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

Abstract

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.

Figure 1

Radar plot showing (A) cognitive and (B) neuropsychiatric variables in the Huntington's disease Young Adult Study The black line shows the standardised mean difference between individuals with premanifest Huntington's Disease (preHD) and controls, with conventional frequentist 95% CI shaded in grey. The red line represents no difference between means (ie, the null hypothesis) and a value within this line represents greater impairment in the preHD group. After false discovery rate correction for multiple comparisons, there were no significant group differences in any cognitive or neuropsychiatric measures. See appendix for further details of these variables (pp 6–12) and discussion (p 22). AMI=apathy motivation index. BIS=Barratt impulsivity scale. ED=extra dimensional. FSBS=frontal systems behavioural scale. IED=intra–extra dimensional set shifting. OCI=obsessive compulsive inventory. OTS=one touch stockings. PAL=paired associates learning. RT=reaction time. RVP=rapid visual processing. RVP A'=a signal detection theory measure of target sensitivity, and mean response latency. SDMT=symbol digit modalities test. SF36=36-item self-report survey. SST=stop signal task. SWM=spatial working memory. SSTAI=Speilberger state trait anxiety inventory. PSQI=Pittsburgh sleep quality index. ZSDS=Zung self-rating depression scale.

Figure 2

Volumetric MRI Boxplots of standardised residuals (covariate adjusted) for volumes of (A) putamen, (B) caudate, (C) whole brain, (D) grey matter, (E) white matter, and (F) ventricles corrected for intracranial volume. Horizontal lines are the medians, boxes are upper and lower quartiles, and whiskers are 1·5 × IQR. Putamen volume was significantly reduced in individuals with preHD compared with controls (FDR=0·03). None of the other brain measures showed significant between-group differences. FDR=false discovery rate correction. PreHD=premanifest Huntington's disease.

Figure 3

Biofluid measures Boxplots of standardised residuals (covariate adjusted) of (A) CSF mutant huntingtin, (B) CSF NfL, (C) plasma NfL, (D) YKL-40, (E) CSF total tau, (F) CSF neurogranin, (G) CSF IL-6, (H) IL-8, and (I) CSF total huntingtin. Horizontal lines are the medians, boxes are upper and lower quartiles, and whiskers are 1·5 × IQR. All analytes were log transformed. As expected, mutant huntingtin was undetectable in all controls. There were significant differences between individuals with preHD and controls for CSF NfL (FDR<0·0001), plasma NfL (FDR=0·01), and CSF YKL-40 (FDR=0·03). No other analytes showed significant group differences. FDR=false discovery rate correction. NfL=neurofilament light protein. IL=interleukin. PreHD=premanifest Huntington's disease.

Figure 4

NfL trajectories Associations of NfL concentration in (A) CSF and (B) plasma with age and CAG repeat count from combined datasets of HD-YAS and HD-CSF (where CAG=Huntington's disease gene carriers' CAG repeat counts). Data were modelled with a polynomial function of age, CAG repeat counts, their squares, and their interactions. NfL concentrations were reverse-transformed from log NfL values. CAG repeat counts are coloured separately and labelled on the right of the image. Shaded in grey is the range between the control curve (dark grey line) and the 95th prediction interval of controls. Dashed arrows show the intercept of NfL trajectory in Huntington's disease and the 95th prediction interval of controls, representing the age at which NfL concentrations become abnormal. Coloured diamonds show the mean age of clinical onset for each CAG based on the Langbehn equation using previously published data. Further details are in the appendix (p 17). NfL=neurofilament light protein.

Figure 5

Disease trajectory in Huntington's disease from early adulthood to manifest disease, , , , , , , , , , , , Evidence-based predictive schematic, with biofluid changes shown in red, brain volumetrics in blue, and functional performance in green. The label HD-YAS shows the range of years to estimated onset represented in our study. NfL and mutant huntingtin are the first pathological changes, occurring at around 24 years before expected symptom onset, with slow increases for approximately 10 years, followed by an acceleration (data from the HD-YAS and the HD-CSF study). Striatal volumes are slightly smaller than those of age-matched controls at the beginning of adulthood (data from the HD-YAS) and start to decline around 18 years before expected symptom onset. Decline is approximately linear, and volume reduction is around 50% of control volume by the time of clinical onset. White matter volume is reduced and shows higher rates of atrophy, than in controls by around 15 years before symptom onset, following a non-linear trajectory. Grey matter loss extends beyond the striatum later, at around 10 years before symptom onset,, after which it progresses non-linearly. Soft motor signs in the form of increased variability in voluntary movements are apparent by 15 years before symptom onset, , , and increase non-linearly., Cognitive changes start to emerge approximately 15 years before expected clinical symptom onset,, , declining slowly, following a non-linear trajectory. HD-YAS=Huntington's disease Young Adult Study. NfL=neurofilament light protein.