Clinical and dopaminergic imaging characteristics of the FARPRESTO cohort of trial-ready idiopathic rapid eye movement sleep behavior patients.

INTRODUCTION: Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects. METHODS: Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios. RESULTS: 365 patients were enrolled, and 289 patients with follow-up (age 67.7 ± 7.3 years, 237 males, mean follow-up 40 ± 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project. CONCLUSIONS: Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization.

Twenty-four-hour blood pressure profile in idiopathic REM sleep behavior disorder.

STUDY OBJECTIVES: To determine whether autonomic dysfunction in idiopathic REM sleep behavior disorder (iRBD) affects circadian blood pressure (BP) profile. METHODS: Twenty-one iRBD (mean age 68.8 ± 6.4, mean age at onset 62.2 ± 9.3), 21 drug-free de novo Parkinson's disease (PD) and 21 control participants (HCs), comparable for age and sex, underwent 24-h ambulatory BP monitoring. A prospective follow-up study was performed to evaluate the occurrence of neurodegenerative disorders in the iRBD cohort. RESULTS: In the iRBD group, nighttime systolic BP (SBP) was higher (124.0 ± 20.0, p = .026), nocturnal BP decrease lower (4.0 ± 8.7% for SBP and 8.7 ± 8.0% for diastolic BP [DBP], p = .001), and nondipping status more frequent (71.4% for SBP and 52.4% for DBP; p = .001 and p = .01, respectively) than in the HCs. Reverse dipping of SBP was found in 23.8% (p = .048) of the iRBD participants. Nondipping status was not associated with differences in gender, age, disease duration, age at disease onset, UPDRS score, presence of antihypertensive therapy, or polysomnographic measures. Patients with PD showed daytime and nighttime BP profiles comparable to those observed in iRBD. A subgroup analysis considering only the participants without antihypertensive therapy (12 iRBD, 12 PD) showed results superimposable on those of the whole iRBD and PD groups. Longitudinal follow-up (mean 5.1 ± 1.9 years) showed no differences in BP profile at baseline between converters (n = 6) and nonconverters. CONCLUSIONS: Twenty-four-hour BP control was impaired in iRBD. This impairment, similar to patterns observed in de novo PD, consisted of reduced amplitude of nocturnal dipping and increased frequency of nondipping status. These findings could have implications for cardiovascular morbidity and mortality in iRBD.

Neurophysiological evaluation of visual function in iRBD: potential role in stratifying RBD conversion risk.

STUDY OBJECTIVES: To evaluate neurophysiological alterations of visual function in idiopathic REM sleep Behavior Disorder (iRBD) both as markers and predictors of neurodegenerative disorders. METHODS: In a longitudinal follow-up study of 46 consecutive iRBD patients (follow-up duration 8.4 ± 3.4 years), the baseline parameters in luminance-contrast pattern (VEPp), red-green color (VEPc) and motion-onset (VEPm) Visual Evoked Potentials in iRBD were compared to early (ePD) and advanced (aPD) Parkinson's Disease subjects. Parameters of latency and amplitude of iRBD converters to neurodegenerative disease were compared with those of the non-converters. RESULTS: The VEP P100 mean latency values for both eyes and for both stimulation checks (30' and 15') were significantly longer in all the three groups of patients as compared to controls; moreover latencies were longer in aPD than in the iRBD group who did not differ from the ePD group. The same held true when we analyzed the number of abnormal subjects belonging to each diagnostic group with a higher number of abnormal subjects in the aPD group compared to both the ePD and in iRBD groups. Chromatic and motion potentials were not different from controls and did not differ in the 3 diagnostic groups. The iRBD subjects who converted to a neurodegenerative disorder showed longer P100 latencies and a higher occurrence of VEPp abnormalities than those who did not convert. Again chromatic and motion VEPs were not different depending on conversion. CONCLUSIONS: In iRBD patients the detection of an abnormal VEPp should be considered as a red flag for possible synnucleinopathy, eventually contributing in stratifying the risk of phenoconversion.

NREM sleep arousal-related disorders reflect cognitive impairment in Parkinson's disease.

BACKGROUND: Sleep disorders and cognitive impairment are frequently reported in Parkinson's disease (PD) as non-motor disabling symptoms. While it is known that REM sleep Behaviour Disorder (RBD) in PD is associated with motor and cognitive decline, little is known about the neurobiological significance of NREM sleep arousal-related disorders. OBJECTIVES: to evaluate the cognitive and clinical correlates of arousal-related disorders in PD. METHODS: Clinical data and video-polysomnography were analysed from one hundred-seventy consecutive subjects with PD. Based on the neuropsychological assessment, the subjects were divided into three groups: no cognitive impairment (PD; n = 58), mild cognitive impairment (PD-MCI; n = 58) and overt dementia (PDD; n = 54). RESULTS: Arousal-related disorders by history were reported in 32.9% of the subjects: 10.3% PD, 31.6% PD-MCI and 59.3% PDD (p = 0.001). Video-PSG captured arousal-related disorders in 1.7% PD, 21.2% MCI-PD and 35.6% PDD (p = 0.001). Arousal-related disorders and RBD were recorded in the same night in 7.7% PD, 9.8% MCI-PD and 15.6% PDD (p = 0.04). Patients with arousal-related disorders captured at V-PSG have a longer disease duration (p = 0.003), higher UPDRS score (p = 0.039), longer duration of treatment with levodopa (p = 0.017) and dopamine agonists (p = 0.018), worse H&Y staging (p = 0.001), lower MMSE score (p = 0.019) and more frequently hallucinations (p = 0.004). In multivariate analysis, cognitive impairment significantly increases the risk of arousal-related disorders (OR 3.387-95% CI 1.395-8.220, p = 0.007). CONCLUSION: Arousal-related disorders appear to be a marker of cognitive decline in PD. Recognizing arousal-related disorders should make clinicians aware of a possible cognitive decline in PD and eventually modify the therapeutic approach.

Assessment of cognitive profile as a prodromal marker of the evolution of rapid eye movement sleep behavior disorder.

STUDY OBJECTIVES: To search for a specific neuropsychological profile in idiopathic REM sleep behavior disorder (iRBD), able to predict the onset of neurodegenerative disorders. METHODS: In a longitudinal follow-up study of 63 consecutive iRBD patients (follow-up duration 6.7 ± 3.8 years), the baseline cognitive profile of converters to neurodegenerative disease was compared with that of the nonconverters. Five cognitive domains were assessed: memory, attention-working memory, executive functions, visuospatial abilities, language. Mild cognitive impairment (MCI) was diagnosed according to the Movement Disorder Society's diagnostic criteria for Parkinson's disease. RESULTS: 30 subjects (47.6%) developed a neurodegenerative disease (latency to conversion 60.33 ± 44.81 months). MCI was found in 50% of the converters and 12% of the nonconverters (p = .001), and its presence conferred a neurodegenerative disease risk of 10% at 3 years, 36% at 5 years, and 73% at 10 years (p = .002). Pathological equivalent scores on at least one neuropsychological test were detected in 46.7% of the converters versus 21.2% of the nonconverters in the memory domain (p = .032), in 40.0% versus 6.1% in that of executive functions (p = .002), and in 20.0% versus 3% in the visuospatial abilities domain (p = .047). On multivariate analysis, impaired executive functions significantly correlated with phenoconversion (p = .018). Lower Mini Mental State Examination (MMSE) scores (p = .004) and memory deficits (p = .031) were found in patients who developed dementia first. CONCLUSIONS: Cognitive profile is useful for stratifying risk of phenoconversion in patients with iRBD. The presence of MCI and impaired executive functions, memory, and visuospatial abilities discriminated the converters. Lower MMSE scores and memory deficits may characterize those subjects who first develop dementia.

Treating sleep apnea in Parkinson's disease with C-PAP: feasibility concerns and effects on cognition and alertness.

BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in Parkinson disease (PD) and is known to contribute to cognitive impairment and daytime sleepiness. We investigated feasibility of continuous positive airway pressure treatment (CPAP) and its effects on subjective daytime sleepiness and cognitive profile in PD plus OSA subjects in a longitudinal three months follow up study. METHODS: Seventy (age 71.7 ± 7.6, disease duration 9.9 ± 12.3, UPDRS-III 33.7 ± 12.5, MMSE 25.3 ± 3.6; years of education 7.7 ± 3.2) out of 228 consecutive PD patients undergoing in-lab video-polysomnography were found to have obstructive sleep apnea. Thirty-six subjects accepted to titrate therapeutic CPAP. Video-polysomnography, neuropsychological battery evaluating different cognitive domains and subjective scales for daytime sleepiness were scheduled at baseline and after three months. All the patients were given educational informations relative to diagnosis of OSA and benefits of OSA treatment, and an individualized training with CPAP. RESULTS: Twenty-seven (75%) subjects dropped out of the study due to CPAP intolerance. No demographic or disease-related variables (in particular, severity of OSA), could be found between subjects who completed the study versus those who dropped out. Nine subjects completed the three-month follow up, and there were no significant changes in subjective sleepiness, neuropsychological scores and sleep structure (except for reduction in apnea/hypopnea index and a trend toward increase in stage N3 sleep). CONCLUSION: Our data show that feasibility of CPAP treatment can be significantly threatened by overall attrition rates. Further studies should consider well-structured adherence promoting interventions. The actual role of OSA as a determinant of the profile of subjective daytime sleepiness and cognition in PD, and the effects of CPAP in PD need to be further studied.

Interictal spiking in adult newly-diagnosed focal epilepsy of unknown cause: The effect of age.

OBJECTIVE: To assess the yield of interictal EEG spiking in standard and whole-night sleep EEGs in elderly subjects with recent-onset focal seizures compared to younger patients. METHODS: Detection of interictal epileptiform abnormalities (IEAs) and rating of mean spike index (number of interictal discharges/minute) values for different sleep stages (NREM stages 1-2 and 3-4 and REM sleep) in standard EEG (S-EEG) and 24-h ambulatory EEG (A-EEG) at first referral in three groups of thirty consecutive outpatients [aged 20-39 (young), 40-59 (adults) and ⩾60years (elderly)], retrospectively selected according to a subsequent diagnosis of focal epilepsy of unknown cause, no sleep disorders or drugs or comorbidities affecting sleep and EEG. RESULTS: Elderly subjects showed a lower rate of IEAs on S-EEG (p<0.01) but a higher propensity for spiking during deep NREM sleep, 11/30 showing IEAs exclusively during stages 3-4. Mean spike index showed a significant increase in IEAs between sleep stages 1-2 and 3-4 in the elderly subjects (p<0.001). CONCLUSIONS: A significant association emerged between IEAs during deep sleep and age (p<0.001). SIGNIFICANCE: EEG recordings covering deep NREM sleep should be recommended when IEAs detection is needed to support a diagnosis of epilepsy in elderly subjects.

Choking in the night due to NFLE seizures in a patient with comorbid OSA.

Awakenings from sleep with gasping and feeling of choking can be due to nocturnal frontal lobe epilepsy (NFLE) as well as sleep apnea (OSA). We describe the case of an overweight man, referred to us with suspected OSA and reporting awakenings from sleep accompanied by gasping and a choking feeling, which proved to be, after investigation, NFLE seizures in a patient with comorbid OSA. We underline that gasping or choking on awakening, especially when accompanied by abnormal motor-behavioral manifestations, should be interpreted with caution. Careful investigation by means of video-polysomnography is warranted in selected cases, including patients with a strong clinical suspicion of sleep apnea.

Sleep disorders and acute nocturnal delirium in the elderly: a comorbidity not to be overlooked.

Delirium is a disturbance of consciousness and cognition that results in a confusional state. It tends to fluctuate in intensity and is often observed in older patients. Sleep is a window of vulnerability for the occurrence of delirium and sleep disorders can play a role in its appearance. In particular, delirious episodes have been associated with obstructive sleep apnoea syndrome, which is reported to be frequent in the elderly. Hereby, we present a case-report documenting the sudden onset of a confusional state triggered by obstructive sleep apnoea-induced arousal, together with a review of the literature on the topic. We emphasise that, among the many pathogenic factors implicated in delirium, it is worth considering the possible link between nocturnal delirium and the occurrence of impaired arousals. Indeed, the complex confusional manifestations of delirium could be due, in part, to persistence of dysfunctional sleep activity resulting in an inability to sustain full arousal during behavioural wakefulness. Arousals can be triggered by sleep disturbances or other medical conditions. Clinicians should be aware that older patients may present disordered sleep patterns, and make investigation of sleep patterns and disorders potentially affecting sleep continuity a key part of their clinical workup, especially in the presence of cognitive comorbidities. Correct diagnosis and optimal treatment of sleep disorders and disrupted sleep can have a significant impact in the elderly, improving sleep quality and reducing the occurrence of abnormal sleep-related behaviours.

Cognitive performances and mild cognitive impairment in idiopathic rapid eye movement sleep behavior disorder: results of a longitudinal follow-up study.

STUDY OBJECTIVES: To investigate the capacity of neuropsychological deficits in idiopathic rapid eye movement sleep behavior disorder (iRBD) to predict the development of dementia and/or parkinsonism. DESIGN: Prospective longitudinal follow-up study. SETTING: Tertiary sleep center. PATIENTS: Twenty patients with initial iRBD (19 males, mean age 66.1 ± 7.1) underwent a clinical and neuropsychological follow-up within a mean of 43 ± 19 months. Neuropsychological performances at baseline were compared with those of healthy controls matched for sex, age, and education. INTERVENTIONS: Discontinuation of clonazepam at least 7 days before the follow-up evaluation. RESULTS: At follow-up, the Wilcoxon test showed a significant worsening of scores on Raven Colored Matrices 47 (P = 0.01), Attentive matrices (P = 0.002), phonemic (P = 0.04) and sematic (P = 0.04) fluency. Thirteen patients (65%) showed cognitive deterioration involving multiple domains. Of these, four patients (20%) maintained a stable cognitive dysfunction and nine (45%) showed a progression of cognitive dysfunction: six (30%) in constructional abilities (P = 0.03), four (20%) in short-term memory (P = NS), three (15%) in executive functions and non-verbal logic (P = NS), one (5%) in verbal fluency (P = NS), and one (5%) in long-term memory (P = NS) (McNemar test). Seven patients (35%) retained a normal cognitive profile. Mild cognitive impairment (MCI) was diagnosed at baseline in seven patients (35%). At follow-up, three of these patients showed overt dementia that was accompanied by parkinsonism in all cases; one had worsened from non-amnesic single-domain to nonamnesic multiple-domain MCI, two were stable, and one patient no longer met the criteria for MCI. Four patients (20%) without MCI at baseline had MCI at follow-up. Patients who developed MCI/dementia had an older age at disease onset (65.8 ± 5.4 versus 56.8 ± 9.3; P = 0.01) compared with those who did not. CONCLUSIONS: Our findings corroborate evidence that visuospatial abilities constitute the area most affected in idiopathic rapid eye movement sleep behavior disorder (learning as a stable deficit and copying as an evolving deficit). Cognitive deterioration, involving mainly nonverbal logic, attention, and executive functions, can be observed in rapid eye movement sleep behavior disorder follow-up, suggesting an underlying evolving degenerative process. Our data confirm that mild cognitive impairment is frequent in idiopathic rapid eye movement sleep behavior disorder. The presence of mild cognitive impairment predicts the eventual risk of developing dementia, which seemed to be associated with parkinsonism.

Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies.

Knowledge of sleep architecture and disorders of nocturnal sleep in dementia with Lewy bodies (DLB) is limited by a lack of systematic video-polysomnographic (video-PSG) investigations. We describe video-PSG findings in 29 consecutive subjects diagnosed with DLB. All the patients underwent a clinical interview and overnight video-PSG monitoring. Twenty-nine nondemented patients with Parkinson's disease (PD) matched for age and sex with the DLB cases were selected for comparison. The DLB subjects showed less 1NREM sleep (P = .000) and more 2NREM sleep (P = .000) than the PD subjects. Sleep apnea (30.7% vs. 34.8%) and periodic limb movements (60.9% versus 50.0%) were frequent in both groups. Disruptive motor behavioral manifestations were more frequent in subjects with DLB (69.6% vs. 26.9%, P = .008) and consisted of not only REM sleep behavior disorder (RBD) but also confusional events (30.3% vs. 3.8%, P = .020) and arousal-related episodes mimicking RBD. Subjects with DLB in whom a sleep disturbance had been the presenting symptom performed better than those with other onset symptoms on both the Mini-Mental State Examination (22.2 ± 4.1 vs. 18.1 ± 4.6, P = .019) and the Frontal Assessment Battery (15.8 vs. 10.3, P = .010). Polysomnographic findings in DLB show a complex mix of overlapping sleep alterations: impaired sleep structure, sleep comorbidities, and various motor-behavioral events (not restricted to RBD). Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities, and consider performing polysomnographic sleep investigations in selected cases. We found evidence that a sleep disturbance as the presenting symptom might indicate a different phenotype of the disease, characterized by milder cognitive impairment.

Dissociated local arousal states underlying essential clinical features of non-rapid eye movement arousal parasomnia: an intracerebral stereo-electroencephalographic study.

Sleep has been shown to be a global phenomenon in which the presence of local processes of both activation and deactivation are finely orchestrated. Dysfunctional and independent action of the systems involved in non-rapid eye movement (NREM) sleep and wakefulness is deemed to be at the basis of arousal parasomnias. We show, in a patient with confusional arousals, persistence of sleep in the hippocampal and frontal associative cortices in contrast to the presence of awakening in the motor, cingulate, insular, amygdalar and temporopolar cortices. The clinical features of the confusional arousals in this patient are highly consistent with a dysfunctional coexistence of local cortical arousal and local cortical sleep.

Episodic cluster headache: NREM prevalence of nocturnal attacks. Time to look beyond macrostructural analysis?

BACKGROUND: A high prevalence of nocturnal sleep-related attacks is reported in patients with cluster headache (CH). Episodic CH is considered closely related to rapid eye movement (REM) sleep. OBJECTIVE: The aim of this study was to analyze the relationships between episodic CH attacks and sleep macrostructure. METHODS: Data were obtained by means of 24-hour continuous ambulatory polysomnography (PSG) capturing CH attacks in 4 out of 7 episodic CH patients (all males; mean age 38.4 +/- 9.2 years) studied. RESULTS: Eight CH attacks were captured during the PSG monitoring; 5 arose from sleep: 4 from non-rapid eye movement (NREM) sleep (stage 2 NREM), and 1 from REM sleep. One patient experienced CH attacks during both NREM and REM sleep in the same night. CONCLUSIONS: In the light of previous literature findings, the prevalence of NREM-related episodic CH attacks observed, and the finding of attacks arising during both REM and NREM sleep in the same subject, suggest that the relationship between CH and sleep stages is heterogeneous, and the existence of a specific macrostructural pattern associated with episodic CH attacks appears to be uncertain. A more comprehensive approach taking into account the microstructure of NREM and REM sleep is expected to provide more in depth information about the pathophysiology of CH, whose complexity might overcome the simplistic dichotomy of REM/NREM staging.

Evidence of dissociated arousal states during NREM parasomnia from an intracerebral neurophysiological study.

STUDY OBJECTIVES: Arousal parasomnias are expressions of sleep/ wake state dissociations in which wakefulness and NREM sleep seem to coexist. We describe the results of a neurophysiological (intracerebral EEG) investigation that captured an episode of confusional arousal. DESIGN: Observational analysis. SETTING: Tertiary sleep center. SUBJECT: A 20-year-old male with refractory focal epilepsy. MEASUREMENTS AND RESULTS: The intracerebral EEG findings documented the presence of a local arousal of the motor and cingulate cortices associated with increased delta activity in the frontoparietal associative cortices; these findings were noted preceding the onset and persisting throughout the episode. CONCLUSIONS: The presence of dissociated sleep/wake states in confusional arousals is the expression not of a global phenomenon, but rather of the coexistence of different local states of being: arousal of the motor and cingulate cortices and inhibition of the associative ones. Whether this is an exclusive feature of NREM parasomnias, or a common substrate on which other triggering elements act, needs to be clarified.

Cognitive performance in REM sleep behaviour disorder: a possible early marker of neurodegenerative disease?

BACKGROUND: Rapid eye movement [REM] sleep behaviour disorder (RBD) may herald neurodegenerative diseases. Neurobiological deficits similar to those identified in neurodegenerative diseases have been reported in idiopathic RBD. Researchers are looking for early markers supporting a possible role of RBD as a harbinger of impending neurodegenerative disease. OBJECTIVE: To examine the neuropsychological functions in idiopathic RBD subjects. Should they be found to present a neuropsychological dysfunction that overlaps that reported in neurodegenerative diseases, it would be possible to consider cognitive deficits as possible early markers of an underlying degenerative process. METHODS: Twenty-three subjects with idiopathic RBD (21 males, mean age 67.0+/-7.0 years) and a group of healthy controls matched for sex, age and education underwent a neuropsychological battery evaluating different cognitive domains. FINDINGS: Considering mean values, poorer performances were observed in the Word Span (p<.001), Rey-Osterrieth's complex figure recall (p=.003), Digit Span (p=.003) and Logic Memory (p=.003) tests. On the basis of equivalent scores, the RBD subjects performed significantly more poorly on tests of visuo-constructional learning abilities (p<.001). INTERPRETATION: Our data show the possible presence of cognitive deficits in RBD defined as idiopathic, sharing common features in particular with Lewy body disease. Neuropsychological evaluation in RBD could lead to presymptomatic identification of neurodegenerative disease, but until more prolonged long-term follow-up data are available, the true neurobiological significance of cognitive deficits in RBD will remain unknown.