bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increasing awareness and interest in AD/ADRD clinical trials using culturally tailored messages: A synthesis of three national surveys, 2019–2021
Authors: Massett Holly A , McGowan Melissa , Simoneau Elizabeth , Bui Elise , Jarvis‐Gibson Jeanne , Mitchell Alexandra , Rehberg Kathryn , Miscally Memi 
Published: December 2022

AbstractBackgroundLimited participation of Black/African American (B/AA), Hispanic/Latino (H/L), and Asian American & Pacific Islander (AAPI) communities in AD/ADRD clinical trials (CT) is partly due to few researchers offering trial opportunities and inadequate CT information that is culturally relevant. We present the results of three National Institute on Aging (NIA) national surveys conducted with B/AA, H/L, and AAPI samples to assess the impact of culturally tailored outreach materials for each group, respectively, on individuals’ likelihood to consider participating in CTs.MethodOnline panel surveys were conducted with B/AA (N = 616; 2019), H/L (N = 545; 2020), and AAPI (N = 756; 2021) individuals who: 1) had a family history AD/ADRD, 2) were caring for an individual with AD/ADRD, or 3) reported no family history of AD/ADRD. The surveys assessed if viewing creative concepts (four print/photo ads developed specifically with and for each population using focus groups) positively impacted participants’ likelihood to consider participating in an AD/ADRD CTs.ResultAfter reviewing their respective ads, B/AA and H/L at‐risk, caregiver, and healthy audiences, and AAPI at‐risk individuals, all significantly increased their reported pre‐posttest “likelihood to consider a CT”. AAPI caregivers started with and maintained a high level of interest but did not change their likelihood to consider a CT. Across all groups, there was a median 12.5% increase of individuals reporting “very” or “extremely interested” in AD/ADRD CTs. Persons with family history had greater increases among B/AA and AAPI, while caregivers did among H/L. Motivating CT messages for all groups were: help/hope for their future generations (family/community) the potential to prevent/treat the disease. B/AA respondents also were motivated to find treatments that could work for all races.ConclusionThe findings highlight that culturally appropriate outreach materials, developed with and for specific groups, can generate significant interest in participation of AD/ADRD clinical trials after viewing only four ads. Though common themes emerged, focus groups and surveys indicated specific yet critical nuances differentiating message preferences across B/AA, H/L, and AAPI groups. This is the only known research to systematically explore AD/ADRD CT communication needs within and across traditionally underserved populations.
The mean diffusion propagator model revealed cortical microstructural changes associated with both amyloid‐β and tau pathology and astroglial activation
Authors: Spotorno Nicola , Strandberg Olof , Vis Geraline , Stomrud Erik , Nilsson Markus , Hansson Oskar 
Published: December 2022

AbstractBackgroundMarkers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Morphometric metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect Aβ‐related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes that could complement morphometric macrostructural measures.MethodWe applied the mean apparent diffusion propagator model (MAP‐MRI) to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐2 cohort. MAP‐MRI extends diffusion tensor imaging and provides metrics sensitive to subtle changes in the cortex. Participants were stratified in Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on Aβ‐ and tau‐PET uptake. Cortical regional values of both MAP‐MRI metrics and CT were compared across groups. Associations between regional values of MAP‐MRI metrics and both Aβ‐ and tau‐PET uptake were also investigated as well as the association between MAP‐MRI metrics and plasma level of GFAP, a marker of astroglial activation (available in 292 participants).ResultMean square displacement (MSD) from MAP‐MRI revealed widespread microstructural differences already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness appeared to be more limited (figure 1). MSD was also highly correlated with both Aβ‐ and tau‐PET uptake even independently from one another (figure 2). Regional MSD values were associated with GFAP with a pattern that resemble Aβ accumulation, and GFAP partially mediated the association between Aβ and MSD. A sensitivity analysis controlling for cortical thickness revealed that the associations between MSD and Aβ‐PET, tau‐PET and GFAP were largely independent from macrostructural changes (figures 2‐3).ConclusionMetrics of cortical microstructural alteration derived from MAP‐MRI are highly sensitive to multiple aspects of the AD pathological cascade. Of particular interest is the link between MSD, Aβ‐PET and GFAP which suggests MSD might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, MSD could help monitoring the response to anti‐Aβ treatments in clinical trials.
Blood immune response genes are correlated with brain glucose metabolism
Authors: Ramos Vanessa G. , Povala Guilherme , De Bastiani Marco Antônio , Bellaver Bruna , Pascoal Tharick A , Ferreira Pamela C.L. , Zimmer Eduardo R. 
Published: December 2022

AbstractBackgroundImaging techniques such as positron emission tomography (PET) have been fundamental to develop our understanding about Alzheimer's disease (AD) underlying features. Evidence suggests that neuroinflammation plays a complex role in the pathophysiology of AD. Nevertheless, whether peripheral inflammation affects brain function remains to be defined. In this context, the integration of blood‐based measures and imaging modalities can facilitate the understanding of the periphery‐brain interface in AD. Here, we developed a method to integrate immune response‐related genes, derived from blood transcriptomics, with [18F] Fluorodeoxyglucose ([18F]FDG)‐PET imaging data. We hypothesized that the differential expression of immune‐related genes would be associated with brain metabolism as indexed by [18F]FDG‐PET signal.MethodBlood transcriptome profiles and imaging data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Differential gene expression analysis was performed in 99 Cognitively Unimpaired (CU) and 218 Cognitively Impaired (CI) individuals, whose differentially expressed genes (DEGs) underwent functional enrichment analysis Gene Ontology (GO). Immune‐related GO terms were clustered by semantic similarity using the GOSemSim method for biological processes ontology. All computations analysis were performed in the R statistical environment. Integration with [18F]FDG‐PET images was performed using voxel generalized linear regression (GLR) models considering the covariates age, gender, education, and APOE ε4 status (RMINC package).ResultsPeripheral blood cells transcriptome analysis identified 10 enriched GO terms associated with the immune response. For each term, the GLR models were used to calculate voxel‐wise associations between [18F]FDG and gene expression, resulting in a t‐statistical map. Figure 1 demonstrated the uncorrected statistically significant correlated voxels (t‐value > 2.0). At the voxel level, biological processes related to regulatory mechanisms of innate immunity presented a 32% Correspondence with [18F]FDG‐PET signal in the gray matter of the medial frontal‐orbital gyrus.ConclusionHere, we demonstrated a significant association between brain glucose metabolism and immune‐related blood DEGs. Our findings suggest that peripheral inflammation that occurs in AD patients might have an impact on [18F]FDG‐PET metabolism.
Genetic analyses of diffusion MRI phenotypes: a lifespan exploration of cSVD determinants
Authors: Grand Quentin Le , Tsuchida Ami , Koch Alexandra , Breteler Monique M.B. , Seshadri Sudha , Tzourio Christophe , Crivello Fabrice , Debette Stéphanie 
Published: December 2022

AbstractBackgroundCerebral small vessel disease (cSVD) is a leading cause of vascular cognitive impairment and dementia. Mounting evidence suggests that early life factors contribute to cSVD. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI‐marker of cSVD in older age, were recently found to show strong associations with white matter microstructure on diffusion tensor imaging (DTI) already in young adults in their twenties. Here we aimed to use multi‐shell diffusion imaging to further explore genetic determinants of white matter microstructure across the adult lifespan and its relation with cSVD.MethodIn 1,758 participants (mean age: 22.1 [18 to 35] years) from the i‐Share student cohort who underwent multi‐shell diffusion imaging, we used neurite orientation dispersion and density imaging (NODDI) to generate tissue‐based markers of white matter microstructure including neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) in 28 brain regions. We ran genome‐wide association studies (GWAS) of all 84 NODDI markers in i‐Share and looked up genome‐wide significant variants in UK Biobank (N = 33,224, mean age: 64.3 [45 to 82] years) to identify loci with a lifecourse effect on these phenotypes. Next, we studied the association of genetically determined WMH volume and blood pressure with NODDI phenotypes in i‐Share using Mendelian randomization (MR).ResultThis first GWAS of 84 NODDI phenotypes in young adults identified 21 genome‐wide significant loci. Three of them, associated mostly with NDI, also showed significant association with NODDI phenotypes in middle‐aged to older UK Biobank participants, including a known WMH locus near VCAN, a cerebrovascular matrisome gene. Using MR we found that genetically determined WMH, previously shown to predict Alzheimer‐type dementia, was associated with lower NDI in young adults. In contrast, genetically determined blood pressure, although an important risk factor for WMH volume, did not show any significant association with NODDI phenotypes in young adults.ConclusionOur results suggest that NODDI markers, especially NDI, have a substantial genetic component already in early adulthood and may inform early mechanisms underlying the vascular contribution to dementia. Replication of these findings in additional CHARGE cohorts (Rhineland study, Framingham Heart study) is underway.
The Neurofilament Surveillance Project (NSP): A biomarker study to sample blood quarterly in familial frontotemporal lobar degeneration
Authors: Acuna‐Narvaez Rachel , Heuer Hilary W. , Forsberg Leah K. , Alward Anne , Graham Danielle , Fishman Ann , Nelson Kevin M , Kolander Tyler , Fillit Howard M , Galpern Wendy R , Hung Serena , Mason Chris , Mignon Laurence , Ni Yan G , Simen Arthur , Tesseur Ina , Tsai Richard , Yeh Felix L , Mester Carly T. , Ljubenkov Peter A. , Rosen Howard J. , Boeve Bradley F. , Boxer Adam L. , Pearlman Rodney , Mitic Laura L ,   NSP Site Investigators
Published: December 2022

AbstractBackgroundIn familial frontotemporal lobar degeneration (f‐FTLD), plasma levels of neurofilament light (NfL) are elevated at least two years prior to symptom onset and predict future clinical status. The Neurofilament Surveillance Project (NSP), an actively recruiting observational study, seeks to obtain higher resolution data of temporal changes in plasma NfL to better understand its clinical utility in f‐FTLD interventional trials. The NSP is a pre‐competitive collaboration sponsored by the Bluefield Project to Cure FTD and funded by biotechnology and pharmaceutical companies and nonprofit organizations.MethodParticipants must be members of families with disease‐causing mutations in C9orf72, MAPT or GRN and enrolled in the ALLFTD natural history study. Up to 335 participants, with roughly equal representation across mutation type, provide plasma quarterly for 3 years (4355 samples total) to enable the observation of peripheral NfL levels longitudinally during disease onset and progression. Plasma is collected by certified mobile research nurses during remote visits, and NfL is measured in batch at least every 6 months. NfL measurements from one plasma aliquot per draw will be correlated with annual assessments obtained in the ALLFTD study, including measures of disease severity (CDRÒ+NACC‐FTLD, CGI, etc.), cognitive function from the UDS Neuropsychology Battery, and volumetric MRI data. Additional plasma aliquots are reserved for future analyses of other biomarkers during the course of the study; another subset of aliquots is reserved to share with interested investigators after the study ends.ResultAs of 1/19/22, the NSP had enrolled 161 participants, including 62 from C9orf72 kindreds, 60 from MAPT kindreds, and 28 from GRN kindreds. One‐hundred forty‐five participants had completed their initial visit, and 109 had completed more than 3, and up to 5, quarterly blood draws. Enrollment and study visits are ongoing despite COVID‐related limitations.ConclusionThe quarterly blood sampling from this study, combined with annual comprehensive clinical assessments through the ALLFTD natural history study, will enable a more detailed understanding of when and how NfL levels change during phenoconversion and/or disease progression in f‐FTLD mutation carriers. These data will be especially informative in the context of the targeted investigational therapeutics for f‐FTLD now entering clinical trials.
The role of Cognitive Reserve and depression on executive functions in older adults: a 10‐year longitudinal study
Authors: Frau Loredana , Jonaitis Erin M. , Koscik Rebecca Langhough , Zuelsdorff Megan , Okonkwo Ozioma C. , Bruno Davide 
Published: December 2022

AbstractBackgroundCognitive reserve (CR) refers to the use of compensatory strategies related to executive functions (EFs) to reduce the negative effects of age‐related brain changes. Depression represents a risk factor for dementia, but little is known about its role in the association between CR and EFs.In the present study, we tested whether depression moderated the association between CR and EFs, and which variables among CR, depression and APOE‐e4 status (e4/non‐e4) predicted conversion to Cognitively Unimpaired‐Declining (CUD; Johnson et al., 2018) and Mild Cognitive Impairment (MCI) from a Cognitively Unimpaired‐Stable (CUS) baseline.Method416 participants were selected from the Wisconsin Registry for Alzheimer’s Prevention. These were native English speakers, aged ≥50, CUS at baseline, and with no history of neurological or psychiatric disorders. Of these, 290 were still CUS, 97 were CUD and 29 had MCI at the 10‐year follow‐up visit. Depression was assessed with the 20‐item Center for Epidemiologic Studies Depression Scale (CES‐D). A standardized composite score from three tests (CFL, Digit Span, Letter‐Number sequencing) estimated EFs. Another composite score, based on the WRAT‐3 Reading subtest (a measure of literacy or premorbid abilities) and years of education estimated CR. A hierarchical linear regression was performed to evaluate the effect of CR and depression on EFs at follow‐up. Baseline demographic variables (age, gender, APOE‐e4) and diagnosis at follow‐up (CUS, CUD, MCI) were entered in Model 1, CR and depression in Model 2, and the CR*Depression interaction in Model 3. Moreover, a multinomial logistic regression was used to predict conversion to CUD and MCI from baseline.ResultModel 3 added significantly onto Model 2 (p = .024), indicating a moderation between CR and depression on EFs. Particularly, the beneficial effects of CR on EFs seem to be mitigated by increasing levels of depression. In the multinomial regression, depression predicted conversion to CUD from CUS while CR, depression and APOE‐e4 predicted conversion to MCI from CUS.ConclusionThese findings support the hypothesis that CR, associated with EFs, may protect against cognitive aging, but also highlight the disruptive effect that depression has on long‐term cognitive health. Further studies may replicate these findings in clinical populations.
Building an Academic Infrastructure for Rigorous Testing of Online Platforms to Support Family Caregivers
Authors: Koeuth Sokha , Kales Helen C , Kern Vincent Joseph , Bouranis Nicole G , Webster Melinda J , Gitlin Laura N. 
Published: December 2022

AbstractBackgroundWith COVID‐19, online opportunities to support families living with dementia are becoming increasingly important. However, academic institutions are typically not prepared to develop and test online platforms. We present a case study to describe steps for creating an infrastructure to test an online platform, WeCareAdvisor (WCA). WCA provides caregivers disease education and tailored strategies to manage dementia‐related behavioral symptoms using the DICE Approach. WCA was previously tested in a small, randomized trial demonstrating positive caregiver outcomes. To advance its evidence‐base, WCA is being tested in a NIA‐funded Stage III efficacy trial with a national sample of 326 caregivers.MethodTo test WCA, an infrastructure in the academic institution had to be created to address HIPAA compliance, privacy considerations, integrate user and developer input, and support rigorous trial methodologies. Through key informant interviews and literature reviews, we established a six‐step process: 1) Identifying and engaging key stakeholders (legal, Information Technology offices, research team, software company); 2) Creating software development agreement with stakeholder input; 3) Detailing scope of work and an oversight structure of software company, 4) Developing formal agreements with the software company, 5) Conducting security assessments with university IT offices; and 6) Establishing formal vendor status of the software company. This also necessitated new roles and responsibilities of research team members.ResultThe six‐step process was labor intensive, transpired over 12 months, and involved over 15 iterative meetings with investigators, project staff, and stakeholders. Careful coordination of stakeholders to provide practical and iterative guidance at each of the six steps was essential. Deliberations resulted in app store access, URLs and domains, and compliance and privacy statements reviewed and approved by various university offices, and then launching WCA on app stores for access by study participants.ConclusionResearchers and academic institutions have varying levels of understanding and readiness to engage in infrastructure development to rigorously test online platforms. Our approach resulted in an effective infrastructure for testing WCA which can be used by other researchers. Development of an infrastructure requires new skills for investigators, engaging multiple stakeholders, appropriately budgeting for this activity, and allocating sufficient start‐up time.
Single‐Molecule Detection of Isoform‐Specific Tau Phosphorylation
Authors: Mallick Parag 
Published: December 2022

AbstractBackgroundPost‐translational modifications (PTMs) contribute to the vast diversity of proteoforms that drive biological processes. Currently, very little is known about the molecular heterogeneity of proteoforms. This gap can be dominantly attributed to a lack of methods to analyze PTMs on intact single protein molecules on a proteome‐scale.MethodHere, we introduce an antibody‐based single‐molecule analysis platform that includes novel biochemistry for single‐protein molecule immobilization, instrumentation for highly sensitive detection, and computation for data interpretation. We use this platform to study Tau proteoforms. Aberrant PTMs on Tau generate a wide diversity of proteoforms that lead to Tau misfolding and aggregation and are associated with neurodegenerative disorders collectively referred to as Tauopathies.ResultFirst, we validate the platform by measuring defined mixtures of recombinant tau proteins. Next, we use the platform to examine tau protein enriched from human induced pluripotent stem cell (iPSC)‐derived neurons and tau‐expressing cell lines. As PTMs can be assigned to individual protein molecules, the platform is able to reveal the molecular heterogeneity of tau proteoforms that is missed by both bulk measurements and by peptide‐centric proteomics approaches.ConclusionUltimately, quantitative analysis of proteoform molecular heterogeneity will lead to a more detailed view of the tau proteoform landscape towards advancing precision medicine of tauopathies, such as Alzheimer’s disease.
Distinct volumetric features of cerebrospinal fluid distribution in idiopathic normal‐pressure hydrocephalus and Alzheimer’s disease
Authors: Kang Kyunghun , Jeong Shin Young , Lee Sang‐Woo , Yoon Uicheul 
Published: December 2022

AbstractBackgroundThe imaging characteristics of ventriculomegaly, high‐convexity tightness, and Sylvian fissure dilation has been called “disproportionately enlarged subarachnoid space hydrocephalus”.ObjectiveTo investigate relationships in cerebrospinal fluid (CSF) volumes between the lateral ventricle, high‐convexity subarachnoid space, and Sylvian fissure region in patients with idiopathic normal‐pressure hydrocephalus (INPH) and Alzheimer’s disease (AD), and to evaluate differences in these volumes among INPH, AD, and healthy controls.MethodsForty‐nine INPH patients, 59 AD patients, and 26 healthy controls were imaged with three‐dimensional MRI.ResultsINPH patients had larger lateral ventricles and CSF spaces of the Sylvian fissure region and smaller high‐convexity subarachnoid spaces than other groups, and AD patients had larger lateral ventricles and CSF spaces of the Sylvian fissure region than the control group. The INPH group showed a negative correlation between lateral ventricle and high‐convexity subarachnoid space volumes, while the AD group showed a positive correlation between lateral ventricle volume and volume for CSF spaces of the Sylvian fissure region. The ratio of lateral ventricle to high‐convexity subarachnoid space volumes yielded an area under the curve of 0.990, differentiating INPH from AD.ConclusionsAssociations between CSF volumes suggest different mechanisms between INPH and AD to explain their respective lateral ventricular dilation. In AD, lateral ventricular enlargement might be associated with brain volume loss through cortical atrophy. In INPH, the lateral ventricles may expand superiorly into the high‐convexity area, and this may further instigate cortical thickening. The ratio of lateral ventricle to high‐convexity subarachnoid space volumes distinguishes INPH from AD with good diagnostic sensitivity and specificity. We propose to refer to this ratio as the VOSS (ventricle over subarachnoid space) index.