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

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

Fig. 1

Examples of individual subject-level data for each imaging modality. Structural MRI: Axial images showing 3D T1-weighted and T2-weighted scans from the TRACK-HD study. T2 FLAIR and T2^* scans are adapted from Duchesne et al. 2019. 3D T1-weighted scan is segmented using MALP-EM [263]. DWI: Neurite Orientation Dispersion and Density Imaging (NODDI) maps. RGB: reg-green-blue colour map indicating eigenvector orientation, ND: neurite density map, ODI: orientation dispersion index map, FW: extracellular free water map (adapted from Kraguljac et al 2021). MRS: Single-voxel Proton MRS: Left Putamen Voxel Placement and LCModel Spectra in Controls and in HD (adapted from Lowe et al., [146]). LCModel outputs: raw spectra (black) and model fits (red); concentrations shown in parts per million (ppm). NAA, N-acetylaspartate; MI, myo-inositol; Cre, creatine; Cho, choline; GLX, glutamate  +  glutamine; PreHD, gene expansion carriers with UHDRS diagnostic confidence level (DCL) < 4 and CAG repeat length > 40; HD, gene expansion carriers with DCL = 4 and CAG repeat length > 36; CTR, clinically well individuals, of a similar age to gene expansion carriers. Functional MRI: Image on the left is a slice from a single EPI volume of a task fMRI timeseries. The image on the right shows a heatmap overlaid on a single EPI volume. The heatmap is produced after fitting a GLM and represents the activity (z-stat) when responding to the n-back task (all conditions, including 0-back) vs. rest. MEG: Raw MEG data (adapted from Proudfoot et al. [264]). Two channels contain obvious artefacts. The door to the magnetically shielded room is opened after 4 seconds of recording. The interference caused by external magnetic fields highlights why effective room shielding is essential. PET: Axial images showing radiotracer uptake in healthy controls for [¹⁸F]FDG (glucose metabolism), [¹¹C]Raclopride (dopamine D2 Receptor), [¹¹C]UCB-J (synaptic vesicle protein 2A) and [¹⁸F]JNJ-42259152 (phosphodiesterase 10A). References: Diffusion Weighted MRI from figure 1 is reprinted from Neuroimage Reports Volume 1 (1), Kraguljac NV, Monroe WS, Anthony T, Jindal RD, Hill H, Lahti AC. Neurite orientation dispersion and density imaging (NODDI) and duration of untreated psychosis in antipsychotic medication-naive first episode psychosis, p 100005, 2021, with permission from Elsevier. T2 Flair and T2* scans from figure 1 are adapted from Scientific Data Volume 6, Duchesne S, Dieumegarde L, Chouinard I, Farokhian F, Badhwar A, Bellec P, Tétreault P, Descoteaux M, Boré A, Houde JC, Beaulieu C, Potvin O. Structural and functional multi-platform MRI series of a single human volunteer over more than fifteen years, p 645, 2019, published by Nature. Published under the Creative Commons Attribution 4.0 https://creativecommons.org/licenses/by/4.0/