The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies.

Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French-Canadians are known. GBA was fully sequenced using targeted next generation and Sanger sequencing in French-Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)-sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity-by-descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism-chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French-Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

EEG rhythmic and arrhythmic spectral components and functional connectivity at resting state may predict the development of synucleinopathies in idiopathic REM sleep behavior disorder.

STUDY OBJECTIVES: Idiopathic/isolated REM-sleep behavior disorder (iRBD) often precedes the onset of synucleinopathies. Here, we investigated whether baseline resting-state EEG advanced spectral power and functional connectivity differ between iRBD patients who converted towards a synucleinopathy at follow-up and those who did not. METHODS: Eighty-one participants with iRBD (66.89±6.91 years) underwent a baseline resting-state EEG recording, a neuropsychological assessment and a neurological examination. We estimated EEG power spectral density using standard analyses and derived spectral estimates of rhythmic and arrhythmic components. Global and pairwise EEG functional connectivity analyses were computed using the weighted phase-lag index (wPLI). Pixel-based permutation tests were used to compare groups. RESULTS: After a mean follow-up of 5.01±2.76 years, 34 patients were diagnosed with a synucleinopathy (67.81±7.34 years) and 47 remained disease-free (65.53±7.09 years). Among patients who converted, 22 were diagnosed with Parkinson's disease and 12 with dementia with Lewy bodies. As compared to patients who did not convert, patients who converted exhibited at baseline higher relative theta standard power, steeper slopes of the arrhythmic component and higher theta rhythmic power mostly in occipital regions. Furthermore, patients who converted showed higher beta global wPLI but lower alpha wPLI between left temporal and occipital regions. CONCLUSION: Analyses of resting-state EEG rhythmic and arrhythmic components and functional connectivity suggest an imbalanced excitatory-to-inhibitory activity within large-scale networks, which is associated with later development of a synucleinopathy in iRBD patients.

How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder.

Parkinsonism, as a gradually progressive disorder, has a prodromal interval during which neurodegeneration has begun but cardinal manifestations have not fully developed. A systematic direct assessment of this interval has never been performed. Since patients with idiopathic REM sleep behaviour disorder are at very high risk of parkinsonism, they provide a unique opportunity to observe directly the development of parkinsonism. Patients with idiopathic REM sleep behaviour disorder in an ongoing cohort study were evaluated annually with several quantitative motor measures, including the Unified Parkinson's Disease Rating Scale, Purdue Pegboard, alternate-tap test and timed up-and-go. Patients who developed parkinsonism were identified from this cohort and matched according to age to normal controls. Their results on motor testing from the preceding years were plotted, and then assessed with regression analysis, to determine when markers first deviated from normal values. Sensitivity and specificity of quantitative motor markers for diagnosing prodromal parkinsonism were assessed. Of 78 patients, 20 developed parkinsonism. On regression analysis, the Unified Parkinson's Disease Rating Scale first intersected normal values at an estimated 4.5 years before diagnosis. Voice and face akinesia intersected earliest (estimated prodromal interval = 9.8 years), followed by rigidity (4.4 years), gait abnormalities (4.4 years) and limb bradykinesia (4.2 years). Quantitative motor tests intersected normal values at longer prodromal intervals than subjective examination (Purdue Pegboard = 8.6 years, alternate-tap = 8.2, timed up-and-go = 6.3). Using Purdue Pegboard and the alternate-tap test, parkinsonism could be detected with 71-82% sensitivity and specificity 3 years before diagnosis, whereas a Unified Parkinson's Disease Rating Scale score >4 identified prodromal parkinsonism with 88% sensitivity and 94% specificity 2 years before diagnosis. Removal of action tremor scores improved sensitivity to 94% and specificity to 97% at 2 years before diagnosis (cut-off >3). Although distinction between conditions was often difficult, prodromal dementia with Lewy bodies appeared to have a slower progression than Parkinson's disease (prodromal interval = 6.0 versus 3.8 years). Using a cut-off of Unified Parkinson's Disease Rating Scale >3 (excluding action tremor), 25% of patients with 'still-idiopathic' REM sleep behaviour disorder demonstrated evidence of possible prodromal parkinsonism. Therefore, using direct assessment of motor examination before parkinsonism in a REM sleep behaviour disorder, we have estimated a prodromal interval of ∼4.5 years on the Unified Parkinson's Disease Rating Scale; other quantitative markers may detect parkinsonism earlier. Simple quantitative motor measures may be capable of reliably detecting parkinsonism, even before a clinical diagnosis can be made by experienced movement disorders neurologists.

Clinical prediction of Parkinson's disease: planning for the age of neuroprotection.

As a chronic progressive disease, Parkinson's disease (PD) has a presymptomatic interval; that is, a period during which the pathological process has begun, but motor signs required for the clinical diagnosis are absent. The ability to identify this preclinical stage may be critical in the development and eventual use of neuroprotective therapy. Recently proposed staging systems of PD have suggested that degeneration may occur initially in areas outside the substantia nigra, suggesting that non-motor manifestations may be markers of presymptomatic PD. Decreased olfaction has recently been demonstrated to predict PD in prospective pathological studies, although the lead time may be relatively short, and the positive predictive value is low. Idiopathic RBD has a very high predictive value, with approximately 50% of affected individuals developing PD or dementia within 10 years. This implies that idiopathic RBD patients are ideal candidates to test potential preclinical markers. However, the specificity of symptom screens for RBD is not established, not all persons with PD develop RBD, and there are only limited ways to predict which RBD patients will develop PD. Other simple screens based upon autonomic symptoms, depression and personality changes, quantitative motor testing and other sleep disorders may also be useful markers, but have not been extensively tested. Other more expensive measures such as detailed autonomic testing, cardiac MIBG-scintigraphy, dopaminergic imaging and transcranial ultrasound may be especially useful in defining disease risk in those identified through primary screening.

Markers of neurodegeneration in idiopathic rapid eye movement sleep behaviour disorder and Parkinson's disease.

Idiopathic rapid eye movement sleep behaviour disorder is an important risk factor in the development of Parkinson's disease. Numerous potential predictive markers of Parkinson's disease may present before motor symptoms emerge, but testing of these markers in rapid eye movement sleep behaviour disorder has been performed only in small studies. There has been no comparison of markers between patients with idiopathic rapid eye movement sleep behaviour disorder and Parkinson's disease, and between men and women. We evaluated an array of potential Parkinson's disease predictive markers in 159 patients; including 68 with idiopathic rapid eye movement sleep behaviour disorder, 36 controls, 34 Parkinson's patients with rapid eye movement sleep behaviour disorder and 21 Parkinson's patients without rapid eye movement sleep behaviour disorder. Compared with controls, patients with idiopathic rapid eye movement sleep behaviour disorder demonstrated substantial olfactory loss (P < 0.001). Olfaction was more impaired in Parkinson's disease than idiopathic rapid eye movement sleep behaviour disorder and did not differ between Parkinson's patients with, or without, rapid eye movement sleep behaviour disorder. Numerous measures of motor function including the Unified Parkinson Disease Rating Scale alternate tap, Purdue Peg Board and Timed 'Up and Go' were impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.01). All of these motor measures were worse with Parkinson's disease than with idiopathic rapid eye movement sleep behaviour disorder, regardless of rapid eye movement sleep behaviour disorder status. Autonomic symptoms and systolic blood pressure drop were impaired in patients with idiopathic rapid eye movement sleep behaviour disorder compared with controls (P = 0.003). Orthostatic abnormalities in Parkinson's disease were found in the group with rapid eye movement sleep behaviour disorder (P < 0.001). However, Parkinson's patients without rapid eye movement sleep behaviour disorder were not different than controls and had less impairment than those with idiopathic rapid eye movement sleep behaviour disorder (P = 0.004) and Parkinson's patients with rapid eye movement sleep behaviour disorder (P < 0.001). Colour vision was impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.001). However, only Parkinson's patients with rapid eye movement sleep behaviour disorder had abnormalities significantly different than controls (P < 0.001), and there were significant differences between Parkinson's patients with or without rapid eye movement sleep behaviour disorder (P < 0.04). Idiopathic rapid eye movement sleep behaviour disorder patients had slightly increased harm avoidance scores on personality testing (P = 0.04). Other than slightly better performances among women in the Purdue Peg Board, there was no difference in any measure between men and women, suggesting similar pathogenic processes underlying rapid eye movement sleep behaviour disorder. Patients with idiopathic rapid eye movement sleep behaviour disorder demonstrate abnormalities in numerous potential markers of neurodegenerative disease--these markers are heterogeneous, generally correlate with each other and occur equally in men and women. Although these abnormalities are usually intermediate between control values and Parkinson's patients, autonomic dysfunction and colour vision appear to be more linked to rapid eye movement sleep behaviour disorder status than Parkinson's disease, suggesting a unique pathophysiology of these abnormalities.

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.

Parkinson's Disease Genetic Loci in Rapid Eye Movement Sleep Behavior Disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a prodromal condition for Parkinson's disease (PD) and other synucleinopathies, which often occurs many years before the onset of PD. We analyzed 261 RBD patients and 379 controls for nine PD-associated SNPs and examined their effects, first upon on RBD risk and second, on eventual progression to synucleinopathies in a prospective follow-up in a subset of patients. The SCARB2 rs6812193 (OR = 0.67, 95 % CI = 0.51-0.88, p = 0.004) and the MAPT rs12185268 (OR-0.43, 95 % CI-0.26-0.72, p = 0.001) were associated with RBD in different models. Kaplan-Meier survival analysis in a subset of RBD patients (n = 56), demonstrated that homozygous carriers of the USP25 rs2823357 SNP had progressed to synucleinopathies faster than others (log-rank p = 0.003, Breslow p = 0.005, Tarone-Ware p = 0.004). As a proof-of-concept study, these results suggest that RBD may be associated with at least a subset of PD-associated genes, and demonstrate that combining genetic and prodromal clinical data may help identifying individuals that are either more or less susceptible to develop synucleinopathies. More studies are necessary to replicate these results, and identify more genetic factors affecting progression from RBD to synucleinopathies.

Effects of the amyloid protein precursor of Alzheimer's disease and other ligands of the LDL receptor-related protein on neurite outgrowth from sympathetic neurons in culture.

The amyloid protein precursor (APP) of Alzheimer's disease can stimulate neurite outgrowth in vitro. The receptor responsible for this effect has not been identified. Kunitz protease inhibitor (KPI)-containing forms of APP bind to the low-density lipoprotein receptor-related protein (LRP). As LRP may regulate neurite outgrowth, we examined whether the effects of APP are mediated by LRP. Inhibitors of LRP decreased neurite outgrowth from chick sympathetic neurons. Most LRP ligands (alpha2-macroglobulin, lactoferrin, and lipoprotein lipase) stimulated outgrowth. However, in soluble form, the KPI-containing APP751 was a weak inhibitor of outgrowth. In substrate-bound form, both APP751 and APP695 (which does not bind to LRP) stimulated outgrowth. Thus the effect of substrate-bound APP on neurite outgrowth is not mediated by LRP.

Inhibition of neurite outgrowth from chick sympathetic neurons by cholinesterase inhibitors is not mediated by binding to cholinesterases.

Several studies have suggested a role for cholinesterases in regulating neurite outgrowth. Some acetylcholinesterase (AChE) inhibitors can inhibit neurite outgrowth, but it is unclear if this is due to inhibition of AChE. In this study, the effect of cholinesterase inhibitors on neurite outgrowth from chick sympathetic neurons was examined. Very high (micromolar) concentrations of tacrine and BW284c51 were needed to inhibit neurite outgrowth. In contrast, nanomolar concentrations were required to block cholinesterase activity. No correlation was found between the type of inhibitor or potency of cholinesterase inhibition and inhibition of neurite outgrowth. Both tacrine and BW284c51 were neurotoxic at concentrations that inhibited outgrowth. Therefore, the action of cholinesterase inhibitors on neurite outgrowth may be due to non-specific toxicity rather than to cholinesterase binding.

Restless legs syndrome outside the blood-brain barrier--exacerbation by domperidone in Parkinson's disease.

INTRODUCTION: Models of dopaminergic function in restless legs focus on central dopaminergic neurons. Domperidone, a peripheral dopamine blocker that cannot cross the blood-brain barrier, is commonly used in Parkinson's disease. After encountering a case of restless legs syndrome that dramatically worsened with domperidone, we assessed whether Parkinson's patients may have exacerbation of restless legs with domperidone. METHODS: From two Parkinson's disease cohorts, we assessed restless legs prevalence according to standard criteria, in patients taking vs. not taking domperidone. Regression analysis was performed, adjusting for age, sex, disease duration, UPDRS, dopaminergic medications and other medications. RESULTS: One hundred eighty four patients were assessed, of whom 46 (25%) had restless legs. Thirteen out of twenty seven (48%) patients on domperidone had restless legs compared to 33/157 (21%) without (p = 0.010). Other medications were not associated with restless legs. CONCLUSION: This unexpected finding suggests that dopaminergic neurons outside of the blood-brain barrier may be important in restless legs syndrome pathophysiology.

Doxepin and cognitive behavioural therapy for insomnia in patients with Parkinson's disease -- a randomized study.

INTRODUCTION: Although a variety of pharmacologic and non-pharmacologic treatments are effective for insomnia in the general population, insomnia in Parkinson's disease differs in important ways and may need different treatments. No studies have conclusively demonstrated effective insomnia treatments in Parkinson's disease. METHODS: We conducted a three-arm six-week randomized pilot study assessing non-pharmacologic treatment (cognitive behavioural therapy with bright light therapy) or doxepin (10 mg daily), compared to an inactive placebo in Parkinson's patients with insomnia. Sleep outcomes included insomnia scales, clinical global impression, sleep diaries and actigraphy. Secondary outcomes included motor severity, fatigue, depression and quality of life. RESULTS: 18 patients were randomized, 6 to each group. Compared to placebo, doxepin improved the Insomnia Severity Index (-9 ± 5.4 vs. -2 ± 3.9, p = 0.03), the SCOPA-night score (-5.2 ± 1.5 vs. -2.3 ± 2.8, p = 0.049), the Pittsburgh Sleep Quality Index-sleep disturbances subscale (-0.5 ± 0.5 vs 0.2 ± 0.4, p = 0.02), and both patient and examiner-rated clinical global impression of change (1.7 ± 0.8 vs. 0.5 ± 0.8, p = 0.03 and 1.4 ± 0.5 vs. 0.3 ± 0.5, p = 0.003). On secondary outcomes doxepin reduced the fatigue severity scale (p = 0.02) and improved scores on the Montreal Cognitive Assessment (p = 0.007). Non-pharmacological treatment reduced the Insomnia Severity Index (-7.8 ± 3.8 vs. -2.0 ± 3.9, p = 0.03), and the examiner-reported clinical global impression of change (p = 0.006), but was associated with decline in Parkinson Disease Questionnaire-39. There were no changes in other primary and secondary outcomes, including actigraphy outcomes. Adverse events were comparable in all groups. CONCLUSION: Doxepin and non-pharmacologic treatment substantially improved insomnia in Parkinson's disease. These potential benefits must be replicated in a full confirmatory randomized controlled trial.

Validation of the non-motor symptoms questionnaire (NMS-Quest).

BACKGROUND: Although non-motor manifestations of Parkinson's disease are common and can cause severe disability, they are often under-recognized, leading to missed treatment opportunities. Screening tools for non-motor symptoms are urgently needed. Recently a 30-item screening Non Motor Symptoms Questionnaire was developed. Although some psychometric properties have been evaluated, sensitivity and specificity of the questionnaire have not been systematically assessed. METHODS: Parkinson patients completed Non Motor Symptoms Questionnaire, then underwent a gold-standard clinical evaluation of non-motor symptoms and signs that included extensive standardized questionnaires, cognitive/behavioural assessment, and neurological examination to determine whether each manifestation was present or absent. The sensitivity and specificity of each non-motor symptom, in relation to the gold-standard were estimated. RESULTS: For the 70 participants, the mean age was 66.7+/-9.3, 64% were men, and disease duration was 3.8+/-2.8 years. From the gold-standard evaluation, the prevalence of non-motor manifestations ranged from 8.7% (hallucinations) to 78.3% (nocturia). The mean sensitivity of all Non Motor Symptoms was 63.4%. This varied considerably among different manifestations, ranging from 24% (sleepiness, hyposmia) to 100% (diplopia). By restricting analysis to clinically significant non-motor problems (i.e. those serious enough to warrant treatment), the mean sensitivity increased to 71.8%. The specificity for most items was high, with an overall mean specificity of 88.5%. CONCLUSIONS: For many non-motor manifestations Non Motor Symptoms Questionnaire is an effective screen; however, for manifestations such as somnolence, olfactory loss and apathy, sensitivity is suboptimal. Overall, this questionnaire can be a useful clinical tool for screening non-motor problems in an office setting.

Environmental risk factors for REM sleep behavior disorder: a multicenter case-control study.

OBJECTIVE: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. METHODS: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. RESULTS: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). CONCLUSIONS: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Severity of REM atonia loss in idiopathic REM sleep behavior disorder predicts Parkinson disease.

BACKGROUND: Over 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson disease (PD) or dementia. At present, there is no way to predict who will develop disease. Since polysomnography is performed in all patients with idiopathic RBD at diagnosis, there is an opportunity to analyze if baseline sleep variables predict eventual neurodegenerative disease. METHODS: In a longitudinally studied cohort of patients with idiopathic RBD, we identified those who had developed neurodegenerative disease. These patients were matched by age, sex, and follow-up duration to patients with RBD who remained disease-free and to controls. Polysomnographic variables at baseline (i.e., before development of neurodegenerative disease) were compared between groups. RESULTS: Twenty-six patients who developed neurodegenerative disease were included (PD 12, multiple system atrophy 1, dementia 13). The interval between polysomnogram and disease onset was 6.7 years, mean age was 69.5, and 81% were male. There were no differences between groups in sleep latency, sleep time, % stages 2-4, % REM sleep, or sleep efficiency. However, patients with idiopathic RBD who developed neurodegenerative disease had increased tonic chin EMG activity during REM sleep at baseline compared to those who remained disease-free (62.7 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.020). This effect was seen only in patients who developed PD (72.9 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.002), and not in those who developed dementia (54.3 +/- 10.3, p = 0.28). There was no difference in phasic submental REM EMG activity between groups. CONCLUSIONS: In patients with REM sleep behavior disorder initially free of neurodegenerative disease, the severity of REM atonia loss on baseline polysomnogram predicts the development of Parkinson disease.

Predicting Parkinson's disease - why, when, and how?

Parkinson's disease (PD) is a progressive disorder with a presymptomatic interval; that is, there is a period during which the pathologic process has begun, but motor signs required for the clinical diagnosis are absent. There is considerable interest in discovering markers to diagnose this preclinical stage. Current predictive marker development stems mainly from two principles; first, that pathologic processes occur in lower brainstem regions before substantia nigra involvement and second, that redundancy and compensatory responses cause symptoms to emerge only after advanced degeneration. Decreased olfaction has recently been demonstrated to predict PD in prospective pathologic studies, although the lead time may be relatively short and the positive predictive value and specificity are low. Screening patients for depression and personality changes, autonomic symptoms, subtle motor dysfunction on quantitative testing, sleepiness and insomnia are other potential simple markers. More invasive measures such as detailed autonomic testing, cardiac MIBG-scintigraphy, transcranial ultrasound, and dopaminergic functional imaging may be especially useful in those at high risk or for further defining risk in those identified through primary screening. Despite intriguing leads, direct testing of preclinical markers has been limited, mainly because there is no reliable way to identify preclinical disease. Idiopathic RBD is characterized by loss of normal atonia with REM sleep. Approximately 50% of affected individuals will develop PD or dementia within 10 years. This provides an unprecedented opportunity to test potential predictive markers before clinical disease onset. The results of marker testing in idiopathic RBD with its implications for disease prediction will be detailed.

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.

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.

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.