bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex differences in white matter microstructure in aging and Alzheimer’s disease: A multi‐site free‐water imaging study
Authors: Archer Derek B , Shashikumar Niranjana , Jasodanand Varuna , Moore Elizabeth E. , Pechman Kimberly R. , Bilgel Murat , Beason‐Held Lori L , An Yang , Shafer Andrea T , Risacher Shannon L. , Landman Bennett A. , Jefferson Angela L. , Saykin Andrew J. , Resnick Susan M. , Hohman Timothy J. ,   Alzheimer's Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundSex differences in gray matter alterations in aging and AD have been reported, but there have been few large‐scale studies evaluating white matter microstructure. The goal of this study is to leverage multi‐site harmonized diffusion MRI data in tandem with free‐water (FW) imaging to determine the association between sex and white matter microstructure in aging and AD.MethodThe dataset used in this study leveraged cross‐sectional data from several cohorts of aging [Alzheimer’s Neuroimaging Initiative (ADNI), Baltimore Longitudinal Study of Aging (BLSA), Vanderbilt Memory & Aging Project (VMAP)]. This dataset included 1,898 participants (72±9 years, 59% female). Data was processed using standard preprocessing techniques and followed up with FW postprocessing. FW and FW‐corrected intracellular metrics of fractional anisotropy (FAT), radial diffusivity (RDT), and axial diffusivity (ADT) were then quantified within seven white matter tractography templates (see Figure 1A) and harmonized using the ComBat technique. The sex differences for each microstructural metric were then determined using a linear regression model covarying for age, diagnosis, education, and APOE‐ε4 carrier status. Secondary analyses were conducted to determine sex x diagnosis interactions on white matter microstructure.ResultWhile we found no sex differences in FW, there were significant associations in all intracellular metrics. Females had significantly lower FAT in the association (pFDR=6.62x10‐10), limbic (pFDR=5.28x10‐9), motor transcallosal (TC) (pFDR=0.008), prefrontal TC (pFDR=6.34x10‐6), and projection (pFDR=4.74x10‐20) tracts and significantly lower ADT in the association (pFDR=5.23x10‐10), limbic (pFDR=1.84x10‐6), prefrontal TC (pFDR=4.41x10‐11), and projection (pFDR=5.29x10‐17) tracts. For RDT, females exhibited higher RDT in all tracts (pFDR range: 4.94x10‐16 – 0.022). Illustrations of these results can be found in Figure 1. Sex differences were compared across cohorts and were similar (Figure 2). The only significant sex x diagnosis interaction was for the projection tract RDT measure (pFDR=0.043, Figure 3).ConclusionThis study suggests intracellular microstructural values (i.e., FAT, ADT, RDT) exhibit strong sex differences, whereby females have lower FAT/ADT and higher RDT compared to males. We also found a sex x diagnosis interaction for projection tract RDT, whereby females with AD exhibited lower RDT, but larger studies with more AD cases would be needed to further explore this finding.
White matter hyperintensities in Down syndrome: associations with demographic, genetic, fluid and imaging biomarkers of Alzheimer's disease
Authors: Morcillo‐Nieto Alejandra O. , Zsadanyi Sara E. , Carmona‐Iragui Maria , Montal Victor , Pegueroles Jordi , Aranha Mateus Rozalem , Padilla Concepcion , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Altuna Miren , Giménez Sandra , González‐Ortiz Sofía , Bargalló Núria , Ribas Laia , Arranz Javier , Torres Soraya , Iulita Maria Florencia , Belbin Olivia , Camacho Valle , Alcolea Daniel , Blesa Rafael , Lleó Alberto , Fortea Juan , Bejanin Alexandre 
Published: December 2022

AbstractBackgroundStrong associations between age, Alzheimer’s disease (AD), and vascular risk factors create challenges to delineate the specific relationships between white matter hyperintensities (WMH) and AD pathophysiology. Down syndrome (DS), a genetically determined form of AD, is not typically complicated by systematic vascular risk factors like hypertension and atherosclerosis and can therefore provide critical information in this regard. We aim to further characterize topography of WMH in DS along the AD continuum and define associations with demographic, genetic, fluid and other imaging biomarkers.MethodIn this cross‐sectional study, adults with DS from Down‐Alzheimer Barcelona Neuroimaging Initiative (DABNI) underwent a 3T‐MRI protocol, including 3D‐T1 and 3D‐FLAIR acquisitions. Gray matter (GM) volumes were computed using the CAT12 Toolbox. WMH were segmented using the lesion prediction algorithm implemented in the Lesion Segmentation Toolbox for SPM12. Segmented maps were binarized (threshold of 0.5) and WMH volumes were extracted in each brain lobe, subregions of the corpus callosum, and periventricular versus deep regions (using the standard 10mm limit from the lateral ventricles). Non‐parametric statistical tests were used to assess effects of disease severity on WMH and define associations between WMH and demographic and genetic data, CSF AD biomarkers and GM volumes.ResultsWe included 116 individuals with DS (Table 1). WMH volume was higher in prodromal and demented groups for all brain regions (Fig 1). Moreover, WMH increased with disease severity such that the demented group demonstrated larger WMH volume than the prodromal group in periventricular regions, frontal and temporal lobes, and body and splenium subregions of the corpus callosum. Total WMH volume was associated with age but not sex, intellectual disability or APOE haplotype (Fig 2). Total WMH volume was negatively related to CSF Aβ42/40 ratio and positively related to CSF t‐tau and p‐tau‐181 concentrations (Fig 3). Associations with GM volumes were widespread, but strongest in parieto‐occipital‐temporal regions.ConclusionWMH increases with AD pathology and the emergence of clinical symptoms in DS, a population with lower vascular risk factors. It also relates to neurodegeneration in typical AD regions at both asymptomatic and symptomatic stages. Altogether, this suggests that WMH might be intrinsically related to AD pathophysiological processes.
Non‐amnestic initial cognitive symptoms have faster trajectories of clinical progression than amnestic symptoms in Alzheimer’s, Lewy body and mixed dementia neuropathologies
Authors: Pillai Jagan A. , Bena James , Leverenz James B. 
Published: December 2022

AbstractBackgroundDiagnostic guidelines currently exist for typical and atypical Alzheimer’s disease (AD). Significant heterogeneity exists among initial predominant clinical symptoms among Lewy body‐related pathology (LRP) in addition to primary AD pathology (ADP) and. However, the clinical relevance of initial amnestic or non‐amnestic cognitive symptoms among them are unclear. Our objective was to determine if initial cognitive symptoms had similar rates of functional decline across ADP, LRP and mixed ADP‐LRP neuropathologies.MethodA retrospective longitudinal cohort study was conducted among 2422 participants with autopsy confirmed ADP, LRP, or mixed ADP‐LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019. All participants had a Clinical Dementia Rating‐Global (CDR‐G) scale ≤1 at initial clinical visit. The primary outcome of interest was Clinical Dementia Rating‐sum of boxes (CDR‐SB). Linear mixed models adjusted for baseline CDR‐SB, age, sex, education and APOEε4 status were used to evaluate longitudinal outcomes. Multiple imputations using fully conditional specification was performed to account for missing data in the multivariable modelsResult2422 Participants (1187 with ADP, 904 with ADP‐LRP and 331 with LRP) had a mean (SD) interval of 5.5 (2.8) years from initial visit to autopsy. Language symptoms had a consistently faster rate of decline per year than amnestic symptoms across all three pathologies (ADP, β 0.29, [95%CI, 0.16 to 0.41], p<0.001; LRP, β 0.69 [95%CI, 0.44 to 0.94], p<0.001;ADP‐LRP, β 0.40, [95%CI, 0.22 to 0.57], p<0.001). Executive symptoms had a faster rate of decline than amnestic symptoms in ADP, β 0.36, [95%CI, 0.21 to 0.51], p<0.001 and ADP‐LRP, β 0.25 [95%CI, 0.07 to 0.42], p = 0.008. Visuospatial symptoms had a faster rate of decline than amnestic symptoms in ADP‐LRP, β 0.38 [95%CI, 0.12 to 0.65], p = 0.013.ConclusionNon‐amnestic phenotypes have faster trajectories of clinical progression than amnestic across three pathology subgroups. Language phenotypes have the fastest progression.
Higher arterial stiffness and systolic blood pressure are differentially associated with lower perfusion in subcortical and cortical gray matter regions
Authors: Lipford Megan E. , Lockhart Samuel N. , Coffin Claudia Ashlyn , Suerken Cynthia , Bateman James R. , Barcus Richard A. , Whitlow Christopher T. , Craft Suzanne , Hughes Tim M. 
Published: December 2022

AbstractBackgroundHigher arterial stiffness is associated with lower regional cerebral blood flow (CBF) in older adults. Cortical CBF also correlates with higher systolic blood pressure (SBP). We examined relationships of lobar and deep gray matter CBF with both SBP and arterial stiffness.MethodParticipants of the Clinical Core of the Wake Forest Alzheimer’s Disease Research Center completed baseline clinical examination including measures of: arterial stiffness, blood pressure, medication review, APOE genotyping, 3T MRI, detailed cognitive testing, and cognitive adjudication. T1 structural and pseudocontinuous arterial spin labeling (pcASL) MRI were used to quantify gray matter (GM) CBF in AAL atlas regions. GM CBF was quantified into lobar (frontal, temporal, parietal, occipital), subcortical (caudate, putamen, pallidum, and thalamus), Cingulate/Insula, and posterior (cerebellum and vermis) regions. Arterial stiffness was measured twice in the supine position and averaged to quantify carotid‐femoral pulse wave velocity (cfPWV). Associations for cfPWV and systolic blood pressure (SBP) with GM CBF ROIs was examined by multivariable linear regression models adjusted for age, race, gender, education, hypertension medications, and APOE‐e4 carrier status.Result:Among 404 participants (70±8 years; 39 dementia, 139 MCI, 226 normal cognition), higher cfPWV and SBP were differentially associated with regional GM CBF (Fig 1 & 2). Higher cfPWV was associated with lower subcortical GM CBF (p=0.04) (Table 1). Higher SBP was associated with lower GM CBF in frontal (p=0.03), temporal (p=0.02) and occipital lobes (p=0.01) (Table 1).ConclusionDeep subcortical brain structures may be at greater risk of damage from high arterial stiffness because they are perfused by arteries which branch relatively upstream of other branching arteries, as evidenced by lower GM CBF. High SBP may predict vascular damage in cortical regions manifested as lower GM CBF. These differential relationships with deep and cortical perfusion support and extend prior observations in this group relating vascular risk factors to abnormalities in white matter micro‐ and macro‐ structure, lower total CBF, and lower cognitive performance.
Higher arterial stiffness and systolic blood pressure are differentially associated with lower perfusion in subcortical and cortical gray matter regions
Authors: Lipford Megan E. , Lockhart Samuel N. , Coffin Claudia Ashlyn , Suerken Cynthia , Bateman James R. , Barcus Richard A. , Whitlow Christopher T. , Craft Suzanne , Hughes Tim M. 
Published: December 2022

AbstractBackgroundHigher arterial stiffness is associated with lower regional cerebral blood flow (CBF) in older adults. Cortical CBF also correlates with higher systolic blood pressure (SBP). We examined relationships of lobar and deep gray matter CBF with both SBP and arterial stiffness.MethodParticipants of the Clinical Core of the Wake Forest Alzheimer’s Disease Research Center completed baseline clinical examination including measures of: arterial stiffness, blood pressure, medication review, APOE genotyping, 3T MRI, detailed cognitive testing, and cognitive adjudication. T1 structural and pseudocontinuous arterial spin labeling (pcASL) MRI were used to quantify gray matter (GM) CBF in AAL atlas regions. GM CBF was quantified into lobar (frontal, temporal, parietal, occipital), subcortical (caudate, putamen, pallidum, and thalamus), Cingulate/Insula, and posterior (cerebellum and vermis) regions. Arterial stiffness was measured twice in the supine position and averaged to quantify carotid‐femoral pulse wave velocity (cfPWV). Associations for cfPWV and systolic blood pressure (SBP) with GM CBF ROIs was examined by multivariable linear regression models adjusted for age, race, gender, education, hypertension medications, and APOE‐e4 carrier status.ResultAmong 404 participants (70±8 years; 39 dementia, 139 MCI, 226 normal cognition), higher cfPWV and SBP were differentially associated with regional GM CBF (Fig 1 & 2). Higher cfPWV was associated with lower subcortical GM CBF (p=0.04) (Table 1). Higher SBP was associated with lower GM CBF in frontal (p=0.03), temporal (p=0.02) and occipital lobes (p=0.01) (Table 1).ConclusionDeep subcortical brain structures may be at greater risk of damage from high arterial stiffness because they are perfused by arteries which branch relatively upstream of other branching arteries, as evidenced by lower GM CBF. High SBP may predict vascular damage in cortical regions manifested as lower GM CBF. These differential relationships with deep and cortical perfusion support and extend prior observations in this group relating vascular risk factors to abnormalities in white matter micro‐ and macro‐ structure, lower total CBF, and lower cognitive performance.
A Genome‐Wide Search for Pleiotropy in Cognitive Domain Scores
Authors: Kang Moonil , Mez Jesse B. , Ang Ting Fang Alvin , Devine Sherral A. , Mukherjee Shubhabrata , Trittschuh Emily H. , Saykin Andrew J. , Crane Paul K. , Au Rhoda , Lunetta Kathryn L. , Farrer Lindsay A. 
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWASs) have identified loci for Alzheimer’s disease (AD)‐related cognitive traits, and genetic correlations among these traits suggest that a single gene may affect them jointly, i.e., pleiotropy.MethodWe conducted GWASs for scores previously generated by factor analyses for cognitive domains—executive function, language, and memory—using longitudinal data from 7,503 Framingham Heart Study (FHS) and 6,758 National Alzheimer’s Coordinating Center (NACC) subjects who had an average of five and three exams, respectively. We averaged domain scores for each participant by weighting down scores at the visit without normal cognition and used the sum of weights to account for heterogeneous residual variances. The association of each domain score with 8.9 million genetic variants (MAF>0.01), imputed using the TOPMed reference panel (GRCh38), was tested separately in each dataset using linear models including age, sex, education level, and five principal components of ancestry as covariates. Results from FHS and NACC datasets were combined by meta‐analyses using the inverse‐variance method. Pleiotropy for each pair of cognitive domains was evaluated using PLACO (pleiotropic analysis under the composite null hypothesis).ResultScores for paired cognitive domains were moderately genetically correlated—executive function and language (ρP
=0.46, ρG
=0.69), executive function and memory (ρP
=0.39, ρG
=0.43), language and memory (ρP
=0.44, ρG
=0.46). Pleiotropy analyses revealed genome‐wide significant associations for all paired domain scores with many variants in the APOE region (p<3.91×10‐9 for each). For pleiotropy of executive function and language, we identified genome‐wide significant associations with DOK5 (rs28663252, p=4.51×10‐8) and suggestive associations with SOX14 (rs55829884, p=8.03×10‐8), IL20RB (rs11925531, p=9.26×10‐8), and RIMS2 (rs140291972, p=8.76×10‐7). We also found suggestive associations for pleiotropy of language and memory with LHFPL4 (rs2936482, p=5.08×10‐8) and for pleiotropy of executive function and memory with MC4R (rs1943220, p=7.54×10‐8) and CDH20 (rs78756286, p=1.50×10‐7).ConclusionWe identified significant evidence of pleiotropy for multiple cognitive domains, and these findings may improve the interpretation of the genetic basis of cognition and AD‐related traits. These results highlight the benefits of factor scores derived from groups of subjects assessed with various cognitive tests and pleiotropy analysis as a tool for identifying genes that contribute to performance in multiple cognitive domains.
Dementia neuropsychiatric prevalence, severity, and correlates in community‐dwelling Thai older adults
Authors: Hinton Ladson , Wang Kaipeng , Levkoff Sue E , Chuengsatiansup Komatra , Sihapark Siranee , Gallagher‐Thompson Dolores , Chen Hongtu 
Published: December 2022

AbstractBackgroundThailand is experiencing a rapid increase in the number of older persons with dementia, yet little is known about the nature and consequences of dementia neuropsychiatric symptoms (NPS), particularly outside of clinical settings. We examined the prevalence, severity, and correlates of NPS, including correlation with family caregiver burden and distress, among community‐dwelling Thai older adults with probable dementia.MethodsThis study is based on analysis of baseline data from a hybrid type III cluster randomized design comparing two different implementation approaches of an evidence‐based exercise intervention for persons with dementia. A three‐step recruitment process was used for recruiting participants from the local healthcare system and included clinical case confirmation of probable degenerative dementia. To be eligible, participants needed to be age 60 and above, have probable dementia, have 1 or more NPS, be ambulatory, and have an adult (age 18+) family caregiver. 353 participants enrolled in the study and completed based assessments, including NPS assessment, caregiver stress associated with NPS, as well as other care recipient and caregiver characteristics. We examined NPS severity with caregiver distress and used ordinary least squares (OLS) regression to examine associations between PWD and caregiver characteristics and NPS severity.ResultsNPS prevalence varied from 18% for appetite/eating changes to 42% for delusions. NPS severity was significantly (P < .05) associated with caregiver stress for all individual NPS. Among PWD characteristics, higher ADL score (less functional impairment) was inversely associated with NPS total severity (b = ‐0.16, p < 0.05). More physical role limitation was significantly associated with higher NPS total severity (b = 0.77, p < 0.001). Among caregivers’ characteristics, higher burden was significantly associated with higher NPS total severity (b = 0.19, p < 0.001).ConclusionsOur study found that NPS are common among community dwelling PWD in Thailand and are associated with adverse impacts on both PWD and family caregivers. These findings highlight the clinical importance of NPS symptoms among Thai older adults. The high prevalence of psychotic symptoms in this community sample is noteworthy and deserves further attention. Results of the parent intervention study will be reported in 2023.
The importance of Communication and Education: Lessons learned from AGREEDementia
Authors: Rosen Allyson C. ,   AGREEDementia
Published: December 2022

AbstractBackgroundWhen and how to communicate effectively the results of genetic and biomarker based prediction, detection, and quantification of the brain substrates of dementia involve important ethical and legal issues critical for precision medicine. AGREEDementia is an open working group that focuses on informed discussions and development of educational material to support communication and use of this information.MethodMembers attend two meetings monthly via videoteleconference. One meeting is a targeted working group that focuses on the following: 1. People with Symptoms, 2. People without Symptoms, 3. Research, 4. Ethics/Healthcare Law, 5. Diversity. Members also attend a monthly “all hands” meeting where they receive updates from other groups, partner organizations, and hear presentations on emerging research and resources.ResultOver the past few years AGREEDementia has produced several collaborative papers, webinars, and decision tools for people considering undergoing biomarker testing that will be discussed. Membership continues to grow to over 120 though level of involvement varies. The group is largely comprised of academic researchers (76%) including neurologists, neuropsychologists, clinical trial coordinators, ethicists, and healthcare lawyers. The second largest subgroup was from advocacy groups and stakeholders (18%) and 6% are students. Collaborations with other organizations including the NIA, Alzheimer’s Association/ISTAART, the Lewy Body Dementia Association, Association for Frontotemporal Dementia, and Cohen Veterans Bioscience greatly enrich the group by publicizing conferences and collaborating on papers and products. The Alzheimer’s & Dementia Outreach, Recruitment & Engagement at NIA also disseminates decision tools and other materials. Over time, the stakeholder group developed from an audience providing consultation to a creative force that pioneered a program to support people with cognitive dysfunction attending AAIC and other scientific conferences. The Diversity workgroup was added in order to mentor and teach research staff in sensitive outreach to diverse cohorts. The ongoing, monthly, lecture series and links to all these materials are hosted at a website, AGREEDementia.com.ConclusionWith controversies around how best to integrate biomarker and genetic information into clinical care, when to share research data with the public, and implement novel biomarker‐based therapies, AGREEDementia has provided an open forum for all to visit and consult.