Disentangling nigral and putaminal contribution to motor impairment and levodopa response in Parkinson’s disease

Abstract

The extent to which the degeneration of the substantia nigra (SN) and putamen each contribute to motor impairment in Parkinson’s disease (PD) is unclear, as they are usually investigated using different imaging modalities. To examine the pathophysiological significance of the SN and putamen in both motor impairment and the levodopa response in PD using diffusion microstructure imaging (DMI). In this monocentric retrospective cross-sectional study, DMI parameters from 108 patients with PD and 35 healthy controls (HC) were analyzed using a voxel- and region-based approach. Linear models were applied to investigate the association between individual DMI parameters and Movement Disorder Society Unified Parkinson’s Disease Rating Scale-Part 3 performance in ON- and OFF-states, as well as the levodopa response, controlling for age and sex. Voxel- and region-based group comparisons of DMI parameters between PD and HC revealed significant differences in the SN and putamen. In PD, a poorer MDS-UPDRS-III performance in the ON-state was associated with increased free fluid in the SN (b-weight = 65.79, p = 0.004) and putamen (b-weight = 86.00, p = 0.006), and contrariwise with the demise of cells in both structures. The levodopa response was inversely associated with free fluid both in the SN (b-weight = −83.61, p = 0.009) and putamen (b-weight = −176.56, p < 0.001). Interestingly, when the two structures were assessed together, the integrity of the putamen, but not the SN, served as a predictor for the levodopa response (b-weight = −158.03, p < 0.001). Structural alterations in the SN and putamen can be measured by diffusion microstructure imaging in PD. They are associated with poorer motor performance in the ON-state, as well as a reduced response to levodopa. While both nigral and putaminal integrity are required for good performance in the ON-state, it is putaminal integrity alone that determines the levodopa response. Therefore, the structural integrity of the putamen is crucial for the improvement of motor symptoms to dopaminergic medication, and might therefore serve as a promising biomarker for motor staging.

Cerebellar, Not Nigrostriatal Degeneration Impairs Dexterity in Multiple System Atrophy

“…This pattern is consistent with a neurodegenerative loss of cells. 19 Nigral free-fluid fraction was significantly larger in MSA-P (V-CSF, P < 0.001, t = 6.22, Cohen's d = À1.47) and MSA-C patients (P < 0.001, t = 3.85, d = À1.42) compared to HCs, with no difference between the MSA subtypes. Correspondingly, a decrease in V-extra was observed in patients with MSA-P compared to those with MSA-C (P = 0.035, t = À2.525, d = 0.38) and HCs (P = 0.002, t = À3.60, d = 0.71), but no difference was observed between patients with MSA-C and HCs.…”

“…This was accompanied by a strong increase in the free interstitial fluid. With respect to the increased free fluid, partial neuroinflammation is conceivable as well, because this has also been described in MSA alongside neurodegeneration, 36 and both neuroinflammation 18 and neurodegeneration 19 can lead to increased interstitial fluid. The similar pattern of parameter alterations in the GM area of the dentate nucleus can be attributed to the fact that the efferent axons in the dentate nucleus hilus constitute a substantial proportion of the ROI 37 .…”

“…Although primarily developed for WM, multicompartment dMRI metrics have been employed to investigate gray matter (GM) also. 19,26 T1w imaging datasets were spatially normalized using CAT12 (http://www.neuro.uni-jena. de/cat/), and dMRI images were coregistered to the T1w images.…”

“…This approach thus allows for disentangling the microstructure from the effects of macroscopic tissue geometry such as fiber crossings. DMI has been applied in recent studies and detects degenerating neuronal somata and loss in the extracellular matrix by a decrease in the parameter “V‐extra,” whereas degenerating dendrites and myelinated axons are detected through a decrease in “V‐intra.” Moreover, an increase in free interstitial fluid (resulting from the loss of both axons and cell bodies or inflammation) leads to an elevated “V‐CSF.” 17‐20 …”

“…Moreover, an increase in free interstitial fluid (resulting from the loss of both axons and cell bodies or inflammation) leads to an elevated "V-CSF." [17][18][19][20] This study employed DMI to 1 elucidate microstructural correlates of the distinct clinical phenotypes of MSA-P and MSA-C and to 2 disentangle the contribution of nigrostriatal and cerebellopontine degeneration to impaired dexterity in MSA-P and MSA-C.…”