Biomarkers of conversion to α-synucleinopathy in isolated rapid-eye-movement sleep behaviour disorder.

Patients with isolated rapid-eye-movement sleep behaviour disorder (RBD) are commonly regarded as being in the early stages of a progressive neurodegenerative disease involving α-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy. Abnormal α-synuclein deposition occurs early in the neurodegenerative process across the central and peripheral nervous systems and might precede the appearance of motor symptoms and cognitive decline by several decades. These findings provide the rationale to develop reliable biomarkers that can better predict conversion to clinically manifest α-synucleinopathies. In addition, biomarkers of disease progression will be essential to monitor treatment response once disease-modifying therapies become available, and biomarkers of disease subtype will be essential to enable prediction of which subtype of α-synucleinopathy patients with isolated RBD might develop.

Systematic video-analysis of motor events during REM sleep in idiopathic REM sleep behavior disorder, follow-up and DAT-SPECT.

Abnormal motor manifestations in REM sleep are the most visible feature of idiopathic REM sleep behavior disorder (iRBD), which precedes the overt alpha-synucleinopathy. The aim of this study was to perform a systematic visual analysis of the motor events (ME) captured during video-polysomnography, and clarify their relation to the disease severity. Thirty-four iRBD patients (5 women, 29 men; age 67.7 ± 7.2) with a mean follow-up duration 2.9 ± 1.1 years. and 33 controls (10 women, 23 men; age 61.5 ± 8.2) were examined. The ME captured during REM sleep were classified into four categories, previously defined by Frauscher et al. according to clinical severity: minor/simple jerks, major, complex and violent. An average frequency of 110.8 ± 75.2 ME per hour were identified in iRBD, 7.5 ± 11.6 in the controls (p < 0.001). Of these ME, 68.4% were classified as minor/simple jerks, 9.3% as major, 21.7% as complex and 0.7% as violent. The ME frequency was negatively associated with tracer binding on dopamine transporter single-photon emission computed tomography (DAT-SPECT); the association was stronger for caudate nucleus compared to putamen. During follow-up seven patients (24.1%) phenoconverted, yielding a yearly phenoconversion rate 8.3%. Violent ME were associated with increased hazard ratio for phenoconversion in frequency (p = 0.012) and total duration (p = 0.007). Patients with higher amounts of violent ME had a greater risk of phenoconversion; therefore, their role as a predictor should be considered. Additionally, ME were associated with nigrostriatal degeneration, according to DAT-SPECT. These findings indicate that the degree of the clinical severity of motor manifestations in iRBD reflects the severity of the disease.

Relations of non-motor symptoms and dopamine transporter binding in REM sleep behavior disorder.

The aim of this study was to evaluate associations of motor and non-motor symptoms with dopamine transporter binding in prodromal stage of synucleinopathies. We examined 74 patients with idiopathic REM sleep behavior disorder (RBD), which is a prodromal synucleinopathy, and 39 controls using Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test (UPSIT), Farnsworth-Munsell 100 hue test, orthostatic test, Scales for Outcomes in PD-Autonomic, Beck depression inventory-II, State-Trait Anxiety Inventory, and video-polysomnography. Electromyographic muscle activity during REM sleep was quantified according to Sleep Innsbruck-Barcelona criteria. In 65 patients, dopamine transporter single-photon emission computed tomography (DAT-SPECT) imaging was performed, putaminal binding ratio was calculated and scans were classified as normal, borderline, or abnormal. Compared to controls, RBD patients had significantly more severe scores in all examined tests. Patients with abnormal DAT-SPECT had higher MDS-UPDRS motor score (p = 0.006) and higher prevalence of orthostatic hypotension (p = 0.008). Putaminal binding ratio was positively associated with UPSIT score (p = 0.03) and negatively associated with tonic (p = 0.003) and phasic (p = 0.01) muscle activity during REM sleep. These associations likely reflect simultaneous advancement of underlying pathology in substantia nigra and susceptible brainstem and olfactory nuclei in prodromal synucleinopathy.

Simultaneous tonic and phasic REM sleep without atonia best predicts early phenoconversion to neurodegenerative disease in idiopathic REM sleep behavior disorder.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep without atonia (RWA) is the main polysomnographic feature of idiopathic REM sleep behavior disorder (iRBD) and is considered to be a promising biomarker predicting conversion to manifested synucleinopathy. Besides conventionally evaluated tonic, phasic and any RWA, we took into consideration also periods, when phasic and tonic RWA appeared simultaneously and we called this activity "mixed RWA." The study aimed to evaluate different types of RWA, to reveal the most relevant biomarker to the conversion. METHODS: A total of 55 patients with confirmed iRBD were recruited with mean follow-up duration 2.3 ± 0.7 years. Scoring of RWA was based on Sleep Innsbruck Barcelona rules. Positive phenocoversion was ascertained according to standard diagnostic criteria during follow-up. Receiver operator characteristic analysis was applied to evaluate predictive performance of different RWA types. RESULTS: A total of nine patients (16%) developed neurodegenerative diseases. Yearly phenoconversion rate was 5.5%. Significantly higher amounts of mixed (p = 0.009), tonic (p = 0.020), and any RWA (p = 0.049) were found in converters. Optimal cutoffs differentiating the prediction were 16.4% (sensitivity 88.9; specificity 69.6) for tonic, 4.4% (sensitivity 88.9; specificity 60.9) for mixed, and 36.8% (sensitivity 77.8; specificity 65.2) for any RWA. With area under the curve (AUC) 0.778, mixed RWA has proven to be the best predictive test followed by tonic (AUC 0.749) and any (AUC 0.710). CONCLUSIONS: Mixed, tonic and any RWA may serve as biomarkers predicting the conversion into neurodegenerative disease in iRBD. The best predictive value lies within mixed RWA, thus it should be considered as standard biomarker.

Fragmentary myoclonus in idiopathic rapid eye movement sleep behaviour disorder.

Fragmentary myoclonus is a result of muscle activity consisting of brief potentials in surface electromyography during polysomnography. Excessive fragmentary myoclonus is defined by increased intensity of the potentials. A few studies report excessive fragmentary myoclonus occurrence in neurodegenerative diseases. Because idiopathic rapid eye movement sleep behaviour disorder is considered as an early stage of neurodegeneration with involvement of the brainstem, we charted the prevalence and quantified the intensity of excessive fragmentary myoclonus in idiopathic rapid eye movement sleep behaviour disorder. Twenty-nine patients (one woman, 28 men, mean age 68 years, SD 6.2) and 29 controls (two women, 27 men, mean age 65.6 years, SD 8.6) underwent polysomnography. Fragmentary myoclonus potentials were identified and counted according to internationally used criteria. Fragmentary myoclonus intensity was quantified by the fragmentary myoclonus index. Excessive fragmentary myoclonus was diagnosed in 75.9% (22 subjects) in idiopathic rapid eye movement sleep behaviour disorder, while in 34.5% (10 subjects) among the controls (p = 0.003). Quantitative analysis showed a wide-range fragmentary myoclonus index in idiopathic rapid eye movement sleep behaviour disorder (4.0-632.4; median 60.7) and in the controls (0.8-938.1; median 34.3). The overall difference in fragmentary myoclonus index was not significant between the groups; however, patients with idiopathic rapid eye movement sleep behaviour disorder showed trends for higher fragmentary myoclonus index scores in wakefulness (p = 0.027), N1 (p = 0.032), N3 (p = 0.046) and R (p = 0.007). Fragmentary myoclonus index does not correlate with age, idiopathic rapid eye movement sleep behaviour disorder duration or R stage atonia deficiency. The prevalence of excessive fragmentary myoclonus is higher in idiopathic rapid eye movement sleep behaviour disorder compared with the controls, so fragmentary myoclonus should be taken into account in future research of rapid eye movement sleep behaviour disorder and motor control in sleep.

Olfaction and Colour Vision: What Can They Tell Us about Parkinson's Disease?

Parkinson's disease is a neurodegenerative disorder with the pathological accumulation of alpha synuclein in the brain and peripheral nerve tissue. Early stages of synucleinopathies, often present clinically with rapid eye movement (REM) sleep disorder (RBD). Clinical markers that indicate early progression from RBD to manifest synucleinopathies include abnormal dopamine transporter (DAT) imaging, motor and non-motor symptoms. Despite the high diagnostic strength of DAT imaging and motor abnormalities, they are not the earliest biomarkers. Non-motor signs of neurodegeneration such as colour vision and olfaction abnormalities are detectable by clinical examination as early as 20 years before disease onset. Detailed analysis of olfactory and colour vision dysfunction can provide valuable information regarding brain pathologies, further specifying clinical phenotypes, and giving clues to underlying pathophysiological mechanisms in Parkinson's disease and related disorders.