Nigral Pathology Contributes to Microstructural Integrity of Striatal and Frontal Tracts in Parkinson's Disease

Abstract

BackgroundMotor 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 magnetic resonance imaging (MRI) can detect microstructural alterations of the SN and its tracts to (sub)cortical regions, but their pathological sensitivity is still poorly understood.ObjectiveTo unravel the pathological substrate(s) underlying microstructural alterations of SN, and its tracts to the dorsal striatum and dorsolateral prefrontal cortex (DLPFC) in PD.MethodsCombining post‐mortem in situ MRI and histopathology, T1‐weighted and diffusion MRI, and neuropathological samples of nine PD, six PD with dementia (PDD), five dementia with Lewy bodies (DLB), and 10 control donors were collected. From diffusion 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.ResultsCompared 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 MD of the SN and FA of SN‐caudate nucleus tract were associated with SN dopaminergic loss. Whereas increased MD of the SN‐DLPFC tract was associated with increased SN Lewy neurite load.ConclusionsIn 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. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amelioration of Motor Performance and Nigrostriatal Dopamine Cell Volume Using a Novel Far-Infrared Ceramic Blanket in an A53T Alpha-Synuclein Transgenic Parkinson’s Disease Mouse Model

“…Skilled motor behaviors require bihemispheric coordination and participation of striatal outputs originating from two neuronal groups identified by distinctive expression of D1 or D2 dopamine receptors [14]. Degeneration of the substantia nigra and its tract to the striatum occurs in PD patients, and is associated with motor severity on the Unified Parkinson's Disease Rating Scale (UPDRS) [15,16]. Skilled movements occur when output pathways work together, but toxic conversion and accumulation of alpha-synuclein protofibrils arise in PD [17].…”