Nigral neuropathology of Parkinson’s motor subtypes coincide with circuitopathies: a scoping review

Abstract

The neuropathological substrates of Parkinson’s disease (PD) patients with motor subtypes tremor-dominance (TD), non-tremor dominance (nTD), postural instability and gait difficulty (PIGD), and akinetic-rigid (AR) are not completely differentiated. While extensive pathological research has been conducted on neuronal tissue of PD patients, data have not been discussed in the context of mechanistic circuitry theories differentiating motor subtypes. It is, therefore, expected that a more specific and tailored management of PD symptoms can be accomplished by understanding symptom-specific neuropathological mechanisms with the detail histology can provide. This scoping review gives an overview of the literature comparing TD and nTD PD motor subtypes by clarify observed pathology with underlying physiological circuitry theories. Studies using an array of pathological examination techniques have shown significant differences between TD and nTD PD subtypes. nTD PD patients show higher neuronal loss, gliosis, extraneuronal melanin deposits, and neuroaxonal dystrophy in multiple subregions of the substantia nigra (SN) related to the overactivity of the indirect motor loop. TD patients show more severe cell loss specifically in medial SN subdivisions, and have damage in the retrorubral field A-8 that projects to the dorsolateral striatum and ventromedial thalamus in the direct motor loop. Pathological studies are consistent with neuroimaging data and support contemporary mechanistic circuitry theories of PD motor symptom genesis. Further multimodal neuroimaging and histological studies are required to validate and expand upon these findings.

Diagnostic utility of 7T neuromelanin imaging of the substantia nigra in Parkinson’s disease

“…In particular, there is greater degeneration of ventrolateral SNpc which connects to the dorsal putamen resulting in striato-thalamo-cortical dysfunction 50 and inhibition of the direct pathway 51 . These findings corroborate pathophysiological mechanisms with tremor being mediated by a cerebello-thalamo-cortical network rather than nigrostriatal pathways 52 . Histologically, SNpc cell loss also correlates with severity of AR symptoms 53 .…”

Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease

“…The CI-PD and nCI-PD groups differed in terms of motor disease subtype at the time of diagnosis. Our data indicate that CI dysfunction is significantly more common in the non-TD form of iPD, which has also been shown to harbor more severe neurodegeneration 40 . The mechanism underlying this association is currently unknown but may be related to more widespread and severe neuronal dysfunction and loss in CI-PD, induced by the CI deficiency.…”