In vivo mapping of striatal microstructure in Huntington’s disease with Soma and Neurite Density Imaging
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Background
Huntington’s Disease (HD) is an inherited neurodegenerative disorder characterised by pro-gressive cognitive and motor decline largely due to the loss of striatal medium spiny neurons in the basal ganglia. No disease-modifying therapies exist, but novel clinical trials are ongo-ing. Non-invasive imaging biomarkers sensitive to HD neuropathology are essential for eval-uating therapeutic effects. Soma and Neurite Density Imaging (SANDI), a multi-shell diffu-sion-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 po-tential as proxies for HD-related neurodegeneration.
Objective
To characterise HD-related microstructural abnormalities in the basal ganglia using SANDI and examine associations between SANDI indices, volumetric measurements, and motor per-formance.
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 gene-positive individuals (41 premanifest) (Mean Age = 46.1, SD Age = 13.8, 25 females) and 57 healthy controls (Mean Age = 45.0, SD Age = 13.8, 31 females). Gene-positive participants com-pleted Quantitative Motor (Q-Motor) tasks, including speeded and paced finger tapping, which were reduced to one motor performance component. 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 be-tween SANDI indices, Q-Motor performance, and volumetric measures were analysed.
Results
HD was associated with reduced apparent soma density (r = 0.32, p ≤ 0.007) and increased apparent soma size (r = −0.45, p < 0.001) and extracellular signal fraction (r = −0.34, p ≤ 0.003) in the basal ganglia, but not the thalami. No differences were found in apparent neurite density (r = −0.18, p = 0.17). Previously reported 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 signifi-cantly 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 meas-ure for HD-related neurodegeneration in clinical trials.
