Michel Panisset

REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease

Objective To determine the frequency of REM sleep behavior disorder (RBD) among patients with PD using both history and polysomnography (PSG) recordings and to further study REM sleep muscle atonia in PD. Background The reported occurrence of RBD in PD varies from 15 to 47%. However, no study has estimated the frequency of RBD using PSG recordings or analyzed in detail the characteristics of REM sleep muscle atonia in a large group of unselected patients with PD. Methods Consecutive patients with PD (n = 33) and healthy control subjects (n = 16) were studied. Each subject underwent a structured clinical interview and PSG recording. REM sleep was scored using a method that allows the scoring of REM sleep without atonia. Results One third of patients with PD met the diagnostic criteria of RBD based on PSG recordings. Only one half of these cases would have been detected by history. Nineteen (58%) of 33 patients with PD but only 1 of 16 control subjects had REM sleep without atonia. Of these 19 patients with PD, 8 (42%) did not present with behavioral manifestations of RBD, and their cases may represent preclinical forms of RBD associated with PD. Moreover, the percentage of time spent with muscle atonia during REM sleep was lower among patients with PD than among healthy control subjects (60.1% vs 93.2%;p = 0.003). ConclusionsRBD and REM sleep without atonia are frequent in PD as shown by PSG recordings.

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.

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.

Significant Linkage of Parkinson Disease to Chromosome 2q36-37

Parkinson disease (PD) is the second most common neurodegenerative disorder, surpassed in frequency only by Alzheimer disease. Elsewhere we have reported linkage to chromosome 2q in a sample of sibling pairs with PD. We have now expanded our sample to include 150 families meeting our strictest diagnostic definition of verified PD. To further delineate the chromosome 2q linkage, we have performed analyses using only those pedigrees with the strongest family history of PD. Linkage analyses in this subset of 65 pedigrees generated a LOD score of 5.1, which was obtained using an autosomal dominant model of disease transmission. This result strongly suggests that variation in a gene on chromosome 2q36-37 contributes to PD susceptibility.

Salivary production in Parkinson's disease

Hypersialorrhea is a common phenomenon in Parkinson disease (PD). The objective of this study was to determine whether patients with PD had an abnormally increased production of saliva and whether the production of saliva could be associated to factors related to either the disease characteristics or to its treatment. A total of 83 patients with PD and 55 control subjects participated in this study. Because of the age difference between the two groups, comparisons were made on a ±2‐year age‐matched sample of 44 PD patients and 44 control subjects. PD patients produced significantly less saliva than control subjects. Correlations were obtained with the 83 PD patients between unstimulated salivary flow and patients characteristics. When controlling for age, sex, and Hoehn and Yahr scale, decreased production of saliva correlated significantly with the dose of levodopa and the symptoms of xerostomia. When controlling for medications, there was no relationship between the production of saliva and the evolution of the disease. This study shows that patients with PD produce less saliva than normal. Factors influencing the production of saliva include the use of levodopa and female gender. Our results may have implications for the treatment of drooling in PD.

Exome Sequencing Identifies FUS Mutations as a Cause of Essential Tremor

Essential tremor (ET) is a common neurodegenerative disorder that is characterized by a postural or motion tremor. Despite a strong genetic basis, a gene with rare pathogenic mutations that cause ET has not yet been reported. We used exome sequencing to implement a simple approach to control for misdiagnosis of ET, as well as phenocopies involving sporadic and senile ET cases. We studied a large ET-affected family and identified a FUS p.Gln290(∗) mutation as the cause of ET in this family. Further screening of 270 ET cases identified two additional rare missense FUS variants. Functional considerations suggest that the pathogenic effects of ET-specific FUS mutations are different from the effects observed when FUS is mutated in amyotrophic lateral sclerosis cases; we have shown that the ET FUS nonsense mutation is degraded by the nonsense-mediated-decay pathway, whereas amyotrophic lateral sclerosis FUS mutant transcripts are not.

Levodopa improves motor function without impairing cognition in mild non-demented Parkinson's disease patients

Objective: The objective of the study was to determine the effects of short-term levodopa administration on motor, cognitive, and psychiatric aspects of Parkinsons disease (PD). Background: The effects of levodopa on mental processes in PD are controversial. Opinions range from the claim that levodopa improves cognition to the opposite view that levodopa causes or exacerbates dementia, delusions, and hallucinations. Of the 800 idiopathic PD patients enrolled in the original DATATOP study, 387 reached the end point of functional disabilities sufficiently severe to require levodopa treatment. There were 263 men and 124 women who were comparable with regard to age, symptom duration of PD, and measures of PD severity. We compared test scores on motor performance, cognitive function, and psychiatric status before levodopa and again within 6 months after initiation of levodopa therapy. Results: Levodopa administration improved all motor functions significantly. The improvement was significantly greater in women than in men. Levodopa administration did not worsen scores on any cognitive tests, and there were quantitatively small but significant improvements in tests of frontal lobe function. Levodopa exerted only minor effects on psychiatric measures. There were small but significant decreases in scores for depression, and increases in vivid dreams and hallucinations. Conclusions: Levodopa administration for up to 6 months in dosages sufficient to improve motor function has only small effects on cognitive function and psychiatric status in mild to moderate PD patients. We conclude that motor symptoms in early PD, which result from dopamine depletion, are dissociable from cognitive functions and psychiatric status, which may be more dependent on nondopaminergic mechanisms.

Double-blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson's disease†‡

We performed a 39‐week, randomized, double‐blind, multicenter study to compare the efficacy, safety, and tolerability of levodopa/carbidopa/entacapone (LCE, Stalevo) with levodopa/carbidopa (LC, Sinemet IR) in patients with early Parkinsons disease (PD). Four hundred twenty‐three patients with early PD warranting levodopa were randomly assigned to treatment with LCE 100/25/200 or LC 100/25 three‐times daily. The adjusted mean difference in total Unified Parkinsons disease Rating Scale (UPDRS) Parts II and III between groups using the analysis of covariance model (prespecified primary outcome measure) was 1.7 (standard error = 0.84) points favoring LCE (P = 0.045). Significantly greater improvement with LCE compared with LC was also observed in UPDRS Part II activities of daily living (ADL) scores (P = 0.025), Schwab and England ADL scores (blinded rater, P = 0.003; subject, P = 0.006) and subject‐reported Clinical Global Impression (CGI) scores (P = 0.047). There was no significant difference in UPDRS Part III or investigator‐rated CGI scores. Wearing‐off was observed in 29 (13.9%) subjects in the LCE group and 43 (20.0%) in the LC group (P = 0.099). Dyskinesia was observed in 11 (5.3%) subjects in the LCE group and 16 (7.4%) in the LC group (P = 0.367). Nausea and diarrhea were reported more frequently in the LCE group. LCE provided greater symptomatic benefit than LC and did not increase motor complications.

Sleep and quantitative EEG in patients with progressive supranuclear palsy

Sleep architecture and quantitative EEG from wakefulness and REM sleep were studied in six patients (mean age, 70.5 years) with progressive supranuclear palsy (PSP) and compared with that of six control subjects (mean age, 69.8 years). Particular attention was given to quantifying REM sleep variables because of the known PSP-associated degeneration of the pedunculopontine tegmentum (PPT)-a critical structure in REM sleep generation. Patients with PSP had a shorter total sleep time, a lower sleep efficiency, a drastic reduction in sleep spindles, an atonic slow-wave sleep, and a lower percentage of REM sleep. The lower percentage of REM sleep was the result of both a reduction in the number of REM periods and a reduction in mean period of duration. REM density was also reduced while REM efficiency, atonia, and phasic EMG were similar to control values. REM sleep findings are consistent with the known role of the PPT in REM sleep induction. A slowing of the awake EEG was found for the six frontal leads and for C4, P4, and T4 in PSP patients. The frontal EEG slowing found in wakefulness is in accord with imaging and neuropsychological studies showing impairment of the frontal lobes in these patients. REM sleep EEG was not significantly slower in any regions. Because all previous studies on PSP have relied on visual inspection of the EEG tracings, the present finding of EEG slowing in the frontal lobes (rather than in the temporal regions or diffusely) suggests that our quantitative EEG approach may be more useful in determining specific regions of impaired cortical activity.