Current Treatment Options for REM Sleep Behaviour Disorder

The symptomatic treatment of REM sleep behaviour disorder (RBD) is very important to prevent sleep-related falls and/or injuries. Though clonazepam and melatonin are usually considered the first-line symptomatic therapy for RBD, their efficiency has not been proven by randomized clinical trials. The role of dopamine agonists in improving RBD symptoms is controversial, and rivastigmine, memantine, 5-hydroxytryptophan, and the herbal medicine yokukansan have shown some degree of efficacy in short- and medium-term randomized clinical trials involving a low number of patients. The development of potential preventive therapies against the phenoconversion of isolated RBD to synucleinopathies should be another important aim of RBD therapy. The design of long-term, multicentre, randomized, placebo-controlled clinical trials involving a large number of patients diagnosed with isolated RBD with polysomnographic confirmation, directed towards both symptomatic and preventive therapy for RBD, is warranted.

VMAT2 availability in Parkinson’s disease with probable REM sleep behaviour disorder

REM sleep behaviour disorder (RBD) can be an early non-motor symptom of Parkinson’s disease (PD) with pathology involving mainly the pontine nuclei. Beyond the brainstem, it is unclear if RBD patients comorbid with PD have more affected striatal dopamine denervation compared to PD patients unaffected by RBD (PD-RBD−). To elucidate this, we evaluated the availability of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in 15 PD patients with probable RBD (PD-RBD+), 15 PD-RBD−, and 15 age-matched healthy controls (HC) using [11C]DTBZ PET imaging. This technique measured VMAT2 availability within striatal regions of interest (ROI). A mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. We observed a significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, our results revealed that PD-RBD+ had lower VMAT2 availability compared to HC in all these regions except for the subthalamus and substantia nigra, while PD-RBD− was significantly lower than HC in all these regions. PD-RBD− showed a negative relationship between motor severity and VMAT2 availability within the left caudate. Our findings reflect that both PD patient subgroups had similar denervation within the nigrostriatal pathway. There were no significant interactions detected between radioligand binding and clinical scores in PD-RBD+. Taken together, VMAT2 and striatal dopamine denervation in general may not be a significant contributor to the pathophysiology of RBD in PD patients. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.

VMAT2 Availability in Parkinson’s Disease with REM Sleep Behaviour Disorder

REM sleep behaviour disorder (RBD) is an early sleep disturbance symptom of Parkinson’s disease (PD) thought to be caused by the disruption of normal basal ganglia function due to neurodegeneration. To further elucidate the neuropathological contribution of RBD in PD, we aimed to characterize the role of vesicular monoamine transporter 2 (VMAT2), an index of nigrostriatal dopamine innervation, in PD patients with RBD (PD-RBD+). We identified 15 PD-RBD+, 15 PD patients without RBD (PD-RBD–) and 15 age matched healthy controls (HC) who underwent [11C]DTBZ PET imaging. This technique measures VMAT2 availability within striatal regions of interest (ROI). Mixed effect model was used to compare the radioligand binding of VMAT2 between the three groups for each striatal ROI, while co-varying for sex, cognitive function and depression scores. Multiple regressions were also computed to predict clinical measures from group condition and VMAT2 binding within all ROIs explored. Significant level was set at p < 0.05 (Bonferroni corrected). We observed significant main effect of group condition on VMAT2 availability within the caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and subthalamus. Specifically, we observed that both PD-RBD + and PD-RBD– group had lower VMAT2 availability compared to HC. PD-RBD– showed a negative relationship between motor severity and VMAT2 availability within the left caudate. This relationship was not found in the PD-RBD + group. Our findings reveal that both PD patient subgroups had reduced VMAT2 levels relative to HC—which reflects denervation within the nigrostriatal pathway. No significant interactions were detected between radioligand binding and clinical scores in PD-RBD+. Taken together, we found limited evidence that VMAT2 may contribute differently in PD-RBD + relative to PD-RBD–. Future studies are encouraged to explore other underlying neural chemistry mechanisms contributing to RBD in PD patients.

Neurochemical Features of Rem Sleep Behaviour Disorder

Dopaminergic deficiency, shown by many studies using functional neuroimaging with Single Photon Emission Computerized Tomography (SPECT) and Positron Emission Tomography (PET), is the most consistent neurochemical feature of rapid eye movement (REM) sleep behaviour disorder (RBD) and, together with transcranial ultrasonography, and determination of alpha-synuclein in certain tissues, should be considered as a reliable marker for the phenoconversion of idiopathic RBD (iRBD) to a synucleopathy (Parkinson’s disease –PD- or Lewy body dementia -LBD). The possible role in the pathogenesis of RBD of other neurotransmitters such as noradrenaline, acetylcholine, and excitatory and inhibitory neurotransmitters; hormones such as melatonin, and proinflammatory factors have also been suggested by recent reports. In general, brain perfusion and brain glucose metabolism studies have shown patterns resembling partially those of PD and LBD. Finally, the results of structural and functional MRI suggest the presence of structural changes in deep gray matter nuclei, cortical gray matter atrophy, and alterations in the functional connectivity within the basal ganglia, the cortico-striatal, and the cortico-cortical networks, but they should be considered as preliminary.

Quantitative sensory testing and norepinephrine levels in REM sleep behaviour disorder – a clue to early peripheral autonomic and sensory dysfunction?

Introduction Studies have reported autonomic impairment in patients with idiopathic REM sleep behaviour disorder (iRBD), which is considered a prodromal stage of alpha-synucleinopathies. It is still debated whether central or peripheral pathologies are first manifestations of alpha-synucleinopathies. This study aimed to characterize autonomic and somatosensory function in iRBD patients. Methods This cross-sectional prospective case–control study included 17 iRBD patients (mean age 66.3 ± 9.2 years) and 16 healthy controls (HCs, 66.6 ± 11.3 years). Quantitative sensory testing, neurological and neuropsychological assessments, norepinephrine blood plasma levels, tilt table examination with orthostatic blood pressure, and heart rate variability were carried out. Longitudinal data of 10 iRBD patients, including neurological, neuropsychological, and tilt table examination, were assessed. Results iRBD patients more frequently presented with orthostatic dysfunction than HCs (70.6% vs. 6.3%, p < 0.0001). Supine norepinephrine plasma levels were normal, but lower in iRBD (249.59 ± 99.78 pg/ml iRBD, 354.13 ± 116.38 pg/ml HCs, p < 0.05). Quantitative sensory testing revealed impaired cold (CDT) and vibration detection thresholds (VDT) on the foot in iRBD (CDT foot iRBD − 1.24 ± 0.31, HCs − 9.89E-17 ± 0.25, VDT iRBD − 1.11 ± 0.47, HCs − 1.46E-16 ± 0.25, p < 0.05). Cold detection thresholds differed between the foot and hand among iRBD patients (foot − 1.24 ± 0.31, hand − 0.56 ± 0.25, p < 0.05). Longitudinal data revealed an increase in maximum systolic and diastolic orthostatic blood pressure changes and a decrease in the Valsalva ratio in the follow-up group (p < 0.05). Conclusion This study revealed autonomic dysfunction with somatosensory impairment, and decreased norepinephrine levels in iRBD, which may serve as a possible prodromal marker for developing alpha-synucleinopathy.

REM Sleep Behaviour Disorder in Multiple System Atrophy: From Prodromal to Progression of Disease

A higher frequency of motor and breathing sleep-related disorders in multiple system atrophy (MSA) populations is reported. REM sleep behaviour disorder (RBD) is one of the most robust markers of an underlying alpha-synucleinopathy. Although a large corpus of literature documented the higher prevalence of RBD in MSA, few studies have systematically investigated the prevalence of RBD as mode of disease onset and its role in disease progression. Moreover, there has been increasing interest in phenoconversion into synucleinopathies of cohorts of patients with isolated RBD (iRBD). Finally, some studies investigated RBD as predictive factor of conversion in isolated autonomic failure, a synucleinopathy presenting with autonomic failure as the sole clinical manifestation that could convert to a manifest central nervous system synucleinopathy. As the field of neurodegenerative disorders moves increasingly towards developing disease-modifying therapies, detecting individuals in the prodromal stage of these synucleinopathies becomes crucial. The aims of this review are to summarise (1) the prevalence of RBD during the course of MSA and as presenting feature of MSA (iRBD), (2) the RBD features in MSA, (3) MSA progression and prognosis in the subgroup of patients with RBD predating disease onset, and (4) the prevalence of MSA conversion in iRBD cohorts. Moreover, we summarise previous results on the role of RBD in the context of isolated autonomic failure as marker of phenoconversion to other synucleinopathies and, in particular, to MSA.