MRI T₂ and T₂* relaxometry to visualize neuromelanin in the dorsal substantia nigra pars compacta

Visualizing gradual changes in neuromelanin distribution within the substantia nigra is an important metric used to monitor the progression of Parkinsonism. This study aimed to identify the origin of the mismatch region between magnetic resonance transverse relaxation times (T₂ and T₂*) in the substantia nigra and investigate its feasibility and implications for in vivo detection of neuromelanin as a clinical biomarker. The relationships between neuromelanin distribution assessed by histological staining and the area of T₂ and T₂* mismatch determined by high- and low-resolution magnetic resonance relaxometry at 7T were directly compared in two normal and one depigmented substantia nigra collected at postmortem. In vivo feasibility of assessing T₂ and T₂* mismatch, clinically, was investigated using 3T magnetic resonance imaging. In the normal postmortem substantia nigra tissue, the T₂ and T₂* mismatch region exhibiting a linear pattern was strongly colocalized with neuromelanin distribution along the dorsal substantia nigra pars compacta, but a negligible amount of dorsal mismatch was observed in the depigmented brain. The regions of T₂ and T₂* mismatch from MRI, neuromelanin pigments from histology, and elevated iron signals from mass spectrometry were spatially overlapped for a normal postmortem brain. In preliminary in vivo studies, a similar, linear T₂ and T₂* mismatch region was observed in the dorsal area of the substantia nigra in eight normal subjects; this mismatch was significantly obscured in eight Parkinson's disease patients. The length of the dorsal linear mismatch line based on the T₂*-T₂ mask was significantly shorter in the Parkinson's disease patients compared to normal controls; this result was corroborated by reduced striatal uptake of [¹⁸F] FP-CIT dopamine transporters assessed by positron emission tomography scans. In conclusion, the measurement of T₂ and T₂* mismatch could serve as a complementary imaging biomarker to visualize the dorsal region of the substantia nigra pars compacta, which contains large amounts of neuromelanin.