NEUROPATHOLOGY OF THE GLOBUS PALLIDUS IN X-LINKED DYSTONIA PARKINSONISM

X-linked Dystonia Parkinsonism (XDP) is a hereditary neurodegenerative movement disorder originating from Panay Island, Philippines, with no available disease-modifying treatments. Striatal pathology is strongly implicated in XDP disease pathogenesis; however, the neuropathological architecture of striatal outflow targets has not been profiled in detail. One such outflow target is the globus pallidus (GP), which has been implicated in other movement disorders, including Huntington’s and Parkinson’s disease. While neuroimaging studies of XDP patients report GP atrophy, neurochemical and neuropathological characterisation of the post-mortem human XDP GP has not been undertaken. Using the largest cohort to date, our results provide novel immunohistochemical evidence of significant pallidal neuronal loss in the external (GPe) and internal (GPi) segments of GP tissue from 19 XDP and 12 age-matched neurologically normal cases. In particular, greater pallidal neuron loss in the XDP GPi was observed in cases with a longer disease duration. We additionally report a significant disease duration-dependent reduction of enkephalin⁺ and substance P⁺ striatopallidal woolly fibres within the XDP GPe and GPi pallidal segments, respectively. Interestingly, the loss of substance P⁺ woolly fibre immunoreactivity in the XDP GPi coincides with the extent of substance P⁺ immunoreactivity loss in the XDP substantia nigra. Together, these findings indicate widespread neuronal and neurochemical dysfunction in the XDP GPe and GPi. Indubitably, given our findings strongly implicate the GP region as a major component of XDP disease pathogenesis, this study is part of ongoing research to extensively characterise neuropathological changes in the human XDP GP.