Neuroimaging to Facilitate Clinical Trials in Huntington’s Disease: Current Opinion from the EHDN Imaging Working Group

Article type: Research Article

Authors: Hobbs, Nicola Z.^{a; *} | Papoutsi, Marina^{a; b} | Delva, Aline^{c; d} | Kinnunen, Kirsi M.^b | Nakajima, Mitsuko^a | Van Laere, Koen^{e; f} | Vandenberghe, Wim^{c; d} | Herath, Priyantha^g | Scahill, Rachael I.^a

Affiliations: [a] HD Research Centre, UCL Institute of Neurology, UCL, London, UK | [b] IXICO plc, London, UK | [c] Department of Neurosciences, KU Leuven, Belgium | [d] Department of Neurology, University Hospitals Leuven, Belgium | [e] Department of Imaging and Pathology, Nuclear Medicine and Molecular Imaging, KU Leuven, Belgium | [f] Division of Nuclear Medicine, University Hospitals Leuven, Belgium | [g] Alnylam Pharmaceuticals, Cambridge MA, USA

Correspondence: [*] Correspondence to: Nicola Hobbs, PhD, Huntington’s Disease Centre, UCL Institute of Neurology, 2nd Floor Russell Square House, 10-12 Russell Square, London WC1B 5EH, UK. E-mail: [email protected].

Abstract:  Neuroimaging is increasingly being included in clinical trials of Huntington’s disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD.

Keywords: Neuroimaging, Huntington’s disease, clinical trial, magnetic resonance imaging, positron-emission tomography, magnetoencephalography

DOI: 10.3233/JHD-240016

Journal: Journal of Huntington's Disease, vol. Pre-press, no. Pre-press, pp. 1-37, 2024