Mélanie Vendette

Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

Objective: Idiopathic REM sleep behavior disorder (RBD) is a potential preclinical marker for the development of neurodegenerative diseases, particularly Parkinson disease (PD) and Lewy body dementia. However, the long-term risk of developing neurodegeneration in patients with idiopathic RBD has not been established. Obtaining an accurate picture of this risk is essential for counseling patients and for development of potential neuroprotective therapies. Methods: We conducted a follow-up study of all patients seen at the sleep disorders laboratory at the Hôpital du Sacré Coeur with a diagnosis of idiopathic RBD. Diagnoses of parkinsonism and dementia were defined according to standard criteria. Survival curves were constructed to estimate the 5-, 10-, and 12-year risk of developing neurodegenerative disease. Results: Of 113 patients, 93 (82%) met inclusion criteria. The mean age of participants was 65.4 years and 75 patients (80.4%) were men. Over the follow-up period, 26/93 patients developed a neurodegenerative disorder. A total of 14 patients developed PD, 7 developed Lewy body dementia, 4 developed dementia that met clinical criteria for AD, and 1 developed multiple system atrophy. The estimated 5-year risk of neurodegenerative disease was 17.7%, the 10-year risk was 40.6%, and the 12-year risk was 52.4%. Conclusions: Although we have found a slightly lower risk than other reports, the risk of developing neurodegenerative disease in idiopathic REM sleep behavior disorder is substantial, with the majority of patients developing Parkinson disease and Lewy body dementia.

Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease.

To investigate the frequency and subtypes of mild cognitive impairment (MCI) in idiopathic rapid eye movement sleep behavior disorder (RBD) and Parkinsons disease (PD) in association with RBD.

REM SLEEP BEHAVIOR DISORDER PREDICTS COGNITIVE IMPAIRMENT IN PARKINSON DISEASE WITHOUT DEMENTIA

Objective: To assess the relationship between the presence of REM sleep behavior disorder (RBD) and the cognitive profile of nondemented patients with Parkinson disease (PD). Background: Cognitive impairment is an important nonmotor symptom in PD. Waking EEG slowing in nondemented PD has been related to the presence of RBD, a parasomnia affecting brainstem structures and frequently reported in PD. For this reason, RBD may be associated with cognitive impairment in PD. Methods: Thirty-four patients with PD (18 patients with polysomnographic-confirmed RBD and 16 patients without RBD) and 25 healthy control subjects matched for age and educational level underwent sleep laboratory recordings and a comprehensive neuropsychological assessment. Results: Patients with PD and concomitant RBD showed significantly poorer performance on standardized tests measuring episodic verbal memory, executive functions, as well as visuospatial and visuoperceptual processing compared to both patients with PD without RBD and control subjects. Patients with PD without RBD had no detectable cognitive impairment compared to controls. Conclusions: This study shows that cognitive impairment in nondemented patients with Parkinson disease (PD) is closely related to the presence of REM sleep behavior disorder, a sleep disturbance that was not controlled for in previous studies assessing cognitive deficits in PD. GLOSSARY: BDI-II = Beck-II Depression Inventory; DLB = dementia with Lewy bodies; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders; EOG = electro-oculograms; ICSD = International Classification of Sleep Disorders; MMSE = Mini-Mental State Examination; PD = Parkinson disease; PD-NRBD = patients with PD without RBD; PD-RBD = patients with concomitant RBD; RAVLT = Rey Auditory Verbal Learning Test; RBD = REM sleep behavior disorder; UPDRS = Unified Parkinsons Disease Rating Scale.

REM sleep behaviour disorder in Parkinson’s disease is associated with specific motor features

Background: Rapid eye movement (REM) sleep behaviour disorder (RBD) is commonly associated with Parkinson’s disease (PD), and recent studies have suggested that RBD in PD is associated with increased cognitive impairment, waking EEG slowing, autonomic impairment and lower quality of life on mental health components. However, it is unclear whether the association of RBD in PD has implications for motor manifestations of the disease. Methods: The study evaluated 36 patients with PD for the presence of RBD by polysomnography. Patients underwent an extensive evaluation on and off medication by a movement disorders specialist blinded to the polysomnography results. Measures of disease severity, quantitative motor indices, motor subtypes, complications of therapy and response to therapy were assessed and compared using regression analysis that adjusted for disease duration and age. Results: Patients with PD and RBD were less likely to be tremor predominant (14% vs 53%; p<0.02) and had a lower proportion of their Unified Parkinson Disease Rating Scale (UPDRS) score accounted for by tremor (8.2% vs 19.0%; p<0.01). An increased frequency of falls was noted among patients with RBD (38% vs 7%; p = 0.04). Patients with RBD demonstrated a lower amplitude response to their medication (UPDRS improvement 16.2% vs 34.8%; p = 0.049). Markers of overall disease severity, quantitative motor testing and motor complications did not differ between groups. Conclusions: The presence of altered motor subtypes in PD with RBD suggests that patients with PD and RBD may have a different underlying pattern of neurodegeneration than PD patients without RBD.

Rapid Eye Movement Sleep Behavior Disorder and Risk of Dementia in Parkinson's Disease: A Prospective Study

One of the most devastating nonmotor manifestations of PD is dementia. There are few established predictors of dementia in PD. In numerous cross‐sectional studies, patients with rapid eye movement (REM) sleep behavior disorder (RBD) have increased cognitive impairment on neuropsychological testing, but no prospective studies have assessed whether RBD can predict Parkinsons dementia. PD patients who were free of dementia were enrolled in a prospective follow‐up of a previously published cross‐sectional study. All patients had a polysomnogram at baseline. Over a mean 4‐year follow‐up, the incidence of dementia was assessed in those with or without RBD at baseline using regression analysis, adjusting for age, sex, disease duration, and follow‐up duration. Of 61 eligible patients, 45 (74%) were assessed and 42 were included in a full analysis. Twenty‐seven patients had baseline RBD, and 15 did not. Four years after the initial evaluation, 48% with RBD developed dementia, compared to 0% of those without (P‐adjusted = 0.014). All 13 patients who developed dementia had mild cognitive impairment on baseline examination. Baseline REM sleep atonia loss predicted development of dementia (% tonic REM = 73.2 ± 26.7 with dementia, 40.8 ± 34.5 without; P = 0.029). RBD at baseline also predicted the new development of hallucinations and cognitive fluctuations. In this prospective study, RBD was associated with increased risk of dementia. This indicates that RBD may be a marker of a relatively diffuse, complex subtype of PD.

Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder.

For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying “preclinical” neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein‐mediated neurodegenerative disease—this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease.

Manifestations of Parkinson disease differ in association with REM sleep behavior disorder

REM sleep behavior disorder (RBD) is commonly associated with Parkinson disease (PD), but it is unclear whether this association has implications for disease manifestations. We evaluated 36 PD patients for the presence of RBD by polysomnography. Patients underwent an extensive evaluation by a movement disorders specialist blinded to polysomnography results. Severity of motor manifestations, autonomic, visual, psychiatric, and olfactory dysfunctions and quality of life (QOL) were assessed, and compared using regression analysis that adjusted for disease duration, age and sex. Severity of motor manifestations did not differ between groups. However, the presence of RBD in PD was strongly associated with symptoms and signs of orthostatic hypotension (systolic blood pressure lying to standing = −25.7 ± 13.0 mmHg vs. −4.9 ±14.1, P < 0.001); and orthostatic symptom prevalence = 71% vs. 27%, P = 0.0076). There was no association between RBD and other autonomic symptoms. Color vision was worse in patients with RBD, but olfactory dysfunction did not differ between groups. The prevalence of depression, hallucinations, paranoia, and impulse disorders did not differ between groups. Emotional functioning and general health QOL measures were lower in those with RBD, but there were no differences between groups on disease‐specific indices or on measures of overall physical QOL. These findings suggest that the pathophysiology of RBD and nonmotor manifestations of PD, particularly autonomic dysfunction, are linked.

Executive dysfunction and memory impairment in idiopathic REM sleep behavior disorder

Background: Idiopathic REM sleep behavior disorder (iRBD) might be a stage in the development of neurodegenerative disorders, especially Parkinson disease and dementia with Lewy bodies. Recent studies showing a slowing of waking EEG in iRBD suggest that iRBD is associated with cognitive impairment. Objective: To compare patients with iRBD on measures of cognitive function and quantitative waking EEG. Methods: Fourteen patients with iRBD and 14 healthy control subjects matched for age and educational level were studied. Subjects underwent an extensive neuropsychological evaluation and waking EEG recordings. Results: Compared to controls, patients with iRBD showed a lower performance on neuropsychological tests measuring attention, executive functions, and verbal memory. Moreover, patients with iRBD showed EEG slowing (higher delta and theta power) during wakefulness in all brain areas compared to controls. However, no correlation was found between performance on cognitive tests and quantitative waking EEG in patients with iRBD. Conclusion: This study shows a co-occurrence of impaired cognitive profile and waking EEG slowing in patients with idiopathic REM sleep behavior disorder similar to that observed in early stages of some synucleinopathies.

Idiopathic REM sleep behavior disorder in the transition to degenerative disease

Idiopathic REM sleep behavior disorder (RBD) predicts Parkinsons disease (PD) and dementia. However, the nature of the disease that emerges from RBD has not been fully characterized. Since 2004, we have been conducting a prospective study of idiopathic RBD patients, providing an opportunity to directly observe patients as they transitioned to a defined neurodegenerative syndrome. Patients with idiopathic RBD underwent an extensive annual evaluation of motor function, olfaction, color vision, autonomic function, cognition and psychiatric symptoms. Neurodegenerative disease was defined according to standard criteria. We compared these measures in patients who had developed PD to those with dementia, all within the first year of developing disease. Of 67 patients, 6 developed PD and eleven developed dementia. Except for cognitive functioning, all tests of olfaction, color vision, autonomic function, depression, and quantitative measures of motor speed were similar in patients with PD and dementia. Of dementia patients, seven met criteria for probable Lewy body dementia (LBD) and four for Alzheimers disease (or, possible LBD). In all probable LBD cases, the diagnosis was made because of parkinsonism, with no patient experiencing hallucinations or fluctuations. Patients with “Alzheimers disease” seemed to have LBD, as they demonstrated typical LBD cognitive profiles on neuropsychological testing and were indistinguishable from LBD patients in ancillary measures. Therefore, among RBD patients with new‐onset LBD, hallucinations or fluctuations are absent, suggesting that RBD is a reliable early sign of LBD. The indistinguishability of dementia and PD in all ancillary measures suggests a single unitary “RBD‐then‐neurodegeneration” process, the clinical presentation of which depends upon selective neuronal vulnerability.

Abnormal metabolic network activity in REM sleep behavior disorder.

Objective: To determine whether the Parkinson disease–related covariance pattern (PDRP) expression is abnormally increased in idiopathic REM sleep behavior disorder (RBD) and whether increased baseline activity is associated with greater individual risk of subsequent phenoconversion. Methods: For this cohort study, we recruited 2 groups of RBD and control subjects. Cohort 1 comprised 10 subjects with RBD (63.5 ± 9.4 years old) and 10 healthy volunteers (62.7 ± 8.6 years old) who underwent resting-state metabolic brain imaging with 18F-fluorodeoxyglucose PET. Cohort 2 comprised 17 subjects with RBD (68.9 ± 4.8 years old) and 17 healthy volunteers (66.6 ± 6.0 years old) who underwent resting brain perfusion imaging with ethylcysteinate dimer SPECT. The latter group was followed clinically for 4.6 ± 2.5 years by investigators blinded to the imaging results. PDRP expression was measured in both RBD groups and compared with corresponding control values. Results: PDRP expression was elevated in both groups of subjects with RBD (cohort 1: p < 0.04; cohort 2: p < 0.005). Of the 17 subjects with long-term follow-up, 8 were diagnosed with Parkinson disease or dementia with Lewy bodies; the others did not phenoconvert. For individual subjects with RBD, final phenoconversion status was predicted using a logistical regression model based on PDRP expression and subject age at the time of imaging (r2 = 0.64, p < 0.0001). Conclusions: Latent network abnormalities in subjects with idiopathic RBD are associated with a greater likelihood of subsequent phenoconversion to a progressive neurodegenerative syndrome.