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. 2025 Nov;14(4):396-402.
doi: 10.1177/18796397251366900. Epub 2025 Aug 13.

Bias in HD-ISS staging introduced by the FreeSurfer cross-sectional stream: Insights from the Huntington's Disease Young Adult Study (HD-YAS)

Harry Knights  1 , Annabelle Coleman  1 , Mena Farag  1 , Michela Leocadi  1 , Michael Murphy  1 , Kate Fayer  1 , Olivia Thackeray  1 , Douglas Langbehn  2 , Nicola Hobbs  1 , Sarah J Tabrizi  1 , Rachael I Scahill  1 ; HD-YAS investigators
Affiliations

Bias in HD-ISS staging introduced by the FreeSurfer cross-sectional stream: Insights from the Huntington's Disease Young Adult Study (HD-YAS)

Harry Knights et al. J Huntingtons Dis. 2025 Nov.

Abstract

Huntington's Disease Integrated Staging System (HD-ISS) stages are likely inclusion criteria in future clinical trials. Stage 1 volumetric cut-offs were derived using the FreeSurfer longitudinal stream (LG). However, trials will require cross-sectional stream (CS) application with one MRI. Volumetric outputs are not robust to software type or version. T1-weighted images from 88 participants with MRIs from baseline and follow-up HD-YAS visits were segmented using both streams. CS calculated smaller caudate and putamen volumes adjusted for total intracranial volume, with greater reduction for larger volumes, shifting towards HD-ISS stage 1. CS-specific cut-offs need to be established before application to clinical trials.

Keywords: FreeSurfer; HD-ISS; MRI; caudate; huntington's disease; putamen; segmentation.

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Conflict of interest statement

Declaration of conflicting interestsSJT is an Associate Editor of the Journal of Huntington's Disease, but was not involved in the peer-review process and did not have access to any information regarding peer-review.

Figures

Figure 1.
Figure 1.
Bland-Altman plots with differences represented as cross-sectional (CS) – longitudinal (LG) stream volumes
Figure 1.
Figure 1.
Bland-Altman plots with differences represented as cross-sectional (CS) – longitudinal (LG) stream volumes
Figure 2.
Figure 2.
HD-ISS staging according to the FreeSurfer cross-sectional (CS) and longitudinal (LG) streams
See this image and copyright information in PMC

References

    1. Handsaker RE, Kashin S, Reed NM, et al. Long somatic DNA-repeat expansion drives neurodegeneration in huntington’s disease. Cell 2025; 188: 623–639.e19. - PMC - PubMed
    1. Hong EP, MacDonald ME, Wheeler VC, et al. Huntington’s disease pathogenesis: two sequential components. J Huntingtons Dis 2021; 10: 35. - PMC - PubMed
    1. Scahill RI, Zeun P, Osborne-Crowley K, et al. 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. Lancet Neurol 2020; 19: 502–512. - PMC - PubMed
    1. Tabrizi SJ, Langbehn DR, Leavitt BR, et al. Biological and clinical manifestations of huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009; 8: 791–801. - PMC - PubMed
    1. Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 2013; 12: 637–649. - PubMed

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