bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex and aging signatures in human CSF proteomics and their link to neurologic diseases
Authors: Sung Yun Ju , Seo Da Hun , Lee Cheol Min , Timsina Jigyasha , Wang Lihua , Ruiz Agustin , Pastor Pau , Park Taesung , Cruchaga Carlos 
Published: December 2023

AbstractBackgroundSex and age are major risk factors for several chronic diseases. Recent human and mouse studies of age‐related molecular changes in blood provided new insights into age‐related disease biology. Cerebrospinal fluid (CSF) is more closely related to brain than blood and can provide additional insights to sex and age‐related brain diseases.MethodWe measured over 7000 proteins in CSF from 998 healthy individuals representing middle and old age (43‐91) across four multiple cohorts. After stringent QC, we performed weighted gene co‐expression network analysis (WGCNA) to group CSF proteins with similar sex and age trajectories. Each cluster was then tested for aging and sex differences. Cell‐type enrichment and disease ontology enrichment was also performed.ResultCo‐expression network analysis identified 24 modules for CSF 4926 proteins. Sex difference was detected for 2949 proteins (1730 were higher in females; 1219 were higher in males). Aging signature was detected for 4480 proteins (2999 increasing; 1481 decreasing with age). The pink module (containing SERPINA3, TREML2, and additional 197 proteins) had proteins higher in males and increasing with ages and were enriched in endothelial cell (P = 0.04). Cardiovascular diseases (FDR = 2.6E‐9), ischemic stroke (FDR = 1.7E‐7) and Alzheimer’s disease (AD) (FDR = 7.3E‐3) were significantly enriched in this module. The blue module (containing APOE, APP and additional 681 proteins) had proteins higher in females and decreasing with ages, were enriched in microglia and macrophage (P = 0.01). AD (FDR = 0.043) and vascular dementia (FDR = 0.025) were enriched. The yellow module (containing SMPD1, GNS, CTSB and additional 331 proteins) had proteins higher in females and non‐linear aging trajectory (increasing until 70 years old and decreasing) were enriched in neurons (P = 4.6E‐9). Lysosomal storage diseases (FDR = 3.4E‐03) showed enrichment for them. Among the 46 plasma proteins showing conserved aging signature in mice and humans (Lehallier et al 2019), 20 proteins including TNFSF15 and PPBP were also conserved in CSF. In addition, nine of them show the sex‐specific signature conserved across all three datasets.ConclusionOur study in CSF proteomic signatures identified clusters of proteins in distinct patterns and their relation to Alzheimer’s disease and other neurodegeneration. More detailed characterization of proteomic signatures for other age‐related chronic diseases is underway.
Reduction of apathy and caregiver distress using a combination of tetrahydrocannabinol and melatonin in dementia due to Alzheimer’s disease
Authors: Gutierrez Evelyn , Sanchez Laura Tatiana , Arbelaez María Juanita , Tangarife Maria Alejandra , Delgado‐Murillo Laura , Rodriguez‐Soacha Diego , Shahnawaz Saadia S , Ghazaryan Varduhi , Naranjo Maria Paula , Venegas Margarita , Silva‐García David , Pujals Karen Y , De Jesus William Julio , Grimaldi Claudia , Mukunda Ram , Hong L Elliot , Lanctôt Krista L. 
Published: December 2023

AbstractBackgroundApathy is one of the most frequent and long‐lasting neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD). Up to 78% of AD patients exhibit apathy, which is related to caregiver distress, decreased quality of life, and increased morbidity. While many medications and behavioral interventions are used to treat apathy, the effects are often limited and lack in‐depth research to support these approaches. We present preliminary data for improvement in NPI‐apathy (NPI‐ap) scores and NPI Caregiver Distress (NPI‐D) scores using IGC‐AD1, a tetrahydrocannabinol (THC) and melatonin combination.MethodTwelve patients with mild (15.38%) to moderate (84.6%) AD (NIA‐criteria, 10‐active, 2‐placebo, 81.5±5.5yrs, 69.2% women) participated in a three Cohort, Phase‐1, MAD, safety and tolerability trial (IND146069, NCT04749563). In Cohort‐1, IGC‐AD1 was administered QD at 1ml for 14‐days (EOT). In Cohorts‐2 and 3, one ml BID and TID were administered respectively, with a minimum of 4‐days washout between Cohorts. Solicited and non‐solicited adverse events (AEs) were monitored daily.In each Cohort, seven participants (5‐active, 2‐placebo) had apathy at baseline, as rated by the NPI‐ap. They were administered the NPI‐ap at EOT and the Wilcoxon matched pairs signed‐rank test (R‐Studio, dplyr) was used to compare the difference in NPI‐ap scores between baseline and EOT. A similar analysis was carried out for NPI‐D.ResultIn Cohort‐1 mean NPI‐ap at baseline and EOT was 5.4 and 3 respectively (mean difference = ‐2.4, v = 6, p = 0.091). In Cohort‐2 mean NPI‐ap at baseline and EOT was 5.2 and 2.4 respectively (mean difference = ‐2.8, v = 6, p = 0.087). In Cohort‐3 mean NPI‐ap at baseline and EOT was 5.2 and 2.6 respectively (mean difference = ‐2.6, v = 6, p = 0.087). Results for NPI‐D: (Cohort‐1:mean difference = ‐0.6, 37.5%, v = 6, p = 0.075; Cohort‐2:mean difference = ‐1.8, 69.2%, v = 15, p = 0.028; Cohort‐3:mean difference = ‐0.2, 12.5%, v = 2, p = 0.5). No serious AEs, no deaths, and no dropouts due to AEs were reported. No major changes in concomitant medications were observed.ConclusionAs IGC‐AD1 contains THC, the results are intriguing because cannabis use has been associated with apathy but also increased empathy and sociality. In Cohort‐1, Cohort‐2, and Cohort‐3 NPI‐ap was reduced 44.44%, 53.85%, and 50% respectively. These results, while not statistically significant (p>0.05), appear clinically significant (reduction≥30%). A larger placebo‐controlled study is warranted.
Maya Angelou Center for Health Equity Caregiver College: a culturally‐relevant training for African American Alzheimer’s disease caregivers
Authors: Caban‐Holt Allison M , Starks Takiyah D. , Lloyd Shawnta' , Ford Anita , McCall Sole' , Eale Samuela B. , Fuller Lori , Byrd Goldie S. 
Published: December 2023

AbstractBackgroundAfrican American (AA) caregivers of patients with Alzheimer’s disease (AD) and related disorders can play a critical role in maintaining patient health. The Maya Angelou Center for Health Equity at Wake Forest University School of Medicine Caregiver College (MC2) aims to (1) improve informal caregivers’ knowledge of AD and related disorders, (2) enhance the quality of life for AD patients and caregiver’s by providing awareness of and access to resources that can help reduce caregiver burden, (3) provide strategies to effectively manage patient symptoms associated with AD, and (4) fill gaps in culturally relevant health education and awareness on AD, brain health, and dementia caregiving skills for AAs.MethodThe 40‐hour inaugural session of MC2 was conducted in‐person in October 2022. Educational sessions were facilitated by experts in various fields including AD, social work, nursing, aging, nutrition, and pharmacy. Topics covered over the course of the educational week included: Alzheimer’s Disease Overview, Health Disparities in AAs, Risk Factors for AD, End of Life Planning, and Caregiver Health. The 21‐item Dementia Knowledge Assessment Tool (DKAT), version 2 (Toye, et al. 2013) was used to track changes in AD knowledge and awareness. A DKAT pre‐test was administered before the educational sessions began on Day 1, and a post‐test assessment was administered at the end of the last educational session on Day 5.ResultAttendees (N = 21) are African American (100%), primarily female (90.48%), with an average age of 66.8 years (range 42‐82 years, 1 missing value). DKAT assessments from the week‐long educational training, showed an 8% increase in knowledge about AD in this sample of dementia caregivers based on a 5.7 percentage point increase on the DKAT from an average of 71.4% correct pre‐training to an average of 77.1% correct post‐training.ConclusionFindings suggest that community‐based educational training is a useful strategy for improving AD knowledge and resource awareness for AA informal caregivers. Results will be used to expand this training to include community members who will be engaged through presentations by attendees of the MC2.
Correlations between [18F]flutemetamol PET and region‐matched postmortem integrated density measures of cyano‐flutemetamol signal in Aβ plaques
Authors: Abrahamson Eric E , Buckley Christopher , Pemberton Hugh , Farrar Gill , Smith Adrian , Ikonomovic Milos D 
Published: December 2023

AbstractBackgroundThe binding substrates of [18F]flutemetamol and [11C]PiB PET consist of fibrillar amyloid‐β (Aβ) aggregates in morphologically and structurally distinct diffuse plaques (DP) and cored plaques (CP) which are present at different proportions across brain regions in Alzheimer’s disease (AD). To account for this heterogeneity, an unbiased quantitative measure integrating plaque size and density of amyloid‐β (Aβ) fibrils in plaques could help avoid false positive results, improve imaging‐to‐autopsy correlations, and further advance our understanding of pathological substrates for binding of amyloid PET tracers.MethodSixteen subjects underwent [18F]flutemetamol PET imaging in the pivotal Phase III end‐of‐life study (Study GE067‐007 and GE067‐026) and later came to autopsy (mean imaging‐to‐autopsy interval was 111 ± 87.6 days). [18F]flutemetamol SUVRpons values in four neocortical regions were correlated with region‐matched postmortem measures of cyano‐flutemetamol labeling of all plaques, as well as CP and DP separately, using percent area coverage, mean grayscale intensity of fluorescence, or a combination of the two measures referred to as integrated density.ResultIn the analysis of all cyano‐flutemetamol‐labeled plaques, [18F]flutemetamol SUVRpons values were more closely associated with integrated density measures than percent area coverage and mean grayscale values. Similarly, when CP and DP were analyzed separately, the integrated density values showed the closest association with neocortical region‐matched [18F]flutemetamol SUVRpons values. When area coverage of CP and DP were each expressed as a fraction of total plaque area coverage with or without integrating fluorescence intensity values, [18F]flutemetamol SUVRpons values within each region of interest were associated with the DP, but not the CP, area coverage measure.ConclusionThe association of antemortem [18F]flutemetamol PET and region‐matched postmortem integrated density measurements of cyano‐flutemetamol labeled plaques further supports the hypothesis that amyloid PET signal is influenced both by plaque size and Aβ fibril density within DP and CP. Further elucidating the relative contributions of each plaque type to the retention of amyloid PET radioligands could influence how a positive amyloid PET signal is interpreted in relation to postmortem pathology data.
TNFα‐mediated inflammation in mouse models of VCID
Authors: Krick Katelynn E , Sudduth Tiffany L , Johnson Sherika , Rogers Colin B , Weekman Erica M , Wilcock Donna M. 
Published: December 2023

AbstractBackgroundTumor necrosis factor alpha (TNFα) is a prominent pleiotropic cytokine with dichotomous effects. Primarily produced in the brain by glial cells, TNFα interacts with two subtypes of TNF receptors (TNFRs) that dictate the cellular response, be that pro‐ or anti‐inflammator. The diverse cellular responses include cell survival, cell death, proliferation, and angiogenesis. Due to the critical role inflammation plays in the pathogenesis of Alzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID), understanding the specific roles of pleiotropic cytokines like TNFa in dementia‐causing diseases will provide mechanistic and therapeutic insights. Both inhibition of soluble TNFα (sTNFα) and deletion of pro‐inflammatory TNF receptor 1 (TNFR1) have been shown to decrease severity of amyloid deposition in AD models. However, similar studies have not been conducted regarding VCID outcomes.MethodThis study sought to examine gene and protein expression of TNFα and the two receptors, TNFR1 and TNFR2, within two mouse models of VCID; the hyperhomocysteinemia (HHcy)‐induced VCID co‐morbid with amyloid deposition and aged Tg2576 with severe cerebral amyloid angiopathy (CAA)‐associated VCID. Measures were taken via qPCR for mRNA assessment and Meso Scale Discovery assays (MSD) for protein quantification.ResultIn HHcy‐induced VCID, TNFα mRNA levels were significantly increased regardless of the presence of amyloid deposition. Similarly, protein levels of TNFα trended higher in HHcy groups compared to their controls regardless of amyloid presence. Levels of TNFR1 mRNA trended lower in the HHcy model but was significantly increased in HHcy‐amyloid co‐morbid mice. When investigated in aged Tg2576 mice with CAA, TNFR1 protein expression increased at older timepoints compared to younger, and against wild type controls. Anti‐inflammatory and innate immune‐associated TNFR2 was increased at 20 months in CAA mice when compared to age‐matched controls.ConclusionThese findings display differences in gene and protein expression of TNFa and its receptors in two models of VCID. The unique expression in these models merits further research into the differences in TNF‐mediated inflammation in VCID. Further research is also necessary to determine potential therapeutic advantages of drugs such as TNFα inhibitors in cases of VCID with and without amyloid deposition.
Pseudo‐temporal models of Alzheimer’s Disease progression across brain‐derived transcriptomics, proteomics, and metabolomics
Authors: Heath Laura M , Batra Richa , Cary Gregory A. , Wiley Jesse C , Poehlman William L. , Linden Abby Vander , Krumsiek Jan , Arnold Matthias , Kaddurah‐Daouk Rima F. , Carter Gregory W , Greenwood Anna K 
Published: December 2023

AbstractBackgroundWe applied a pseudo‐temporal model to multi‐omic data from individuals with heterogeneous neuropathology to examine molecular changes across the spectrum of Alzheimer’s Disease (AD) progression.MethodsManifold learning algorithms ‘order’ samples based on similarity of expression or abundance patterns to calculate a ‘trajectory’ of disease progression. We applied this approach to RNAseq (N = 1078), TMT‐proteomics (N = 602), and metabolomics (N = 500) profiles of human postmortem brain samples from the ROS/MAP study within the Accelerating Medicine Partnership‐AD consortia (AMP‐AD); 318 individuals were included in all three ‐omics datasets. Analyses were stratified by sex. We examined associations between pseudotime, a quantitative measure of progress along each trajectory, and neuropathological and clinical endpoints. We calculated differential expression or abundance along each trajectory. For transcriptomic and proteomic data, we used gene set enrichment analyses to identify significant GO terms changing along the trajectory and grouped them into 19 distinct AD‐relevant biological domains. We similarly annotated changing metabolic pathways along metabolomic trajectories.ResultsPseudotime estimates were significantly associated with AD status such that “early” (low pseudotime) samples were enriched for controls, and “late” (high pseudotime) samples were enriched for cases, in all ‐omics. Omic‐specific pseudotimes were weakly correlated with each other (Pearson’s r for: RNAseq vs proteomics: 0.39; RNAseq vs metabolomics: 0.28; proteomics vs metabolomics: 0.41). Proteins involved in mitochondrial metabolism and synaptic function were downregulated in early stages in both sexes, while transcriptomic trajectories indicated early sex‐specific differences in synaptic function and immune response. In both sexes, metabolic amino acid and lipid pathways were perturbed in early stages, though specific pathways were different; early Phosphatidylcholine and Leucine, Isoleucine, and Valine Metabolism perturbations were especially prominent in women, while early Glutathione Metabolism perturbations were more prominent in men.ConclusionsDespite differences in the biological nature of the data used to order trajectories, pseudotime was associated with multiple measures of AD progression across all three ‐omics. Each analysis provided a unique snapshot of molecular change across AD progression. Sex‐specific differences, especially those noted early in disease trajectories, may provide crucial insights into key processes driving disease in women and men.
Do the benefits of education for late‐life cognition change across birth cohorts? Assessing period effects in the Health and Retirement Study
Authors: Eng Chloe W. , Glymour M. Maria , Rehkopf David 
Published: December 2023

AbstractBackgroundEducation consistently predicts late‐life cognition, but studies rarely consider the transformation of education that current older adults experienced across the 20th century. We assess whether the relationship between education and late‐life cognition remains constant across birth cohorts spanning over 40 years of changing social investments and progress.MethodUS Health and Retirement Study participants (age 50+) were enrolled at multiple points between 1998 and 2018, allowing for the study of participants of different birth years at the same age (n = 28,299 participants and 151,514 visits across all available data collection waves). US‐born participants with at least one memory measurement were stratified into eight birth cohorts of approximately five years each, spanning more than 40 years. Mixed models with random intercepts for each participant investigated the presence of effect modification across birth cohorts for the education‐dementia relationship. Age was not evenly distributed across birth cohorts; therefore models were additionally run restricted to ten‐year age groups. Secondary analyses investigated whether period effects further existed by race and gender. All models adjusted for age, quadratic age, gender, race, cognitive practice effects, childhood census region, and parental education.ResultEarlier birth cohorts showed larger associations between education and late‐life cognition, with each additional year increase in schooling associated with a 0.10 SD (95% CI: 0.09, 0.11) higher memory score in the earliest cohort compared to the latest (interaction p‐value <.0001). Findings were consistent when restricting analyses to age groups. Effects of education across cohorts also slightly differed by gender, with increased education being associated with larger gender disparities in memory of 0.04 SD (95% CI: 0.02, 0.06) more per year of schooling in the latest cohort compared to the earliest (interaction p‐value <.0001), and by race, with a narrowing of racial disparities in later cohorts for the cognitive benefits of increased education (interaction p‐value <.0001).ConclusionEach year increase in attained education had overall larger effects among earlier cohorts, though this may differ across sociodemographic and age groups. Future research is needed to examine whether differences arise from historical transformations of the educational experience or from changes in downstream economic opportunities across time periods.
White Matter Hyperintensity Growth/Regression quantification: MarkVCID multi‐site Instrumental Validation
Authors: Bahrani Ahmed A , Abner Erin L , Powell David K , Gold Brian T. , Wilcock Donna M. , Jicha Gregory A , Ali Doaa 
Published: December 2023

AbstractBackgroundWhite matter hyperintensities (WMH) are one of the main recognized biomarkers for the small vessel diseases related to the vascular contributions to cognitive impairment and dementia (VCID). WMH found to be dynamic, increasing in volume, but also stability or even decreasing in volume over time. The ability to measure and track such longitudinal change over periods of time, as short as one‐year, is critical for both mechanistic discoveries and for the informed future use of biomarkers to track disease modification in clinical trials of VCID. The NINDS‐funded MarkVCID Consortium engaged to test such a protocol for cross‐site inter‐rater and test‐retest reliability to establish instrumental validation of this candidate biomarker for VCID.MethodT1 and 3D FLAIR MRI acquisitions were collected longitudinally and analyzed across six independent sites, using a unique post‐acquisition processing protocol. The analytic platform was built within a Singularity Container to provide the necessary software tools for rigorous uniform co‐registration and intensity corrections that enabled precise measurement of WMH change in regard to growth, stability and regression over a one‐year interval. Baseline and 12‐month follow‐up scans were acquired across MarkVCID sites and pooled to generate the validation dataset used for cross‐site inter‐rater reliability (n = 30). To evaluate test‐retest reliability, two baseline scans (acquired approximately one‐week apart) were independently co‐registered to the 12‐month follow‐up scan (n = 18). Cross‐site inter‐rater and test‐retest reliability were assessed using intraclass correlational analyses (ICC).ResultICC values for test‐retest reliability of WMH growth and regression were 0.97 and 0.94 respectively. Mean ICC values for cross‐center WMH masks were 1.0 for both time points, see Fig. 1 and 2, and WMH growth and regression were 0.99 for both see Fig. 3 and 4.ConclusionThe present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one‐year period as measured by cross‐site inter‐rater and test‐retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.