Cortical and Striatal Functional Connectivity in Juvenile-Onset Huntington's Disease

Area of Science:

• Neuroscience
• Genetics
• Neurology

Background:

• Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene.
• Juvenile-Onset Huntington's Disease (JoHD) presents with early, severe motor symptoms.
• Early studies suggest subcortical atrophy in JoHD despite relatively preserved cortical volume.

Purpose of the Study:

• To investigate resting-state functional connectivity in cortical and subcortical brain regions in JoHD.
• To test the hypothesis of preserved cortical networks but altered striatal connectivity in JoHD.
• To explore associations between connectivity, disease burden, and clinical outcomes in JoHD.

Main Methods:

• Resting-state functional MRI was used to analyze brain connectivity in JoHD participants (n=19) and gene-non-expanded controls (n=64).
• Canonical cortical networks and striatal connectivity were assessed.
• Linear mixed-effects models were employed to determine group differences and clinical associations.

Main Results:

• JoHD participants exhibited reduced connectivity in the left somatomotor network and striatal circuits.
• Cortical network connectivity was largely typical in JoHD.
• Striatal connectivity correlated with disease burden and cognitive function, while somatomotor connectivity did not correlate with clinical outcomes.

Conclusions:

• Findings support the antagonistic pleiotropy hypothesis in JoHD, suggesting early neural advantages may precede striatal vulnerability.
• Reduced left-lateralized somatomotor hypoconnectivity in JoHD aligns with prior research on excitotoxicity and circuit vulnerability.
• The study highlights the complex interplay of genetic factors and neural network alterations in JoHD progression.