Neuropathological findings and in vivo imaging correlates of the red nucleus compared to those of the substantia nigra pars compacta in parkinsonisms

Introduction: The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms. Methods: In vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by alpha-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations. Results: The RN had greater neuron (t(23) = 3.169, P = 0.004) and glial cell densities (t(23) = 2.407, P = 0.025) than the SNc, whereas the SNc had greater alpha-synuclein (t28 t 28 = 4.614, P < 0.0001) and tau burden (t(24) = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or alpha-synuclein (Ps > 0.092). QSM associated with tau burden (r r = 0.49, P = 0.038) in the SNc, but not the RN. Conclusions: The RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms.