Idiopathic REM sleep behavior disorder in the transition to degenerative disease

Idiopathic REM sleep behavior disorder (RBD) predicts Parkinson's 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 Alzheimer's 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 “Alzheimer's 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. © 2009 Movement Disorder Society     

A population‐based study on combined markers for early Parkinson's disease

The prerequisite for an earlier diagnosis of Parkinson's disease (PD) are markers that are both sensitive and specific for clinically definite PD and its prediagnosic phases. Promising candidates include enlarged hyperechogenicity of the substantia nigra (SN+) on transcranial sonography (TCS) and hyposmia. However, despite good sensitivity and specificity, both markers have yet failed to yield reliable predictions. We pursue the possibility of combined use in an ongoing population‐based cohort. Subjects were recruited from 10,000 inhabitants of Luebeck/Germany aged 50 to 79 years and additional PD patients from our outpatient clinic. After neurological examination, 715 subjects were grouped into clinically definite PD (n = 106), possible prediagnostic PD (ppPD; n = 73), and a control group subdivided into healthy individuals (n = 283) and controls with diseases other than PD (n = 253). Subjects underwent TCS and smell testing. Sensitivity and specificity of SN+ and hyposmia were good for PD; however, positive predictive values (PPV) of both SN+ (5.2%) and olfaction (2.5%) were low. At least one positive/both positive markers were present in 33%/1% of healthy controls, 33%/2% of diseased controls, 62%/7% of ppPD, and 94%/51% of PD. When combining SN+ and hyposmia, PPV increased to 17.6%, with a sensitivity of 51% and a specificity of 98%. Both SN+ and hyposmia offer good enrichment towards PD and ppPD, are stable against other diseases, and the combination of markers highly increases specificity. However, if the combination of SN+ and hyposmia were used as criterion for PD diagnosis, almost half of clinically definite PD and more than 90% of ppPD would have been missed. © 2014 International Parkinson and Movement Disorder Society     

Anger in Parkinson's disease: A case‐control study

Cognitive‐psychiatric features of Parkinson's disease (PD) are common and they may be as disabling as the motor features of the disease. PD has been associated with stoic and inflexible personality traits. While many features of personality have been studied in PD, a systematic study of anger trait and anger expression in PD has not been performed. We used the Spanish adapted version of the state–trait anger Expression Inventory‐2 (STAXI‐2), comprised of six scales and an anger expression index, to measure anger trait and anger expression. There were 126 PD patients with depressive symptoms and 126 age‐ and gender‐matched controls. PD patients had lower levels of state anger (15.8 ± 3.1 vs. 17.9 ± 5.3, P < 0.001), trait anger (19.2 ± 5.3 vs. 20.7 ± 6.0, P < 0.05), anger expression‐out (9.0 ± 2.5 vs. 10.5 ± 3.0, P < 0.001), and anger expression index (26.1 ± 8.8 vs. 29.6 ± 9.4, P = 0.002); and higher levels in anger expression‐in (14.0 ± 3.4 vs. 12.2 ± 3.2, P < 0.001), anger control‐out (18.6 ± 5.0 vs. 16.1 ± 5.0, P < 0.001), and anger control‐in (14.3 ± 4.7 vs. 13.0 ± 4.5, P < 0.05) than controls. These differences persisted in analyses adjusting for age, gender, and depressive symptoms. Conclusions: PD patients showed lower levels of external expression of anger and higher levels of control of anger. Our results demonstrate another dimension to the stoic personality trait seen in PD. © 2007 Movement Disorder Society     

Decreased phasic EMG activity during rapid eye movement sleep in treatment‐naïve Parkinson's disease: Effects of treatment with levodopa and progression of illness

Rapid eye movement (REM) sleep behavior disorder (RBD) is frequently associated with Parkinson's disease (PD) and may anticipate its diagnosis by several years. We assessed the presence of motor dyscontrol during REM sleep in treatment‐naïve PD patients and investigated the putative effect of levodopa (L ‐dopa) treatment on motor activity. Overnight sleep studies were performed on 15 previously untreated PD patients and 14 controls at baseline, again after a 3‐ to 9‐month treatment period with a low dose of L ‐dopa, and 2 to 5 days after treatment discontinuation (in 8 patients). No differences in sleep parameters were observed across groups or treatment conditions. None of the patients met criteria for RBD at baseline, whereas 5 patients were symptomatic at the time of the second sleep study. A quantitative analysis of electromyographic (EMG) activity during REM sleep showed a lower phasic twitching activity in untreated PD than in controls. However, an increase in both phasic twitching and tonic activity was found after treatment with L ‐dopa. Discontinuation of treatment resulted in a return to pretreatment values of phasic but not of tonic EMG activity. Thus, the increase in phasic activity seems to depend on the effects of L ‐dopa, whereas the increase in tonic EMG activity during REM sleep might be caused by other factors such as the progression of disease. Potential implications for the understanding of the relationship between RBD and PD are discussed. © 2002 Movement Disorder Society     

Rapid eye movement sleep behavior disorder and subtypes in autopsy-confirmed dementia with Lewy bodies

The purpose of this study was to determine whether dementia with Lewy bodies with and without probable rapid eye movement sleep behavior disorder differ clinically or pathologically. Patients with dementia with Lewy bodies (DLB) with probable rapid eye movement sleep behavior sleep disorder (n = 71) were compared with those without it (n = 19) on demographics, clinical variables (core features of dementia with Lewy bodies, dementia duration, rate of cognitive/motor changes), and pathologic indices (Lewy body distribution, neuritic plaque score, Braak neurofibrillary tangle stage). Individuals with probable rapid eye movement sleep behavior disorder were predominantly male (82% vs 47%) and had a shorter duration of dementia (mean, 8 vs 10 years), earlier onset of parkinsonism (mean, 2 vs 5 years), and earlier onset of visual hallucinations (mean, 3 vs 6 years). These patients also had a lower Braak neurofibrillary tangle stage (stage IV vs stage VI) and lower neuritic plaque scores (18% vs 85% frequency), but no difference in Lewy body distribution. When probable rapid eye movement sleep behavior disorder developed early (at or before dementia onset), the onset of parkinsonism and hallucinations was earlier and Braak neurofibrillary tangle stage was lower compared with those who developed the sleep disorder after dementia onset. Women with autopsy-confirmed DLB without a history of dream enactment behavior during sleep had a later onset of hallucinations and parkinsonism and a higher Braak NFT stage. Probable rapid eye movement sleep behavior disorder is associated with distinct clinical and pathologic characteristics of dementia with Lewy bodies.     

Validation of the MDS research criteria for prodromal Parkinson's disease: Longitudinal assessment in a REM sleep behavior disorder (RBD) cohort

Background : Recently, the International Parkinson and Movement Disorder Society introduced the prodromal criteria for PD. Objectives Our study aimed to examine diagnostic accuracy of the criteria as well as the independence of prodromal markers to predict conversion to PD or dementia with Lewy bodies. Methods : This prospective cohort study was performed on 121 individuals with rapid eye movement sleep behavior disorder who were followed annually for 1 to 12 years. Using data from a comprehensive panel of prodromal markers, likelihood ratio and post‐test probability of the criteria were calculated at baseline and during each follow‐up visit. Results : Forty‐eight (39.7%) individuals with rapid eye movement sleep behavior disorder converted to PD/dementia with Lewy bodies. The prodromal criteria had 81.3% sensitivity and 67.9% specificity for conversion to PD/dementia with Lewy bodies at 4‐year follow‐up. One year before conversion, sensitivity was 100%. The criteria predicted dementia with Lewy bodies with even higher accuracy than PD without dementia at onset. Those who met the threshold of prodromal criteria at baseline had significantly more rapid conversion into a neurodegenerative state (4.8 vs. 9.1 years; P < 0.001). Pair‐wise combinations of different prodromal markers showed that markers were independent of one another. Conclusion : The prodromal criteria are a promising tool for predicting incidence of PD/dementia with Lewy bodies and conversion time in a rapid eye movement sleep behavior disorder cohort, with high sensitivity and high specificity with long follow‐up. Prodromal markers influence the overall likelihood ratio independently, allowing them to be reliably multiplied. Defining additional markers with high likelihood ratio, further studies with longitudinal assessment and testing thresholds in different target populations will improve the criteria. © 2017 International Parkinson and 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     

Sleep and Parkinson's disease: A review of case‐control polysomnography studies

The link between Parkinson's disease (PD) and certain primary sleep disorders has yet to be clarified. We performed a systematic review of case‐control polysomnography studies to evaluate the relationship between PD and sleep disorders. A PubMed literature search and bibliography review yielded 15 case‐control polysomnography studies in patients with PD. Studies differed by recruitment methods, duration of polysomnography monitoring, and sleep parameters measured. Subjective sleepiness was greater in patients than controls (50%–66% vs 2.9%–12%) despite lack of objective increase in daytime sleepiness by mean sleep latency testing. The 4 case‐control polysomnography studies investigating rapid eye movement behavior disorder support a higher prevalence in PD (0%–47% vs 0%–1.8% in controls), although differences in diagnostic criteria hamper interpretation. The preponderance of evidence did not support an increased incidence of obstructive sleep apnea (27%–60% vs 13%–65%) or periodic leg movements of sleep in patients compared to controls. Adequately powered, prospective studies with uniform methodology and healthy controls are needed to further address the association and pathophysiological significance between PD and sleep problems. © 2012 Movement Disorder Society     

Surface EMG activity during REM sleep in Parkinson's disease correlates with disease severity

ObjectivesOver 40% of individuals with Parkinson's disease (PD) have rapid eye movement sleep behavior disorder (RBD). This is associated with excessive sustained (tonic) or intermittent (phasic) muscle activity instead of the muscle atonia normally seen during REM sleep. We examined characteristics of manually-quantitated surface EMG activity in PD to ascertain whether the extent of muscle activity during REM sleep is associated with specific clinical features and measures of disease severity.MethodsIn a convenience sample of outpatients with idiopathic PD, REM sleep behavior disorder was diagnosed based on clinical history and polysomnogram, and severity was measured using the RBD sleep questionnaire. Surface EMG activity in the mentalis, extensor muscle group of the forearms, and anterior tibialis was manually quantitated. Percentage of REM time with excessive tonic or phasic muscle activity was calculated and compared across PD and RBD characteristics.ResultsAmong 65 patients, 31 had confirmed RBD. In univariate analyses, higher amounts of surface EMG activity were associated with longer PD disease duration (srho = 0.34; p = 0.006) and greater disease severity (p < 0.001). In a multivariate regression model, surface EMG activity was significantly associated with RBD severity (p < 0.001) after adjustment for age, PD disease duration, PD severity and co-morbid sleep abnormalities.ConclusionSurface EMG activity during REM sleep was associated with severity of both PD and RBD. This measure may be useful as a PD biomarker and, if confirmed, may aid in determining which PD patients warrant treatment for their dream enactment to reduce risk of injury.     

Performance of the Movement Disorders Society criteria for prodromal Parkinson's disease: A population‐based 10‐year study

Objective: We aimed to identify prodromal Parkinson's disease (PD) and its predictive accuracy for incident PD in an unselected elderly population and to estimate the relevance of this approach for future neuroprotection trials. Methods: We applied the recently published Movement Disorders Society (MDS) research criteria for prodromal PD to participants of the prospective population‐based Bruneck Study of the 2005 assessment (n = 574, ages 55‐94 years). Cases of incident PD were identified at 3‐year, 5‐year, and 10‐year follow‐up visits. We calculated predictive accuracies of baseline prodromal PD status for incident cases, and, based on them, estimated sample sizes for neuroprotection trials with conversion to PD as the primary outcome. Results: Baseline status of probable prodromal PD (n = 12) had a specificity in predicting incident PD of 98.8% (95% confidence interval, 97.3%‐99.5%), a sensitivity of 66.7% (29.6%‐90.8%), and a positive predictive value of 40.0% (16.7%‐68.8%) over 3 years. Specificity remained stable with increasing follow‐up time, sensitivity decreased to 54.6% (28.0%‐78.8%) over 5 years and to 35.0% (18.0%‐56.8%) over 10 years, whereas positive predictive value rose to 60.0% (31.2%‐83.3%) and 77.8% (44.3%‐94.7%), respectively. Sample size estimates at 80% power in an intention‐to‐treat approach ranged from 108 to 540 patients with probable prodromal PD depending on trial duration (3‐5 years) and effect size of the agent (30%‐50%). Conclusions: Our findings show that the MDS criteria for prodromal PD yield moderate to high predictive power for incident PD in a community‐based setting and may thus be helpful to define target populations of future neuroprotection trials. © 2018 International Parkinson and Movement Disorder Society     

Objective sleep data as predictors of cognitive decline in dementia with Lewy Bodies and Parkinson's disease

IntroductionParkinson's disease (PD) and Dementia with Lewy Bodies (DLB) prognosis depends on cognitive function evolution. Sleep disorders, as objectivated by polysomnography (PSG), are intimately connected with PD and DLB pathophysiology, but have seldomly been used to predict cognitive decline.Methods20 DLB and 49 PD patients underwent one-night in-lab video-PSG. Sleep variables were defined, including REM sleep motor events, Tonic and phasic REM sleep muscular tone and RBD diagnosis. Cognitive state (assessed with the Global Deterioration Scale (GDS) was collected from case files for 6 months intervals, for a maximum period of 3.5 years or until death/drop-out.). The relation between PSG data at baseline and variation of GDS scores over time was tested with mixed linear regression analysis.ResultsGDS scores were higher in DLB, than in PD. We confirmed significant cognitive decline in both disorders, but no significant differences in progression between them. There were no significant interactions between PSG data and GDS variation for the entire group and DLB separately. In PD patients, there was a significant interaction between RBD diagnosis and tonic excessive muscular tone and GDS increase.ConclusionOur data suggests that PSG data can be useful in predicting cognitive decline in PD but not in DLB patients. In PD patients, an RBD diagnosis is predictive of cognitive deterioration, confirming the notion that this non-motor symptom relates to a malignant sub-type. Tonic excessive muscular activity, but not other RBD features, had predictive value in this group, pointing to a specific relation with the disease pathophysiology.     

Incidence of Parkinson's disease and parkinsonism in northern Sweden: A population‐based study

The differential diagnosis of parkinsonian disorders is difficult, especially early in the course of the diseases. The clinical subtypes of Parkinson's disease (PD) have not so far been described in newly diagnosed patients. We present a prospective incidence cohort study of patients with idiopathic parkinsonian syndromes in the Umeå region in northern Sweden identified over a 4‐year period. The clinical diagnoses were re‐evaluated at follow‐up visits at 12 months. We found 138 patients with parkinsonism: 112 PD, 12 multiple system atrophy with predominant parkinsonism (MSA‐P), six progressive supranuclear palsy (PSP) and eight unclassifiable patients. The crude incidences for all age ranges per 100,000 were: PD 19.7 (95% confidence interval 16.1–23.3); MSA‐P 2.1 (1.1–3.7); PSP 1.1 (0.4–2.4); idiopathic parkinsonism 24.3 (20.2–28.4). Age‐standardized to the average Swedish population 2004–2007: PD 22.5 (18.3–26.7); MSA‐P 2.4 (1.2–4.2); PSP 1.2 (0.4–2.6); idiopathic parkinsonism 27.5 (22.9–32.1). The crude annual incidence rate for PD, with exclusion of patients with normal dopamine receptor uptake (FP‐CIT‐SPECT), was 18.8 per 100,000 (95% confidence interval 15.2–22.4), age‐adjusted to the average Swedish population 2004 to 2007: 21.5 (17.4–25.6). The incidence rates did not differ significantly between men and women. The cumulative incidence of PD up to 89 years of age was for men 3.4%, for women 2.6%, and for both sexes combined 2.9%. The annual incidence rates found for PD, idiopathic parkinsonism, MSA‐P and PSP are among the highest reported. © 2010 Movement Disorder Society