bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the feasibility and acceptability of a comprehensive resilience‐building psychosocial intervention (CREST) for people with dementia in the community: A non‐randomised feasibility study
Authors: Doyle Priscilla A , Gallagher Niamh , Smyth Siobhán , Casey Dympna 
Published: December 2020

AbstractBackgroundA dementia diagnosis can prevent people from participating in society, leading to a further decline in cognitive, social and physical health. However, it may be possible for people with dementia to continue to live meaningful lives and continue to participate actively in society if a supportive psychosocial environment exists. This feasibility study seeks to create such an environment by determining the feasibility of conducting a multifaceted complex resilience‐building psychosocial intervention for people with dementia and their caregivers living in the community.MethodTen participants with dementia and their primary caregivers living in the community were recruited and received the CREST intervention. The intervention provided (a) a 7‐week cognitive stimulation programme (CST) followed by an 8‐week physical exercise programme for people with dementia and (b) a 6‐week educational programme for caregivers. Members of the wider community were invited to a dementia awareness programme and GP practices to a dementia‐training workshop. Trained professionals delivered all intervention components. Outcomes assessed the feasibility and acceptability of all study processes such as: recruitment; intervention content and delivery; and data collection methods.ResultRecruiting participants was difficult, with local community organisations/groups proving more successful than GP practices. Preliminary results indicate that participants (people with dementia and carers) enjoyed the content of the CREST intervention, that the delivery method and timing worked well and overall they found the programme beneficial. Carers reported that the educational programme provided them with valuable information which was accessible and easy to understand. However, the group activities and learning from each other was identified as crucial to their enjoyment and learning. The people with dementia likewise enjoyed the CST and exercise components, some reporting that the CST enhanced their concentration and that exercising with an exercise buddy was more sociable and enjoyable.ConclusionThe evidence from participants indicates that CREST is feasible and acceptable to carers and people with dementia in the community.
Hippocampal metabolism and memory impairment in diet‐induced insulin‐resistant mice are reversed by diet normalization
Authors: Garcia‐Serrano Alba M. , Duarte Joao M.N. 
Published: December 2020

AbstractBackgroundEpidemiological evidence suggests that obesity and type 2 diabetes (T2D) increase the risk for dementia. Brain metabolic dysfunction plays a role in obesity and T2D‐induced memory impairments. We aimed at investigating the potential for reversibility of metabolic alterations in the hippocampus and cortex, as well as memory performance in mice fed a high‐fat and high‐sucrose diet (HFHSD) that develop a metabolic syndrome with insulin resistance, progressing to T2D.MethodAge matched control mice were fed a control diet with 10% fat (CD). Diabetic mice were exposed to HFHSD (60%‐fat in chow, plus 20% sucrose in drinking water) for 6 months. A group of mice was fed the same diet for 4 months, followed by a dietary switch to the 10%‐fat diet for 2 months (RD). Metabolic profiles of the hippocampus and cortex were measured longitudinally by magnetic resonance spectroscopy (MRS) at 9.4T before dietary interventions, and after 4 and 6 months. Glucose tolerance tests were performed at the same time points. Memory performance was assessed at the end of the study through an object relocation and novel object recognition tasks.ResultHFHSD‐fed mice developed overweight, glucose intolerance and insulin resistance, which recovered to control values upon diet reversing (all P<0.01 for RD vs. HFHSD). HFHSD‐fed mice showed poorer memory performance in both object recognition tasks (both P<0.001 vs. CD). Mice in the RD group showed memory performance similar to controls. At 4 months of HFHSD, the hippocampal metabolic profile showed a prominent increment in taurine concentration (P<0.01 vs. baseline). This change persisted until the end of the study in HFHSD mice (P<0.01 vs. baseline), but recovered to baseline levels in mice of the RD group (P<0.05 vs. HFHSD). These metabolic changes were not observed cortex.ConclusionWe conclude that T2D and T2D‐induced memory impairment are promoted by a diet rich in fat and sugar. As in other T2D models, the diabetic hippocampus shows increased concentration of taurine in the MRS‐detected metabolic profile. Brain alterations were reversed upon dietary switch from HFHSD to a regular diet.
Health utility in preclinical and prodromal AD compared to controls: EQ5D data from the Swedish Biofinder Study
Authors: Gustavsson Anders , Raket Lars Lau , Lilja Mathias , Rutten‐Jacobs Loes , Fues‐Wahl Hanna , Bagijn Marloes , Hansson Oskar , Palmqvist Sebastian 
Published: December 2020

AbstractBackgroundHealth utility values (e.g. as assessed with EuroQoL 5 domains, EQ5D) are central for the health economic evaluation of candidate treatments for Alzheimer's disease (AD). Currently available estimates in early stages of disease including preclinical and prodromal AD are limited, and do not separate patients by biomarker status.MethodBaseline data from the longitudinal Swedish BioFINDER study on patients in different stages of AD and cognitively healthy controls were analyzed. Subjects were either cognitively unimpaired healthy elderly controls sampled from a population‐based cohort, or patients with cognitive complaints (subjective cognitive decline (SCD) or mild cognitive impairment (MCI)), but without dementia, referred to memory clinics. Health utility was assessed with EQ5D (3 level version) recalculated into a utility index with the UK tariff; higher scores representing higher utility. Cerebrospinal fluid amyloid biomarker positive subjects were defined as prodromal AD if they met criteria for MCI and otherwise defined as preclinical AD.ResultFive‐hundred‐ninety‐nine non‐dementia subjects aged between 60 and 88 years were assessed at baseline. Individuals with SCD or MCI reported lower health utility (n=245, mean=0.78, 95% CI 0.75‐0.80) compared to cognitively healthy elderly controls (n=354, mean 0.90 95% CI 0.88‐0.91), regardless of biomarker status. Prodromal AD patients reported higher health utility (n=79, mean=0.81, 95% CI 0.77‐0.85) compared to amyloid‐negative MCI patients (n=54, mean=0.71, 95% CI 0.64‐0.77). Prodromal AD patients were less often smoking, fewer had prior ischemic heart disease and were less often treated with anti‐depressants, compared to amyloid‐negative MCI patients. Subjects with preclinical AD reported health utility (n=114, mean 0.86, 95% CI 0.83‐0.88) which were similar to amyloid‐negative cognitively unimpaired (i.e. SCD and controls) (n=305, mean=0.87, 95% CI 0.86‐0.89).ConclusionHealth utility was lower in biomarker confirmed preclinical and prodromal AD patients compared to cognitively healthy controls. The analysis suggests that amyloid biomarker status is an important determinant of health utility in patients with MCI. This may be explained by more severe co‐morbidities in biomarker negative patients. In particular, the cause of their cognitive symptoms (e.g. cardiovascular disease) may be associated with a greater impact on their quality of life in early stages of disease.
Cognitive dysfunction induced by ketamine and xylazine anesthesia is associated with tau hyperphosphorylation following CaMKII activation
Authors: Brouillette Jonathan , Hector Audrey , McAnulty Christina , Piche‐Lemieux Maude‐Eloise , Alves‐Pires Claire , Buée‐Scherrer Valérie , Buee Luc 
Published: December 2020

AbstractBackgroundRecent studies indicate that anesthesia is likely to contribute to the development and exacerbation of neurodegenerative disorders such as Alzheimer’s disease (AD). Although it is well established that tau hyperphosphorylation is induced following anesthesia and is a major neuropathological hallmark of AD, the relationship between tau pathology and post‐anesthetic memory impairment remains unclear. The main objective of this study was to determine if tau phosphorylation and cognitive function in mice are altered by ketamine/xylazine, a common regimen of general anesthesia used in animal research and veterinary medicine.MethodMice were anesthetized with intraperitoneal (ip) injections of ketamine/xylazine, and tau phosphorylation was evaluated in hypothermic and normothermic conditions 1 h and 6 h following anesthesia. To delineate the mechanisms underlying tau phosphorylation, we assessed by electrophoresis the levels of phosphorylation and activity of various kinases and phosphatases known to regulate tau phosphorylation. Post‐anesthetic memory deficits induced by ketamine/xylazine were examined in two different behavioral paradigms, the Y maze and passive avoidance task (PAT).ResultKetamine and xylazine have an additive and rapid effect on the phosphorylated state of tau. Mechanistically, we found that activation of calmodulin‐dependent protein kinase II (CaMKII) is the major upstream molecular event leading to tau hyperphosphorylation following ketamine/xylazine anesthesia in mice. Moreover, we observed that intracerebroventricular (icv) injection of the selective CaMKII inhibitor KN93 attenuated tau hyperphosphorylation and post‐anesthetic memory deficits induced by ketamine/xylazine in the Y maze and PAT paradigms. Ketamine/xylazine also had a marked impact on many other key molecular signaling pathways involving ERK, GSK3, STEP, Akt, Src, and the GluN2B subunit of the NMDAR.ConclusionThis study demonstrates that cognitive impairments induced by ketamine/xylazine exposure are associated with tau hyperphosphorylation mainly through CaMKII activation in mice. Our results also revealed major molecular and cognitive effects of the widely used anesthetic ketamine/xylazine in animal research and veterinary practice, and call for high precaution and careful monitoring when used in laboratory animal settings to avoid artifactual results.
Ventricular anteroposterior ratio is the most reliable feature to differentiate bvFTD from healthy controls and other dementias
Authors: Manera Ana Laura , Dadar Mahsa , Collins Louis , Ducharme Simon 
Published: December 2020

AbstractBackgroundUsing morphometric analysis, we recently found ventricular expansion to be the most prominent differentiator of behavioural‐variant frontotemporal dementia (bvFTD) from healthy controls and a potentially sensitive marker of disease progression [Manera et al. 2019]. Here, we performed volumetric analysis on the lateral ventricles to find a reliable differentiator of bvFTD from Alzheimer’s Disease (AD), mild cognitive impairment (MCI), the language variants of FTD (Semantic‐Variant, SV, and Progressive‐Nonfluent‐Aphasia, PNFA), and controls.MethodWe included 825 subjects (59 bvFTD, 28 SV, 30 PNFA, 322 MCI, 127 AD, and 259 controls) with a total of 3800 timepoints from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). Lateral ventricles were automatically segmented for all timepoints, using a previously validated pipeline. Using a lobe atlas, ventricular volumes (VV) were calculated for frontal, parietal, temporal, and occipital lobes in the left and right hemispheres. Using coronal slice y=120 in the brain atlas, ventricles were also divided into anterior and posterior halves. All volumes were normalized for intracranial volume and log‐transformed to achieve normal distribution. Regression models were used to assess volumetric and ratio differences between cohorts at baseline (Model1:feature∼1+Diagnostic‐Group+Age+Sex). Longitudinal mixed‐effects models were used to assess longitudinal differences in ventricular features (antero‐posterior ventricular ratio and total VV) between bvFTD and other cohorts (Model2:feature∼1+ Diagnostic‐Group +Age+ Diagnostic‐Group:Age+Sex+1|ID). The variables of interest were Diagnostic‐Group (Model 1) and the interaction between Diagnostic‐Group and Age (Diagnostic‐Group:Age, Model 2). ID was considered as a categorical random effect. All results were corrected for multiple comparisons (Bonferroni).ResultFigures 1 and 2 show the volumetric and ratio differences between cohorts. Controlling for age and sex, the antero‐posterior ratio was the only feature that was significantly different in bvFTD (Mean±SD:1.37±0.47) compared to all other diagnostic groups (Controls:1.00±0.24,p<0.001; MCI: 0.97±0.22,p<0.001; AD: 0.92±0.22,p<0.001; SV:1.00±0.22,p<0.001; PNFA:1.12±0.48,p=0.004). Total ventricle volume increased with age in all cohorts (p<0.001,Figure 3). bvFTD patients showed a faster increase in the ventricular antero‐posterior ratio compared to all other diagnostic groups (Figure 4, p<0.01).ConclusionThe antero‐posterior ratio of the lateral ventricles, in both cross‐sectional and longitudinal analyses, was the most reliable ventricular feature differentiating bvFTD from controls and other dementias.
Depression accelerates longitudinal progression of hippocampal atrophy and cognitive decline in preclinical Alzheimer’s disease
Authors: Park Jee Eun , Byun Min Soo , Yi Dahyun , Lee Jun Ho , Byeon Gihwan , Jung Gijung , Lee Jun‐Young , Kim Yu Kyeong , Sohn Chul‐Ho , Lee Dong Young 
Published: December 2020

AbstractBackgroundAlthough depression is very common in the preclinical stage of Alzheimer’s disease (AD), it is still unclear whether depression moderates the progression of AD or not. In the present study, we aimed to investigate the moderation of depression on the relationship between β‐amyloid (Aβ) deposition and progression of hippocampal atrophy and cognitive decline in cognitively normal (CN) older adults.MethodTwo‐hundred eighty nine CN older adults (55–90 years; 48.4% female; 14.2% Aβ+) from an ongoing prospective cohort study, the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), were followed up for 24 months. All participants underwent annual clinical assessments on depressive symptoms and cognitive function, and biennial [11C] Pittsburgh compound B‐PET and three‐dimensional MRI scans. Depression was defined based on the following: 1) depression diagnosed by a psychiatrist, 2) Geriatric Depression Scale score ≥ 11, or 3) the presence of any depressive symptom on Neuropsychiatric Inventory.ResultAmong the subjects, 73.4% (n = 212) were followed up for two years and twelve converted to mild cognitive impairment. Association between Aβ and depression was not observed at baseline. There was a significant Aβ positivity x Depression x Time interaction effect on hippocampal volume (F = 4.252, p = 0.042) and verbal memory (F = 7.488, p = 0.007) even after controlling for age, sex, educational level, APOE genotype, subjective memory complaint, and baseline white matter hyper intensity volume. Aβ positive individuals with depression showed faster decline of hippocampal atrophy and verbal memory decline than those in other subgroups for two years.ConclusionThe findings indicate that the presence of depression may accelerate hippocampal atrophy and episodic memory loss in older adults with preclinical AD.
The IUSM‐Purdue Alzheimer’s Disease Drug Discovery Center: A member of the NIH‐funded TREAT‐AD consortium
Authors: Palkowitz Alan David , Lamb Bruce T. , Oblak Adrian L. , Reeves Cristian A. Lasagna , Territo Paul R. , Rizzo Stacey J. Sukoff 
Published: December 2020

AbstractBackgroundThe Target Enablement to Advance Therapeutics for Alzheimer’s Disease (TREAT‐AD) Consortium is a newly formed NIA initiative designed to accelerate the discovery of new medicines for Alzheimer’s Disease. It is comprised of two drug discovery centers: OPEN‐AD and the Indiana University School of Medicine‐Purdue University Alzheimer’s Disease Drug Discovery Center (IUSM‐Purdue ADDD Center). The strategic goal of the consortium is to integrate sophisticated capability for early drug discovery and contribute to a broad study of emerging Alzheimer’s Disease target hypotheses to create new classes of potential therapeutics.MethodThe TREAT‐AD consortium will establish itself as a strategic and operational partner for the NIA‐Funded AMP‐AD, MODEL‐AD other AD directed translational research programs. By design, this will provide drug discovery capability to bridge the foundational work in target discovery (AMP‐AD) with newly discovered molecules characterized in next generation AD animal models based on human pathology, genetics and translational biomarkers (MODEL‐AD). Additionally, the TREAT‐AD consortium will make all data and research tools available to the scientific community to catalyze new research efforts.ResultThe IUSM‐Purdue ADDD Center has assembled a world‐class team of scientists and capabilities that will pursue a research strategy focusing on neuro‐immune pathways implicated in Alzheimer’s Disease with the following aims: Create a dynamic portfolio of well characterized AD drug discovery targets representing novel intervention hypotheses that capitalizes on significant investments in basic research and emerging disease understanding. Perform advanced pre‐clinical target validation and enablement studies to prioritize the best opportunities for therapeutic discovery. Create high quality and well characterized Lead molecules for prioritized targets that meet rigorous milestone criteria and are valued opportunities for further translational investment. Create a robust and flexible data sharing platform to enable global researchers with data and Target Enablement Packages to expand on the work of the Center.ConclusionThis presentation will provide an overview of the TREAT‐AD Consortium and the scientific strategy and plans for the IUSM‐Purdue ADDD Center.
Lifetime cigarette smoking and later‐life brain health: The population‐based 1946 British Birth Cohort
Authors: James Sarah‐Naomi , Lane Christopher A , Parker Thomas D , Keshavan Ashvini , Buchanan Sarah M , Keuss Sarah E , Cash David M , Malone Ian B , Barnes Jo , Sudre Carole H , Coath William , Prosser Lloyd , Nicholas Jennifer M , Murray‐Smith Heidi , Wong Andrew , Hughes Alun , Chaturvedi Nishi , Fox Nick C , Richards Marcus , Schott Jonathan M 
Published: December 2020

AbstractBackgroundCigarette smoking is implicated as a risk factor for dementia, but the underlying mechanisms are poorly understood. In a population‐based sample free of dementia, we examine associations between smoking patterns over the life course and imaging markers associated with dementia.MethodDementia‐free participants from Insight 46 (n=458, 49% female, age 69‐71), a sub‐study of the 1946 British Birth Cohort, underwent 18F‐florbetapir Aβ‐PET and multi‐modal MR imaging including T1, T2, FLAIR and multi‐shell diffusion‐weighted sequences. Information on smoking frequency and cessation (current/former/never) were obtained at multiple timepoints, spanning ages 15‐69 years. Pack‐years were calculated as number of cigarettes smoked/day divided by 20, multiplied by years of smoking. Age and sex adjusted regression analyses examined relationships between smoking metrics and later‐life imaging measures; including Aβ‐PET status, brain, hippocampal and white matter hyperintensity (WMH) volumes, normal appearing white matter (NAWM) fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI) and orientation dispersion index (ODI), and Alzheimer’s disease (AD)‐related cortical thickness.ResultIncreased smoking pack‐years was associated with alterations in NAWM microstructure metrics (lower FA and NDI; higher MD and ODI) and smaller brain and hippocampal volume (Figure 1). There was no significant relationship with Aβ‐PET status (OR=0.99 [95% CI 0.97,1.01]), WMH volume or AD‐related cortical thickness (Figure 1). Unlike current smokers (n=16, 3%), former smokers (n=285, 61%) had comparable NAWM microstructure metrics to those who had never smoked (n=163, 35%).ConclusionIn a population‐based sample without dementia or other major neurological problems, increased smoking frequency and duration over 50 years was associated with altered white matter microstructural metrics, and smaller brain and hippocampal volumes. However, there was no evidence that smoking was associated with markers of AD pathology (amyloid‐PET, AD‐related cortical thickness) or cerebral small vessel disease (WMH). Former smokers were comparable to non‐smokers on measures of microstructural metrics, suggesting that smoking‐related microstructural changes may at least partly be reversible. Stopping or reducing smoking may help reduce risks to brain health via microstructural pathways.
Computerized neuropsychological tests undertaken on digital platforms are cost effective, achieve high engagement, distinguish and are highly sensitive to longitudinal change: Data from the PROTECT and GBIT studies
Authors: Hampshire Adam , Ballard Clive , Williams Gareth 
Published: December 2020

AbstractBackgroundCost effective and sensitive neuropsychological measures are needed for cohort studies and clinical trials.Method10,000 people from the PROTECT on‐line cohort study (people > 50) in the UK participated in a longitudinal study of computerized neuropsychology using the PROTECT and COGTRACK batteries (attention, sustained attention, working memory, executive function, episodic memory, reaction time). A factor analysis mapped tasks to key cognitive domains and evaluated changes associated with age and MCI. Monte Carlo methodology was used to identify the best composite for sensitivity to change in cognitively normal individuals (training set) and in MCI. Using ADNI methodology the sample size required to detect a 25% treatment effect with 80% power to a 5% level of significance was determined. The GBIT study is a collaboration with the BBC using a digital platform to assess people across the lifespan. The assessment included computerized neuropsychological assessment (same domains assessed in PROTECT), and a lexicon assessment.Result10,714 people participated (73% female, mean age 61.7). The 5 factors were confirmed, and performance on these domains was highly correlated with increasing age (p<0.0001) and distinguished MCI from cognitively normal individuals (p<.0001). 92% of participants completed follow‐up neuropsychological testing. An optimal composite of 8 items spanning these domains achieved an effect size of 0.50 for change at 1 year in the 9051 individuals with normal cognition, requiring 1017 participants per arm for a prevention RCT. The same composite achieved an effect size of 0.83 for 1 year change in 783 people with stage 2 or stage 3 MCI, requiring 360 people per arm for an RCT. Power was further improved over 2 years, with enrichment factors and with repeated testing to reduce variability. The GBIT study recruited >240,000 participants, identifying age related decline in all aspects of cognitive function, except the lexicon which increased with age. Lifestyle factors significantly influenced age related changes.ConclusionDigital platforms provide a cost effective ($4 per participant per year) and engaging way to conduct cohort studies and clinical trials. Computerized neuropsychology on digital platforms achieved high levels of sensitivity to change with clear advantages for clinical trials.