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

Background: Huntington′s Disease (HD) is an inherited neurodegenerative disorder characterised by progressive cognitive and motor decline resulting from atrophy within basal ganglia networks. Although no disease–modifying therapies currently exist, several novel clinical trials are ongoing. Sensitive non–invasive imaging biomarkers are therefore essential for evaluating therapeutic effects. Soma and Neurite Density Imaging (SANDI), a multi–shell diffusion–weighted imaging model, estimates intracellular signal fractions arising from sphere–shaped soma that show promise as proxies for HD–related neurodegeneration. Although HD is rare, it offers a valuable model for understanding other neurodegenerative diseases due to its clear genetic cause and shared patterns 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 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, apparent soma size, apparent 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. These differences were more pronounced at HD–Integrated Staging System 0–1 than 2–3. 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 apparent 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. Reduced apparent soma density and increased apparent 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 for clinical trials of disease–modifying therapies for HD and other neurodegenerative diseases.