Cholinergic and striatal dopaminergic dysfunction using pet as a risk marker for developing a neurodegenerative disease in patients with idiopathic rapid eye movement sleep behaviour disorder

Abstract

Introduction Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by dream enactment behaviours during REM sleep, due to loss of normal motor atonia. Previous studies have shown dopaminergic dysfunction in idiopathic RBD (iRBD) is predictive of developing a synucleinopathy, such as Parkinson’s disease (PD), multiple system atrophy (MSA) or dementia with Lewy bodies (DLB). IRBD needs to be distinguished from secondary RBD which can be seen in narcolepsy, obstructive Sleep apnea (OSA) and in patients taking exogenous serotonin- elevating medications, such as selective serotonin reuptake inhibitors (SSRI’s). We postulate that subjects with iRBD will tend to have a higher level of dopaminergic and cholinergic dysfunction reflective of their higher risk for developing a synucleinopathy compared to healthy controls and patients with secondary RBD. Materials and methods In a prospective study, 10 patients with RBD (mean age 60.8 ± 11.1), were assessed and recruited by the movement disorders clinic (University of British Columbia), from 2005 to 2012. Patients were followed serially for 12 to 84 months to monitor for the development of a neurodegenerative disease. Baseline PET imaging was performed on all 10 subjects, using radiotracers [11C] PMP (acetylcholinesterase) and [11C] dihydrotetrabenazine (DTBZ) for vesicular monoamine transporter type 2(VMAT2). PMP k3 was determined based on either striatal input or shape analysis and was judged to be reduced when values were below 2 SD of the corresponding values in healthy controls. Results Ten patients were diagnosed with RBD in a sleep lab prior to PET scanning. Three had OSA requiring CPAP and of those, two are on SSRI’s for depression. One additional patient has narcolepsy. PMP and DTBZ binding were normal in these four subjects. Of the remaining 6 (presumed iRBD) subjects, four had reduced occipital cortical cholinergic innervation and two of these subjects also had reduced striatal DBTZ uptake, compared to control data. Two patients have developed parkinsonism and another mild cognitive impairment, 2 to 4 years after scanning, and all showed significantly reduced occipital PMP compared to controls (0.0212 ± 0.0010 vs. 0.0250 ± 0.0011, t = 4.86, p = 0.0028). IRBD patients also had reduced thalamic cholinergic function compared to secondary RBD (0.0674 ± 0.0107 vs. 0.0776 ± 0.0037, p = 0.0193). Conclusion Decline in DBTZ and PMP in cortical and subcortical structures of patients with iRBD likely reflects dopaminergic and cholinergic dysfunction during the premotor stages of neurodegenerative disease. Previous studies have shown reduced cholinergic innervation in PD patients with RBD compared to those without. To our knowledge, this is the first time in vivo cholinergic dysfunction has been shown in iRBD. Disrupted occipital cholinergic function may predict patients at greater risk of progressing to a synucleinopathy. Monitoring cholinergic dysfunction in an iRBD population may provide further insight into the pathophysiology of RBD and subsequent neurodegeneration. Acknowledgements CIHR, TRIUMF.