F009 Distinct morphologic and metabolic brain traits in pediatric-Onset Huntington disease: evidence from RAREST-JHD study

<h3>Background</h3> Pediatric-onset (PO) Huntington disease (HD) displays a phenotype different to adult-onset HD (AOHD), with hypokinetic movement disorders (e.g. rigidity, bradykinesia and dystonia) rather than chorea typical of AOHD. <h3>Objectives</h3> To uncover pathophysiologic-based biomarkers specific to POHD. <h3>Methods</h3> RAREST-JHD is a 3-year prospective study assessing clinical, genetic and imaging characteristics of young HD patients, to identify potential biomarkers of disease. We included adult patients (aged &gt;18 years) previously diagnosed with POHD (adolescent onset) only if with an HTT mutation &gt;60 CAG repeats, and adult patients previously diagnosed with AOHD (adult onset) with an HTT mutation &lt;60 CAG repeats. All patients were included in the ENROLL-HD platform. RAREST-JHD included AOHD patients matched for disease duration. Simultaneous hybrid imaging using [18F]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography plus magnetic resonance imaging (FDG-PET/MRI), alongside clinical assessment using standardized HD scales. Exploratory longitudinal analyses were also performed. <h3>Results</h3> Striatal volume loss was remarkable and more severe in POHD (n=5) than AOHD (n=14). Widespread, markedly altered glucose metabolism occurred in POHD cortex, but not AOHD cortex, consistent with differences in clinical progression. While brain volume changes were relatively similar among the three, longitudinally followed-up, POHD patients, alterations in glucose metabolism were highly individualized, with greater annual changes in metabolism linked to more severe worsening in annualized dystonia, parkinsonism and independence scores. <h3>Conclusions</h3> POHD patients’ brains displayed distinct morphologic and metabolic traits versus AOHD, with longitudinal changes mirroring clinical progression. Hybrid FDG-PET/MRI highlighted a variable regional brain dysfunction in vivo, as a biological consequence of highly expanded CAG repeats. Findings provide further evidence POHD is a distinct disease from AOHD.