bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of Alzheimer’s Disease GWAS with Molecular QTLs Reveals Prioritized Risk Genes and Disease‐associated Molecular Alterations
Authors: Kucukali Fahri , Sleegers Kristel ,   EADB
Published: December 2023

AbstractBackgroundDespite the success of genome‐wide association studies (GWAS) to identify genetic variants associated with complex diseases, as the majority of these variants reside in non‐coding genome, one important task is to link these variants to disease‐associated molecular alterations in risk genes. To this end, we developed a systematic gene prioritization methodology that integrated our recent Alzheimer’s disease (AD) GWAS meta‐analysis with molecular quantitative trait loci (QTL) in disease‐relevant tissues and identified highly likely candidate risk genes and molecular alterations within the majority of 42 novel loci identified. In this subsequent study, we updated our pipeline with new molecular QTL catalogues and analyzed the complete landscape of AD risk.MethodWe performed GWAS‐QTL integration in AD‐relevant tissues and cells by querying the lead variants in each locus in the molecular QTL catalogues, (ii) investigating genetic colocalization between GWAS and molecular QTL signals using coloc, and (iii) conducting transcriptome, methylome, and proteome‐wide association studies (TWAS/MWAS/PWAS) using the EADB stage I meta‐analysis GWAS on 85,934 cases and 401,577 controls. The updated gene prioritization pipeline included new analyses based on new brain protein expression QTL (pQTL), cell‐type‐specific expression QTL (ct‐eQTL), expression QTL (eQTL), histone acetylation QTL (haQTL), and methylation QTL (mQTL) catalogues. Moreover, we used Nanopore RNA sequencing to further investigate risk‐associated splicing events revealed by splicing QTL (sQTL) integration.ResultOur brain ct‐eQTL coloc results showed that while the most risk‐associated gene expression alterations are specific to microglia, the proportion of astrocyte‐specific eQTL colocalizations were doubled compared to the previous studies. These included EGFR, a previously prioritized gene due to bulk brain eQTL coloc hits, whose downregulation was regulated by the protective signal specifically in astrocytes. Importantly, in a previously unresolved locus we could prioritize HS3ST5 through astrocyte‐specific eQTLs as well. Furthermore, pQTL coloc and PWAS prioritized SNX1, a previously prioritized gene at a lower confidence together with neighboring FAM96A gene, by implicating its genetic downregulation with increased AD risk.ConclusionOur updated pipeline systematically prioritized AD risk genes and disease‐associated molecular alterations in the majority of risk loci, and contributed to better interpretation of AD GWAS and understanding of genetically‐associated molecular mechanisms underlying AD risk.
T‐PEP Related Presentation: Alzheimer’s disease pathogenic protein SORLA forms homodimer potentially required for its function
Authors: Kitago Yu 
Published: December 2023

AbstractBackgroundSo far, many genetic and molecular studies have indicated that the single‐pass transmembrane receptor SORLA can cause Alzheimer’s disease (AD) when mutated, but the detailed mechanism of how SORLA is involved in the pathogenesis of AD is still unknown. SORLA has a unique domain architecture including a huge, multidomain extracellular region with a Vps10p domain and 6 tandem repeats of fibronectin‐type‐III (3Fn) domains plus a short cytoplasmic tail. Although this unique composition must be essential for its potential function as a guiding molecule for protein sorting inside cells, there has been limited information about its overall molecular architecture. We are focusing on the function of SORLA in guiding trafficking along with the retromer complex, and recently found SORLA seems to form homodimers on the cell surface, which correlates with its function.MethodWe employed a highly efficient recombinant expression system for extracellular proteins using mammalian cells that enables detailed biochemical analysis. Using this technique, we produced recombinant secreted protein samples of the whole ectodomain and some fragments derived from human SORLA, and investigated its dimerization property by pull‐down assay followed by SDS PAGE and native PAGE. To investigate the three‐dimensional architecture, we ran a structural prediction using the amino acid sequence of SORLA’s ectodomain only without its signal sequence, propeptide, transmembrane region, and cytoplasmic region, using the program AlphaFold2.ResultOur biochemical experiments showed that human SORLA has homodimer forming property through its Vps10p domain and 3Fn domains. For theVps10p domain especially, it is indicated that the major fraction forms a homodimer in solution. Based on current structural information, we successfully created a mutant that forms covalent bound homodimer with an artificially introduced intermolecular disulfide bond. Interestingly, the predicted model of the ectodomain shows a folded compact structure, indicating that SORLA’s ectodomain forms a large globular shape on the surface of cells.ConclusionOur biochemical experiments showed that SORLA has two putative, opposite‐facing dimeric interfaces. Along with the computational molecular prediction, we propose that SORLA forms polymeric fibril‐like high dimensional structure inside the tubular endosomal membrane, supported by the retromer oligomer from the cytoplasmic side.
Effect of Diet on Cognitive Function and Gut Microbiota in Aged Rats.
Authors: Solch‐Ottaiano Rebecca J , Harper Colin , Engler‐Chiurazzi Elizabeth , Wang Hanyun , Ouvrier Blake , McDonald Katherine , Bix Gregory J , Biose Ifechukwude Joachim , Maraganore Demetrius M 
Published: December 2023

AbstractBackgroundMany patients with mild cognitive impairment and Alzheimer’s disease have alterations in the gut microbiota. Dietary consumption directly modulates gut microbiota; therefore, the quality of a diet may impact cognitive function and susceptibility to memory impairments. We hypothesized that consumption of the Mediterranean diet (MeDi) versus the Western diet (WD) will improve cognitive function through beneficial changes to the gut microbiota.MethodTwelve‐month‐old male Fischer 344 rats (n = 14/group) were randomly assigned to a MeDi, WD, or Chow diet (positive control to MeDi) for three months. Animals then underwent neurobehavioral assessments (n = 10/group) including the Morris water maze and radial arm water maze to assess aspects of short‐ and long‐term memory. Data were analyzed via One‐ or Two‐Way Repeated Measures ANOVA where appropriate. Fecal samples were collected prior to the behavior. Microbial composition was determined by 16S rRNA sequencing.ResultThe MeDi and WD groups consumed more kcals (p<0.05) at various weeks and weighed more compared to the chow group (p<0.05). There was no difference in time to reach the platform between the MeDi and WD or Chow groups in the Morris water maze, however, animals consuming the chow diet were quicker to reach the platform compared to the WD (p = 0.046). There were no differences in total errors measured by the radial arm water maze (p = 0.50) between diets. Gut microbiota composition (β‐diversity) was distinct between diets (Weighted and Unweighted UniFrac, p<0.001).ConclusionThere were no differences in short‐ or long‐term memory in aged animals consuming a MeDi or WD for three months. Diet‐modulated the gut microbiota as exhibited by differences in β‐diversity between the MeDi, WD, and Chow. As animals consumed a chow diet throughout their lifespan, the MeDi or WD may need to be started earlier in life to exhibit differences.
Funding: NIH Mentoring Research Excellence in Aging and Regenerative Medicine5P20GM103629‐10
Expositions of children’s drawings to reduce stigma regarding the elderly and dementia
Authors: Bormans Kasper , Zwakhalen Sandra ,   Health Sciences Research
Published: December 2023

AbstractBackgroundDementia and old age are overloaded with stigma and harmful connotations. The elderly are predominantly portrayed and perceived as depressed, lonely and dependent. This negative perspective encourages mutual avoidance behavior and confronts the elderly with a social death. Looking through the eyes of children at the challenges of the future in elderly care can benefit the public health sector.MethodIn this study, we collected 796 children’s drawings from 98 children of 10 years old from 4 elementary schools. Every child completed a 16‐week educational trajectory with positive interventions to connect generations. Pre‐ and post‐intervention, the children made portraits of elderly people and grandparents who are neutral, happy or unhappy. The drawings are implicit instruments for accessing and visualizing children’s hidden perceptions of old age and dementia. The evolutions in the pre‐ and post‐measurements demonstrate the mental landscape of children, and of society as a whole, is malleable and open to change.ResultThe artistic exhibition reached over 3000 visitors in 3 weeks and received a lot of national media attention. The novelty is in the simplicity. The unprejudiced viewpoint of children can deliver society a more constructive approach of the elderly, and people with dementia in particular. Children can teach us to focus more on dignity, positivity and humanity.ConclusionThis research indicates that the perspective of children can help the general public to nuance the negative view of old age and dementia. Positive qualities of children can be used to lighten the burden of dementia for society.
Microstructural integrity and structural connectivity of medial temporal lobe subregions is related to Alzheimer’s pathology
Authors: Adams Jenna N. , Granger Steven J. , Taylor Lisa M. , Kim Soyun , Harrison Theresa M. , Harris Alyssa L. , McMillan Liv , Colon‐Perez Luis , Keator David B. , Yassa Michael A. 
Published: December 2023

AbstractBackgroundThe earliest effects of Alzheimer’s disease pathology on medial temporal lobe (MTL) gray matter microstructure and white matter connectivity are still unknown. Here, we applied ultra‐high‐resolution diffusion MRI to characterize microstructural integrity and structural connectivity of the MTL, and tested associations with Alzheimer’s pathology and memory performance in cognitively normal older adults.Method83 participants (M = 71.7yrs, 66% female) received structural and ultra‐high‐resolution diffusion MRI (0.67×0.67×3mm). Subsamples received [18F]‐florbetapir (FBP) to measure Aβ (n = 77; global summary SUVR), [18F]‐MK6240 to measure tau (n = 23; entorhinal SUVR), and performed an object mnemonic discrimination task (n = 74). Structural MRI was processed with ASHS to obtain MTL ROIs (Fig1). Diffusion MRI was processed with FSL DTIfit to calculate mean diffusivity (MD), an index of cellular integrity. Tractography was performed with DSI Studio. ROI‐to‐ROI streamlines were calculated (Fig3A) and used for structural connectivity graph analyses of the MTL network. Analyses controlled for age and sex, with scan interval and education in relevant models.ResultEntorhinal MK6240 SUVR was associated with increased MD in transentorhinal cortex (BA35; r = 0.72, p<0.001), entorhinal cortex (EC; r = 0.61, p = 0.004), and dentate gyrus (DG; r = 0.46, p = 0.04; Fig2A), while global FBP SUVR was associated with higher MD in EC (r = 0.25, p = 0.03). Worse mnemonic discrimination performance was associated with increased MD in DG (r = ‐0.29, p = 0.01), with trends in EC (r = ‐0.23, p = 0.06) and CA3 (r = ‐0.20, p = 0.09; Fig2B). The number of streamlines between EC and DG was not significantly associated with entorhinal MK6240 SUVR (r = ‐0.32, p = 0.17), FBP SUVR, or mnemonic discrimination (ps>0.37). Lower global efficiency of the MTL network was associated with increased entorhinal MK6240 SUVR (r = ‐0.50, p = 0.025) yet better mnemonic discrimination performance (r = ‐0.28, p = 0.02; Fig3B).ConclusionEntorhinal tau pathology and memory performance are closely related to microstructural integrity and structural connectivity of the MTL, suggesting tau‐related MTL neurodegeneration may drive early memory decline.
Dietary patterns, cardiometabolic and brain health in the PREVENT Dementia Cohort
Authors: Gregory Sarah , Dounavi Maria‐Eleni , Low Audrey , Ntailianis Georgios , O'Brien John T , Parra‐Rodriguez Mario A , Shannon Oliver M , Stevenson Emma , Ritchie Craig W , Ritchie Karen , Wells Katie , Muniz‐Terrera Graciela 
Published: December 2023

AbstractBackgroundThe Mediterranean diet (MedDiet) has been associated with better cardiometabolic and brain health. Research has suggested differences in these associations between men and women, with men typically reported to benefit more from higher MedDiet adherence. However there remains a lack of research in this area in non‐Mediterranean countries. This study aimed to explore cross‐sectional associations between MedDiet adherence in the PREVENT Dementia cohort (UK and Ireland), stratified by sex.MethodAfter deriving scores to quantify adherence to the MedDiet (MEDAS, MEDAS continuous and Pyramid), we used linear regression and linear mixed effects models to test for associations between the MedDiet scores, cardiometabolic health (blood pressure, BMI, glycemia, cholesterol, triglycerides) and brain health (white matter hyperintensity volume (WMHV), cortical thickness, hippocampal subfield volumes, cognition). Propensity scores were calculated to strengthen causality inferences from the data, and used as covariates along with total energy intake and Western diet scores.ResultWe included 533 participants, mean age 51.25 (±5.40) years, majority women (60.0%). Higher MedDiet scores (MEDAS data presented) were associated with lower blood pressure (systolic ß: ‐1.16, p:0.009; diastolic ß: ‐1.00, p<0.001) and BMI (ß: ‐0.53, p<0.001). There were significant interactions between MedDiet and sex for diastolic blood pressure and hip‐to‐waist ratio. When stratified by sex, women had significant positive associations between MedDiet scores and blood pressure (systolic ß: ‐1.45, p: 0.006; diastolic ß: ‐1.29, p<0.001), BMI (ß: ‐0.51, p: 0.02) and glycemia (Pyramid only: ß: ‐0.11, p: 0.02), whereas men only had a significant association with BMI (ß: ‐0.45, p: 0.02) (Figure 1). There were no significant associations between dietary scores and any markers of brain health. An exploratory path analysis found a significant mediation between the Pyramid MedDiet score, pulse pressure and WMHV (Figure 2), which was only seen in women.ConclusionThere were significant associations between higher MedDiet scores and better cardiometabolic health, particularly for women. There were no direct associations with brain health outcomes, however a path analysis suggested a mediating effect of pulse pressure between the MedDiet and WMHV. Sex‐stratified nutritional guidelines to support better cardiometabolic health, may lead to better brain health and warrant further investigation.
Brain glutathione may be associated with white matter hyperintensities in patients with cardiovascular disease
Authors: Chen Jinghan Jenny , Herrmann Nathan , Survilla Kate , Black Sandra E. , Ramirez Joel , Andreazza Ana C. , Oh Paul I. , Gallagher Damien , Graham Simon J. , Lanctôt Krista L. 
Published: December 2023

AbstractBackgroundWhite matter hyperintensity (WMH) is a marker of age‐related cerebrovascular damage and is correlated with cognitive impairment; ischemia and inflammatory mechanisms have been proposed to be involved in its pathogenesis. These processes are associated with oxidative stress (OS), which may impair cellular function and affect antioxidant balance; however, the role of central antioxidant responses is still unclear.MethodPatients (age 55‐85) with ≥2 vascular risk factors or a previous vascular event were assessed at baseline for an exercise rehabilitation program. All participants completed the Montreal Cognitive Assessment (MoCA). Baseline WHM severity was determined using the standardized Canadian Dementia Imaging Protocol and semiautomatic protocols. Brain glutathione (GSH) at baseline was obtained in the anterior cingulate (AC) and occipital region (OC) using 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b).ResultOf 30 participants (mean age: 66.2 ± 7.42 SD; 80% male) currently enrolled, brain volumetric measurements were completed for 25 participants. Lower MoCA score was associated with greater total WMH volume, controlling for age (b[SE] = ‐0.017 [0.005], t(22) = ‐3.24, p = 0.004); this relationship remained significant when controlling for years of education separately (b[SE] = ‐0.016 [0.006], t(22) = ‐2.86, p = 0.01). Correcting for cerebrospinal fluid volume, lower AC‐GSH level was associated with higher deep WMH volume in the medial middle frontal (MMF) region of interest (b[SE] = ‐0.056 [0.023], t(23) = ‐2.38, p = 0.026), but not with MMF paraventricular WMH volume. After controlling for age, the model was no longer significant (F (2, 22) = 2.87, p = 0.078). No significant associations were found between OC‐GSH and occipital lobe WMH.ConclusionAs expected, total white matter hyperintensity volume was associated with poorer global cognition. In the medial middle frontal (MMF) region of interest, higher deep WMH was associated with lower GSH levels, suggesting altered brain antioxidant levels may be associated with the presence or formation of WMH. Recruitment is ongoing, and additional participants are needed to reinforce findings and to control for confounders in the analysis.
Loss of Progranulin Results in Increased Pan‐Cathepsin Expression
Authors: Anderson Abigail , Gillett Drew A , Boles Jake , Wallings Rebecca L , Tansey Malu Gámez 
Published: December 2023

AbstractBackgroundMutations in the progranulin (PGRN) encoding gene, GRN, cause familial frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis and is also implicated in Parkinson’s disease. These mutations result in decreased PGRN expression. PGRN is highly expressed in peripheral immune cells and microglia and regulates cell growth, survival, repair, and inflammation. As well, PGRN is implicated in regulating lysosome function, however, the exact role of PGRN in lysosomal function and how this contributes to inflammation and degeneration is not entirely understood. To better understand the role of PGRN in regulating lysosome function, I examined how loss of GRN impacts lysosomal and cathepsin activity.MethodUsing mouse embryonic fibroblasts (MEFs), I performed immunocytochemistry and immunoblotting assays to analyze fluorescent signal from LAMP1 (lysosomal marker) and BMV109 (marker for cathepsin activity).ResultGRN‐/‐ MEFs exhibit increased expression of pan‐cathepsin activity relative to GRN+/+ MEFs, and significantly impacts expression of LAMP1.ConclusionThe significant increase in pan‐cathepsin activity in the GRN‐/‐ MEFs confirms that PGRN loss does alter cathepsin expression, which may be a result of compensatory mechanisms happening within the cell. Further investigations will include assessing LAMP1 and BMV109 expression in microglia from from GRN‐/‐ mice, in the hopes to understand the role of PGRN in lysosomal function in immune cells of the central nervous system and the diseases in which it is implicated.
Changes in Brain Glutathione in patients with mild vascular cognitive impairment
Authors: Chen Jinghan Jenny , Herrmann Nathan , Survilla Kate , Black Sandra E. , Ramirez Joel , Andreazza Ana C. , Oh Paul I. , Gallagher Damien , Graham Simon J. , Lanctôt Krista L. 
Published: December 2023

AbstractBackgroundOxidative stress (OS) has been implicated in age‐related neurodegeneration and may be important in prodromal states such as mild vascular cognitive impairment (mVCI). Higher peripheral OS is reported in mVCI patients; however, the role of central antioxidant defenses in mVCI is unclear. Glutathione (GSH) is a major brain antioxidant, and so brain GSH in possible mVCI vs. controls was assessed.MethodPossible mVCI patients (1 standard deviation (SD) below population norms in verbal memory, executive function (EF), processing speed, or working memory, age 55‐85, and currently enrolled in a cardiac rehabilitation program due to having 2 or more vascular risk factors or previous vascular event) and cognitively‐normal (CN) controls are recruited from a 6‐month exercise rehabilitation program. All participants received 1H magnetic resonance spectroscopy (MEscher–GArwood Point Resolved Spectroscopy) to quantify brain GSH at baseline in the anterior cingulate (AC) and occipital region (OC). Spectroscopic analysis was completed using the Gannet toolkit (vers. 3.1) in Matlab (vers. 2020b), a cut‐off of 20% was used to reject spectra of poor quality.ResultIn 30 participants (mVCI n = 16, CN n = 14), anterior cingulate (AC) GSH (I.U. ± SD) was higher in mVCI (1.86 ± 0.45) compared to CN (1.63 ± 0.50) (F(1,18.8) = 4.6, P = 0.04), this difference became trending after correcting for cerebrospinal fluid volume ((F(1,18.2) = 3.9, P = 0.06). No difference was detected for OC‐GSH before or after correcting for cerebrospinal fluid volume. Higher AC‐GSH was correlated with lower Montreal Cognitive Assessment score (rho (26) = ‐0.42, p = 0.02).ConclusionPreliminary data suggest an upregulation in anterior cingulate glutathione in mVCI, which might reflect a compensatory increase in antioxidants as a response to increase peripheral oxidative stress previously reported in these patients. Recruitment is ongoing and additional participants are needed to reinforce findings.