Progression of clinical markers in prodromal Parkinson’s disease and dementia with Lewy bodies: a multicentre study

Abstract

The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behavior disorder (iRBD) is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical endpoints. In this study, we combined prospective follow-up data from 28 centers of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behavior disorder subjects were assessed for prodromal Parkinson’s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson’s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151-560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory, and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive, and certain autonomic markers, the only robust difference in progression between Parkinson’s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicenter study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical endpoints and sample size estimates to inform future neuroprotective trials.

Turning alterations detected by mobile health technology in idiopathic REM sleep behavior disorder

“…First, although the sample size is large for these speci c groups, it may still be too small to consider all confounding factors. However, the pattern of non-motor features in our iRBD cohort is comparable to previous cohorts with con rmed high conversion rates (15), which argues for the relevance of the reported ndings. An important strength of the study is the strict inclusion criteria for iRBD (PSG-con rmed, absence of subthreshold parkinsonism) and PD (drug-naïve and con rmed by dopaminergic imaging).…”

“…The group of iRBD is at high risk of conversion to alpha-synucleinopathy and is thus target of several studies focusing on markers to track motor progression over time (3,15). Still, the relevance of subtle motor impairment, its progression over time, and the "application" of potential compensation mechanisms in prodromal PD stages are still not well understood.…”

Shorter self-reported sleep duration in men is associated with worse virtual spatial navigation performance

“…In certain cases, poorer sleep may in fact be associated with better cognitive function, which would be supported by our finding of men with greater sleep inertia, greater difficulty waking up and a lower sleepiness resolution index trending towards having better navigation performance, albeit non-significant associations. In line with this, converting to Lewy-Body Dementia and Parkinson's Disease Dementia is associated with improved sleep quality, as indicated by a lower severity of insomnia, and having frequent insomnia symptoms has been found to be associated with better cognitive performance 19,27 . Thus, poorer sleep may be associated with better navigation performance depending on the variables examined, warranting further studies to confirm this hypothesis.…”

Presymptomatic amyotrophic lateral sclerosis: from characterization to prevention

“…If these prodromal syndromes are also a feature of apparently sporadic forms of ALS, the recognition of MMI in the general population provides an opportunity to study presymptomatic ALS at a much larger scale and, in combination with emerging biomarkers, to effect earlier diagnosis and treatment. To appreciate the potential importance of these prodromal states to understanding presymptomatic ALS, it is helpful to consider the role of MCI in Alzheimer's disease and the role of prodromal clinical markers such as REM sleep behavior disorder in Parkinson's disease [14].…”