Reduced striatal vesicular monoamine transporter 2 in REM sleep behavior disorder: imaging prodromal parkinsonism

Leah C Beauchamp,Victor L Villemagne,Ashley I Bush,Kevin J Barnham,David I Finkelstein,Vincent Doré,Christopher C Rowe

doi:10.1038/s41598-020-74495-x

Abstract

Motor deficits in parkinsonism are caused by degeneration of dopaminergic nigral neurons. The success of disease-modifying therapies relies on early detection of the underlying pathological process, leading to early interventions in the disease phenotype. Healthy (n = 16), REM sleep behavior disorder (RBD) (n = 14), dementia with Lewy bodies (n = 10), and Parkinson’s disease (PD) (n = 20) participants underwent 18F-AV133 vesicular monoamine transporter type-2 (VMAT2) PET to determine the integrity of the nigrostriatal pathway. Clinical, neurophysiological and neuropsychological testing was conducted to assess parkinsonian symptoms. There was reduced VMAT2 levels in RBD participants in the caudate and putamen, indicating nigrostriatal degeneration. RBD patients also presented with hyposmia and anxiety, non-motor symptoms associated with parkinsonism. 18F-AV133 VMAT2 PET allows identification of underlying nigrostriatal degeneration in RBD patients. These findings align with observations of concurrent non-motor symptoms in PD and RBD participants of the Parkinson’s Progression Markers Initiative. Together, these findings suggest that RBD subjects have prodromal parkinsonism supporting the concept of conducting neuroprotective therapeutic trials in RBD-enriched cohorts. Ongoing longitudinal follow-up of these subjects will allow us to determine the time-window of clinical progression.

Highlights

Parkinson’s disease (PD) is associated with a period of latency in which dopaminergic neurodegeneration is occurring, yet no overt signs of parkinsonism are evident
There was a higher proportion of men in all clinical groups compared with healthy controls (HC), and the REM sleep behavior disorder (RBD) patients were younger than HC (63.5 [9.9] vs. 72.9 [5.1] years, P = 0.02)
Severe cognitive impairment was present in patients with dementia with Lewy bodies (DLB), as well as motor impairment in the DLB and PD groups compared to HC

Summary

Introduction

Parkinson’s disease (PD) is associated with a period of latency in which dopaminergic neurodegeneration is occurring, yet no overt signs of parkinsonism are evident. Diagnosis of PD is based on clinical assessment and relies heavily upon the presentation of movement dysfunction At this stage, it is estimated that there is already an irreversible loss of 50–70% of dopaminergic terminals in the putamen, based on post-mortem studies[1] and in vivo neuroimaging of patients in the early stages of unilateral motor impairment[2]. Between the extensive neurodegeneration that occurs before the onset of motor symptoms and the high likelihood of progression from RBD to a parkinsonism, neuroimaging assessment of the presynaptic nigro-striatal pathway in RBD patients may help the early identification of patients that are likely to progress to PD or another form of parkinsonism and provide a clinical marker for enrolment into preclinical trials. Compared to DAT SPECT, VMAT2 PET imaging has improved image quality and quantification[13], as such, we sought to investigate the dopamine system in RBD patients using the high affinity [ 18F]AV-133 PET tracer which selectively binds to VMAT2

Methods

Results

Conclusion