Volumetric MRI-Based Biomarkers in Huntington's Disease: An Evidentiary Review

Abstract

Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder that is caused by expansion of a CAG-repeat tract in the huntingtin gene and characterized by motor impairment, cognitive decline, and neuropsychiatric disturbances. Neuropathological studies show that disease progression follows a characteristic pattern of brain atrophy, beginning in the basal ganglia structures. The HD Regulatory Science Consortium (HD-RSC) brings together diverse stakeholders in the HD community—biopharmaceutical industry, academia, nonprofit, and patient advocacy organizations—to define and address regulatory needs to accelerate HD therapeutic development. Here, the Biomarker Working Group of the HD-RSC summarizes the cross-sectional evidence indicating that regional brain volumes, as measured by volumetric magnetic resonance imaging, are reduced in HD and are correlated with disease characteristics. We also evaluate the relationship between imaging measures and clinical change, their longitudinal change characteristics, and within-individual longitudinal associations of imaging with disease progression. This analysis will be valuable in assessing pharmacodynamics in clinical trials and supporting clinical outcome assessments to evaluate treatment effects on neurodegeneration.

Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment

“…Martinez-Horta et al ( 68 ) detected by PET that deterioration in apathy (as measured by the short version of the Problem Behaviors Assessment) significantly correlated with hypometabolism in the PFC, while the changes in depressive scores were correlated with hypometabolism in parietal-temporal regions in patients with pre-symptomatic Huntington's disease. In HD, decreases in the volume of the caudate, putamen, and the globus pallidus had the strongest correlations with clinical outcome measures for both motor and cognitive functions ( 69 ), however there is increasing evidence supporting the potential involvement of frontal lobe volume loss ( 68 , 70 ).…”

A natural history study to track brain and spinal cord changes in individuals with Friedreich’s ataxia: TRACK-FA study protocol

“…In this study validation of biomarkers is achieved through several different methods, including a multicentre approach, independent imaging analysis performed by IXICO, control of MRI scanner differences, and the relationship of neuroimaging measures to functional and biospecimen measures. This use of a harmonized and multicentre approach aims to deliver a large multi-modal neuroimaging dataset which in the future can be used to assess the variability and generalizability of finding across studies, more robustly inform future clinical trial design and serve to combine with prospectively acquired interventional data enhancing the statistical power of future studies [ 87 , 88 ].…”

Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities

“…Structural MRI is a well-established technique which has already been employed in clinical trials 21,102 . Studies have highlighted disease-related atrophy centred in the striatum and throughout the white matter in HD gene carriers at least 15 years before onset 103 with progressive involvement of the cortex as symptom onset approaches 104 .…”

“…These issues may be addressed by conducting clinical trials using biomarkers (single or signature) (Panel 2) as primary endpoints in the very early phases of the disease, before the emergence of detectable clinical symptoms (Stage 0 and 1 in the Huntington Disease Integrated Staging System-HD-ISS 123 ). Regulatory authorities consider such designs possible 124 , but the actual roadmap is still unclear, despite important inroads in form of guidance documents 125 and fruitful collaborations between the academia and industry 102 . Even if traditional methods for demonstration of a clinically meaningful effect will not be applicable at those early stages, we need a mechanism to show that treatments are of value for far-from-clinical motor onset individuals 126 .…”