Biomedical subjects

Aron S Buchman

Publications and source records attributed to Aron S Buchman.

10 recordsLinked to original sources

PubMed2026

Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analysed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer's disease metabolome. A PD acylcarnitine signature was further replicated in human post-mortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.

Humans↗

PubMed2025

Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci. METHODS: By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's disease and other common age-related clinical and neuropathologic traits were examined. RESULTS: First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10-4). CONCLUSIONS: While still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.

Humans↗

PubMed2007

Change in motor function and risk of mortality in older persons.

OBJECTIVES: To assess the association between change in motor function and mortality. DESIGN: Prospective, observational cohort study. SETTING: Approximately 40 retirement communities across the Chicago metropolitan area participating in the Rush Memory and Aging Project. PARTICIPANTS: Eight hundred thirty-seven community-based older persons without dementia. MEASUREMENTS: Change in composite measures of motor performance and muscle strength. RESULTS: During a mean follow-up of 2.2 years, 81 persons died. In a proportional hazards model adjusted for age, sex, education, and body mass index, each 1-unit increase in the level of baseline motor performance was associated with an approximately 10% decrease in risk of mortality (hazard ratio (HR)=0.901, 95% confidence interval (CI)=0.863-0.941), and each unit of annual increase in motor performance was associated with an approximately 11% decrease in the risk of mortality (HR=0.887, 95% CI=0.835-0.942). In a similar model, each 1-unit increase in the level of baseline strength was associated with an approximately 9% decrease in the risk of mortality (HR=0.906, 95% CI=0.859-0.957), and each 1-unit annual increase in strength was associated with an approximately 10% decrease in the risk of mortality (HR=0.898, 95% CI=0.809-0.996). These results were similar when men and women were analyzed separately and after controlling for physical activity, cognition, and chronic disorders. When motor performance and muscle strength were examined in a single model, only baseline and annual change in motor performance were associated with mortality. CONCLUSION: Level and rate of change in strength and motor performance are associated with mortality. The attenuation of the association between strength and mortality by motor performance suggests that motor function is not a unitary process and that its components may vary in their associations with adverse health consequences in older persons.

Aged, 80 and over↗

PubMed2006

Eosinophilia, myositis, and myasthenia gravis associated with a thymoma.

Hypereosinophilia has been associated with a wide variety of systemic disorders, including myositis. Myositis develops in a minority of patients with myasthenia gravis associated with a thymoma. We present a patient who developed a life-threatening myopathy in which testing demonstrated the concurrence of hypereosinophilia, myositis, and myasthenia gravis associated with thymoma. Thymoma-associated T-cell abnormalities may well have contributed to this rare association. This case underscores the need to reevaluate constantly the presumed cause of clinical complaints, as more than one cause may be present.

Aged↗

PubMed2005

Enhancement of motor rehabilitation through the use of information technologies.

The recent development of information technologies has dramatically increased the tools available for facilitating motor rehabilitation. This review focuses on technologies which can be used to augment movement-related information both to patients as well as to their therapists. A brief outline of the motor system emphasizes the role of spinal motor neurons in the control of voluntary movement and rehabilitative efforts. Technologies which induce passive motion to stimulate spinal motor output as well as technologies that stimulate active voluntary movements are discussed. Finally, we review technologies and notational methods that can be used to quantify and assess the quality of movement for evaluating the efficacy of motor rehabilitation efforts. We conclude that stronger evidence is necessary to determine the applicability of the wide range of technologies now available to clinical rehabilitation efforts.

Biotechnology↗

PubMed2005

The Rush Memory and Aging Project: study design and baseline characteristics of the study cohort.

The long-term objective of the Rush Memory and Aging Project is to identify the postmortem indices linking genetic and environmental risk factors to the development of Alzheimer's disease (AD). The overall study design involves a detailed assessment of risk factors for AD in older persons without known dementia who agree to annual clinical evaluation and organ donation at the time of death. In contrast to other clinical-pathologic studies which are conducted on special populations, the Rush Memory and Aging Project enrolled a cohort with much greater diversity in terms of educational attainment, in addition to gender, race, and ethnicity. From September of 1997 through April of 2005, more than 1,000 older persons without known dementia from more than 30 residential facilities across the Chicago metropolitan area agreed to participate. Their mean age was 81 years, about a third had 12 or fewer years of education, a third were men, and about 10% were members of a racial or ethnic minority group. More than 950 already have completed their baseline clinical evaluation.

Activities of Daily Living↗

PubMed2005

Botulinum toxin injections for children with excessive drooling.

The objective of this study was to evaluate the feasibility of ultrasonography-guided injections of botulinum toxin A into the parotid glands of children with severe drooling (sialorrhea). Excessive drooling is common in children with chronic neurologic disorders. Preliminary observations in adults suggest that injections of botulinum toxin A into the parotid glands can decrease drooling, but the optimal dose, sites of injection, and concomitant use of imaging during injections and its use for children have not been established. Ultrasonography was used to guide the injection of botulinum toxin (10-25 IU) into both parotid glands of nine children with excessive drooling. Subjective and objective measures of the severity of drooling were collected before and after botulinum toxin A injections. A booster injection was provided if the initial response was inadequate. Injections were well tolerated, and no adverse reactions were observed. Ultrasonography revealed that the parotid gland showed a variable depth, extent, and vascularization. Eight of nine patients needed a booster injection after 1 month. Objective measures of drooling severity were improved in seven of nine patients. However, subjective improvement was reported in only three of nine patients, and this improvement was functionally significant in only one patient. Although intraparotid injection of botulinum toxin A is safe and causes a reduction in saliva production in children, the doses used in this study did not result in functionally significant improvement. Higher doses of botulinum toxin A in the parotid glands or concomitant injections into the submandibular glands can increase the efficacy of these injections. Variability in size, depth, and vascular supply of the parotid gland suggests the importance of ultrasonography guidance for optimizing injections. These results underscore the need for further studies to establish the efficacy of this treatment in children.

Adolescent↗

PubMed2004

Stiff-person syndrome following West Nile fever.

BACKGROUND: Stiff-person syndrome is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase (GAD), the key enzyme in gamma-aminobutyric acid synthesis. In most cases, a trigger cannot be identified. OBJECTIVE: To describe a 41-year-old man who developed stiff-person syndrome and antibodies to GAD following acute West Nile virus infection. DESIGN: A case report and a search in GenBank for common epitopes. RESULT: The search revealed a stretch of 12 amino acids in the NS1 protein of West Nile virus with a high degree of homology to the GAD65 region (an isoform of GAD) containing the PEVKEK motif. CONCLUSION: Cross-reactivity between antibodies directed against West Nile virus and GAD may have contributed to the development of stiff-person syndrome in this patient.

Adult↗

PubMedDate not supplied

Harm avoidance and disability in old age.

The relation of personality to disability in old age is not well understood. The authors examined the relation of harm avoidance, a trait indicating a tendency to worry, fear uncertainty, be shy, and tire easily, to disability in a group of 474 older persons without dementia. Participants completed the 35-item Harm Avoidance scale. Disability was assessed with the Rosow-Breslau scale, a self-report measure of physical mobility. Performance-based tests of lower limb functions were also administered from which composite measures of gait, balance, and strength were derived. In a logistic regression model controlled for age, sex, education, and lower limb function, persons with high levels of harm avoidance were nearly three times as likely to report mobility limitations as persons with low levels, and these effects largely reflected fatigability and fear of uncertainty. The association of harm avoidance with disability was not explained or modified by frailty, physical activity, depressive symptoms, neuroticism, extraversion, or cognition. The results suggest that harm avoidance is associated with disability in old age.

Activities of Daily Living↗

PubMedDate not supplied

Correlates of life space in a volunteer cohort of older adults.

The authors measured the spatial extent of movement of older persons (i.e., life space) and examined factors that are related to life space. A larger life space was positively correlated with self-report measures of disability. In generalized logit models adjusted for demographics and time of year, a larger life space was associated with less visual impairment, higher levels of lower extremity motor performance, global cognition, and social involvement, and with personality and purpose in life. The results suggest that the range of environmental movement in older adults is a useful indicator of health in old age and may complement measures of disability.

Activities of Daily Living↗