Resting-state connectivity stratifies premanifest Huntington\u2019s disease by longitudinal cognitive decline rate

Pablo Polosecki,Eduardo Castro,Cristina Sampaio,Dorian Pustina,Guillermo A Cecchi,Andrew Wood,Irina Rish,John H Warner

doi:10.1038/s41598-020-58074-8

Pablo Polosecki, Eduardo Castro + Show 6 more

Open Access

https://doi.org/10.1038/s41598-020-58074-8

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Abstract

Patient stratification is critical for the sensitivity of clinical trials at early stages of neurodegenerative disorders. In Huntington’s disease (HD), genetic tests make cognitive, motor and brain imaging measurements possible before symptom manifestation (pre-HD). We evaluated pre-HD stratification models based on single visit resting-state functional MRI (rs-fMRI) data that assess observed longitudinal motor and cognitive change rates from the multisite Track-On HD cohort (74 pre-HD, 79 control participants). We computed longitudinal performance change on 10 tasks (including visits from the preceding TRACK-HD study when available), as well as functional connectivity density (FCD) maps in single rs-fMRI visits, which showed high test-retest reliability. We assigned pre-HD subjects to subgroups of fast, intermediate, and slow change along single tasks or combinations of them, correcting for expectations based on aging; and trained FCD-based classifiers to distinguish fast- from slow-progressing individuals. For robustness, models were validated across imaging sites. Stratification models distinguished fast- from slow-changing participants and provided continuous assessments of decline applicable to the whole pre-HD population, relying on previously-neglected white matter functional signals. These results suggest novel correlates of early deterioration and a robust stratification strategy where a single MRI measurement provides an estimate of multiple ongoing longitudinal changes.

Highlights

Patient stratification is critical for the sensitivity of clinical trials at early stages of neurodegenerative disorders
Using data from the Track-On Huntington’s disease (HD) cohort (Table 1), we first evaluated the test-retest reliability of full-brain functional connectivity density (FCD) maps (46667 voxels) and evaluated models that stratify the pre-HD population by longitudinal cognitive decline based on single-visit FCD maps
We evaluated the within-subject similarity of baseline and follow-up FCD maps, irrespective of a neurological signature of interest. This we evaluated the ability to identify (“fingerprint”) individuals on follow-up visits based on the correlations of follow-up and baseline FCD maps (Methods, “FCD test-retest reliability”)

Summary

Introduction

Patient stratification is critical for the sensitivity of clinical trials at early stages of neurodegenerative disorders. Stratification models distinguished fast- from slow-changing participants and provided continuous assessments of decline applicable to the whole pre-HD population, relying on previously-neglected white matter functional signals. These results suggest novel correlates of early deterioration and a robust stratification strategy where a single MRI measurement provides an estimate of multiple ongoing longitudinal changes. The availability of genetic tests has enabled large neuroimaging studies, such as PREDICT-HD7 and TRACK-HD8,9, which have followed patients and controls over several years, even before motor-based diagnosis These cohorts provide opportunities for moving beyond descriptive statistical observations toward assessments that provide predictions at an individual level. Previously-overlooked correlates of disease progression may be found by analyses designed to reflect these major aspects of functional networks

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