Inhibition in Parkinson’s disease: A focus on prepulse inhibition and Rapid eye movement sleep Behavior Disorder (RBD).

Summary

Background: α-synucleinopathies are characterized by degeneration of the nigrostriatal pathway and midbrain dopamine function. These disorders, including Parkinson’s disease (PD), are associated with sensorimotor gating deficits and show an increased prevalence of the parasomnia REM sleep behaviour disorder (RBD). Converging evidence supports a key role of the central dopamine system and striatum in the regulation of prepulse inhibition (PPI), a measure of sensorimotor gating, which has received little attention with regard to Parkinsonism. Although the dopamine system is associated with daytime motor function in Parkinsonism, the relation to the increased motor activity during REM sleep as seen in RBD is unclear.

Aim: The objective of this thesis was 1) to examine prepulse inhibition of the acoustic blink reflex in patients with idiopathic REM sleep behaviour disorder (iRBD), Parkinson’s disease (PD), multiple system atrophy (MSA), and healthy subjects, 2) to study the relation between PPI, cognitive function, and the striatal dopamine transporter in PD, and 3) to investigate the relation between increased EMG-activity during sleep and dopamine function, as measured with 123I-FP-CIT SPECT in patients with iRBD, PD, and healthy subjects.

Method: Objective 1) 10 patients with MSA, 12 patients with iRBD, 40 patients with PD, and 20 healthy subjects were assessed with prepulse inhibition of the acoustic blink reflex; Objective 2) 38 patients with PD were assessed with prepulse inhibition and cognitive tests. A subset of these patients had 123I-FP-CIT-SPECT scanning; Objective 3) 10 patients with iRBD, 10 PD patients with RBD (PD+RBD), 10 PD patients without RBD (PD-RBD), and 10 healthy controls were assessed with polysomnography and 123I-FP-CIT SPECT.

Results: Objective 1: Non-parametric analyses showed that MSA patients had significantly lower PPI, as measured with max-amplitude, than iRBD and PD patients on the 60 ms–85 dB and 120 ms–85 dB inter stimulus intervals (ISI). The same relation was found when using area under the curve. No differences were found between groups for the 30 ms-85dB and 300 ms-85dB (ISI). Furthermore, blink reflex characteristics such as habituation did not differ between patient groups and healthy controls. Objective 2: Patients with high-PPI performed better on cognitive measures tapping attention and processing speed than patients with low-PPI. In addition, we found significant correlations between PPI and 123I-FP-CIT uptake in the striatum. Objective 3: Patients with iRBD and PD+RBD had increased phasic EMG-activity compared to healthy controls. 123I-FP-CIT uptake in striatum was highest in controls, less in patients with iRBD, and lowest in patients with PD. In iRBD patients EMG-activity in the mentalis muscle was correlated to 123I-FP-CIT uptake in striatum. In PD patients EMG-activity was correlated to anti-Parkinson medication.

Conclusions: The present study showed that PPI is markedly reduced in MSA. This may be due to the pronounced severity of striatal and brainstem dysfunction. PPI may be a non-invasive neurophysiological measure that can aid in the differential diagnosis between PD and MSA.
Furthermore, we found that the level of PPI in PD is related to attention and processing speed, and to the density of dopamine transporters in the striatum.
Moreover, our results support the hypothesis that increased EMG-activity during REM sleep in iRBD is associated with the nigrostriatal dopamine system, while EMG-activity during REM-sleep in PD is associated with dopaminergic medication.