bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient intracellular degradation of tau in neurons through engineered nuclear transport
Authors: Cho Yongku P. 
Published: December 2020

AbstractBackgroundTargeted protein degradation is an attractive modality of therapeutic intervention for a wide range of neurodegenerative diseases. Intervention at the protein level is highly desired since pathogenic changes such as conformational change or post‐translational modifications can be directly targeted.MethodWe designed protein constructs that contain an intracellular binding domain for targeting tau fused to a domain for recruiting the ubiquitination machinery. We expressed these constructs in a cultured human cell line and dissociated cultures of mouse hippocampal neurons expressing human tau. We assessed the degradation of human tau using fluorescence microscopy and by tau quantification using immunoblotting.ResultWe found that the ubiquitin ligase substrate adaptor speckle‐type POZ protein (SPOP), when fused to camelid‐derived single‐domain antibody fragments (nanobodies), allows efficient degradation of nanobody binding proteins imported to the nucleus. We found that the endogenous SPOP domain contains a strong nuclear localization signal, resulting in nuclear accumulation and aggregation of tau. Based on this we hypothesized that the strong nuclear localization signal overloaded the intracellular protein degradation capacity, disrupting the cellular homeostasis. To test this, we engineered SPOP variants with altered nuclear transport efficiency. The engineered variants altered the degree of tau degradation and nuclear accumulation. Interestingly, this regulated degradation approach resulted in preferential degradation of tau dissociated from the microtubule, leading to nearly exclusive colocalization of tau to the microtubule in mammalian cells and primary mouse hippocampal neurons.ConclusionThe new constructs developed here allow fine tuning of nuclear translocation rate and degradation efficiency of tau. This controlled degradation strategy may be beneficial in developing therapeutic approaches for regulated tau degradation without overloading the proteasomal capacity.
‘δ’ is for dementia: Genomic architecture of the latent variable δ homolog (dEQ) in Mexican Americans and non‐Hispanic Whites
Authors: Colmenarez Micaela , Silzer Talisa , Royall Donald R. , Palmer Raymond F. , Barber Robert , Phillips Nicole 
Published: December 2020

AbstractBackgroundThe latent variable δ homolog (dEQ) has been established as a reliable indicator of cognitive performance and a predictor of future dementia. Here, we sought to identify genetic variants underlying dEQ in both non‐Hispanic White (NWH) and Mexican American (MA) populations, hypothesizing that novel genomic risk loci for dementia will be implicated in the MA cohort.MethodGenotyping was performed on the TARCC cohort using the Illumina® MEGA Array, which includes ∼1.7 million SNPs. dEQ was generated by Donald Royall and Ray Palmer (UT Health Science Center @ San Antonio) for the entire genotyped cohort (nNHW = 1572; nMA = 1030). Association testing was conducted using PLINK (Purcell et al., 2007) according to standard procedures (Anderson et al., 2010).ResultThe primary genetic association with dEQ in NHW is the TOMM40/APOE locus (rs4420638, p = 9.477 × 10−32); the association for this locus in the MA cohort was much less significant (p = 3.886 × 10−5). Among MAs, three interesting and unique loci emerged as suggestive: XIRP2 (chr2, rs7595556 p = 8.165 × 10−6), KIF13a (chr6, rs7766167, p = 3.404 × 10−6), and LINC00907 (chr18, rs237972, p = 7.88 × 10−7).ConclusionThe loci discovered in the MA cohort have not previously been implicated in dementia/Alzheimer’s disease; interestingly, however, variants in these genes have been associated with metabolic phenotypes that are particularly relevant to the pathophysiology of cognitive decline in MAs: BMI, diabetic neuropathy, epigenetic aging, and childhood obesity. Further investigation of these genomic regions may shed light on the mechanisms by which metabolic syndromes may confer risk for earlier onset of age‐related cognitive decline in MAs.
Association between cerebrospinal fluid biomarkers of neurodegeneration and PET measurements of synaptic density in Alzheimer’s disease
Authors: Mecca Adam P. , Ashton Nicholas J , Chen Ming‐Kai , O'Dell Ryan S. , Naganawa Mika , Toyonaga Takuya , Harris Joanna E. , Bartlett Hugh H. , Banks Emmie R. , Kominek Victoria L. , Nabulsi Nabeel B. , Najafzadeh Soheila , Wyk Brent C. Vander , Brinkmalm Ann , Kvartsberg Hlin , Schöll Michael , Arnsten Amy F.T. , Huang Yiyun , Blennow Kaj , Zetterberg Henrik , Carson Richard E. , van Dyck Christopher H. 
Published: December 2020

AbstractBackgroundStudies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early Alzheimer’s disease (AD). The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. The relationship of PET measures of synaptic density and cerebrospinal fluid (CSF) biomarkers may provide important information related to neuronal damage and synaptic health.MethodsSV2A binding was measured with [11C]UCB‐J–PET in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT from 60 or 90 min after a bolus injection of [11C]UCB‐J. Binding potential non‐displaceable (BP
ND) was calculated using SRTM2 and a centrum semiovale reference and converted to a distribution volume ratio (DVR) with a cerebellum reference. CSF biomarkers of AD, as well as synaptic and neuronal health were assayed, including Aβ42, Aβ40, total tau (t‐tau), phosphorylated tau (p‐tau), neurofilament light chain (NFL), growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptosomal‐associated protein 25 (SNAP‐25), and synaptotagmin‐1 (SYT‐1).ResultsSynaptic density was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. There were significant group differences in Aβ42, Aβ42/Aβ40, t‐tau, p‐tau, GAP‐43, Ng, SNAP‐25 short, and SNAP‐25 total. In the overall sample, only Aβ42 (r=0.40, P=0.03) and Aβ42/Aβ40 (r=0.48, P=0.01) had significant correlations with synaptic density in the hippocampus. Aβ42/Aβ40 (r=0.46), t‐tau (r=‐0.38), p‐tau (r=‐0.40), NFL (r=‐0.42), GAP‐43 (r=‐0.46), and SNAP‐25 total (r=‐0.49) were significantly correlated with synaptic density in a composite of commonly affected AD regions (P<0.05, Figure 1). Most CSF biomarkers were significantly correlated with synaptic density in the neocortex only (Figure 2). In addition, CSF Aβ42/Aβ40 and synaptic density were significantly correlated in regions of the medial temporal lobe (Figure 2).ConclusionThis study explores the relationship between synaptic density and CSF biomarkers of neuronal and synaptic health in AD. The spatial relationship between synaptic density reductions and CSF synaptic biomarkers may provide valuable information that will contribute to the understanding of AD and lead to novel treatments and therapeutic biomarkers.
Lifestyle and genetic risk: Revisiting the association with incident dementia
Authors: Faul Jessica D , Ware Erin B , Kabeto Mohammed U , Langa Kenneth M , Llewellyn David J , Galama Titus 
Published: December 2020

AbstractBackgroundPrevious work using data from the UK Biobank has shown that both unfavorable lifestyle and genetic risk are associated with higher dementia risk; however, it is not known whether these results transfer to more representative samples and across country.MethodsData come from the Health and Retirement Study (HRS), a cohort study of Americans 65 years of age and older without dementia at baseline. Adults of European descent are included in the analyses. Dementia was determined using Medicare claims from 2000‐2016. 6,870 individuals were followed for an average of 11 years (Median 12; IQR 8.6 – 15.6 years) with mean age of 68.8 (5.4). Polygenic scores (PGS) for dementia from 2 large, replicated genome‐wide association studies (Lambert et al. and Kunkle et al.) were used along with a weighted lifestyle score (including measures of smoking, drinking, and physical activity) to predict incident dementia. The association between the PGS and lifestyle was assessed using ordered logistic regression. Cox proportional hazard regression models were used to examine the association of genetic risk, lifestyle, and the interaction with time to incident dementia.ResultOverall, 22.9% (n=1,580) were diagnosed with dementia during the observation period. 23.8% of participants had a favorable lifestyle, 50.7% had a moderately favorable lifestyle, and 25.5% had an unfavorable lifestyle. There was no significant association between the lifestyle score and either PGS. The effect of PGS on time to dementia was significant with and without adjustment for covariates (age, sex, education, wealth, comorbidities) with higher genetic risk conferring an increased risk for dementia (hazard ratio highest PGS group compared to lowest 1.37 [95% CI [1.17, 1.61]). Individuals with a favorable lifestyle at baseline were significantly less likely to develop dementia adjusting for PGS and covariates (adjusted hazard ratio 0.85 [95% CI, 0.74‐0.99]). Results were similar regardless of which PGS was used. There was no significant interaction between genetic risk and lifestyle.ConclusionThese findings demonstrate that an unhealthy lifestyle and genetic risk are associated with higher dementia risk. Results from a nationally‐representative sample of older adults in the United States are comparable with those from UK Biobank.
Comparison of baseline characteristics of African‐American/black and non‐Hispanic white family caregivers in Tele‐Savvy: An online psychoeducation program
Authors: Bonds Kalisha , Griffiths Patricia , Higgins Melinda , Nocera Joe R , Epps Fayron , Brewster Glenna S , Hepburn Kenneth 
Published: December 2020

AbstractBackgroundTele‐Savvy is an NIA‐funded 3‐arm randomized controlled longitudinal trial of a fully online psychoeducation program. Tele‐Savvy is specifically designed to promote caregiver mastery by enhancing caregivers’ abilities to manage daily challenges to reduce caregiver distress.MethodThis presentation reports on the baseline characteristics of 209 family caregivers (159 non‐Hispanic White [NHW] and 50 African American/Black [AA] family caregivers). Bivariate analysis was conducted to compare group differences among AA and NHW family caregivers.ResultAA caregivers reported their persons living with Alzheimer’s disease and related dementias (AD/ADRD; PWD) were more dependent. AA caregivers reported their PWDs had significantly worse performance of activities of daily living (e.g., toileting, grooming) (p < .001) and significantly worse performance of instrumental activities of daily living (e.g., transportation, managing finances) (p = .007). AA caregivers reported their PWDs had significantly more disruptive behaviors (p = .010) and significantly worse neuropsychiatric behaviors (e.g., delusions, disinhibition) (p = .025) than were reported by NHW caregivers regarding their PWDs. In addition, AA caregivers reported better caregiving experiences. AA caregivers reported significantly less personal strain (p = .019), significantly better caregiver competence (p < .001), significantly better management of their caregiving situation (p = .001), and significantly better management of the behavioral symptoms associated with AD/ADRD (p = .009) than NHW caregivers. AA caregivers reported significantly better mindful self‐care in the domain of self‐compassion and purpose (i.e., a sense of meaning when getting through difficult situations) (p = .015) compared to NHW caregivers.ConclusionAA caregivers recruited into Tele‐Savvy have reported quantitative baseline characteristics similar to previous caregiving studies, which portray AA caregivers as less distressed and better prepared for AD/ADRD caregiving than NHW caregivers. This longitudinal study will enable us to see if AA and NHW caregivers change on these dimensions over time in similar or different ways. We will interview some of the caregivers to see if AA and NHW caregivers experience similar or different patterns of distress than explained through quantitative measures. Continuation in Tele‐Savvy will provide an opportunity to assess the extent to which both groups respond to the intervention.
Metabolite differences in vascular dementia and control human brain tissue
Authors: Hammond Tyler C. , Xing Xin , Nelson Peter T. , Ham Stephanie , Lin Ai‐Ling 
Published: December 2020

AbstractBackgroundVascular dementia is the second most common cause of dementia worldwide and is characterized by cerebrovascular pathology that presents as an amnestic dementia syndrome like Alzheimer’s disease. The main neuropathological and clinical features for vascular dementia have been described elsewhere, but little is understood about the underlying metabolic processes that may contribute to vascular dementia. Here we measure the metabolites of control brains and brains with cerebrovascular pathology to understand how they differ.MethodThe global biochemical profiles of post‐mortem human brain tissue from the gray matter of Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 52 subjects with cerebrovascular pathology and 46 controls were analyzed and metabolites were compared. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch’s two‐sample t‐test and random forest to rank metabolites in order of importance for predicting cerebrovascular pathology presence in tissue.ResultMany of the metabolites in the top 20 most important predictors for cerebrovascular pathology overlapped with metabolites deemed important in predicting Alzheimer’s disease, including memantine, sphingadienine, N‐acetylasparagine, N‐acetyl‐aspartyl‐glutamate (NAAG), glycerophosphorylcholine, guanidinoacetate, dimethylglycine, pipecolate, and phosphatidylserine. However, there were quite a few predictors which were unique to predicting cerebrovascular pathology, including 7‐hydroxycholesterol – common to atherosclerotic plaques, methylphosphate – an intermediate of purine and pyrimidine metabolism, 2‐methylcitrate/homocitrate – part of the TCA cycle, tryptophan – a precursor of serotonin and melatonin, 2‐hydroxystearate – a fatty acid, glutamate – the most abundant fast excitatory neurotransmitter, and beta‐hydroxyisovalerate – associated with smoking.ConclusionMany metabolites differed between the brains with cerebrovascular pathology and control brains. Some metabolite differences were the same as those seen in Alzheimer’s disease, and could be because many of the people in our cohort with cerebrovascular pathology also had Alzheimer’s pathology. Many of the metabolite differences were specific to cerebrovascular pathology including the well‐known lifestyle factors high cholesterol and smoking, and other metabolites which are critical to maintaining brain function, including changes in neurotransmitters, essential amino acids, fatty acids, TCA cycle intermediates, and nucleic acid intermediates. Further studies are needed to examine whether these metabolites are consistently altered in cerebrovascular disease.
HAPPCAP‐AD (Human‐Application Combined Approach for Prevention of Alzheimer's Disease): A novel feasibility study of a personalized midlife intervention to prevent AD
Authors: Ganmore Ithamar , Ravona‐Springer Ramit , Livny Abigail , Matatov Adar , Ziat Adi , Bem‐Moshe Ariela , Beeri Michal Schnaider 
Published: December 2020

AbstractBackgroundDeveloping efficient Alzheimer's disease (AD) prevention strategies is imperative as AD has no cure. Physical inactivity, obesity, type 2 diabetes [T2D], hypertension, smoking, depression, and low educational attainment, are the seven major potentially modifiable risk factors showing consistent association with AD. We have launched a novel, "real‐life", feasibility study of personalized 18‐months intervention for prevention of cognitive decline in middle‐aged individuals at high AD risk due to a parental family history. Our study implements an innovative approach combining a smartphone application (app) with study team guidance through phone‐calls. Our aims are to investigate: 1) The feasibility of our novel intervention and factors associated with adherence to it; 2) Whether our intervention improves AD risk factors and whether greater adherence is associated with larger improvement; and 3) Whether our intervention improves cognition and cerebral blood flow.MethodWe will recruit one hundred 40‐65 years old AD patients' offspring, to two groups (67 at the intervention group and 33 at the passive control). All participants will have at least two risk factors of the seven major modifiable AD risk factors. The 18‐months intervention will include advice for risk factors improvement, interactive follow‐up using a smartphone app and dynamic feedback on risk factors management for its modification, through both the app and the study team.ResultRecruitment has recently begun, through publishing an online eligibility questionnaire. Thus far, 200 individuals have completed the questionnaire, with 113 fulfilling eligibility criteria‐ among them 86% with physical inactivity, 87% with obesity, 38% with T2D, 17% with hypertension, 13% smoking, and 32% with depression. Thus far 33 participants have been recruited‐ Among them, 10 participants have completed the baseline evaluation, and have been randomized to the study's arms (8 of them had started the active intervention, with an average app‐adherence of 83%). additional 23 participants have completed partial base‐line evaluation.ConclusionResults of this study will provide feasibility data on the adherence to the human‐app approach, characteristics of those who adhere, on whether the approach improves risk factors, and will provide initial data on intervention effects on cognition. At AAIC, interim results will be presented.
Are U.S. clinical trial sites in the right places to meet the demand for the population density of those over 60?
Authors: Stanton Sean , Dwyer John , Ward Nichol , Vradenburg George , Taylor James 
Published: December 2020

AbstractBackgroundThere are approximately 31 drugs in phase 3 and 68 drugs in phase 2 development for memory impairment. It is reported that there are approximately 200 sites in the US that are capable of randomizing 25 subjects per year. The current demand for participants is approximately 25,277 across 55 studies requiring this type of enrollment. That means we would need approximately 505 clinical trials sites capable of randomizing at least 25 subjects per year. Is it possible to meet this demand? Prior to answering this question we researched where in the US the population is located for people >60 years of age. We also researched where clinical trial sites were in relation to this population. And lastly, how many of these sites have done at least 1 memory study in the last 2 years. To determine if the US has sites positioned in the right places to meet the demand from both the patient and the industry/NIH for Alzheimer’s disease. If yes, can we increase capacity to meet the patient enrollment needs? If no, what do we need to do organically to grow sites to meet this demand.MethodThe population was surveyed using the US Census and plotted graphically using. The data can be seen in the graphs. Data on the site locations was compiled though clinical trials.gov. The data on Alzheimer’s sites was also collected from ClinicalTrials.Gov. The data on the Global Alzheimer’s Sites was supplied by GAP. Each data set has scatter plotResultThe results are plotted on the graphs below.ConclusionThe site locations do not align cohesively with the population greater the 60 years of age. As the demand of subject enrollment increases there is further pressure on existing sites within overly saturated clinical trial site zones while other zones offer no clinical trial sites within 50 miles. This will continue to lead to low performance and delayed timelines. We will offer answers to expanding site capabilities, organically growing zones in void of clinical trial sites, and also teaching sites interested in stopping Alzheimer’s the dynamics to being successful in clinical trials for Alzheimer’s Disease.
Protocol for a scoping review of the collection, analysis and reporting of variables related to cultural and linguistic diversity in dementia clinical trials and cohort studies
Authors: Sabates Julieta M , Croy Samantha , Lampit Amit , Low Lee‐Fay , Coase Daniel , de Crespigny Fleur , Day Robert , Dobson Annette , Elliott Cerise L , Ellis Stephanie , Etherington Cathy , Geronimo Mary Ann , Hlis Danijela , Maruff Paul T , Moxey Annette , Straiton Nicola , Temple Jeromey , Brijnath Bianca 
Published: December 2020

AbstractBackgroundEthnic minority communities and people living with dementia have been under‐represented in epidemiological studies. Concurrently, there are limited insights into how to analyse and report on a minimum set of variables related to cultural and linguistic diversity in such studies. In light of increased cultural and ethnic diversity in national populations, this review aims to investigate the collection, reporting and analysis of variables related to cultural and linguistic diversity in epidemiological dementia studies, and to identify best practice exemplars to inform recommendations for accurately capturing cultural diversity in future studiesMethodEmbase, PsycINFO, Medline, CENTRAL and CINAHL will be searched for peer‐reviewed studies published between January 2000 and January 2020. Selection criteria are: epidemiological dementia research studies (including clinical trials and cohort studies) focusing on cultural and ethnic minorities or cultural and ethnic difference, and undertaken in high‐income countries. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines will be used to report findings.ResultResults will describe the variables related to cultural and linguistic diversity, the related measures used, how such variables are treated (e.g. categorical or continuous) and triangulated, what corrections are made (if any) for variables such as time lived in country of settlement, and how these are analysed to inform understanding of dementia among ethnic minorities in high‐income countries.ConclusionBased on these findings, best practice exemplars will be identified, and recommendations made for a minimum and consistent set of variables relating to ethnic diversity to be collected and reported. The study addresses methodological uncertainties around which variables to collect and how to bring them together in a robust analysis that accounts for the cultural and pathological heterogeneity often found among ethnic minority study participants living with dementia.Reference
1Australian Institute of Health and Welfare 2018. Older Australia at a glance. 2L. F., Barcenilla‐Wong, A. L., and Brijnath, B. 2019. Including ethnic and cultural diversity in dementia research. Medical Journal of Australia, 211, 345. 3World Bank Country and Lending groups.https://datahelpdesk.worldbank.org/knowledgebase/articles/906519#High_income. Accessed 14 January 2020.