REM sleep without atonia and vestibular-evoked myogenic potentials: clinical brainstem dysfunction in early-stage Parkinson's disease and isolated REM sleep behavior disorder.

OBJECTIVE: To determine whether the onset of rapid eye movement (REM) sleep behavior disorder (RBD) is associated with changes in brainstem neuronal pathway dysfunction as reflected by vestibular-evoked myogenic potentials (VEMPs) and to evaluate associations between VEMPs and REM sleep without atonia (RSWA) in patients with early-stage Parkinson's disease (PD) and isolated RBD (iRBD). METHODS: Eighty-two early-stage PD patients, 40 iRBD patients, and 41 healthy control individuals underwent one-night video-polysomnography (vPSG) and VEMPs examination. We compared cervical (cVEMP), ocular (oVEMP), and masseter (mVEMP) VEMP parameters among PD with RBD (PD + RBD), PD without RBD (PD-RBD), iRBD, and control groups and analyzed correlations between VEMPs and RSWA in PD and iRBD groups. RESULTS: The PD + RBD group showed delays in bilateral cVEMP (Lp13, Ln23, Rn23: all p < 0.05) and oVEMP (Ln10, Rn10, Rp15: all p < 0.05) peak latencies compared with the PD-RBD group. Total cVEMP scores were higher in the PD + RBD group than in the iRBD group (p = 0.033). In PD patients, phasic RSWA was correlated with total cVEMP scores (p = 0.003), and tonic RSWA was correlated with left oVEMP scores (p = 0.013). CONCLUSIONS: Brainstem neurophysiology as evidenced by altered VEMPs in patients with PD and iRBD could reflect disease evolvement. Moreover, VEMPs alterations may vary depending on the presence of RBD in PD patients. The associations between altered RSWA and VEMP parameters highlight the meaningfulness of detecting brainstem dysfunction in early-stage PD.

Generalized EEG Slowing Across Phasic REM Sleep, Not Subjective RBD Severity, Predicts Neurodegeneration in Idiopathic RBD.

Purpose: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is the prodromal marker of α-synuclein degeneration with markedly high predictive value. We aim to evaluate the value of electroencephalography (EEG) data during rapid eye movement (REM) sleep and subjective RBD severity in predicting the conversion to neurodegenerative diseases in iRBD patients. Methods: At the baseline, iRBD patients underwent clinical assessment and video-polysomnography (PSG). Relative spectral power for nine frequency bands during phasic and tonic REM sleep in three regions of interest, slow-to-fast ratios, clinical and PSG variables were estimated and compared between iRBD patients who converted to neurodegenerative diseases (iRBD-C) and iRBD patients who remained disease-free (iRBD-NC). Receiver operating characteristic (ROC) curves evaluated the predictive performance of slow-to-fast ratios, and subjective RBD severity as assessed with RBD Questionnaire-Hong Kong. Results: Twenty-two (33.8%) patients eventually developed neurodegenerative diseases. The iRBD-C group showed shorter total sleep time (p < 0.001), lower stage 2 sleep percentage (p = 0.044), more periodic leg-movement-related arousal index (p = 0.004), increased tonic chin electromyelographic activity (p = 0.040) and higher REM density in the third REM episode (p = 0.034) than the iRBD-NC group. EEG spectral power analyses revealed that iRBD phenoconverters showed significantly higher delta and lower alpha power, especially in central and occipital regions during the phasic REM state compared to the iRBD-NC group. Significantly higher slow-to-fast ratios were observed in a more generalized way during the phasic state in the iRBD-C group compared to the iRBD-NC group. ROC analyses of the slowing ratio in occipital areas during phasic REM sleep yielded an area under the curve of 0.749 (p = 0.001), while no significant predictive value of subjective RBD severity was observed. Conclusion: Our study shows that EEG slowing, especially in a more generalized manner during the phasic period, may be a promising marker in predicting phenoconversion in iRBD, rather than subjective RBD severity.

Inhibition of Spinal 5-HT3 Receptor and Spinal Dorsal Horn Neuronal Excitability Alleviates Hyperalgesia in a Rat Model of Parkinson's Disease.

Pain in Parkinson's disease (PD) is increasingly recognized as a major factor associated with poor life quality of PD patients. However, classic therapeutic drugs supplying dopamine have limited therapeutic effects on PD-related pain. This suggests that there is a mechanism outside the dopamine system that causes pain in PD. Our previous study demonstrated that 6-OHDA induced PD model manifested hyperalgesia to thermal and mechanical stimuli and decreased serotonin (5-hydroxytryptamine; 5-HT) in the spinal dorsal horn (SDH). Several 5-HT receptor subtypes have been confirmed to be associated with nociception in the spinal cord, such as 5-HT1A receptor, 5-HT1B receptor, 5-HT2 receptor, 5-HT3 receptor, and 5-HT7 receptor. Most research has shown that 5-HT1A receptor and 5-HT3 receptor play a key role in pain transmission in the spinal cord. We hypothesized that hyperalgesia of 6-OHDA rats may be related to increased excitability of SDH neurons, and functional change of 5-HT3 receptor may reverse the hyperalgesia of 6-OHDA lesioned rats and decrease cell excitability of SDH neurons. To test this hypothesis, we used whole-cell patch-clamp and pharmacological methods to evaluate the effect of 5-HT3 receptor and 5-HT1A receptor on the hyperalgesia of 6-OHDA rats. The results suggested that increased excitability in SDH neurons could be reversed by 5-HT3 receptor antagonist ondansetron (20 µmol/L) and palosetron (10 µmol/L), but not 5-HT3 receptor agonist m-CPBG (30 µmol/L) and SR 57,727 (10 µmol/L), 5-HT1A receptor agonist 8-OH DPAT (10 µmol/L) and eptapirone (10 µmol/L) and 5-HT1A receptor antagonist WAY-100635 (10 µmol/L) and p-MPPI (10 µmol/L). Intrathecal injection of ondansetron (0.1 mg/kg) but not m-CPBG (0.1 mg/kg), 8-OH DPAT (0.1 mg/kg), and WAY-100635 (0.1 mg/kg) significantly attenuated the mechanical hyperalgesia and thermal hyperalgesia in 6-OHDA lesioned rats. In conclusion, the present study suggests that inhibition of spinal 5-HT3 receptor and SDH neuronal excitability alleviates hyperalgesia in PD rats. Our study provides a novel mechanism or therapeutic strategy for pain in patients with PD.

Increased Serum Cystatin C in Early Parkinson's Disease with Objective Sleep Disturbances.

BACKGROUND: Sleep disturbance is one of the major non-motor symptoms which cause the disability of Parkinson's disease (PD) patients. Cystatin C (CysC) is a more sensitive biomarker than serum creatinine or estimated glomerular filtration rate. Previous studies have reported altered CysC levels in neurodegenerative disorders and sleep disorders. This study aimed to explore the correlations of serum CysC levels and objective sleep disturbances in early PD. METHODS: We recruited 106 early PD patients and 146 age- and sex-matched controls. All participants underwent clinical investigation and video-polysomnography. Sleep parameters and serum levels of CysC were measured. Then, we investigated the relationships between CysC and clinical variables and objective sleep disturbances in early PD patients. RESULTS: The mean serum level of CysC was significantly higher in patients with early PD (1.03 ± 0.19 mg/L) compared to controls (0.96 ± 0.15 mg/L, P = 0.009). There were significantly positive correlations between serum CysC levels and age (r = 0.334, P < 0.001), gender (r = 0.264, P = 0.013), and creatinine levels (r = 0.302, P = 0.018) in early PD patients. Increased serum CysC levels in early PD patients were significantly associated with higher apnea and hypopnea index (AHI) (r = 0.231, P = 0.017), especially hypopnea index (r = 0.333, P < 0.001). In early PD patients, elevated serum CysC levels were positively correlated with oxygen desaturation index (r = 0.223, P = 0.021), percentage of time spent at oxygen saturation (SaO2) <90% (r = 0.644, P < 0.001), arousal with respiratory event during sleep (r = 0.247, P = 0.013). On the contrary, the elevated serum CysC levels were negatively correlated with mean and minimal SaO2(r = -0.323, -0.315, both P = 0.001) in PD patients. CONCLUSIONS: The level of serum CysC was higher in early PD patients. PD patients with elevated serum CysC levels had more respiratory events and more severe oxygen desaturation. Therefore, the serum CysC levels may predict the severities of sleep-disordered breathing problems in early PD patients.

Two polysomnographic features of REM sleep behavior disorder: Clinical variations insight for Parkinson's disease.

INTRODUCTION: Loss of REM sleep muscle atonia (RWA) and dream-enactment behavior (DEB) are two associated features of REM sleep behavior disorder (RBD), which is frequently associated with Parkinson's disease (PD). Few studies have examined both DEB and RWA simultaneously in patients with PD. This study aimed to evaluate relationships between RWA, DEB and clinical characteristics of PD. METHODS: We conducted overnight polysomnography in 145 patients with PD. DEB (motor behaviors and/or vocalizations during REM) and increased RWA (IRWA; tonic and phasic chin EMG density ≥ 30% and ≥15%, respectively) were identified. Patients were categorized as clinical RBD (DEB and IRWA), sub-DEB positive (DEB only), subclinical RBD (IRWA only), or normal REM sleep. RESULTS: Patients with DEB had higher Hoehn and Yahr (H&Y) stage, Unified Parkinson's Disease Rating Scale (UPDRS) III score, levodopa equivalent dose(LEDs), and worse cognition. RWA was associated with H&Y stage, LEDs, cognition, and sleep structure in all patients. PD duration was associated with RWA, but not DEB. The PD patients who exhibited clinical or subclinical RBD, compared to sub-DEB positive, had higher H&Y stage, UPDRS III score and LEDs, lower cognitive score, worse sleep structure than the PD + cREM group. CONCLUSION: Both DEB and RWA were associated with severity of PD illness. Subclinical RBD might have different disease progression from sub-DEB positive. DEB symptoms may fluctuate or disappear whereas RWA may continue to develop as PD progresses. Differences in the course of DEB and RWA may reflect the difference in the degeneration process of neurodegenerative disorders.

Clinical correlates of rapid eye movement sleep without atonia in Parkinson's disease.

OBJECTIVE: The aim of the present study was to investigate the relationship between rapid eye movement (REM) sleep without atonia (RWA) and Parkinson's disease (PD) progression. METHODS: We quantified tonic and phasic RWA by performing polysomnography in 198 PD patients. We then correlated the extent of RWA with clinical patient characteristics. RESULTS: PD patients were categorized into quartiles of tonic and phasic RWA. We found that patients with more RWA tended to be older and have longer PD duration, a greater likelihood of REM sleep behavior disorder (RBD), more advanced Hoehn & Yahr (H&Y) stage, a higher dose of parkinsonian medication, poorer cognitive performance, worse quality of life, and more severe sleep disturbance. After adjusting for age, sex, and PD duration, patients in the highest two RWA quartile were more likely to have severe PD (H&Y stage ⩾ 3.0) than those in the lowest RWA quartile. CONCLUSIONS: These findings provide evidence that RWA, especially with regard to tonic muscle activity, is associated with PD severity. SIGNIFICANCE: Further studies are warranted to determine the importance and utility of assessing RWA to evaluate sleep in PD patients.