White matter connectivity networks predict levodopa-induced dyskinesia in Parkinson’s disease

Abstract

Background Although levodopa-induced dyskinesia-relevant white matter change has been evaluated, it is uncertain whether these changes may reflect the underlying predisposing conditions leading to the development of levodopa-induced dyskinesia. Objective To elucidate the role of white matter connectivity networks in the development of levodopa-induced dyskinesia in drug-naïve Parkinson's disease. Methods We recruited 30 patients who developed levodopa-induced dyskinesia within 5 years from MRI acquisition (vulnerable-group), 47 patients who had not developed levodopa-induced dyskinesia within 5 years (resistant-group), and 28 controls. We performed comparative analyses of whole-brain white matter integrity and connectivity using tract-based spatial and network-and degree-based statistics. We evaluated the predictability of levodopa-induced dyskinesia development and relationship with its latency, using the average connectivity strength as a predictor in Cox-and linear-regression, respectively. Results Mean-diffusivity was lower mainly at the left frontal region in the vulnerable-group compared to the resistant-group. Network-based statistics identified a subnetwork consisting of the bilateral fronto-striato-pallido-thalamic and lateral parietal regions (subnetwork A) and degree-based statistics identified four subnetworks (hub-subnetwork) consisting of edges centered on the left superior frontal gyrus, left putamen, left insular, or left precentral gyrus, where the vulnerable-group had stronger connectivity compared to the resistant-group. Stronger connectivity within the subnetwork A and hub-subnetwork centered on the left superior frontal gyrus was a predictor of levodopa-induced dyskinesia development independent of known risk factors and had an inverse relationship with its latency. Conclusions Our data suggest that white matter connectivity subnetworks within corticostriatal regions play a pivotal role in the development of levodopa-induced dyskinesia.

Effects of Dihydropyridines on the Motor and Cognitive Outcomes of Patients with Parkinson's Disease

“…It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors. [44][45][46][47] This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine-related motor symptoms. 12 Rather, it is speculated that DHPs may have a beneficial effect on the extranigral system.…”

“…Contrary to expectations, we found that DHPs did not have beneficial effects on the nigrostriatal dopaminergic density at diagnosis and longitudinal motor prognosis. It is well known that the baseline nigrostriatal dopamine level is the main contributor to the development of LID and WO, 42,43 although other clinical and imaging parameters are also contributing factors 44‐47 . This may be because DHPs have no neuroprotective effects on nigral dopaminergic neurons or their related clinical characteristics, which may be in agreement with the results of the isradipine trial focusing on the progression of nigral dopamine‐related motor symptoms 12 .…”

Multimodal Imaging of Substantia Nigra in Parkinson's Disease with Levodopa‐Induced Dyskinesia

“…In addition, a study using network-and degreebased statistics observed stronger connectivity within the four subnetworks consisting of edges centered on the superior frontal gyrus, putamen, insular, and precentral gyrus. 57 Taken together, these studies showed that altered signals originating from basal ganglia might result in a reinforced motor drive to cortical activity and ultimately trigger involuntary movements. 58,59 The altered FC between SNpc and putamen found in our study could relate to the excessive activity in LID.…”