Midbrain hyperechogenicity in idiopathic REM sleep behavior disorder

Recent studies have reported an increased risk to develop Parkinson's disease (PD) in patients with idiopathic RBD (iRBD). Midbrain hyperechogenicity is a common transcranial sonography (TCS) finding in PD and has been suggested as a PD risk‐marker in nonparkinsonian subjects. The objective of this study is to assess midbrain echogenicity by TCS in patients with iRBD and compare the findings with the healthy controls. TCS was performed in 55 iRBD patients and in 165 age and sex‐matched controls. The area of echogenicity in the SN region in the iRBD group was significantly increased compared with the control group (P < 0.001). About 19 (37.3%) of patients with iRBD were found to have SN hyperechogenicity when compared with 16 (10.7%) of the controls (P < 0.001). This is the first case‐control study assessing midbrain echogenicity in a large iRBD cohort compared to age‐ and sex‐matched healthy individuals. The finding of an increased prevalence of hyperechogenicity in a subgroup of individuals with a priori increased risk for PD supports the potential role of hyperechogenicity as a risk marker for PD. The prospective follow‐up of this iRBD cohort is needed to establish if those with midbrain hyperechogenicity will go on to develop clinically defined PD or not. © 2009 Movement Disorder Society     

Relationship of substantia nigra hyperechogenicity to risk of Lewy body disease in idiopathic REM sleep behavior disorder patients: a longitudinal study

BackgroundWe examined the relationship between baseline substantia nigra (SN) echogenicity on transcranial sonography (TCS) images and medium-to long-term developments of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) in idiopathic RBD (IRBD) patients.MethodsFrom 2007–2009, TCS and odor identification tests were performed in 34 consecutive IRBD patients (67.9 ± 6.1 years). A medical chart review was conducted in August 2019 to investigate the development of PD or DLB.ResultsOf the 34 IRBD patients, 14 (41.2%) showed SN hyperechogenicity (SN+) on TCS at baseline. There were no significant differences in age, Unified Parkinson's Disease Rating Scale (UPDRS) score, Mini-Mental State Exam (MMSE) score, or odor identification (OSIT-J) score between the SN+ and SN normoechogenicity (SN−) groups at baseline. The phenoconversion rate was 57.4% (n = 8) in the SN+ group (mean 5.8 years from baseline TCS), and 25.0% (n = 5) in the SN− group (mean 8.6 years from baseline TCS). Of those with phenoconversions, there were five PD patients and three DLB patients in the SN+ group, and one PD patient and four DLB patients in the SN− group. The SN+ group had a higher estimated risk for disease development than the SN− group. The coexistence of SN+ with functional anosmia may predict a short-term Lewy body disease onset risk.ConclusionA single baseline TCS for IRBD patients may be a suitable test for screening and predicting groups at high-risk for developing PD or DLB. This may help to select appropriate IRBD patients in clinical trials for disease modifying therapy to prevent progression to PD or DLB.     

Five‐year follow‐up of substantia nigra echogenicity in idiopathic REM sleep behavior disorder

Hyperechogenicity of the substantia nigra visualized by transcranial sonography occurs in most Parkinson's disease (PD) patients. Idiopathic rapid eye movement (REM) sleep behavior disorder (IRBD) subjects eventually develop PD and other synucleinopathies. This study was undertaken to evaluate whether in IRBD, transcranial sonography identifies subjects who convert to PD and other synucleinopathies, and whether substantia nigra echogenic size changes with time. It was a prospective study in which 55 IRBD patients underwent transcranial sonography at baseline and were invited to follow‐up after 5 years. Patients were assessed by the same experienced sonographer who was blinded to clinical data and baseline transcranial sonography results, and used the same equipment and adjustments. Twenty‐one (38.2%) subjects were diagnosed with a synucleinopathy (PD in 11, dementia with Lewy bodies in nine, and multiple system atrophy in one). Sensitivity of baseline substantia nigra hyperechogenicity for the development of a synucleinopathy was 42.1%, specificity 67.7%, positive predictive value 44.4%, negative predictive value 65.6%, and relative risk 1.29. No differences were detected between the first and second examination in mean size of the substantia nigra (0.20 ± 0.09 cm² vs. 0.19 ± 0.07 cm²; P = 0.777) and in percentage of patients with substantia nigra hyperechogenicity (33.3% vs. 42.8%, P = 0.125). Transcranial sonography of the substantia nigra alone is not a useful tool to identify IRBD subjects at risk for the development of PD or a synucleinopathy after 5 years of follow‐up. In IRBD, transcranial sonography cannot be used to monitor the degenerative process in the substantia nigra, because echogenicity size remains stable over time. © 2014 International Parkinson and Movement Disorder Society     

Impaired decision-making in idiopathic REM sleep behavior disorder

BackgroundPatients with REM sleep behavior disorder (RBD) frequently develop Parkinson’s disease (PD), which can impair decision-making ability. This study was undertaken to investigate decision-making ability and its relation to olfactory function in patients with idiopathic RBD.MethodsThis study used the Iowa Gambling Task (IGT) and the Sniffin’ Stick Test for examination of 38 patients with idiopathic RBD (iRBD) and 34 age-matched healthy control subjects (HC). Associations between these test results and other clinical RBD variables were also assessed.ResultsTotal IGT score and Sniffin’ Stick Test scores were significantly lower in the iRBD group than in the HC group. The iRBD group IGT scores in the first, third, and final blocks were significantly lower than those of the HC group. In the iRBD group, no association was found between the total IGT score and the Sniffin’ Stick Test score or any clinical RBD variable.ConclusionsImpaired decision-making associated with iRBD can herald PD. However, decision-making disability is thought to appear irrespective of olfactory dysfunction and progression of RBD pathology.     

Olfactory dysfunction in idiopathic REM sleep behavior disorder

BackgroundOlfactory dysfunction is frequently observed in patients with idiopathic REM sleep behavior disorder (iRBD) such as Parkinson’s disease or dementia with Lewy bodies.MethodsOlfactory function tests using Sniffin’ Sticks and Odor Stick Identification Test for Japanese (OSIT-J) were performed in 73 consecutive middle-aged (range, 50–69 years) patients with iRBD, 33 consecutive older-aged (71–82 years) patients with iRBD, and 28 control subjects (55–70 years).ResultsOdor identification was more frequently impaired than odor threshold or discrimination among the iRBD group and allowed better discrimination between the middle-aged iRBD group and age-adjusted control subjects. The area under the curve for threshold, discrimination, identification, TDI score and OSIT-J score determined from receiver operating characteristic curves were 0.831 (0.753–0.909), 0.761 (0.666–0.855), 0.938 (0.894–0.982), 0.939 (0.897–0.981), and 0.965 (0.931–0.999), respectively. Discrimination and identification scores were significantly lower in the older-aged iRBD group than in the middle-aged iRBD group. A significant correlation was observed between the identification score on Sniffin’ Sticks and OSIT-J score (r = 0.5910, P < 0.0001, n = 106, Spearman’s rank).ConclusionAnosmia/hyposmia may be a feature of iRBD. Olfactory dysfunction in iRBD is a consistent, widespread central nervous abnormality of different olfactory modalities with different cognitive complexity.     

Odor identification test as an indicator of idiopathic REM sleep behavior disorder

Reduction of olfactory function in idiopathic rapid‐eye‐movement (REM) sleep behavior disorder (iRBD) is of the same magnitude as that found in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We assessed olfactory function using the Odor Stick Identification Test for Japanese (OSIT‐J) in 48 Japanese patients with iRBD, 21 with PD, and 34 with obstructive sleep apnea syndrome (OSAS). Possible score of the OSIT‐J ranges from 0 to 12. OSIT‐J scores were 4.9 ± 2.8 in patients with iRBD, 4.8 ± 2.8 in patients with PD, and 9.9 ± 1.4 in OSAS patients. An OSIT‐J score of 8.5 was associated with a sensitivity of 88.2 and 85.3%, respectively, and specificity of 83.3 and 85.7%, respectively, in differentiating iRBD or PD patients from OSAS patients. Odor identification is impaired in Japanese patients with iRBD and PD. The results suggest that OSIT‐J, which is a short and simple nonlexical olfactory identification test, can be useful as a clinical indicator for iRBD with Lewy body formation and is appropriate in the Japanese elderly population. © 2008 Movement Disorder Society     

Polysomnographic diagnosis of idiopathic REM sleep behavior disorder

The presence of either excessive tonic chin EMG activity during REM sleep, or excessive phasic submental or limb EMG twitching is required to diagnose REM sleep behavior disorder (RBD). The aim was to identify cut‐off values and to assess the sensitivity and specificity of these values taken separately or combined to diagnose idiopathic RBD patients. Eighty patients presenting with a clinical diagnosis of idiopathic RBD and 80 age‐ and gender‐matched normal controls were studied in the sleep laboratory. Receiver operating characteristic curves were drawn to find optimal cut‐off values for three REM sleep EMG parameters. Tonic and phasic EMG activity were measured in the chin, but not in the limbs. Videos were examined during the recording but were not systematically reviewed by the authors. Total correct classification of 81.9% was found for tonic chin EMG density ≥30%; 83.8% for phasic chin EMG density ≥15% and 75.6% for ≥24 leg movements per hour of REM sleep. Five patients did not fulfill any of these three polysomnographic (PSG) criteria. Conversely, one subject of the control group met the PSG criteria for RBD. This study estimates the diagnostic value of a visual scoring method for the diagnosis of idiopathic RBD and establishes cut‐off values to be used in clinical and research set‐ups. For the five RBD patients who did not show chin EMG abnormalities, it cannot be excluded that they had increased phasic EMG activity in the upper limbs and presented visible motor activity. © 2010 Movement Disorder Society     

Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder

More than 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson's disease or Lewy body dementia. Symptom screens and metaiodobenzylguanine (MIBG)‐scintigraphy suggest autonomic abnormalities in idiopathic RBD, but it is unclear whether autonomic abnormalities can predict neurodegenerative disease. From a cohort of 99 patients with idiopathic RBD, we selected those who developed parkinsonism or dementia. These were matched by age, sex, and follow‐up duration to patients with RBD who remained disease free and to matched controls. From the polysomnographic trace performed at baseline evaluation, measures of beat‐to‐beat RR variability including time domains (mean RR‐interval and RR‐standard deviation) and frequency domains (low and high frequency components) were retrospectively assessed. Twenty‐one patients with idiopathic RBD who developed neurodegenerative disease were included (Parkinson's disease‐11, multiple system atrophy‐1, and dementia‐9). Age at PSG was 66 years, and 86% were male. PSG was performed on average 6.7 years before defined neurodegenerative disease. Comparing all patients with idiopathic RBD to controls, there were significant reductions in RR‐standard deviation (24.6 ± 2.2 ms vs. 35.2 ± 3.5 ms, P = 0.006), very low frequency components (238.6 ± 99.6 ms² vs. 840.1 ± 188.3 ms², P < 0.001), and low frequency components (127.8 ± 26.3 ms² vs. 288.7 ± 66.2 ms², P = 0.032). However, despite clear differences between patients with idiopathic RBD and controls, there were no differences in any measure between those who did or did not develop disease. RR‐variability analysis demonstrates substantial autonomic dysfunction in idiopathic RBD. However, this dysfunction is identical in patients who will or will not develop defined neurodegenerative disease. This suggests that autonomic dysfunction is linked with RBD independent of associated Parkinson's disease or Lewy body dementia. © 2010 Movement Disorder Society     

Rhythmic movements in idiopathic REM sleep behavior disorder.

Reported are two cases of video-PSG captured head-rolling occurring, in the context of REM Sleep Behavior Disorder (RBD) episodes, in two patients affected with idiopathic RBD and without past personal or familiar history of Rhythmic Movement Disorder during sleep. It has been speculated that the activation of neuronal pathways which underlie REM-related loss of motor control in RBD, may involve the Central Pattern Generator neuronal networks leading to the induction of Rhythmic Movements during RBD episodes, thereby allowing the re-emergence, in pathological conditions in later life, of a motor behavior typically seen in the early stage of life.     

Non-rapid eye movement sleep characteristics in idiopathic REM sleep behavior disorder

This study investigated slow waves (SW; >75μV and <4Hz) characteristics in patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD). Thirty patients with iRBD and 30 age- and sex-matched healthy subjects underwent one polysomnographic (PSG) nocturnal sleep recording. SW automatic detection was performed on F3, C3, P3, and O1 leads and SW characteristics were derived (SW density, amplitude, frequency, slope, and duration of negative and positive phases). We also compared iRBD patients and control subjects on PSG variables and delta (0.25-4.0Hz) spectral power. No between-group differences were found on PSG variables, delta spectral power, or SW characteristics. Results show no SW abnormalities in iRBD patients compared to healthy participants, which suggests similar level of synchronization of thalamo-cortical neurons during N-REM sleep.     

Autonomic dysfunction and phenoconversion in idiopathic REM sleep behavior disorder

Clinical Autonomic Research - REM sleep behavior disorder (RBD) is a common finding among patients with synucleinopathies. We aimed to determine the degree of autonomic dysfunction in patients...     

Investigation of autonomic function in idiopathic REM sleep behavior disorder

Idiopathic REM sleep behavior disorder (iRBD) has been suggested as an early "pre-motor" stage of Parkinson's disease (PD) in a significant proportion of cases. We investigated autonomic function in 15 consecutive iRBD patients and compared these findings to PD patients and healthy controls. All participants underwent cardiovascular autonomic function testing, and were rated on the COMPASS scale. Symptomatic orthostatic hypotension was present in two iRBD patients, two PD patients and none of the healthy controls. In the tilt table examination, blood pressure changes were similar between iRBD patients and healthy controls. In the PD group, blood pressure drops were more pronounced. In the orthostatic standing test, iRBD patients had higher blood pressure changes than healthy controls. Highest drops were found in PD. Valsalva ratio was lower in iRBD and PD compared to healthy controls. Total COMPASS score was higher in iRBD compared to healthy controls. Highest scores were found in PD. These results support the presence of autonomic dysfunction in iRBD. On several measures, dysfunction was intermediate between healthy controls and PD consistent with the concept that iRBD can be manifestation of synuclein-associated neurodegenerative disorders. Follow-up studies are needed to determine whether iRBD patients with dysfunction on several autonomic domains are at particular risk for developing one of these diseases.     

Longitudinal assessment of olfactory function in idiopathic REM sleep behavior disorder

ObjectiveIdiopathic REM sleep behavior disorder (IRBD) is an early marker of Lewy body disorders and is linked to olfactory loss. We evaluated whether olfactory function deteriorates with time in IRBD. Progressive smell loss could be a useful way in which to monitor the effect of disease-modifying interventions in subjects with IRBD.MethodsWe conducted a prospective study in which 19 IRBD patients and 19 healthy age and sex matched controls underwent serial clinical evaluations and olfactory identification testing. We used the 40-item University of Pennsylvania Smell Identification Test (UPSIT) at baseline and after 1.5, 3 and 4 years, and olfactory detection testing with the Smell Threshold Test (STT) at baseline and after 1.5 and 4 years.ResultsMean UPSIT score was lower (poorer smell identification) in patients than in controls at baseline, 1.5-, 3-, and 4-year assessments. Mean STT score was higher (poorer smell detection ability) in patients than in controls at 1.5- and 4-year evaluations. At 4 years, there were no differences between patients and controls in the rate of change of UPSIT (P = 0.093) and STT (P = 0.964) scores from baseline. Three patients were diagnosed with Parkinson's disease at 3-year evaluation and one with multiple system atrophy at 4-year assessment. At 4 years, UPSIT and STT scores did not change from baseline in these four patients.ConclusionsIn IRBD, olfactory identification and detection deficits do not worsen over time. Serial olfactory tests may not serve as an outcome measure in future disease-modifying trials in IRBD.     

Plasma immune markers in an idiopathic REM sleep behavior disorder cohort

IntroductionIncreasing evidence shows a strong association between idiopathic REM sleep behavior disorder (iRBD) and α-synucleinopathies. Recent studies have indicated an inflammatory mechanism in the pathogenesis of α-synucleinopathies. Whether peripheral inflammatory cytokines are altered in iRBD and can be biomarkers for predicting phenoconversion remains unclear.MethodsWe collected baseline plasma samples from 77 consecutive iRBD patients and 64 age- and sex-matched healthy controls. Ten cytokines were measured: Interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-α. All iRBD patients underwent clinical assessment tests at baseline, and 75 were prospectively followed and received assessments for parkinsonism or dementia. Cox regression analyses were used to evaluate the predictive value of plasma cytokines in a follow-up period of 6.0 years.ResultsTNF-α and IL-10 were significantly elevated in iRBD compared with controls (both p < 0.001). IL-6/IL-10 and IL-8/IL-10 were significantly reduced in iRBD than in controls (p = 0.001, p < 0.001, respectively). After a median follow-up of 3.7 years, 16 iRBD patients developed neurodegenerative synucleinopathies. iRBD patients with higher TNF-α/IL-10 levels were more likely to develop neurodegenerative diseases (adjusted HR 1.07, 95% CI 1.01–1.14). The coexistence of elevated TNF-α/IL-10 and possible mild cognitive impairment predicted an early conversion of iRBD to neurodegenerative synucleinopathies (adjusted HR 4.17, 95% CI 1.47–11.81).ConclusionsOur study supported the early involvement of peripheral inflammation in prodromal α-synucleinopathy. Plasma cytokines may be predictive of disease conversion in iRBD, while large-scale longitudinal studies are warranted to validate the assumption.     

Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder

Idiopathic REM sleep behavior disorder (RBD) may represent prodromal synucleinopathies. We report markedly reduced cardiac (123)I-metaiodobenzylguanidine uptake, consistent with the loss of sympathetic terminals, in idiopathic RBD. We also demonstrate that this reduction is of the same magnitude as that found in patients with Parkinson disease. The results are consistent with the hypothesis that idiopathic RBD in older patients is a forme fruste of Lewy body disease.     

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.     

Heart rate variability in Parkinson disease and idiopathic REM sleep behavior disorder

Purpose

Heart rate variability, a marker of autonomic function modulation, is known to be blunted in Parkinson disease, although data remains conflicting and a putative modifying role of REM sleep behavior disorder persists unclarified.

Methods

We assessed ten patients with idiopathic REM sleep behavior disorder patients, 18 patients with Parkinson disease and REM behavior disorder and eight patients with Parkinson disease without REM sleep behavior disorder. Heart rate variability analysis was performed in 5-min epochs selected from wake, Non-REM and REM polysomnography records. We compared heart rate variability measures by stage between two sets of groups: Parkinson disease vs. idiopathic RBD and patients with vs. without RBD, by using repeated measures ANOVA.

Results

There were no heart rate variability differences between Parkinson disease and idiopathic REM sleep behavior disorder groups. There were significant stage vs. group interactions (p?=?0.045) regarding the high frequencies components when comparing patients with and without REM sleep behavior disorder, with the former presenting lower values and attenuation of sleep stage variations.

Conclusion

Our study suggests that RBD is related with reduction in parasympathetic modulation of heart rate variability and blunting of sleep stage related variations.