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.

[Sleepiness among adolescents: etiology and multiple consequences]. / La somnolence chez les adolescents: étiologie et conséquences multiples.

Over the past century a dramatic decline in sleep duration among adolescents, such as more than one hour of sleep loss per night, has been reported. A debt in sleep duration could lead to sleep deprivation, a major risk factor associated with daytime sleepiness. Sleepiness refers to the inability to maintain an adequate level of alertness during the day which may result in more or less being able to control falling asleep at inappropriate times. This literature review updates on sleepiness regarding its characteristics, etiology and consequences on adolescents. Studies revealed that from 25 % to 78 % of adolescents had reported sleepiness. Its manifestations may include heavy lids, yawns, difficulties to concentrate and emotional irritability. In addition, while it is recommended that adolescents under 18 years-old should sleep from eight to ten hours a night, only 63 % of them actually do so. The etiology of sleep deprivation and sleepiness in this population can be explained by various biological and societal factors. First, the sleep-wake cycle of adolescents shows a biological shift from the beginning of pubertal maturation, described as a perfect storm. It refers to a social jetlag by going to sleep and waking up later and accumulating a sleep debt during weekdays which they try to reimburse during weekends. This phenomenon can be explained by physiological changes such as a slower accumulation of sleep pressure. In addition to this perfect storm, environmental and societal factors contribute to the social jetlag and reduce sleep duration in adolescents. Screen exposure before bedtime can delay sleep and wake onset, which is a risk factor for sleeping debt. Substance use such as caffeine, cigarettes or electronic vaporizer, ADHD or freely available medication, alcohol, cannabis use or drug consumption could further disrupt sleep-wake cycle by stimulating, depressing or otherwise disrupting the central nervous system. Early, before 8:30 am, class start times have been associated with chronic sleep deprivation, higher level of sleepiness and delayed melatonin peak secretion. Adolescents working or doing extracurricular occupations for more than 20hours a week are more at risk for reduced sleep duration and sleepiness. Parental supervision about sleep during the weekdays were associated with more appropriate bedtime. Adolescents from low socio-demographic characteristics and from minority ethnic groups have reported displaying a shorter sleep duration. Finally, sleep disorders of a physiological origin such as narcolepsy, sleep apnea or restless legs syndrome, may explain the sleep deprivation and sleepiness. Sleep deprivation and sleepiness in adolescents have consequences on their health. Cognitive functioning, such as problem solving, attention or memory, as well as school performance, can be compromised by sleep deprivation and sleepiness. At the psychological level, adolescents reporting sleepiness are more prone to display mental health problems: associations were found between sleepiness and subjective perception of depression, anxiety, somatic complaints as well as with antisocial behaviors. Finally, 68 % of 16 year-old adolescents reported they drove a car, and the reported sleepiness could lead to road accidents due to reduced attentional functioning, reaction time and decision-making abilities. In the United-States, from 7 % to 16.5 % of deadly accidents were related to driving while drowsy. Highlighting etiology and problems associated with sleep deprivation and sleepiness in adolescents could guide researchers and clinicians towards the development of possible interventions. Public health measures and knowledge transfer programs regarding modifiable psychosocial and societal factors associated with sleep-wake bioregulation could increase awareness in parents as well as in political and societal decision makers.

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.

Cognitive impairment in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterised by repetitive cessation or reduction of airflow due to upper airway obstructions. These respiratory events lead to chronic sleep fragmentation and intermittent hypoxemia. Several studies have shown that OSA is associated with daytime sleepiness and cognitive dysfunctions, characterized by impairments of attention, episodic memory, working memory, and executive functions. This paper reviews the cognitive profile of adults with OSA and discusses the relative role of altered sleep and hypoxemia in the aetiology of these cognitive deficits. Markers of cognitive dysfunctions such as those measured with waking electroencephalography and neuroimaging are also presented. The effects of continuous positive airway pressure (CPAP) on cognitive functioning and the possibility of permanent brain damage associated with OSA are also discussed. Finally, this paper reviews the evidence suggesting that OSA is a risk factor for developing mild cognitive impairment and dementia in the aging population and stresses the importance of its early diagnosis and treatment.

Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

OBJECTIVES: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

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.

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.

Effects of melatonin and bright light administration on motor and sensory symptoms of RLS.

BACKGROUND: A close temporal relationship was shown between the onset of melatonin secretion at night and the worsening of restless legs syndrome (RLS) symptoms, suggesting that melatonin may play a role in the genesis of this phenomenon. To test this hypothesis we studied the effects of the administration of exogenous melatonin and, conversely, the suppression of endogenous melatonin secretion by bright light exposure on the severity of RLS symptoms. METHODS: Eight RLS subjects were studied in three conditions: at baseline, after administration of melatonin and during bright light exposure. The severity of RLS symptoms was assessed by the suggested immobilization test (SIT), which allows quantification of both sensory and motor manifestations (SIT-PLM) of RLS. RESULTS: Analyses showed a significant increase of SIT-PLM index when subjects received exogenous melatonin compared to both baseline and bright light conditions, but bright light exposure had no effect on leg movements compared to the baseline condition. Analyses also revealed a small but significant decrease in sensory symptoms with bright light exposure compared to baseline. CONCLUSION: Exogenous melatonin may have a detrimental effect on motor symptoms, and bright light exposure produced small but significant improvement of leg discomfort. The study shows the interest of using the SIT to measure outcome of intervention in RLS. Further studies will be needed to assess the therapeutic value of bright light in RLS.

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.

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.

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.

Neurobiology of sleep disturbances in neurodegenerative disorders.

This review presents sleep disturbances and their underlying pathophysiology in three categories of neurodegenerative disorders namely tauopathies, synucleinopathies, and Huntington's disease (HD) and prion-related diseases. Sleep abnormalities are a major and early feature of neurodegenerative disorders, especially for synucleinopathies, HD and prion-related diseases, in which the sleep-related brainstem regions are severely altered and impaired sooner than in most of the tauopathies. In synucleinopathies, HD and prion-related diseases, specific sleep disturbances, different from those observed in tauopathies, are considered as core manifestations of the disease and in some cases, as preclinical signs. For this reason, the evaluation of sleep components in these neurodegenerative disorders may be useful to make a diagnosis and to assess the efficacy of pharmacotherapy. Since sleep disruption may occur early in the course of neurodegeneration, sleep disturbance may serve as groundwork to study the efficacy of neuroprotective agents to prevent or delay the development of a full-blown neurodegenerative disorder. The cause of sleep disturbances in neurodegenerative disorders may be attributed to several factors, including age-related modifications, symptoms of the disease, comorbid conditions and the neurodegenerative process itself.

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.

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.

Effects of obstructive sleep apnea on cognitive function: a comparison between younger and older OSAS patients.

BACKGROUND AND PURPOSE: Patients with obstructive sleep apnea syndrome (OSAS) present cognitive deficits similar to those observed with aging. The aim of the study was to assess the effects of age on cognitive functions in OSAS patients. It was hypothesized that older OSAS patients will exhibit significant cognitive dysfunction relative to younger OSAS patients and controls. PATIENTS AND METHODS: Younger and older OSAS patients were compared to younger and older control subjects (age cut-off set at 50 yrs). Participants underwent a polysomnographic (PSG) and neuropsychological evaluation. Variables were analyzed by two-way analyses of variance (ANOVAs) with two factors: Group (control and OSAS) and Age (younger and older). Additionally, we evaluated the contribution of attentional deficits to cognitive dysfunction for each subgroup of patients by using Spearman correlation coefficients. RESULTS: No Group-by-Age interaction was found for any neuropsychological variables (p<0.05). However, main Group and Age effects were found. Correlations indicated that attentional deficits contributed importantly to a poorer cognitive performance in younger OSAS patients only (p<0.01). CONCLUSIONS: Our results are in agreement with those of the literature for both OSAS-related and aging-related cognitive deficits but did not demonstrate that age interacts with the effects of the OSAS condition to make those cognitive deficits worse.

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.

The effect of gender on autonomic and respiratory responses during sleep among both young and middle-aged subjects.

BACKGROUND AND OBJECTIVES: Sleep affects the control of circulation and respiratory function. Gender and age are also known to have a profound impact on the neural control of circulation. We investigated whether gender affects sleep-related cardiovascular and respiratory responses and whether these vary according to healthy subjects being young or middle-aged. METHODS: We studied 32 subjects: 8 women and 8 men aged 20-30 years (young), and 8 women and 8 men aged 50-60 years (middle-aged). Young women were under oral contraceptive therapy and middle-aged women were postmenopausal and not receiving hormonal replacement therapy. One-night polysomnography was used to assess RR variability during non-rapid eye movement (NREM) (stage 2) and rapid eye movement (REM) sleep. Low-frequency (LF) and high-frequency (HF) components, in normalized units (LFnu and HFnu) and LF/HF ratio were calculated on five-minute segments selected across the night and averaged for each sleep stage. The respiration frequency in NREM and REM sleep was also measured. Interaction between gender, age and sleep on autonomic and respiration variables was assessed by 2 x 2 x 2 analysis of variance (ANOVA). RESULTS: Compared to men, women had a greater NREM-to-REM increment in LFnu (gender-by-state interaction, p<0.01), a greater decrement in HFnu (interaction, p<0.01) and a greater increment in LF/HF (interaction, p<0.05). Women also showed a more pronounced increase in respiratory frequency during REM sleep compared to men in both groups of age (gender-by-state interaction, F=7.1, p<0.05). No gender-by-age-by-state interaction was observed to affect autonomic and respiration variables. CONCLUSION: NREM-to-REM excitatory cardiac and respiratory responses are more marked among women compared to men, regardless of their hormonal status and whether they are young or middle-aged.