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F05 Biological and clinical characteristics of gene carriers far from predicted onset in the hd-yas study: a cross-sectional analysis
  1. Rachael Scahill1,
  2. Paul Zeun1,
  3. Katherine Osborne-Crowley1,
  4. Eileanoir Johnson1,
  5. Sarah Gregory1,
  6. Christopher Parker1,
  7. Jessica Lowe1,
  8. Akshay Nair1,
  9. Claire O’Callaghan1,
  10. Christelle Langley2,
  11. Marina Papoutsi3,
  12. Peter McColgan1,
  13. Carlos Estevez Fraga1,
  14. Kate Fayer1,
  15. Henny Wellington1,
  16. Filipe Brogueira Rodrigues1,
  17. Lauren Byrne1,
  18. Amanda Heslegrave1,
  19. Harpreet Hyare1,
  20. Cristina Sampaio4,
  21. Henrik Zetterberg1,
  22. Hui Zhang5,
  23. Edward Wild1,
  24. Geraint Rees1,
  25. Trevor Robbins2,
  26. Barbara Sahakian2,
  27. Douglas Langbehn6,
  28. Sarah Tabrizi1
  1. 1UCL Queen Square Institute of Neurology, London, UK
  2. 2University of Cambridge, Cambridge, UK
  3. 3IXICO plc, London, UK
  4. 4CHDI Management/CHDI Foundation, Princeton, NJ, USA
  5. 5Computer Science and Centre for Medical Image Computing, UCL, London, UK
  6. 6University of Iowa, Iowa City, IA, USA


Background Disease-modifying treatments are in development for Huntington’s disease (HD); crucial to their success in delaying or preventing onset is to identify a timepoint when there is a measurable biomarker of early neurodegeneration while clinical function is still intact.

Aims We aimed to identify the earliest HD changes and the most promising measures for efficacy endpoints in future preventative therapeutic trials.

Methods We recruited 64 young adult preHD ~24 years from predicted clinical onset (mean (SD) age 29.0 (5.6) years) and 67 matched controls (29.1 (5.7) years). All participants underwent detailed clinical, cognitive and neuropsychiatric assessments. Imaging assessments included volumetric MRI, diffusion imaging and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and cerebrospinal fluid (CSF) collection. We performed a cross-sectional analysis using general least-squares linear models to assess for group differences and associations with age and CAG. Results were corrected for multiple comparisons using false discovery rate (FDR).

Results We found no significant evidence of cognitive or psychiatric impairment in preHD (FDR > 0.22). The PreHD cohort had smaller putamen volumes (FDR = 0.03), but this was not related to predicted years to onset. There were no group differences in other brain imaging measures (FDR > 0.16). CSF and plasma neurofilament light (NfL) (FDR < 0.0001 and FDR=0.01) and YKL-40 (FDR = 0.03) were elevated in preHD and disease-related NfL elevations were more likely in individuals closer to expected clinical onset (FDR < 0.0001).

Conclusions With no evidence of cognitive or psychiatric impairment but with sensitive measures of neurodegeneration starting to rise, this stage of preHD may represent an appealing time to initiate future disease-modifying prevention treatments. CSF NfL may be a promising marker of disease progression in future early preHD trials.

  • premanifest
  • neuroimaging
  • diofluids

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