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Rare variant associations with late‐life cognitive performance
No full textBackground:
Despite evidence that Alzheimer's Disease (AD) is a highly heritable disease, there remains substantial “missing” heritability, likely due to the clinical and neuropathologic heterogeneity inherent in the disease. Here, we leverage sensitive longitudinal cognitive measures as endophenotypes in a rare variant analysis to identify novel genetic drivers of cognitive decline in aging and disease.
Method:
We leveraged 8 cohorts of cognitive aging with whole genome sequencing data from the AD Sequencing Project to conduct rare variant analyses of multiple domains of cognition (N = 8,481; mean age=73; 56% female; 52% cognitively unimpaired). Harmonized scores for memory, executive function, and language were derived using confirmatory factor analysis models. Longitudinal scores were generated for each domain using linear mixed model regressions. Participants of European ancestry inferred using SNPweights and 1000G reference panel were included. Variants included had a minor allele frequency 10. All tests were adjusted for sex, baseline age at cognitive assessment, sequencing center and platform, and the first 5 principal components of genetic ancestry. Correction for multiple comparisons was completed using the false discovery rate (FDR) procedure.
Result:
We identified 9 genes associated with our cognitive domains. Two genes (APOE, PSEN1) were associated with baseline memory (both pFDR=0.07), one (PEDS1‐UBE2V1) with baseline language (pFDR=0.01), and six (HPN, HPN‐AS1, GAB1, CXCL3, SIGIRR, PLA2G4A) with executive function decline (pFDR range=0.01‐0.08). SIGIRR, PLA2G4A, and HPN all had high impact variants contributing to the gene score that were significantly associated with executive function decline.
Conclusion:
These results highlight novel rare variants associated with cognition. GAB1 is an AGORA nominated gene target for potential AD treatment. Decreased expression was found in cholinergic neurons in AD patients and decreased learning and memory in a mouse model of AD. PLA2G4A has increased expression in AD patients that is evident in early stages but is decreased in healthy aging brains. Future work will incorporate other ancestries
First Postgraduate Medical Education by Telephone in State and Nation presented by IU School of Medicine and Indiana State Medical Association in 1950
No full textInterplay between age, APOE Ɛ4 and the metabolome in plasma and brain in Alzheimer's disease
No full textAge and the ε4 variant of the apolipoprotein E gene (APOE ε4) are two major drivers of Alzheimer's disease (AD). APOE is also the major determinant of longevity. How age and APOE interact in the development of AD is largely unknown. In this study we integrate metabolomics (N = 274,259) and proteomics (N = 54,219) data in plasma from the UK Biobank with the metabolomics (N = 514) and proteomics (N = 618) data in brain from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) to understand the interplay of age, APOE ε4 and metabolome in the development of AD. We find that levels of β-hydroxybutyrate (BHBA) and branch-chained amino acids (BCAAs) are dysregulated in plasma and brains of AD patients. APOE ε4 carriers manifest significantly higher plasma concentration of BHBA that is detectable as early as 37 years of age and remains high throughout the studied age range of 37-73 whereas the plasma concentrations of BCAAs decline in APOE ε44 carriers after the age of 58 years. Proteomic signatures of APOE ε4, BHBA and BCAAs suggest downregulation of lysosome, immune and insulin-like growth factor (IGF1) transport/uptake pathways in plasma, and downregulation of the tricarboxylic acid (TCA) cycle, neurexins/neuroligins and clathrin-mediated endocytosis pathways in brain. Our data identifies two major shifts in metabolism occurring decades apart over the age course in AD in APOE ε4 carriers. These include early ketogenesis that manifests around late 30 s and gluconeogenesis, which manifests around the age of 60 years
Disabled Youth's Cultural Ways of Knowing and Doing in Special Education: Implications and Strategies
No full textAs section leader of the ‘diversity/multicultural’ portion of the International Handbook of Special Education: Implications and Strategies, I have spent considerable time reflecting on the conceptualization of disability at the intersections of multiple non-dominant identity markers in relation to strategies benefiting disabled youth. My reflections have been heavily influenced by Waitoller and Thorius’s (2022) critical scholarship on centering and sustaining disabled youth’s assets within educational spaces. Their work alongside the scholarship of those with multiple intersectional identities (e.g., scholars of Color, disabled scholars, disabled scholars of Color), has supported an evolution of thinking around difference encapsulated in two main ideas: a) disability is part of the fabric of human variance encompassing identity formation, a connection to disability culture/s and communities, and a way of knowing that is contributive, beneficial, and evolving and (b) disability can be located as a counterhegemonic construct to disrupt “normalcy and its location in the bodies and minds of those with dominant identity markers” (Thorius, 2019, p. 212)
Why is the uptake of gene therapy in hemophilia less than expected?
No full textGene therapy has held promise to cure hemophilia since factor (F)VIII and FIX were cloned more than 40 years ago. However, scientific understanding of the adeno-associated virus, the predominant vector used in gene therapy, has been insufficient to overcome many of the hurdles encountered, resulting in failed clinical studies, marginal efficacy, unfavorable benefit/risk, or phase 3 studies that do not sufficiently support wide commercial use. However, a functional cure, defined as permanent factor levels of at least 40%, has seen durable success in some FIX gene therapy recipients. Less success has been seen for FVIII gene therapy. Additional reasons for slow commercial uptake include the need to establish complex reimbursement processes for very high-priced drugs
HECLIP: histology-enhanced contrastive learning for imputation of transcriptomics profiles
No full textMotivation: Histopathology, particularly hematoxylin and eosin (H&E) staining, is pivotal for diagnosing and characterizing pathological conditions by visualizing tissue morphology. However, H&E-stained images inherently lack molecular resolution, necessitating costly and labor-intensive technologies like spatial transcriptomics (ST) to uncover spatial gene expression patterns. There is a critical need for scalable computational methods that can bridge this imaging-transcriptomics gap.
Results: We present histology-enhanced contrastive learning for imputation of profiles (HECLIP), an innovative deep learning framework designed to infer spatial gene expression profiles directly from H&E-stained histology images. HECLIP employs an image-centric contrastive learning strategy to capture morphological features relevant to molecular expression. By minimizing dependence on ST data, HECLIP enables accurate and biologically meaningful predictions of gene expression. Extensive benchmarking on publicly available datasets demonstrates that HECLIP outperforms existing methods. Ablation studies confirm the contribution of each model component to its overall performance.
Availability and implementation: The source code for HECLIP is freely available at: https://github.com/QSong-github/HECLIP
Sex Differences in Neuropsychiatric Symptoms Associated with Agitation in Frontotemporal Lobar Degeneration
No full textBackground:
Agitation is a clinically significant symptom contributing to behavioral and psychological symptoms of dementia (BPSD) but is poorly understood across the different syndromes related to Frontotemporal Lobar Degeneration (FTLD). This study investigates sex differences in agitation across FTLD‐related syndromes and its relationship to various neuropsychiatric symptoms (NPS).
Method:
We analyzed data from 1,654 participants (916 males, 738 females; average ages 65.8 and 65.9, respectively) from the National Alzheimer's Coordinating Center (NACC) and ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study with a FTLD‐related syndrome: behavioral variant FTD (bvFTD), Primary Progressive Aphasia (non‐fluent variant (nfvPPA), semantic variant (svPPA)), Corticobasal syndrome (CBS) and Progressive Supranuclear Palsy (PSP). Participants’ symptoms were assessed using the Neuropsychiatric Inventory (NPI). Prevalence ratios and odds ratios were computed to assess the likelihood of NPS comorbidities when agitation was present in males and females. Principal Component Analysis (PCA) was performed to identify NPS associated with agitation and how they varied by sex.
Result:
Males were more likely to experience anxiety (bvFTD: p <0.001, CBS: p <0.01, PSP: p <0.0001), apathy (nfvPPA: p <0.01, PSP: p <0.01), depression (bvFTD: p <0.0001, PSP<0.01), disinhibition (nfvPPA: p <0.0001), PSP: p <0.001), and motor symptoms (bvFTD: p <0.01, CBS: p <0.01) when agitation was present. In contrast, females had a higher likelihood of experiencing disinhibition in svPPA (p <0.001). These findings suggest that agitation is associated with a wider range of NPS in males than in females. Agitation and NPS are especially prominent in males with PSP.
Conclusion:
This study reveals significant sex differences in NPS in FTLD‐related syndromes when agitation is present. Males and especially PSP, are more likely to experience a broader range of NPS in association with agitation. These findings underscore the need for further investigation into the underlying mechanisms driving these sex differences, particularly focusing on the neurobiological impact of agitation, the recognition of symptoms in the presence of greater behavioral disturbances, and potential variations from informant reports. Understanding these factors will provide valuable insights into the role of agitation in the presentation of NPS across FTLD‐related syndromes. Ultimately, addressing these gaps will enhance our ability to effectively treat and manage agitation in both male and female patients with FTLD‐related syndromes
Prospective Multicenter Longitudinal Measurement of Liver Stiffness in School-Age Children With Cholestatic Liver Disease
No full textBackground and aims: A multicenter prospective longitudinal study of vibration-controlled transient elastography (VCTE) in school-age children with biliary atresia (BA), alpha-1 antitrypsin deficiency (a1-AT) and Alagille syndrome (ALGS) was undertaken to test the hypothesis that there would be measurable disease progression over 2 years.
Methods: Vibration-controlled transient elastography was performed annually for 2 years in children with BA, a1-AT and ALGS.
Results: Valid liver stiffness measurement (LSM) was determined at baseline/second follow-up in 254/180 (71%), 104/58 (56%) and 100/61 (61%) participants (mean elapsed time 2.27 years) with BA, a1-AT and ALGS, respectively. Modeling did not reveal a relationship between LSM and time since baseline: BA 1.2% (-1.6, 4.2%), a1-AT 0.1% (-3.8, 4.2%), and ALGS 3.6% (-2.9, 10.5%) LSM (% change/year; mean [95% confidence interval]). Similarly, mean LSM did not change significantly from baseline to visit 2 (BA 13.6 + 11.0 vs 15.1 + 12.8; a1-AT 7.8 + 5.1 vs 8.5 + 7.6; ALGS 10.6 + 9.4 vs 12.2 + 12.1 kPa, mean + standard deviation). Albumin and total bilirubin levels did not change in these participants. Platelet counts dropped at rates that were similar to a national representative sample, the National Health and Nutrition Examination Survey (ie, 5000 to 7000/μL per year).
Conclusion: Surprisingly, longitudinal measurement of LSM and laboratory parameters of liver disease severity over 2 years in school-age children with compensated BA, a1-AT, and ALGS did not reveal significant change, consistent with slow progression of cholestatic liver disease in this age group. These findings have implications for both clinical care and interventional trials in this patient population
Mental health trajectory throughout high school football career: a four-year prospective cohort study
No full textIntroduction: Repetitive head impacts may contribute to long-term neurological disorders, including chronic traumatic encephalopathy (CTE), and mental health decline often precedes cognitive symptoms. Adolescent athletes are especially vulnerable, yet prospective data on mental health trajectory across high school athletic career are limited.
Aim: To examine the mental health changes of high school football players across multiple seasons of participation.
Methods: This prospective cohort study included 6 high schools across southern Indiana for 4 consecutive seasons from July 2021 to February 2025. Participants included male high school football players and noncontact athletes (ages 13-18) in tennis, cross-country, and swimming. Sensor installed mouthguards were utilized to measure head impacts and surveys were conducted pre and post season to assess anxiety and depressive symptoms.
Results: A total of 371 adolescent athletes participated in this longitudinal study, including 275 high school football players (mean [SD] age, 15.3 [1.2] years) and 96 non-contact control athletes (mean [SD] age, 15.9 [1.2] years), with varying lengths of participation across 4 years of study. Depression and anxiety symptoms remained consistent across 1 season (pre vs. postseason) in both groups, as illustrated by non-significant group by time interaction in PHQ-9 [b=-0.11, 95%CI(-0.98, 0.76), p=0.814] or GAD-7 [b=0.09, 95%CI(-0.62, 0.79), p=0.806]. The same pattern was observed for those who participated in 2 consecutive seasons [PHQ-9 b=-0.01, 95%CI (-0.96, 0.98), p=0.980; GAD-7 b=0.42, 95%CI(-0.43, 1.27), p=0.33]. However, among those with 3 consecutive years of participation, there was significant seasons (pre vs. post) by year (1st vs. 3rd year) interaction in depression symptoms in the football group [PHQ-9: b=1.50, 95%CI (0.32, 2.66), p=0.015], a pattern not observed in the control group.
Discussion: Our data suggest that mental health wellbeing remain consistent across 1 to 2 years of high school sports participation, regardless of head impact exposure or types of sports they play (football or non-contact sports). However, psychological burden may accumulate over multiple years of football participation
Thermodynamic and Structural Investigations of Protein Mutations Using λ-Dynamics
No full textIUIThe λ-dynamics (λD) alchemical free energy method is a powerful tool to
investigate the impact that an amino acid change has on the stability of a protein or a protein
complex. This method simultaneously calculates thermodynamic relative free energy
changes (ΔΔGs) due to protein perturbations and generates simulation trajectories that
allow the specific origin of the thermodynamic change to be identified. Historically,
alchemical investigations of protein mutations have encountered difficulties when the
perturbation involved buried small-to-large changes, changes to backbone flexibility,
and/or changes in charge. However, such perturbations frequently arise when studying
disease-linked protein mutations. In this thesis, λD was used to model mutations in the 20S
proteasome, the insulin receptor, and the RNA exosome complex, demonstrating its ability
to model each kind of challenging protein mutations listed above.
Using multisite λ-dynamics (MSλD), a series of thermal-sensitive mutants in the
proteasome subunit, Pup2 (C76R, T113M, and L204Q) were investigated. The
thermodynamic results revealed a large ΔΔGbind of 5 kcal/mol accompanying the C76R
mutation. Complimentary stabilization by the T113M and L204Q variants was observed at
lower temperatures (30 °C) but disappeared at higher temperatures (50 °C).
The insulin ValA3Leu mutation gives the clinically observed insulin Wakayama a
140-500-fold worse binding affinity for the insulin receptor. This loss of binding, along
with the binding trends of six other insulin A3 variants, were successfully captured with λD. Structural investigation revealed that the substantially worse impact from LeuA3 stems
from a steric clash with Leu’s second Cδ.
With λD, a series of challenging EXOSC3 mutations were analyzed, including the
neurodegenerative disorder-linked D132A, A139P, G191C, and G191D and the variant of
uncertain significance (VUS) G135R. All of these variants were found to destabilize
EXOSC3 folding while A139P, G191D, and G135R were also found to negatively impact
binding affinity. Structural analysis identified a clear rationale for the thermodynamic
impact of all EXOSC3 variants. This study concludes that the VUS G135R is likely
pathogenic. This work demonstrates the utility of λD in investigations including extremely
challenging protein mutations in macromolecular complexes and applies this tool to
explain disease-linked missense mutations and to predict the significance of a VUS
mutation