Continuous Dopaminergic Stimulation Improves Cortical Maladaptive Changes in Advanced Parkinson's Disease.

BACKGROUND: With the progression of Parkinson's disease (PD), pulsatile treatment with oral levodopa causes maladaptive changes within basal ganglia-thalamo-cortical circuits, which are clinically expressed as motor fluctuations and dyskinesias. At the level of the motor cortex, these changes may be detected using transcranial magnetic stimulation (TMS), as abnormal corticospinal and intracortical excitability and absent response to plasticity protocols. OBJECTIVE: We investigated the effect of continuous dopaminergic stimulation on cortical maladaptive changes related to oral levodopa treatment. METHODS: Twenty patients with advanced PD were tested using TMS within 1 week before and again 6 months after the introduction of levodopa-carbidopa intestinal gel. We measured resting and active motor thresholds, input/output curve, short interval intracortical inhibition curve, cortical silent period, and response to intermittent theta burst stimulation. Patients were clinically assessed with Part III and Part IV of the Movement Disorders Society Unified Parkinson's Disease Rating Scale. RESULTS: Six months after the introduction of levodopa-carbidopa intestinal gel, motor fluctuations scores (P = 0.001) and dyskinesias scores (P < 0.001) were reduced. Resting and active motor threshold (P = 0.012 and P = 0.015) and x-intercept of input/output curve (P = 0.005) were also decreased, while short-interval intracortical inhibition and response to intermittent theta bust stimulation were improved (P = 0.026 and P = 0.031, respectively). Changes in these parameters correlated with clinical improvement. CONCLUSIONS: In patients with advanced PD, switching from intermittent to continuous levodopa delivery increased corticospinal excitability and improved deficient intracortical inhibition and abnormal motor cortex plasticity, along with amelioration of motor fluctuations and dyskinesias. Continuous dopaminergic stimulation ameliorates maladaptive changes inflicted by chronic pulsatile dopaminergic stimulation. © 2022 International Parkinson and Movement Disorder Society.

Sex differences in Parkinson's disease: A transcranial magnetic stimulation study.

BACKGROUND: Demographic and clinical studies imply that female sex may be protective for PD, but pathophysiological evidence to support these observations is missing. In early PD, functional changes may be detected in primary motor cortex using transcranial magnetic stimulation. OBJECTIVE: We hypothesised that if pathophysiology differs between sexes in PD, this will be reflected in differences of motor cortex measurements. METHODS: Forty-one newly diagnosed PD patients (22 males, 19 females) were clinically assessed using MDS-UPDRS part III, and various measures of cortical excitability and sensorimotor cortex plasticity were measured over both hemispheres, corresponding to the less and more affected side, using transcranial magnetic stimulation. Twenty-three healthy (10 men, 13 women) participants were studied for comparison. RESULTS: Among patients, no significant differences between sexes were found in age, age of diagnosis, symptom duration, and total or lateralized motor score. However, male patients had disturbed interhemispheric balance of motor thresholds, caused by decreased resting and active motor thresholds in the more affected hemisphere. Short interval intracortical inhibition was more effective in female compared to male patients in both hemispheres. Female patients had a preserved physiological focal response to sensorimotor plasticity protocol, whereas male patients showed an abnormal spread of the protocol effect. CONCLUSION: The study provides one of the first neurophysiological evidences of sex differences in early PD. Female patients have a more favorable profile of transcranial magnetic stimulation measures, possibly reflecting a more successful cortical compensation or delayed maladaptive changes in the sensorimotor cortex. © 2019 International Parkinson and Movement Disorder Society.

Modulation by Estradiol of L-Dopa-Induced Dyskinesia in a Rat Model of Post-Menopausal Hemiparkinsonism.

Treatment with levodopa (L-dopa) in Parkinson's disease (PD) leads to involuntary movements termed L-dopa-induced dyskinesia (LID). There are contradictory data about the influence of hormone therapy in female PD patients with LID and of 17-ß-estradiol (E2) on animal correlates of LID-abnormal involuntary movements (AIMs). Our aim was to characterize the influence of E2 on motor impairment and AIMs in ovariectomized 6-hydroxydopamine (6-OHDA) rat model of PD. Half of the rats received empty and the other half implants filled with E2. Following the 6-OHDA surgery, the rats received daily treatment with either L-dopa or saline for 16 days. They were assessed for AIMs, contralateral rotations, and FAS. In the L-dopa-treated rats, E2 intensified and prolonged AIMs and contralateral rotations. On the other hand, it had no effect on motor impairment. Postmortem tyrosine hydroxylase immunostaining revealed an almost complete unilateral lesion of nigrostriatal dopaminergic neurons. E2 partially prevented the upregulation of striatal ΔFosB caused by dopamine depletion. L-dopa potentiated the upregulation of ΔFosB within the dopamine-depleted striatum and this effect was further enhanced by E2. We speculate that the potentiating effects of E2 on AIMs and on contralateral rotations could be explained by the molecular adaptations within the striatal medium spiny neurons of the direct and indirect striatofugal pathways.

Effects of L-dopa on expression of prolactin and synaptotagmin IV in 17-beta-estradiol-induced prolactinomas of ovariectomized hemiparkinsonian rats.

Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. Dopamine precursor levodopa (L-dopa) is used as the first-line treatment for PD. Evidence suggests neuroprotective effects of estrogens in PD. Since both 17b-estradiol (E2) and L-dopa act as regulators of prolactin (PRL) secretion from the pituitary gland, we investigated their effect on the expression of PRL in prolactinomas that developed in ovariectomized hemiparkinsonian rats treated with E2. We also investigated the effect of E2 and L-dopa on the expression of synaptotagmin IV (Syt IV), an immediate early gene whose product is abundant in the pituitary gland and was found to be highly co-expressed with PRL in lactotrophs (>90%). The hemiparkinsonian rat model was obtained by unilateral lesioning of dopaminergic nigrostriatal neurons. Rats received silastic tubing implants with E2 and were treated with L-dopa. Enzyme-linked immunosorbent assay and immunohistochemistry were used to assess the serum concentrations of PRL and E2 and expression of PRL and Syt IV in the tissue of adenohypophysis, respectively. We found that high levels of serum E2 were associated with the upregulation of Syt IV and PRL in PRL-ir cells, while treatment with L-dopa decreased the size of prolactinomas and downregulated Syt IV but had no effect on PRL expression or serum concentrations.