Biological and clinical manifestations of Huntington’s disease in gene carriers very far from predicted onset

Abstract

IntroductionCrucial to the future success of treatments in Huntington’s disease is identifying a timepoint where there is a measurable biomarker of early neurodegeneration without detectable changes in clinical function. By performing deep phenotyping in premanifest gene carriers (preHD) further from predicted onset than previously studied, we aimed to identify this timepoint and the best measures for efficacy endpoints in future therapeutic trials.MethodsWe recruited 64 young adult preHD, approximately 24 years from predicted clinical onset, and 67 matched controls. All participants underwent detailed cognitive and neuropsychiatric assessments, multi-modal imaging and collection of blood and cerebrospinal fluid (CSF).ResultsWe found no significant evidence of cognitive or psychiatric impairment in preHD (minimum q>0.22). The PreHD cohort had smaller putamen volumes (q=0.03), but this was not related to predicted years to onset. There were no group differences in other brain imaging measures (q>0.16). CSF and plasma neurofilament light (NfL) (q<0.0001 and q=0.01) and YKL-40 (q=0.03) were elevated in preHD.ConclusionWith normal brain function but with sensitive measures of neurodegeneration starting to rise, this stage of preHD may represent an optimal time to initiate future disease-modifying prevention treatments. CSF NfL appears more sensitive at this time than plasma NfL to monitor treatment response.p.d.zeun@gmail.com