bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of vascular factors and tau deposition on functional brain network connectivity in participants of the Framingham Heart Study
Authors: Rahimpour Yashar , Himali Jayandra J , Beiser Alexa S , Habes Mohamad , O’Donnell Adrienne , Johnson Keith A , Killiany Ronald J , Seshadri Sudha 
Published: December 2020

AbstractBackgroundThe goal of this study was to determine whether vascular factors, expressed as the Framingham Stroke Risk Profile (FSRP), and/or tau deposition impact functional brain connectivity within and between functional brain networks i.e. default mode, frontoparietal, dorsal attention, and ventral attention networks. Regional blood flow measured by fMRI has been used to infer functional brain connectivity. Regions with synchronized blood flow are thought to be functionally connected while areas that have desynchronized blood flow are thought to be less functionally connected. Factors such as age have been linked to a reduction in functional connectivity.Method224 participants (mean age 54±8, 56% men) from the third generation of the Framingham Heart Study were imaged at Boston University from September 2015 to August 2018. Each participant had a high resolution MPRAGE T1 and a seven‐minute resting state fMRI scan. The T1 scans were processed using Freesurfer v6.0 and the resting state fMRI scans with FSL. Functional networks were constructed using the Yeo 7 network atlas (Yeo, 2011). Correlations within and between the functional brain networks were generated and z corrected. The relationship between FSRP, regional amyloid using the Pittsburgh B ligand, tau deposition using Flortaucipir, and functional connectivity were assessed using linear regression models adjusted for age, sex and interval between FSRP (or amyloid and tau) measurements and fMRI.ResultVascular risk factors and tau deposition had opposite impacts on functional connectivity. Increases in the FSRP were linked to increased functional connectivity between the default mode and visual networks, as well as the frontoparietal. Conversely, tau deposition in the inferior temporal, precuneus, and entorhinal cortices was linked to a reduction in functional connectivity within the frontoparietal network, between the default mode and somatomotor, and dorsal attention and somatomotor networks.ConclusionVascular risk factors appear to relate to an enhancement of functional connectivity while regional tau deposition appears to have an adverse impact on both within and between network connectivity. It is plausible that these changes in functional connectivity represent a compensatory response in the brain to alterations in vascular function and the presence of neuropathology in order to maintain cognitive abilities.
Cognitive reserve among potentially inappropriate medication users with and without preclinical Alzheimer’s disease
Authors: Martinez Ashley I. , Jicha Gregory A. , Khouli Riham H. El , Schmitt Frederick A. , Abner Erin L. , Beech Brooke F. , George Rosmy , Hall Megan , Eckmann Lynne , Huffmyer Mark , Moga Daniela C. 
Published: December 2020

AbstractBackgroundAugmenting cognitive reserve (CR) may delay the progression from preclinical Alzheimer’s disease (pAD) to symptomatic AD. Because studies have shown that potentially inappropriate medication (PIM) use may lower CR,1 optimizing individual medication regimens may protect against AD dementia symptomatic onset. We investigated the association between baseline measures of CR and PIM use among participants enrolled in a randomized medication therapy management trial.2
MethodsParticipants completed cognitive tests –Trail Making Tests A and B (TMT) and California Verbal Learning Test Trials 1‐5 (CVLT) – while wearing a 1.5mg scopolamine patch (“challenged”) and again four weeks later under normal conditions (“unchallenged”). Change scores between the challenged and unchallenged tests (standardized for age, sex, and education) were used as a surrogate for CR. The Medication Appropriateness Index for medications considered potentially inappropriate for older adults based on the 2015 Beers Criteria3 served as a measure of PIM use (MAI‐PIM). pAD was defined as total brain relative standardized uptake values > 1.4 using amyloid PET.4Spearman correlation coefficients (rs) assessed the relationship between MAI‐PIM and CR.ResultsIncluded participants (N=79) had mean age 73.9 years [SD 5.9] and were 66% female; 31.6% met pAD criteria. The median (IQR) PIMs reported at baseline was 2 (2‐3). Participants with and without pAD had similar mean (SD) baseline change scores for TMT B minus A (‐0.17 [1.37] and ‐0.13 [1.10] respectively; p=0.90), but lower total CVLT change scores (‐0.85 [0.84] and ‐0.29 [0.83]; p=0.01). Higher MAI‐PIM was also correlated with lower baseline CVLT change scores (rs=‐0.16), driven by the participants with pAD (rs=‐0.33). TMT B minus A change scores and MAI‐PIM were uncorrelated (rs=0.02).ConclusionAmong community‐dwelling non‐demented older adults, executive function and total learning CR was operationalized via participants’ abilities to compensate for anticholinergic challenge. There was a moderate negative correlation between MAI‐PIM and low total learning CR among participants with pAD, but not for those without. These results support the hypothesized relationship between CR and medication appropriateness. References: 1. Moga DC et al. Alzheimers Res Ther. 2017;9(1):36. 2. Moga DC, et al. Trials. 2019;20(1):806. 3. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246.4. Jack CR et al. Brain. 2015;138(12):3747‐3759.
Validity of tau as both a biomarker and target for AD and the dynamics of tau over the course of the disease
Authors: Barthelemy Nicolas R. , Horie Kanta , Sato Chihiro , Li Yan , McDade Eric , Bateman Randall J. 
Published: December 2020

AbstractBackgroundBrain tau aggregates are, together with amyloid plaques, hallmarks of Alzheimer Disease (AD). Structural characterization of tau aggregates in AD, Pick’s disease and Chronic Traumatic Encephalopathy demonstrate distinct folds leading to tau aggregation. However, initiation and propagation mechanisms involved are still unknown. One hypothesis includes modification in tau metabolism affecting tau isoforms abundance and clearance. Understanding these mechanisms can both identify potential targets for treatment, biomarkers for monitoring disease stages and response to tau‐directed therapies.MethodRecent developments in characterizing tau species by Mass Spectrometry in brain and biofluids have provided new insights on the diversity of tau isoforms and their changes associated to Alzheimer’s disease over the course of the disease. We will review past and new results from these techniques and discuss which tau isoforms are the most promising biomarkers to identify and stage AD. We will then discuss how these changes can be related to abnormal tau metabolism and, potentially, aggregation.ResultIn brain, soluble tau is phosphorylated at more than 30 sites and tau phosphorylation occupancy is modified in AD in a site‐dependent manner and appears to occur decades before substantial tau aggregation. Contrarily, AD brain aggregates are hyperphosphorylated compared to AD soluble tau at specific sites. In cerebrospinal fluid (CSF), the longitudinal monitoring of 11 phosphorylated sites in autosomal dominant AD demonstrates different behavior of these sites over disease trajectory. The CSF tau truncation profile, particularly in the protein domain enriched in brain aggregates, changes with disease. This suggests brain tau aggregates may impact the nature of tau isoforms released extracellularly. Yet, initial stages of tau hyperphosphorylation appears to occur many years before substantial tau aggregation. Critically, certain tau hyperphosphorylation sites observed in CSF are recapitulated in plasma tau in the preclinical stages of disease.ConclusionBoth CSF tau phosphorylation and tau truncation profiles can serve as biomarkers to complement p‐tau and tau levels for AD diagnosis and staging. For target validation, the multiplicity of tau isoforms complicates the identification of the most relevant species to target. Notably, the uncertain role of abnormal tau phosphorylation as the initiator or a consequence of tau aggregation remains to be addressed.
Trust thyself: How older black and white adults consider Alzheimer’s disease research participation
Authors: Howell J. Christina , Wharton Whitney , Hodge David A. , Warren Reuben C. , Hu William T. 
Published: December 2020

AbstractBackgroundBlack or African Americans (B/AA) are twice as likely to develop Alzheimer’s disease (AD) but significantly under‐represented in AD research studies, particularly those involving cerebrospinal fluid and PET biomarkers. We previously did not find potential participants to reference Tuskegee Study of Untreated Syphilis (TSUS) as a common reason for non‐participation, but B/AA adults who expressed an interest in research participation were much less likely to follow through than White adults in the Atlanta area. The reason for this is not clear.MethodWe electronically surveyed 158 older B/AA and 216 older non‐Hispanic Whites from Georgia, Alabama, Pennsylvania, and Missouri to assess their trust in AD research and their local academic medical centers (AMC); motivating factors and sources of counsel for participating in a hypothetical AD research study; and knowledge of ethical violations including TSUS and the case of Henrietta Lacks.ResultCompared to White respondents, B/AA respondents were more likely to provide accurate (OR=2.51, 95%CI=1.42‐4.44 p=0.002) as well as inaccurate (OR=3.95, 95%CI=2.37‐6.56, p<0.001) details about TSUS, perceive less equity in AD research (proportional OR 2.10, 95%CI=1.43‐3.09, p<0.001), and report less equity in healthcare at researcher‐affiliated AMCs (proportional OR=2.63, 95%CI=1.73‐3.98, p<0.001) even if they themselves can receive quality care there. State of residence did not greatly influence accuracy of knowledge or perception of equity in research and healthcare. Personal or family history of dementia, altruism, support from a friend or family, and support from a trusted physician were top factors considered by both older B/AA and White adults prior to research participation. Knowledge of TSUS – not Lacks – among older B/AA adults was associated with a shift of trust from community leaders to one’s own healthcare experience at AMCs.ConclusionFamiliarity with TSUS – but not accuracy – impacted factors of mid‐ to low importance in older B/AA adults when considering research participation and, to a lesser degree, perception of healthcare equity. Positive personal healthcare experience can potentially enhance B/AA research participation even if it poorly improves perception of inequity in research and healthcare.
A pilot clinical trial of adapted tango to improve negative health impacts in middle aged African‐American women caregivers of persons with Alzheimer’s disease
Authors: Wharton Whitney , Shin Ryan , Hu William T. , Jeong Leanne , Bay Allison A. , Hart Ariel R. , Ni Liang , Hackney Madeleine E 
Published: December 2020

AbstractBackgroundDementia caregivers have increased risk for psychological and physiological illness including depression, stress, hypertension, diabetes, diminished QOL, low‐grade inflammation and increased mortality. Dementia risk factors include gender, race and family history.MethodThis phase I pilot study evaluated the potential physiological, cognitive, motor, and psychosocial benefits of a 12 week, 20‐lesson adapted Argentine Tango intervention (N=30) to a no‐contact control group (N=10) in middle‐aged (45‐65 years) African American women caregivers of their parent with AD. Blood draw for inflammatory markers was done pre/post intervention/control.ResultWomen were middle age (60.0 yrs), slightly overweight (BMI 30.7) and highly educated (16.3 yrs of education). Significant reductions were noted in pre/post visit change for the Tango group in inflammatory markers including TNFα, interleukin‐7 and interferon‐gamma; maintenance of 30s chair stand performance, balance, and performance on the Tower of London and Stroop interference tests. Other non‐significant trends were noted in caregiving quality of life, gait speed, spatial cognition and executive function.ConclusionThe Tango dance intervention is a promising, non‐pharmaceutical intervention for African American women AD caregivers, for preservation of physiological, psychological and cognitive health.
Analysis of copy number variation in a Turkish dementia cohort
Authors: Dehghani Nadia , Kun‐Rodrigues Celia , Foster Kalina , Hanagasi Hasmet , Lohmann Ebba , Guven Gamze , Bilgiç Başar , Gurvit Hakan , Bras Jose , Guerreiro Rita 
Published: December 2020

AbstractBackgroundCopy number variations (CNVs) arise from copied or deleted regions of the genome. These regions vary in size and may span genes known to play a role in human disease. For example, duplications and triplications of SNCA have been shown to cause forms of Parkinson’s disease, while extra copies of APP are associated with early onset Alzheimer’s disease (AD). We have previously studied a Turkish dementia cohort for variants in known disease‐causing genes for both AD and frontotemporal dementia (FTD) and have also reported variants in the new AD‐associated genes TREM2 and NOTCH3. The goal of the current study was to perform a systematic analysis of CNVs in order to further characterize the genetic causes of dementia in this Turkish dementia cohort.MethodNinety‐nine Turkish individuals, either at risk of dementia due to family history, diagnosed with mild cognitive impairment, AD or FTD, were whole‐genome genotyped using Illumina HumanOmniExpress chips. We used GenomeStudio cnvPartition v3.2.1 plug‐in (Illumina, Inc) to analyze the data.ResultWe did not identify any CNVs segregating with disease in any of the four dementia families present in the studied cohort. We also did not observe any CNVs across our entire data set overlapping genes which have been previously associated with neurodegenerative diseases. We identified 9 distinct CNVs overlapping regions previously reported to have potential disease‐associated gene dosage alterations in patients with dementia phenotypes using PennCNV‐1.0.5; these were confirmed by manually checking CNVs on GenomeStudio. We observed potential disease‐associated CNVs in single individuals overlapping LOC286367, ABCA1, NIPSNAP3A, NIPSNAP3B, OR13C2, OR13C5, OR13C8, OR13C9, OR13D1, CNTN6, NIPA1, CYFIP1, GALNTL6, NLGN1, XPO1, SNORA70B, USP34, and HLA‐G. Additionally, two identical heterozygous duplications spanning MICA were identified in two AD patients; CNVs spanning this gene have been previously reported in four AD patients and no controls.ConclusionIn this study, we integrated whole‐genome genotyping results from a Turkish cohort with previously reported findings and data publicly available to add further evidence to the role of specific CNVs in the pathogenesis of dementia.
Key developmental milestones for tau therapeutics
Authors: Cummings Jeffrey L. 
Published: December 2020

AbstractBackgroundThere have been few breakthroughs and slow progress toward development of disease‐modifying treatments for Alzheimer’s disease (AD) and other neurodegenerative diseases. A biology/biomarker framework is captured in the AD‐disease specific framework focused on amyloid, tau, and neurodegeneration (ATN).MethodRecent developments in basic research — involves advances in both fluid‐ and neuroimaging‐derived biomarkers — has strengthened the foundation of clinical AD research.ResultsWhile much of the focus in recent years has been on amyloid, contemporary studies analyzing the temporal dynamics of tau have suggested that tau pathology better corresponds to the clinical features of AD and may be a viable therapeutic target. As a component of the ATN framework with a known association with AD cognitive impairment, tau and its regulation are well‐positioned for drug discovery programs. Although no disease‐modifying agents are currently approved, approximately 120 potential disease‐modifying anti‐AD agents are in clinical trials. Of these, about 55% incorporate tau and/or inflammatory activity in their mechanisms of action, including at least 4/28 candidates in Phase 3 trials.ConclusionImproved biomarkers, trial designs, outcomes, and population definitions will assist in advancing tau therapeutics.
Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer's disease
Authors: Therriault Joseph , Pascoal Tharick A. , Savard Melissa , Mathotaarachchi Sulantha , Benedet Andréa Lessa , Chamoun Mira , Tissot Cecile , Lussier Firoza Z , Soucy Jean‐Paul , Massarweh Gassan , Gauthier Serge , Rosa‐Neto Pedro 
Published: December 2020

AbstractBackgroundPreclinical models suggest that tau pathology spreads intracellularly, thought to explain the topographical distribution of tau observed in Alzheimer’s disease (AD). However, these findings have yet to be extended to humans.MethodWe assessed 131 cognitively unimpaired elderly and 63 AD individuals who underwent amyloid‐PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, fMRI and diffusion‐weighted MRI. Of the subjects with AD, 11 had behavioural/ dysexecutive AD, 18 had PCA and 11 had Logopenic variant PPA, while 23 subjects had an amnestic presentation (all were Ab+/Tau+). A voxelwise multivariate regression model was employed to determine the peak difference in [18F]MK6240 SUVR between each AD variant and CU elderly, with each clinical diagnosis entered as a different categorical variable and correcting for age, gender and MMSE score. Within each AD variant, the peak voxels derived from the regression model were used to compute the correlation between [18F]MK6240 SUVR in the seed voxel and [18F]MK6240 SUVR in every voxel, thus generating an [18F]MK6240 covariance network for each AD group. The same seeds were also employed in functional connectivity and diffusion tractography analyses in the CU elderly group. To determine whether the topographical distribution of tau pathology is related to connectivity properties of the human brain, we applied regression models to assess the relationship between functional/structural connectivity values from the CU population and [18F]MK6240 in each variant of AD.ResultTau organization differed between AD groups, reflecting clinical phenotypes and organizing within distinct brain networks. Furthermore, structural (Figure 1) and functional (Figure 2) connectivity patterns of the human brain predicted in vivo [18F]MK6240 SUVR across the cerebral cortex in each variant of AD.ConclusionThese results support a framework in which the intrinsic connectivity of the human brain provides a scaffold for tau pathology to spread to anatomically distant regions.
Mild behavioral impairment associates with Alzheimer’s disease biomarkers and greater risk of incident dementia in patients with MCI
Authors: Ismail Zahinoor , Gill Sascha , Wang Meng , Naude James , Smith Eric E. 
Published: December 2020

AbstractBackgroundMild behavioral impairment (MBI) is characterized by later life onset of sustained neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia. Here we assess differences in sustained NPS versus transient NPS versus no NPS, on neuroimaging markers and cognitive scores, and the risk of progression to dementia.MethodData from 764 individuals with MCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed. NPI‐Q items were transformed to MBI domains using a published algorithm. MBI requires sustained NPS for 6 months, thus we grouped individuals based on two visits 6‐months apart as sustained (present at both visits, n=258), transient (present at one visit, n=346), and no NPS (present at neither visit, n=160). For the cross‐sectional analyses, outcomes of interest were matched to the clinical visits assessing NPS. We investigated differences in brain metabolic activity by [18F] fluorodeoxyglucose (FDG)‐PET, and composite scores of executive functioning and memory in these groups using multiple linear regression adjusted for age, sex and education. Time‐varying cox regression models were constructed, adjusting for age, sex, and education to assess if time to dementia is associated with MBI.ResultIn these participants with MCI, compared to individuals with no NPS, sustained NPS was associated with reduced [18F] FDG uptake [Adjusted‐=‐0.06 (SE=0.02); p value=0.003], lower executive functioning scores [Adjusted‐=‐0.28 (SE=0.08); p value=0.001], and memory impairment [Adjusted‐=‐0.38 (SE=0.08); p value=<.001]. Compared to individuals with transient NPS, sustained NPS was also associated with reduced glucose metabolism [Adjusted‐=‐0.03 (SE=0.01); p value=0.018], and lower memory scores [Adjusted‐=‐0.17 (SE=0.06); p value=0.007], but not executive functioning. Compared to no or transient NPS, the risk for incident dementia was highest in the sustained NPS group (HR 1.87, 95% CI 1.50 to 2.34).ConclusionIn a cohort of individuals with MCI, baseline NPS are associated with biomarkers of dementia risk and predict progression to dementia. MBI, as operationalized here by sustained NPS, was associated with worse memory, lower glucose metabolism, and higher risk of incident dementia compared to transient NPS. There is diagnostic and prognostic utility in determining if NPS are sustained or transient, further validating the MBI construct.
The Oxford Brain Health Centre: Embedding dementia research in clinical practice
Authors: O'Donoghue M Clare , Raymont Vanessa , Fossey Jane , Semple Juliet , Griffanti Ludovica , Zokaei Nahid , Nobre Anna Christina , Martos Lola , Mackay Clare 
Published: December 2020

AbstractIntroductionThe Oxford Brain Health Centre (BHC) is an ambitious and innovative joint clinical‐research service that aims to bring UK NHS memory services into the 21st century by addressing gaps between clinical practice and research advances into dementia. This NIHR‐funded partnership between Oxford Health NHS Foundation Trust and the University of Oxford will be the first psychiatry‐led service of its kind, developing the model for a specialist service that can be adopted throughout the UK health service.Methods and MaterialsThe BHC will augment current NHS memory services by providing high‐quality assessments not routinely available in clinical service, e.g. MRI rather than CT brain scans, and developing novel diagnostic tools sensitive to earlier pathological changes. Enhanced information will be fed into clinical notes, improving the quality of information available to clinicians empowered to make more confident and accurate timely diagnoses. The BHC will increase opportunities for patients and relatives to participate in research by embedding research in the clinical service, through use of clinical data for research, completion of additional research assessments, and re‐contact about future research opportunities. All research data collected at the BHC will be made openly available to the scientific community through the BHC Research Database, encouraging collaborative and transparent research. The BHC actively involves public contributors with lived experience at all stages of the development and evolution of the service.ResultsA six‐month pilot of 150 patients from a single memory clinic will launch in early 2020 to demonstrate feasibility and refine procedures, before expanding to other memory clinics. The pilot will incorporate evaluation of service‐user and clinician feedback and health economic measures.ConclusionsTo prepare the UK health system for the future of dementia treatment and ultimately prevention, the BHC will provide a translational interface, enabling new advances in diagnosis, risk reduction and treatment to be rapidly implemented in clinical practice to provide better care for patients.