Bioenergetic dysregulation in the basal ganglia and cerebellum of patients with premanifest and manifest Huntington's disease

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Background Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive motor, cognitive, and psychiatric symptoms. While early striatal degeneration is a well-established hallmark, emerging evidence points to broader network-level dysfunction involving the cerebellum and profound alterations in mitochondrial energy metabolism. However, in vivo studies systematically examining region-specific bioenergetic changes across disease stages are scarce. Methods Using 31 Phosphorus magnetic resonance spectroscopic imaging ( 31 P-MRSI), we quantified metabolite ratios and absolute concentrations of alpha adenosine triphosphate (ATP-α), phosphocreatine (PCr), and inorganic phosphate (Pi) in the anterior basal ganglia and cerebellum of 31 patients with HD (15 manifest, 16 premanifest) and 19 healthy controls without pathogenic HTT expansion (HC). Results Basal ganglia (ATP-α + PCr)/Pi and ATP-α/Pi were significantly elevated in premanifest (+10.0% and + 13.9%) and manifest patients (+16.4% and + 19.2%) compared to HC. High-energy phosphate (HEP) levels showed a stage-dependent pattern, with ATP-α + PCr and ATP-α elevated in premanifest patients (+7.7% and + 3.9%) and reduced in manifest patients (−7.6% and − 12.8%). All metabolite ratios showed no correlation with clinical scores but were inversely associated with subcortical atrophy, particularly in the caudate (rho = −0.327, p = 0.022), putamen ( r = −0.372, p = 0.008), and globus pallidus ( r = −0.327, p = 0.022). Conclusions These findings reveal stage-dependent, region-specific alterations in HEP metabolism in patients with HD. The observed changes in the brain energy metabolism precede motor symptoms and are linked to structural atrophy rather than symptomatic burden, supporting the potential of 31 P-MRSI as a sensitive in vivo biomarker of bioenergetic dysfunction in HD.

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