Authors: Rachael I Scahill, Paul Zeun, Katherine Osborne-Crowley, Eileanoir B Johnson, Sarah Gregory, Christopher Parker, Jessica Lowe, Akshay Nair, Claire O'Callaghan, Christelle Langley, Marina Papoutsi, Peter McColgan, Carlos Estevez-Fraga, Kate Fayer, Henny Wellington, Filipe B Rodrigues, Lauren M Byrne, Amanda Heselgrave, Harpreet Hyare, Cristina Sampaio, Henrik Zetterberg, Hui Zhang, Edward J Wild, Geraint Rees, Trevor W Robbins, Barbara J Sahakian, Douglas Langbehn, Sarah J Tabrizi
Summary: Background: Disease-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.
Methods: We 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.
Findings: Data 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).
Interpretation: We 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.
Funding: Wellcome Trust, CHDI Foundation.
Source: The Lancet Neurology, 2020; 19 (6): 502