Nigral pathology contributes to microstructural integrity of striatal and frontal tracts in Parkinson’s disease

Background Motor and cognitive impairment in Parkinson’s disease (PD) is associated with dopaminergic dysfunction that stems from substantia nigra (SN) degeneration and concomitant α-synuclein accumulation. Diffusion MRI can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood. Objective To unravel the pathological substrate underlying microstructural alterations of the SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD. Methods Combining post-mortem in-situ MRI and histopathology, T1-weighted and diffusion MRI of 9 PD, 6 PD with dementia (PDD), 5 dementia with Lewy bodies (DLB), and 10 control donors were collected. From MRI, mean diffusivity (MD) and fractional anisotropy (FA) were derived from the SN, and tracts between the SN and caudate nucleus, putamen, and DLPFC. Phosphorylated-Ser129-α-synuclein and tyrosine hydroxylase immunohistochemistry was included to quantify nigral Lewy pathology and dopaminergic degeneration, respectively. Results Compared to controls, PD and PDD/DLB showed increased MD of the SN and SN-DLPFC tract, as well as increased FA of the SN-caudate nucleus tract. Both PD and PDD/DLB showed nigral Lewy pathology and dopaminergic loss compared to controls. Increased FA of the SN and SN-caudate nucleus tract was associated with SN dopaminergic loss, while increased MD of the SN-DLPFC tract was associated with increased SN Lewy neurite load. Conclusions In PD and PDD/DLB, diffusion MRI captures microstructural alterations of the SN and tracts to the dorsal striatum and DLPFC, which differentially associates with SN dopaminergic degeneration and Lewy neurite pathology.