Abstract
Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of Lewy-type synucleinopathies (LTS), which can present either with an initial predominant parkinsonism (Parkinson’s disease (PD)) or dementia (dementia with Lewy bodies (DLB)). To provide insights into the underlying pathogenic mechanisms, the lipoprotein and protein glycosylation profile of 82 iRBD patients, collected before and/or after their conversion to an overt LTS, and 29 matched control serum samples were assessed by nuclear magnetic resonance (NMR) spectroscopy. Data were statistically analyzed to identify altered metabolites and construct predictive models. Univariant analysis detected no differences between iRBD patients with an LTS compared to controls. However, significant differences were found when the analysis distinguished between iRBD patients that manifested initially predominant parkinsonism (pre-PD) or dementia (pre-DLB). Significant differences were also found in the analysis of paired iRBD samples pre- and post-LTS diagnosis. Predictive models were built and distinguished between controls and pre-DLB patients, and between pre-DLB and pre-PD patients. This allowed a prediction of the possible future clinical outcome of iRBD patients. We provide evidence of altered lipoprotein and glycosylation profiles in subgroups of iRBD patients. Our results indicate that metabolic alterations and inflammation are involved in iRBD pathophysiology, and suggest biological differences underlying the progression of LTS in iRBD patients. Our data also indicate that profiling of serum samples by NMR may be a useful tool for identifying short-term high-risk iRBD patients for conversion to parkinsonism or dementia.
Highlights
Neurodegeneration associated with aggregated α-synuclein in the form of Lewy bodies and neurites (Lewy-type synucleinopathy; Lewy-type synucleinopathies (LTS)) manifests clinically as a parkinsonism, usually associated with late onset dementia (i.e., Parkinson’s disease (PD))[1], dementia can appear as an early feature and is designated as dementia with Lewy bodies (DLB)[2]
Twenty-seven parameters related to lipoproteins and protein glycosylation were analyzed in 130 serum samples, including controls, pre-LTS, and postLTS iRBD patients
No significant differences were found between pre-LTS or post-LTS iRBD patients compared with controls (Supplementary Table 1)
Summary
Neurodegeneration associated with aggregated α-synuclein in the form of Lewy bodies and neurites (Lewy-type synucleinopathy; LTS) manifests clinically as a parkinsonism, usually associated with late onset dementia (i.e., Parkinson’s disease (PD))[1], dementia can appear as an early feature and is designated as dementia with Lewy bodies (DLB)[2]. The biological basis underlying this clinical heterogeneity remains poorly understood. IRBD patients have no overt neurological diseases, long-term prospective studies show that over 90% of them develop an LTS within 14 years after iRBD diagnosis, and the remaining disease-free patients show short-term risk markers for developing an LTS5,6. IRBD is a clinical marker of the prodromal stage of LTS7, and provides an excellent opportunity to study LTS at early stages. This is important for management at clinical onset, development of early disease-modifying interventions, and selection and stratification in future neuroprotective trials
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