Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.

Rachael I Scahill ,Sarah Gregory,Cristina Sampaio,Filipe B Rodrigues,Amanda Heselgrave,Geraint Rees,Paul Zeun,Henrik Zetterberg,Peter Mccolgan,Katherine Osborne-Crowley,Jessica Lowe,Kate Fayer,Harpreet Hyare,Christelle Langley,Hui Zhang,Douglas R Langbehn ,Trevor W Robbins ,Christopher S Parker ,Lauren M Byrne ,Claire O’callaghan ,Edward J Wild ,Carlos Estévez-Fraga ,Barbara J Sahakian ,Akshay Gopinathan Nair ,Henrietta Wellington ,Eileanoir B Johnson ,Sarah J Tabrizi

doi:10.1016/s1474-4422(20)30143-5

Abstract

SummaryBackgroundDisease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset.MethodsWe did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general least-squares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0·05 deemed a significant result.FindingsData were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29·0 years (SD 5·6) and 29·1 years (5·7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23·6 years (SD 5·8) from predicted onset (FDR 0·22–0·87 for cognitive measures, 0·31–0·91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0·03), but this did not appear to be closely related to predicted years to onset (FDR=0·54). There were no group differences in other brain imaging measures (FDR >0·16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0·0001, =0·01, and =0·03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0·0001).InterpretationWe report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact.FundingWellcome Trust, CHDI Foundation.

Highlights

Huntington’s disease is an autosomal dominant neuro degenerative condition caused by a CAG expansion in the HTT gene, resulting in the expression of mutant huntingtin protein, which is thought to be the predominant toxic agent
61 (91%) of 67 controls and 62 (97%) of 64 premanifest Huntington’s disease gene carriers (preHD) participants were assessed to be suitable for MRI scanning on the day of the procedure and underwent neuroimaging
In the interests of conciseness, we graphically display only selected results: all cognitive and neuropsychiatric results are displayed via radar plots; volumetric imaging results are selected as the most widely used imaging technique in Huntington’s disease and as the only imaging domain showing a significant result; biofluid measures that have previously shown differences in preHD are displayed, plus total huntingtin and neurogranin, which are of substantial interest

Summary

Introduction

Huntington’s disease is an autosomal dominant neuro degenerative condition caused by a CAG expansion in the HTT gene, resulting in the expression of mutant huntingtin protein, which is thought to be the predominant toxic agent. We found robust evidence of disease-related differences across multiple modalities in preHD up to 15 years before expected clinical disease onset. Such differences include increases in biofluid biomarkers of neuronal damage, brain atrophy focused in the subcortical structures accompanied by involvement of white matter networks, and subtle impairment in cognition, motor function, and neuropsychiatry. We are not aware of studies that include a comprehensive, multimodal assessment of adult premanifest gene carriers more than 20 years from predicted onset. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington’s disease gene carriers (preHD) far from predicted clinical symptom onset

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