In vivo mapping of striatal neurodegeneration in Huntington’s disease with Soma and Neurite Density Imaging

Ioakeimidis, Vasileios, Palombo, Marco

, Casella, Chiara, Layland, Lucy, B. McNabb, Carolyn, Schubert, Robin, Pallmann, Philip

, E. Busse, Monica, J. G. Drew, Cheney, Alusi, Sundus, Harrower, Timothy, E. Rosser, Anne and Metzler-Baddeley, Claudia

2025. In vivo mapping of striatal neurodegeneration in Huntington’s disease with Soma and Neurite Density Imaging. eLife

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Abstract

Background: Huntington’s Disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline due to atrophy in basal ganglia networks. No diseasemodifying therapies exist, but novel clinical trials are ongoing. Non-invasive imaging biomarkers sensitive to HD neuropathology are essential for evaluating therapeutic effects. Soma and Neurite Density Imaging (SANDI), a multi-shell diffusion-weighted imaging model, estimates intracellular signal fractions from sphere-shaped soma in grey matter. SANDI-derived apparent soma density and size in the striatum have potential as proxies for HD-related neurodegeneration. While HD is rare, it provides a valuable model for other neurodegenerative diseases due to its clear genetic cause and shared features of protein abnormalities. Objective: To characterise HD-related microstructural abnormalities in the basal ganglia and thalami using SANDI and examine associations between SANDI indices, volumetric measurements, and motor performance. Methods: T1-weighted anatomical and multi-shell diffusion-weighted images (b-values: 200–6,000 s/mm²) were acquired using a 3T Siemens Connectom scanner (300mT/m) in 56 premanifest and manifest HD individuals (MeanAge = 46.1, SDAge = 13.8, 25 females) and 57 healthy controls (MeanAge = 45.0, SDAge = 13.8, 31 females). HD participants completed Quantitative Motor (Q-Motor) tasks, including speeded and paced finger tapping, which were reduced to one principal component of motor performance. Following standard diffusion-weighted data preprocessing, SANDI and diffusion tensor models estimated apparent soma density, soma size, neurite density, extracellular signal fraction, fractional anisotropy, and mean diffusivity. The caudate, putamen, pallidum, and thalamus were segmented bilaterally, and microstructural and volumetric indices were extracted and compared. Correlations between SANDI indices, Q-Motor performance, and volumetric measures were analysed. Results: HD was associated with reduced apparent soma density (rrb = 0.32, p ≤ 0.007) and increased apparent soma size (rrb = 0.45, p < 0.001) and extracellular signal fraction (rrb = 0.34, p ≤0.003) in the basal ganglia, but not the thalami, with largest effects at manifest stage. No differences were found in apparent neurite density (rrb = 0.18, p = 0.17). HD-related increases in fractional anisotropy and mean diffusivity in the basal ganglia were replicated. Q-Motor component scores correlated negatively with apparent soma density and positively with soma size and extracellular signal fraction. SANDI indices and age explained up to 63% of striatal atrophy in HD. Conclusion: SANDI measures detected HD-related neurodegeneration in the striatum, accounted significantly for striatal atrophy, and correlated with motor impairments. Decreased apparent soma density and increased soma size align with ex vivo evidence of medium spiny neuron loss and glial reactivity. SANDI shows promise as an in vivo biomarker and surrogate outcome measure in clinical trials of disease-modifying therapies for HD and other neurodegenerative diseases.

Item Type:	Article
Status:	In Press
Schools:	Schools > Medicine Schools > Psychology Research Institutes & Centres > Cardiff University Brain Research Imaging Centre (CUBRIC) Research Institutes & Centres > Centre for Trials Research (CNTRR)
Publisher:	eLife Sciences Publications
Date of Acceptance:	16 June 2025
Last Modified:	18 Aug 2025 12:15
URI:	https://orca.cardiff.ac.uk/id/eprint/180452

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