Extrastriatal monoaminergic dysfunction and enhanced microglial activation in idiopathic rapid eye movement sleep behaviour disorder

Abstract

Background: The majority of patients diagnosed with idiopathic rapid eye movement sleep behaviour disorder (iRBD) progress over time to a Lewy-type α-synucleinopathy such as Parkinson's disease or dementia with Lewy bodies. This in vivo molecular imaging study aimed to investigate if extrastriatal monoaminergic systems are affected in iRBD patients and if this coincides with neuroinflammation.

Methods: We studied twenty-one polysomnography-confirmed iRBD patients with ¹⁸F-DOPA and ¹¹C-PK11195 positron emission tomography (PET) to investigate extrastriatal monoaminergic function and microglial activation. Twenty-nine healthy controls (n = 9 ¹⁸F-DOPA and n = 20 ¹¹C-PK11195) were also investigated. Analyses were performed within predefined regions of interest and at voxel-level with Statistical Parametric Mapping.

Results: Regions of interest analysis detected monoaminergic dysfunction in iRBD thalamus with a 15% mean reduction of ¹⁸F-DOPA Ki values compared to controls (mean difference = -0.00026, 95% confidence interval [-0.00050 to -0.00002], p-value = 0.03). No associated thalamic changes in ¹¹C-PK11195 binding were observed. Other regions sampled showed no ¹⁸F-DOPA or ¹¹C-PK11195 PET differences between groups. Voxel-level interrogation of ¹¹C-PK11195 binding identified areas with significantly increased binding within the occipital lobe of iRBD patients.

Conclusion: Thalamic monoaminergic dysfunction in iRBD patients may reflect terminal dysfunction of projecting neurons from the locus coeruleus and dorsal raphe nucleus, two structures that regulate REM sleep and are known to be involved in the early phase of PD. The observation of significantly raised microglial activation in the occipital lobe of these patients might suggest early local Lewy-type α-synuclein pathology and possibly an increased risk for later cognitive dysfunction.

Keywords: (11)C-PK11195; (18)F-DOPA; Dementia with Lewy bodies; Idiopathic rapid-eye-movement sleep behaviour disorder; PD; Positron emission tomography.