Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson’s disease. It is the case, however, that partial volume effects from free-water can bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free-water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free-water is elevated in the substantia nigra for Parkinson’s disease compared with controls. This hypothesis was tested between large cohorts of Parkinson’s disease and control participants in a single-site study, and validated against a multi-site study using multiple scanners. The fractional volume of free-water was increased in the posterior region of the substantia nigra in Parkinson’s disease compared with controls in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water corrected fractional anisotropy or free-water corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson’s disease, and this was evidenced across both single-site and multi-site cohorts.
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