bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mild cognitive impairment in novel SPG4/SPAST mutation‐related sporadic late onset hereditary spastic paraplegia: case series
Authors: Meyyazhagan Arun , Rumore Roberto , Gaudiello Fabrizio , Miele Marialuisa , Kawarai Toshitaka , Orlacchio Antonio 
Published: December 2023

AbstractBackgroundMutations and deletions in the SPG4/SPAST gene cause for up to 50% of the autosomal dominant forms of hereditary spastic paraplegia (HSP) and for up to 15% of the sporadic cases. Affected individuals have pyramidal signs in the lower limbs and some present additional features. Cognitive impairment is common in late‐onset forms of HSPs.MethodsThis study examined the cognitive abilities of 20 sporadic late‐onset patients with HSP using next‐generation sequencing. We also used a combination of the Mini‐Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) to assess their cognition.ResultsThe present study led to the discovery of three new pathogenic mutations of the SPG4 gene through evolutionary conservation and analysis of structural models. We also confirmed mild cognitive impairment (MCI) with normal MMSE scores (≥27) and reduced MoCA scores (<26) in these HSP‐SPG4 mutant patients. Such individuals mainly present with impaired executive function, delayed memory, abstraction and language.ConclusionsThe results broaden the mutational space of SPG4‐associated HSP with sporadic late‐onset modality and indicate a combination of reduced MoCA and normal MMSE for diagnosis, indicating that clinicians should consider performing a MoCA to detect MCI in patients with HSP, particularly those with sporadic onset SPG4/SPAST‐HSP.
ADSP Whole Genome Sequencing (WGS) Release 4 Data Update from Genome Center for Alzheimer’s Disease
Authors: Leung Yuk Yee , Lee Wan‐Ping , Kuzma Amanda B , Gangadharan Prabhakaran , Nicaretta Heather Issen , Qu Liming , Ren Youli , Cantwell Laura B , Valladares Otto , Zhao Yi , Iqbal Taha , Schmidt Michael A. , Mena Pedro R. , Vardarajan Badri N , Dalgard Clifton L. , Kunkle Brian W. , Bush William S. , Martin Eden R. , Naj Adam C. , Haines Jonathan L. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerald D. ,   the Alzheimer’s Disease Sequencing Project (ADSP)
Published: December 2023

AbstractBackgroundThe Genome Center for Alzheimer’s Disease (GCAD) coordinates the integration of all available Alzheimer’s disease (AD) relevant whole genome sequencing (WGS) data with the goal of identifying AD risk or protective genetic variants and eventual therapeutic targets. The WGS datasets are generated through collaboration between investigators from the Alzheimer’s Disease Sequencing Project (ADSP) and GCAD. With the goal of minimizing data heterogeneity, introduced by different sequencing protocols and assays, GCAD processes all samples using standardized pipelines and performs quality control (QC)/quality assurance (QA) checks.MethodsRaw sequencing data (FASTQs or BAMs) were aligned to GRCh38/hg38 by BWA, and variant calling and joint genotyping on single nucleotide variants (SNVs), insertions and deletions (indels), were done by GATK. Structural variants (SVs) were called per sample using the Smoove, Manta, and Strelka packages. Preliminary QA checks including sex check, contamination, and genotype concordance were performed followed by QC per ADSP protocol to evaluate the quality of samples and variants. To facilitate access and usage of massive joint‐genotype called VCF files, a compact version for storing variant info and sample genotypes only was released first.ResultsWe dropped 275 (0.7%) samples of poor coverage (<20×), and we flagged 219 (0.6%) samples that were of borderline quality. As a result, the dataset (ADSP Release 4, 2022) includes 36,361 genomes from 40 diverse cohorts with 4 major ancestries: 16,573 Non‐Hispanic Whites, 11,358 Hispanics; 5,422 African Americans; and 2,802 Asians. Data are deeply sequenced (average genome coverage: 40x). All samples’ CRAMs and gVCFs from GATK were deposited into NIAGADS Data Sharing Service (DSS) (https://dss.niagads.org/) for public distribution. Joint‐genotyped called VCFs are undergoing a full QC/annotation process and will be made available. This joint‐genotyped called VCF contains >362M bi‐allelic variants, >58M multi‐allelic variants, with 95% of variants remaining after QC. SV calling is ongoing and data will be ready prior to the conference.ConclusionThe ADSP and GCAD generate high quality SNVs, indels and SV calls. Currently GCAD is preparing the next release of ∼60,000 more ancestrally‐diverse WGS samples sequenced primarily through the ADSP Follow‐Up Study, which we anticipate will be released in 2023 to greatly benefit the AD genetics community.
Cognitive decline and longitudinal atrophy in successful and typical aging
Authors: Pezzoli Stefania , Giorgio Joseph , Chen Xi , Harrison Theresa M. , Jagust William J. 
Published: December 2023

AbstractBackgroundGreater hippocampal volume (HV) and thicker mid‐cingulate cortex (MCC) are features of successful agers (SA), defined as exceptional cognitive performers, compared to typical agers (TA). This study aimed at examining whether SA experience different longitudinal change in cognition and atrophy from TA, and how baseline β‐amyloid (Aβ) affects these relationships.Method190 cognitively normal older adults (70+ years old) underwent 11C‐Pittsburgh compound B (PiB)‐PET to derive baseline Aβ positivity, and longitudinal structural MRI and cognitive testing. A machine learning cognitive‐age model was used to predict participants’ cognitive‐age from cognitive testing. Cognitive‐age gap (CAG = cognitive‐age – chronological age) was computed to represent individual variability in cognitive aging, wherein negative values indicate better cognitive performance than expected for age; SA were below the 20th percentile (n = 39). Linear mixed‐effects models were used to investigate the relationship between longitudinal changes in 1) Preclinical Alzheimer’s Cognitive Composite (PACC), 2) HV, and 3) MCC, with baseline CAG or SA‐status, as well as Aβ‐status as predictors.ResultWe found a significant main effect on PACC for CAG (p<0.001), but not Aβ‐status (p = 0.9), and significant CAG x time (p = 0.002) and Aβ‐status x time (p = 0.02) interactions (Figure 1). Results were similar when participants were dichotomized into SA and TA. In addition, baseline CAG showed significant main effects on 1) HV (p<0.001) and 2) MCC (p = 0.02), but the CAG x time interactions were not significant (HV: p = 0.6; MCC: p = 0.7) (Figure 2). Finally, when CAG, Aβ‐status, and HV were included in the same model to predict PACC change, we found a significant main effect for CAG (p<0.001), significant CAG x time (p = 0.01) and Aβ‐status x time (p = 0.02) interactions, and a marginally significant HV x time interaction (p = 0.06) (Figure 3).ConclusionLower baseline CAG scores, indicating younger cognitive‐age, were related to greater HV and thicker MCC cross‐sectionally, but not longitudinal atrophy differences, suggesting that better cortical integrity in SA may reflect longstanding differences from TA. Lower baseline CAG and Aβ negativity were independently associated with slower cognitive decline. These findings suggest that factors underlying SA include separate contributions of both brain maintenance and reserve.
Leading Multi‐level Change to Build a Better System to Support Family Caregivers
Authors: Parmar Jasneet K , Anderson Sharon Dorothy , Pollard Cheryl , Charles Lesley , Drance Elisabeth , Penner Jamie , Lobchuk Michelle , Carforio Laurie , Leslie Myles , L'Hereux Tanya , McGhan Gwen , Huhn Arlene , Lowther Johnna , Marion Cecelia , Tarnowski Glenda , Weir Carolyn , Melenberg Denise , Pooler Charlotte 
Published: December 2023

AbstractBackgroundWorldwide the care economy is in crisis.[1] The care economy includes both paid and unpaid services provided to populations who are unable to independently support themselves. Family caregivers (FCGs) make up the largest proportion of the care workforce, providing over 90% of care for people with dementia,[2 3] yet they remain marginalized in the existing healthcare systems.[4] While some caregiving scholars call for education to enhance the competencies of health and social care providers to partner effectively with caregivers,[3 4] other stakeholders advocate for broader systemic and policy change.ObjectivesReport on how an academic‐community partnership co‐design group focused on educating about person‐centered supports for FCGs is advocating for systemic change.Project descriptionAdvocacy is a critical population health strategy that emphasizes collective action to effect systemic change. The essential elements of advocacy includes: clear policy goals, solid evidence‐base, values linked to equity, broad coalition support, framing in mass media, and use of policy for change.[5]MethodsDrawing on learning health systems and collective impact approaches, we are weaving together the actions of FCGs, researchers, health and social care providers, leaders, and management to build a No Wrong Door, seamless health & social care support system to enable FCGs to maintain their wellbeing & sustain care.ResultsOur goal is for formal recognition of the FCG role within health and social care policy. Broad consultations with stakeholders, then co‐design of the Caregiver‐Centered Care education built a robust collaborative of Caregiver Champions. While educating the health workforce is a population health approach to address known gaps in supporting and working with FCGs across the care trajectory, [3 4 6] such education is also developing FCG champions who can advocate across settings and communities. Within Alberta, this collective voice has resulted in recognition of FCGs in the new Continuing Care Act, Bill 11.DiscussionAn integrated FCG system is still a work in progress. Many FCGs do not connect with services they need until they are in a crisis.ConclusionNow we are working on strategy mapping to shift the collective focus from reactive problem solving to co‐creating the future.
Effects of Physical Activity Interventions on Brain Metabolites : A systematic review and meta‐analysis
Authors: Moon Chooza , Zhang Meina , Tran‐Dong Melanie , Lee Jihye 
Published: December 2023

AbstractBackgroundPhysical activity is a modifiable behavioral factor that could delay the development of Alzheimer’s disease. Although metabolites detected in the brain correspond to neuronal integrity and neurodegenerative pathologies, we do not clearly understand the effect of physical activity interventions on brain metabolites. The purpose of this systematic review and meta‐analysis was to assess the effect of physical activity on brain metabolites measured by magnetic resonance spectroscopy (MRS).MethodsA systematic search was performed in PubMed, Embase, Web of Science and CINAHL from database inception to November 2022. Eight studies were integrated into the final systematic review and meta‐analysis.ResultsAmong included studies, 5 of the studies were randomized control designs, 1 study was an observational longitudinal study, 1 study was an observational cross‐sectional design, and 1 study was a case‐control design study. These studies involved 312 participants with mean age from 23 to 72. Physical activity interventions included cycling, running, and yoga. We found multiple metabolites are associated with physical activity including Myo‐inositol, choline (Cho), N‐acetyl aspartate (NAA), creatine, glutamate, and glutamine. The brain areas studied in reviewed articles included the hippocampus, frontal, occipital, or thalamus. From the quantitative synthesis, NAA/ Cho was higher in the physical activity group (effect size (ES) = ‐0.30, p = 0.03) than in the control group. However, for NAA (ES = ‐0.22, p = 0.08) and NNA/Cr (ES = 0.03, p = 0.07), the difference between the physical activity group and the control group was not statistically significant.ConclusionEvidence shows that there have been attempts to understand the relationship between physical activity and metabolites. The meta‐analysis demonstrates physical activity may affect changes in NAA/Cho. However, caution needs to be accompanied when interpreting the direct association between physical activity and different brain metabolites due to insufficient data, publication bias, and heterogeneity.
Voxel‐by‐Voxel regression analysis identifies association between postmortem TDP‐43 and antemortem fractional anisotropy within white matter fibers connected to the hippocampus
Authors: Heywood Ashley , Stocks Jane K , Schneider Julie A , Bennett David A. A , Arfanakis Konstantinos , Beg Mirza Faisal , Wang Lei 
Published: December 2023

AbstractBackgroundTAR DNA‐binding protein 43 (TDP‐43), has been shown to be involved in various neurodegenerative disorders involving axonal damage including ALS, FTLD, and LATE. Studying the relationships between postmortem TDP‐43 and antemortem white matter (WM) structural integrity can allow for a better understanding of the disease, rather than exploring clinical presentations alone.MethodsIn‐vivo diffusion‐weighted images were gathered on a 1.5T scanner from subjects from the Religious Orders Study and the Rush Memory and Aging Project. Images were processed using TORTOISE to calculate fractional anisotropy (FA). We utilized the IIT probabilistic WM atlas to identify voxels containing fibers that originate or terminate in the hippocampus. A semi‐quantitative rating of TDP‐43 severity was assessed in 5 brain regions. We utilized regression models to relate postmortem disease and antemortem FA within each voxel. Coexisting disease including β‐amyloid plaques, tau tangles, and cerebrovascular disease were used as covariates, along with demographic variables.ResultsThe 58 subjects were 91.10 (SD = 6.37) years old at death with a median interval from MRI to death of 2.8 years (SD = 1.19). Results revealed a significant negative relationship (p<0.05) between postmortem TDP‐43 and FA within fibers connecting the hippocampus to the parahippocampal and entorhinal cortices, fornix, and lingual gyrus. Preliminary results did not survive multiple comparisons correction.ConclusionsOur findings indicate that greater TDP‐43 disease burden is associated with lower white matter integrity within regions of the limbic system. These findings suggest the TDP‐43 disease process may contribute to reduced structural connectivity between the hippocampus and related regions, which may impact larger brain networks.
Associations between gray and white matter volumes from ex vivo imaging and Alzheimer’s Disease Neuropathologic Change Score in the ACT autopsy cohort
Authors: Choi Seo‐Eun , Mukherjee Shubhabrata , Hunt David , McKown S. Kris , Latimer Caitlin S , Bogdani Marika , Keene Lisa , Keen Amanda , Kern Katie , Balderas Ashley , Shadle Christina , Howard Kim , Nolan Amber L. , Campos John S , Larson Eric B , Keene C Dirk , Crane Paul K , MacDonald Christine 
Published: December 2023

AbstractBackgroundApplications of ex vivo magnetic resonance imaging (MRI) of human brain tissue from autopsy has grown in recent years and can provide useful information that is complementary to data from neuropathological evaluations. We sought to evaluate relationship between gray matter (GM) and white matter (WM) volumes and Alzheimer’s Disease Neuropathologic Change Score (ADNC) in the Adult Changes in Thought (ACT) autopsy cohort.MethodGM and WM volumetric data for 33 regions of interests (ROIs) were derived using FreeSurfer for each hemisphere. The volumes were separated into GM and WM with data provided from left hemisphere or right hemisphere or from both. We adjusted GM volume for each ROI by taking the ratio of total ROI volume and total GM and WM volume across both hemispheres. We adjusted appropriately for brains where we had data from any one hemisphere and standardized each GM ROI volume. We adjusted and standardized for WM ROI volumes similarly. We ran logistic elastic net to model the relationship between dichotomized ADNC score and GM and WM volumes adjusting for age at death, sex and brain volume. We performed additional analyses to determine if the results from primary analyses were driven by “Not” or “High” level of the ADNC score.ResultThere were 143 brains with Freesurfer data that passed quality control. The mean age of death was 91 and 63% were female (Table 1). Odds ratios (OR) obtained from the elastic net regression are presented in Table 2 and they are visualized in Figure 1. Larger fusiform GM volume (OR = 0.8), frontal pole GM volume (OR = 0.89), and temporal pole GM volume (OR = 0.85) were associated with decreased risk of AD in our primary analyses. Cuneus GM volume (OR = 1.08) and precentral WM volume (OR = 1.13) had an inverse relationship in these models. Follow‐up analyses revealed that the fusiform GM volume (OR = 0.75) was significantly smaller for individuals with “High” ADNC score (Table 2).ConclusionPost‐mortem ex vivo imaging may serve a complementary role in autopsy studies. Future efforts will be focused on evaluating relationship between brain volumes and various standard neuropathological variables in larger data sets.
The association of race, sex, and neighborhood disadvantage with baroreflex sensitivity in the U.S. POINTER Neurovascular ancillary study
Authors: McCarron Megan E. , Brinkley Tina E , Leng Xiaoyan , Bailey Margie J , Baker Laura D , Shaltout Hossam A 
Published: December 2023

AbstractBackgroundThe arterial baroreflex maintains stable blood flow to the brain. Reduced baroreflex sensitivity for modulation of heart rate (BRS) has been observed in patients with Alzheimer’s disease (AD) and mild cognitive impairment and may be impacted by race, ethnicity, sex, and socioeconomic factors such as the Area Deprivation Index (ADI), a validated, neighborhood‐level composite index that incorporates 17 social determinants of health. However, these relationships have not been well described.MethodThis study utilized baseline data from 196 participants enrolled in the U.S. POINTER Neurovascular study, an ancillary to the parent U.S. POINTER multi‐site lifestyle intervention trial that adds assessments of autonomic function and vascular structure and function. BRS was calculated from continuous blood pressure and electrocardiogram recording using the slope of the regression line between changes in systolic blood pressure and RR interval values in the same direction, with higher BRS indicating better autonomic function. ADI scores ranging from 1 to 10 were calculated using 9‐digit zip codes, with 10 indicating the greatest disadvantage. Analysis of variance and linear regression were used to evaluate associations between measures of interest.ResultThe average age of the study population was 67.9 ± 5.4 years, 64 (17%) were males, and 60 (30.6%) identified as people of color (POC). Overall, the mean BRS was 9.2 ± 4.6 ms/mmHg, and the average ADI score was 4.56 ± 2.69 (range: 1 to 10), corresponding to a national ADI percentile of 40.7 ± 26.1 (range: 3 to 100). Less than a quarter of participants (n = 42, 21.4%) had an ADI percentile >67, indicating a moderate to high level of neighborhood disadvantage. White participants had lower BRS compared to POC (8.60 ± 4.49 vs. 10.60 ± 4.61 ms/mmHg, p = 0.0048). In a multiple regression model adjusting for demographics and ADI, sex (p = 0.0283), race and ethnicity (p = 0.0049), and education (p = 0.0196) were significantly associated with BRS, indicating better autonomic function in men, POC, and those with higher education. ADI was not associated with BRS.ConclusionRace, ethnicity, and education impact autonomic function. Further investigations are needed to assess the impact of other demographic and socioeconomic factors on neurovascular health.
Assessing the impact of falls on neuropsychiatric symptoms in patients with neurodegenerative disease
Authors: Joghataie Goldin , Dilliott Allison Ann , Frank Andrew R , Lang Anthony E , Roberts Angela C , Troyer Angela , Levine Brian , Arnott Stephen R. , Tan Brian , Fischer Corinne E. , Marras Connie , Kwan Donna , Munoz Douglas , Tang‐Wai David F. , Finger Elizabeth , Rogaeva Ekaterina , Orange Joseph B , Ramirez Joel , Sunderland Kelly M , Zinman Lorne , Binns Malcolm , Borrie Michael , Masellis Mario , Freedman Morris , Montero‐Odasso Manuel , Ozzoude Miracle , Bartha Robert , Swartz Richard H. , Abrahao Agessandro , McIlroy Bill , Strong Michael J. , Tartaglia Carmela 
Published: December 2023

AbstractBackgroundFalls are the most common injury faced by older adults and those with neurodegenerative diseases. Falls can result in concussion/mild traumatic brain injury(mTBI). Concussions in older adults or those with neurodegenerative disease can have a significant impact on behavior as post‐concussion symptoms include neuropsychiatric issues. We hypothesized that there is a relationship between past fall and neuropsychiatric symptoms and neuropsychiatric symptom severity.MethodsWe used data on falls and Neuropsychiatric Inventory (NPI) from the Ontario Neurodegenerative Disease Research Initiative dataset for 480 individuals with neurodegenerative diseases (Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, frontotemporal dementia and vascular cognitive impairment). We used the Chi‐squared and Mann‐Whitney tests to compare frequency of NPI symptoms (anxiety, depression, irritability, disinhibition, apathy, delusions, hallucinations, agitation, euphoria, motor‐disturbance, night‐time behaviour, appetite), and total NPI severity and distress, respectively, between patients with and without falls in the past 12 months.ResultsComparing patients with falls (n = 169; mean‐age = 68.3±9; 36% F) to patients without falls (n = 311; mean‐age = 68.7±7; 32% F), there was a significantly higher frequency of anxiety (Chi‐squared test, X2 (df = 1, N = 480) = 12.859, P‐value = 0.0003); higher median anxiety severity (Mann‐Whitney/Wilcoxon‐test p‐value = 0.0002); and higher median partner anxiety distress (Wilcox test p‐value = 0.0006) in those who had had a previous fall compared to those who had not, even with multiple comparison correction. Depression, apathy, disinhibition, night‐time behaviours, and eating/appetite changes and total NPI severity were significantly worse in those with previous falls but did not survive multiple comparison correction.ConclusionWe found that anxiety frequency, severity and distress were much higher in patients with neurodegenerative disease who had a fall in the preceding 12 months compared to those without falls. Our study suggests that neuropsychiatric symptoms, especially anxiety are frequent and should be assessed in those with previous falls as they can be a consequence of mild brain injury and may contribute to worsening cognition or behaviors.