Prognostic biomarkers in prodromal α-synucleinopathies: DAT binding and REM sleep without atonia.

BACKGROUND: Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a prodromal state of clinical α-synucleinopathies such as Parkinson's disease and Lewy body dementia. The lead-time until conversion is unknown. The most reliable marker of progression is reduced striatal dopamine transporter (DAT) binding, but low availability of imaging facilities limits general use. Our prospective observational study aimed to relate metrics of REM sleep without atonia (RWA)-a hallmark of RBD-to DAT-binding ratios in a large, homogeneous sample of patients with RBD to explore the utility of RWA as a marker of progression in prodromal α-synucleinopathies. METHODS: DAT single-photon emission CT (SPECT) and video polysomnography (vPSG) were performed in 221 consecutive patients with clinically suspected RBD. RESULTS: vPSG confirmed RBD in 176 patients (162 iRBD, 14 phenoconverted, 45 non-synucleinopathies). Specific DAT-binding ratios differed significantly between groups, but showed considerable overlap. Most RWA metrics correlated significantly with DAT-SPECT ratios (eg, Montreal tonic vs most-affected-region: r=-0.525; p<0.001). In patients taking serotonergic/noradrenergic antidepressants or dopaminergic substances or with recent alcohol abuse, correlations were weaker, suggesting a confounding influence, unlike other possible confounders such as beta-blocker use or comorbid sleep apnoea. CONCLUSIONS: In this large single-centre prospective observational study, we found evidence that DAT-binding ratios in patients with iRBD can be used to describe a continuum in the neurodegenerative process. Overlap with non-synucleinopathies and clinical α-synucleinopathies, however, precludes the use of DAT-binding ratios as a precise diagnostic marker. The parallel course of RWA metrics and DAT-binding ratios suggests in addition to existing data that RWA, part of the routine diagnostic workup in these patients, may represent a marker of progression. Based on our findings, we suggest ranges of RWA values to estimate whether patients are in an early, medium or advanced state within the prodromal phase of α-synucleinopathies, providing them with important information about time until possible conversion.

Post-Illumination Pupil Response as a Biomarker for Cognition in α-Synucleinopathies.

Neurodegenerative processes in the brain are reflected by structural retinal changes. As a possible biomarker of cognitive state in prodromal α-synucleinopathies, we compared melanopsin-mediated post-illumination pupil response (PIPR) with cognition (CERAD-plus) in 69 patients with isolated REM-sleep behavior disorder. PIPR was significantly correlated with cognitive domains, especially executive functioning (r = 0.417, p < 0.001), which was more pronounced in patients with lower dopamine-transporter density, suggesting advanced neurodegenerative state (n = 26; r = 0.575, p = 0.002). Patients with mild neurocognitive disorder (n = 10) had significantly reduced PIPR (smaller melanopsin-mediated response) compared to those without (p = 0.001). Thus, PIPR may be a functional-possibly monitoring-marker for impaired cognitive state in (prodromal) α-synucleinopathies.

Treatment of isolated REM sleep behavior disorder using melatonin as a chronobiotic.

Melatonin is recommended as a first-line treatment in isolated REM sleep behavior disorder (iRBD), although no large patient group has been reported. To assess effects, time course and confounding factors in the treatment of patients with iRBD using melatonin, 209 consecutive patients were included in this single-center, observational cohort study. A total of 171 patients had taken melatonin according to our chronobiotic protocol (2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype), 13 had applied melatonin for about 1-3 months, and 25 underwent mixed treatments. In total, 1529 clinical evaluations were performed, including Clinical Global Impression (CGI) and a newly developed RBD symptom severity scale (Ikelos-RS), analyzed using linear mixed models. Validation of Ikelos-RS showed excellent inter-rater reliability (ρ = 0.9, P < .001), test-retest reliability (ρ = 0.9, P < .001) and convergent validity (ρ = 0.9, P < .001). With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 ± 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 ± 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin.

Living in Biological Darkness: Objective Sleepiness and the Pupillary Light Responses Are Affected by Different Metameric Lighting Conditions during Daytime.

Nighttime melatonin suppression is the most commonly used method to indirectly quantify acute nonvisual light effects. Since light is the principal zeitgeber in humans, there is a need to assess its strength during daytime as well. This is especially important since humans evolved under natural daylight but now often spend their time indoors under artificial light, resulting in a different quality and quantity of light. We tested whether the pupillary light response (PLR) could be used as a marker for nonvisual light effects during daytime. We also recorded the wake electroencephalogram to objectively determine changes in daytime sleepiness between different illuminance levels and/or spectral compositions of light. In total, 72 participants visited the laboratory 4 times for 3-h light exposures. All participants underwent a dim-light condition and either 3 metameric daytime light exposures with different spectral compositions of polychromatic white light (100 photopic lux, peak wavelengths at 435 nm or 480 nm, enriched with longer wavelengths of light) or 3 different illuminances (200, 600, and 1200 photopic lux) with 1 metameric lighting condition (peak wavelength at 435 nm or 480 nm; 24 participants each). The results show that the PLR was sensitive to both spectral differences between metameric lighting conditions and different illuminances in a dose-responsive manner, depending on melanopic irradiance. Objective sleepiness was significantly reduced, depending on melanopic irradiance, at low illuminance (100 lux) and showed fewer differences at higher illuminance. Since many people are exposed to such low illuminance for most of their day-living in biological darkness-our results imply that optimizing the light spectrum could be important to improve daytime alertness. Our results suggest the PLR as a noninvasive physiological marker for ambient light exposure effects during daytime. These findings may be applied to assess light-dependent zeitgeber strength and evaluate lighting improvements at workplaces, schools, hospitals, and homes.