alzheimer’s disease, are often rapidly progressive and have unique caregiving demands. Educational tools for caregivers often are inconsistent and may not adequately help people envision future challenges . The study objective is to examine the acceptability of video decision aids for caregivers of people with young‐onset dementia.MethodWe conducted focus groups of caregivers for people with young‐onset dementia, separated by early, moderate, and late stage. Eleven video decision aids total (six per group), each focused on a caregiving topic, were shown. After each video, participants answered six questions about acceptability and then responded to open‐ended questions to explain their ratings. Descriptive statistics were calculated, and themes were summarized.ResultFour focus groups have been completed (n=8, 4 mild, 4 moderate). On a scale of 1 (strongly disagree) to 5 (strongly agree), the mean (SD) ratings were 3.4 (0.43) for learning something new, 2.1 (0.65) for made me feel uncomfortable, 3.7 (0.35) for made me want to learn more, 4.2 (0.58) for how much already knew about this topic, 4.1 (0.42) for important to learn more, 4.4 (0.36) for recommend to others. Videos about talking to your loved one about not driving, choosing a skilled nursing facility, goals of care in advanced dementia, and thinking about medical decisions had the most positive mean ratings. Caregivers reported preferring visual images that match their loved one’s age group, wanting access to information earlier, and preferring to receive access to videos from their healthcare provider. While similar overall, caregivers in the moderate stage reported learning more from an introduction to caregiving video (moderate M=3.25; mild M=2) and more discomfort for the video about stopping driving (moderate M=2.75; mild M=1.75) compared to caregivers in the mild stage.ConclusionVideo decision aids may be an acceptable way to convey information about the unique caregiving demands of those caring for loved ones with young‐onset dementia. Empowering caregivers with information about anticipated medical decisions may reduce caregiver burden and stress, allowing for higher quality of care for loved ones.
The electronic person‐specific outcome measure (ePSOM) development programme: Overall approach
Authors: Saunders Stina , Terrera Graciela Muniz , Evans Alison , Sheehan Shane , Luz Saturnino , Ritchie Craig W. 
Published: December 2020

AbstractBackgroundThe ePSOM development programme is a collaboration between the University of Edinburgh and Alzheimer’s Research UK prompted by the recognition that outcome measures currently used in clinical trials in prodromal and preclinical neurodegenerative diseases do not capture the research participants’ views of effectiveness. A better understanding of earlier manifestations of Alzheimer’s disease and the drive for relevant outcome measures, allied to technological advances in artificial intelligence, have mediated the electronic Person‐Specific Outcome Measure (ePSOM) development programme. The group took the view that ‘maintenance of brain health’ as opposed to ‘avoidance of symptoms’ would form the underpinning narrative in the ePSOM programme and ultimately app design.MethodThere are 4 sequential stages in the ePSOM programme (the first three completed): (1) literature review, (2) focus group study, (3) national survey, and (4) development of an app for capturing person‐specific outcomes. The survey data was analysed using clustering and natural language programming techniques and the results are presented separately. Here, we report the overall approach to the ePSOM programme.ResultOur literature review on patient‐reported outcome measures in the Alzheimer’s disease population showed trials currently do not use any patient‐reported outcome measures. Our focus groups with people living with memory problems; healthy volunteers and health care professionals (n=41) yielded five key domains in relation to what matters to people when developing new treatments for Alzheimer’s disease: Everyday Functioning; Relationships and Social Connections; Enjoying Life; Sense of Identity; and Alleviating Symptoms. Our online survey, which was created based on the literature review and focus groups, was completed by 5807 individuals. 30 clusters of themes emerged from the survey responses.ConclusionThe ePSOM development programme is building evidence in order to deliver the methodology for incorporating personally meaningful outcome measures in Alzheimer’s disease clinical trials. The completed three stages will underpin the ePSOM app, which will be using natural language processing methodologies, and have good psychometric properties enabling the app to be use in regulatory trials.
Viewing some people living with dementia through a lens of complicated grief
Authors: Ione Adrienne 
Published: December 2020

AbstractBackgroundThe concept of human flourishing holds tremendous global value for policy makers and individuals alike, and in no just society should people living with dementia be excluded. Rather than promoting what is commonly discussed as the most disturbing sequala of neurological disorders and related dementias, a few researchers have flipped BPSD (e.g., agitation, ruminating, pacing, etc.) on its head, arguing that these are expressions of agency (Boyle, 2014; Orulv, 2012; Finkle, 2000 and Kales et al., 2015). Regulation of BPSD needs to be relegated to the background, reframed as a form of agency, and therapeutic techniques aimed at increasing flourishing brought into the foreground (Ryan et al., 2013). One challenge with developing a coherent and systematic therapeutic approach for people living with dementia is determining individual needs (Smith et al., 2013). A view of BPSD, expanding on the notion of exercising one’s agency, is the human need for an attachment figure (Walsh et al., 2019). It has long been established that complicated grief leads to negative overall health and life quality consequences (Prigerson et al., 2008). Grounded in attachment theory, Complicated Grief Treatment (CGT) (Shear et al., 2014), one of the only evidence‐based techniques that has been applied to older adults, holds promise for bridging attachment gaps (Meichsner, 2020).MethodActive Capabilities Therapy (ACT), an exploratory, non‐judgmental, integrative, person‐centered approach used to increase flourishing among people living with dementia, incorporates CGT principles.ResultThe 5‐item brief grief questionnaire (BGQ) is used to assess prolonged grief and is included in the intake assessment of people receiving ACT (Shear and Essock, 2002). The BGQ was used as an interview instrument throughout therapy sessions to measure change in grief. To maintain consistency in the evaluation cycle of CGT component of ACT, data were collected through an unbiased random selection of 6 time points, over 3 years of data collection, from a single case study.ConclusionThe efficacy of CGT in people living with dementia, was evidenced by a continued point improvement on the Inventory of Complicated Grief (Prigerson et al., 1995) as well as decreased severity of items listed on NPI‐Q (Cummings, 1994).
Natural genetic variation alters Alzheimer’s‐related gene expression modules in mice
Authors: Wells Ann E. , Raghupathy Narayanan , Robledo Raymond F. , Gatti Daniel M. , Munger Steven C. , Phillips Charles , Ndukum Juliet , Wilcox Troy , Graber Joel , Hibbs Matthew , Langston Michael A. , Churchill Gary A. , Carter Gregory W. , Chesler Elissa J 
Published: December 2020

AbstractBackgroundUnderstanding the genetics of Alzheimer’s disease (AD) has proven difficult in human populations. Using mouse models enables researchers to dissect the genetics of AD‐related pathways. The Diversity Outbred (DO) mice are a heterogenous multi‐parental population created using eight founder strains, mimicking human population structure. The DO provide a new resource to investigate complex diseases, such as AD. Comparing the genetics of individuals with AD to DO mice will enable us to identify AD‐related pathways in mice that can be dissected to better understand AD.MethodGenes identified in the hippocampus of 258 male and female DO mice were grouped into 145 paracliques, unique clusters of correlated genes that are closely related. Paracliques were compared with 30 human gene modules related to AD from the Accelerating Medicines Partnership for Alzheimer’s disease (AMP‐AD). Gene content overlaps were calculated between the AMP‐AD modules and DO paracliques by Jaccard index. Additionally, we mapped and characterized quantitative trait loci (QTL) to determine if summary eigengenes from each paraclique were associated with genetic factors. Both SNP associations and database searches were performed to identify potential genes of interest within the QTL. Paracliques and DO genes identified for significant QTL were compared to the AMP‐AD modules and AGORA to determine their relevance to AD.ResultSignificant QTL were identified for paraclique 56 on chromosome 16. IL6ST, a nominated target in AGORA, was identified within paraclique 56. Additionally, KALRN, a gene that plays a role in decreased anxiety‐related behavior, contextual conditioning, and synapse formation, was identified within the QTL for paraclique 56. KALRN was a member of the AMP‐AD neuronal modules. Furthermore, variants in KALRN were identified in brain eQTL from Alzheimer’s study cohorts and determined to be a candidate gene in AGORA, adding to its potential relevance. Mediation analysis revealed that KALRN is potentially locally regulated by ROGDI. A loss‐of‐function mutation in ROGDI results in Kohlschutter‐Tonz syndrome, which can result in dementia as a symptom.ConclusionThis study identified potential candidate genes in DO mice that have relevance to AD. In sum, this study showcases the potential of utilizing DO mice to translationally investigate AD‐related pathways.
Dementia with Lewy bodies: A differential diagnosis of normal pressure hydrocephalus
Authors: Durand Hélène , Baloglu Seyyid , Bilger Mathias , Ollivier Irène , Cretin Benjamin , Anheim Mathieu , Proust François , Blanc Frédéric , Philippi Nathalie 
Published: December 2020

AbstractBackgroundThe diagnosis of idiopathic normal pressure hydrocephalus (NPH) is challenging and remains overestimated because of the absence of specific clinical, imaging or biological features. It relies on association of classical triad of symptoms (gait disturbance, cognition impairment, urinary symptoms) associated to a ventricular enlargement. Several differential diagnoses should be considered with an initial presentation suggestive of NPH, such as dementia with Lewy bodies (DLB), Alzheimer disease (AD) and vascular dementia (VD). The aim of this study was to identify NPH differential diagnosis as well as to highlight clinical and radiological features that could help questioning this diagnosis, before performing invasive procedures.MethodIn this monocentric retrospective study, we included 42 patients fulfilling the criteria of possible NPH on initial presentation. At the end of the follow‐up, we classified the sample into patients with probable NPH (NPH group ; n = 13), differential diagnosis of NPH (NPH‐ group; n = 21) and dual pathology with criteria of probable NPH (NPH+; n = 8), depending on their outcome after cerebrospinal fluid (CSF) drainage. We collected clinical data, including results of cognitive assessment, as well as results of CSF biomarkers, EEG, functional and morphological neuroimaging. Ventricular enlargement profile was analyzed using different visual measures on MRI.ResultThe main differential diagnosis of NPH was DLB (21/21), mixed with vascular dementia in four cases. None of the patient had a CSF profile suggestive of AD. Regarding clinical features, asymmetric parkinsonism, fluctuations, agitation during sleep, visual hallucinations and visuospatial impairment were significantly more frequent in NPH‐ patients, compared to NPH patients (p=0.033). The callosal angle was significantly more acute (<104° ; p <0.01) and fourth ventricular dilatation greater (>17 mm ; p<0.01) in NPH patients than in NPH‐ patients, while there was no significant difference in the dilatation of lateral ventricles and third ventricle.ConclusionDLB appeared as the main differential diagnosis of NPH. Our results indicate that the existence of asymmetric parkinsonism, fluctuations, agitation during sleep, visual hallucinations or visuospatial impairment, as well as the absence of acute callosal angle or fourth ventricular dilatation should lead to consider DLB as a differential diagnosis of NPH.
Reflective pondering is associated with a global cognitive marker of Alzheimer’s disease risk
Authors: Demnitz‐King Harriet , Whitfield Tim , Schlosser Marco , Barnhofer Thorsten , Collette Fabienne , Klimecki Olga , Lutz Antoine , Schild Ann‐Katrin , Wirth Miranka , Chetelat Gael , Marchant Natalie L , Group Medit‐Ageing Research 
Published: December 2020

AbstractBackgroundReflective pondering is an introspective mechanism conceptualised as actively seeking a solution to one’s problems. Literature has consistently demonstrated positive associations between reflective pondering and improved mental health outcomes in clinical populations. Given that poor mental health (e.g. depression, anxiety) has been associated with increased dementia risk, and that reflective pondering improves mental health, we asked whether reflective pondering could also act as a protective factor against dementia, measured by cognitive function, in older adults.MethodBaseline data from 145 older adults with subjective cognitive decline (SCD; mean age = 72.2) from the SCD‐Well clinical trial and 135 healthy older adults (mean age = 70.5) from the Age‐Well clinical trial were included in this study. All participants completed the reflective pondering subscale of the Rumination Response Scale and a modified version of the Preclinical Alzheimer’s Cognitive Composite (PACC; Donohue et al., 2014). Linear regressions were run to determine the association between reflective pondering and PACC scores in each cohort independently. Analyses controlled for available prognostic characteristics known to be associated with Alzheimer’s disease (e.g. age, sex, education, depressive symptoms and APOE genotype).ResultIn SCD‐Well reflective pondering was positively associated with PACC scores after controlling for age, sex, education and depressive symptoms (β = 0.05, p <.01), with higher levels of reflective pondering associated with better cognition. Similarly, in Age‐Well reflective pondering was also positively associated with PACC scores (β = 0.04, p = .03) aftercontrolling for age, sex, education, depressive symptoms and APOE genotype.ConclusionIn two independent cohorts that included healthy older adults and individuals with SCD, levels of reflective pondering were positively associated with a global cognitive marker of Alzheimer’s risk. Our results introduce preliminary support for reflective pondering as a protective factor for cognitive function. Both SCD‐Well and Age‐Well are clinical trials, thus future work will evaluate the association between changes in reflective pondering due to intervention and cognitive function.