ArticleAnnals of neurology2024
Mutant Huntingtin Drives Development of an Advantageous Brain Early in Life: Evidence in Support of Antagonistic Pleiotropy.
Article in Annals of neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Tandem repeat polymorphisms are associated with brain structure: results of two large population-based studies.Genome medicine · 2026Article
- Observational
- Buried Treasure? Overlooked and Newly Discovered Evolutionary Contributions to Human Brain Diseases.Annals of neurology · 2025Review
- Movement disorders: a brief overview from an evolutionary perspective.Journal of neural transmission (Vienna, Austria : 1996) · 2025Review
- Childhood to Adult Neurodevelopment in Gene-Expanded Huntington's Disease (ChANGE-HD) study protocol: A Prospective Longitudinal Neurodevelopmental Study of Huntington's Disease.medRxiv : the preprint server for health sciences · 2025Article
- Cortical and Striatal Functional Connectivity in Juvenile-Onset Huntington's Disease.Brain sciences · 2025Article
- STRchive: a dynamic resource detailing population-level and locus-specific insights at tandem repeat disease loci.Genome medicine · 2025Article
- When repetita no-longer iuvant: somatic instability of the CAG triplet in Huntington's disease.Nucleic acids research · 2025Review
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Authors and funding
7 authors.
Funding
Abstract
objectiveHuntington's disease (HD) is a neurodegenerative disease caused by a triplet repeat expansion within the gene huntingtin (HTT). Antagonistic pleiotropy is a theory of aging that posits that some genes, facilitating individual fitness early in life through adaptive evolutionary changes, also augment detrimental aging-related processes. Antagonistic pleiotropy theory may explain a positive evolutionary pressure toward functionally advantageous brain development that is vulnerable to rapid degeneration. The current study investigated antagonistic pleiotropy in HD using a years-to-onset paradigm in a unique sample of children and young adults at risk for HD.
methodsCognitive, behavioral, motor, and brain structural measures from premanifest gene-expanded (n = 79) and gene nonexpanded (n = 112) participants (6-21 years) in the Kids-HD study were examined. All measures in the gene-expanded group were modeled using a mixed-effects regression approach to assess years-to-onset-based changes while controlling for normal growth. Simultaneously, structure-function associations were also examined.
resultsDecades from motor onset, gene-expanded participants showed significantly better cognitive, behavioral, and motor scores versus gene nonexpanded controls, along with larger cerebral volumes and cortical features. After this initial peak, a prolonged deterioration was observed in both functional and structural measures. Far from onset, brain measures were positively correlated with functional measures, supporting the view that functional advantages were mediated by structural differences.
interpretationMutant HTT may drive the development of a larger than normal brain that subserves superior early-life function. These findings support the antagonistic pleiotropy theory of HTT in HD, where this gene drives early advantage followed by accelerated aging processes. ANN NEUROL 2024;96:1006-1019.
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