Extending sleep to confirm insufficient sleep syndrome is challenging.

Insufficient sleep syndrome (ISS) is prevalent, but poorly studied. This descriptive study was performed to determine its diagnostic challenges and clinical characteristics in a large (n = 3,461) retrospective sample from a single sleep laboratory. Based on actigraphy, polysomnography and multiple sleep latency tests, we diagnosed "suspected insufficient sleep syndrome" in patients with chronic sleepiness, short time in bed, longer sleep duration during weekends or vacation, and without evidence of other causes of sleepiness. For the diagnosis of "definite insufficient sleep syndrome", we additionally required objectively confirmed resolution of sleepiness with actigraphy-documented extension of time in bed. We diagnosed "suspected insufficient sleep syndrome" in 300 subjects. In 94 subjects, extension of sleep time with consecutive relief of sleepiness was attempted, but only 37 subjects succeeded, often despite being offered several attempts. "Definite insufficient sleep syndrome" was confirmed in 36 patients. In these subjects, mean time in bed after sleep extension was above 8 hr per night and 84 min longer than at baseline. Narcolepsy-like findings were frequently observed before sleep extension, but no sleep onset rapid eye movement sleep on polysomnography. This study indicates that fulfilling the diagnostic criteria of ISS is challenging in clinical practice. It further corroborates the importance of actigraphy and polysomnography for correct diagnosis.

Narcolepsy type 2: A rare, yet existing entity.

Because of unspecific diagnostic criteria, there is much controversy around narcolepsy type 2, its existence and its frequency. With this retrospective and purely descriptive study, we aimed to compare the frequency of narcolepsy type 2 compared to the well-described narcolepsy type 1, in a large (n = 3,782) retrospective sample from a single tertiary sleep centre. After 2 weeks washout of sleep-wake active medication, all patients with excessive daytime sleepiness (n = 1,392) underwent 2 weeks actigraphy, polysomnography and multiple sleep latency test, and all diagnoses were made along current diagnostic criteria. Narcolepsy type 1 was diagnosed in 91 patients, and 191 patients without cataplexy had multiple sleep latency test (MSLT) results indicating narcolepsy. After exclusion of shift work syndrome (n = 19), suspected insufficient sleep syndrome (n = 128), delayed sleep phase syndrome (n = 4) and obstructive sleep apnea (n = 34), six patients were diagnosed with narcolepsy type 2, of whom two patients later developed narcolepsy type 1. Altogether, our observations suggest that narcolepsy type 2 exists, but its frequency may be much lower compared to narcolepsy type 1. In addition, they emphasize the importance of scrupulously excluding other potential causes of sleepiness, if possible, with 2-week actigraphy and polysomnography.

Slow-wave sleep and motor progression in Parkinson disease.

Growing evidence from Alzheimer disease supports a potentially beneficial role of slow-wave sleep in neurodegeneration. However, the importance of slow-wave sleep in Parkinson disease is unknown. In 129 patients with Parkinson disease, we retrospectively tested whether sleep slow waves, objectively quantified with polysomnography, relate to longitudinal changes in Unified Parkinson's Disease Rating Scale motor scores. We found that higher accumulated power of sleep slow waves was associated with slower motor progression, particularly of axial motor symptoms, over a mean time of 4.6 ± 2.3 years. This preliminary finding suggests that deeper sleep relates to slower motor progression in Parkinson disease. Ann Neurol 2019;85:765-770.

In search of cerebrospinal fluid biomarkers of fatigue in multiple sclerosis: A proteomics study.

Fatigue in multiple sclerosis is a very common and cumbersome symptom, but its aetiology is poorly understood. Proteomics is increasingly implemented in multiple sclerosis research, but has not yet been used to study the neurobiological basis of fatigue in multiple sclerosis. To identify potential cerebrospinal fluid biomarkers of fatigue in multiple sclerosis, we collected cerebrospinal fluid of 20 patients with multiple sclerosis with fatigue (MS+), 20 patients with multiple sclerosis without fatigue (MS-), and 20 control subjects without multiple sclerosis and without fatigue (HC). We used a shotgun proteomics approach and label-free quantitative proteomics to analyse the protein content in cerebrospinal fluid. Selected proteins with differential abundance were further validated by immunoblotting. Out of 591 detected cerebrospinal fluid proteins, the abundance of nine proteins differed between the three groups, and seven additional proteins differed between MS+ and MS- patients. Using immunoblot or slot-blot techniques, we confirmed decreased levels of protein kinase C-binding protein NELL2, neural cell adhesion molecule L1-like protein, and reelin in MS+ patients. In conclusion, cerebrospinal fluid proteomics may provide insight into the neurobiological basis of fatigue in multiple sclerosis. The proteins identified to be decreased in MS+ are involved in synaptic plasticity and energy homeostasis, and thus appear as plausible biomarkers of this common symptom.

Validation of the Russian version of the Fatigue Impact Scale and Fatigue Severity Scale in multiple sclerosis patients.

BACKGROUND: Fatigue is a common complaint in patients with multiple sclerosis (MS), and its detection and monitoring are based on self-reported questionnaires. The objective of this study was to validate the Russian translation of the Fatigue Impact Scale (FIS) and the Fatigue Severity Scale (FSS) in MS patients and controls. METHODS: We included 85 MS patients and 250 age-, sex-, and body mass index (BMI)-matched controls. We ascertained in all subjects levels of education, marital status, and comorbidities, such as sleepiness (using the Epworth Sleepiness Scale, ESS), anxiety and depression (using the Hospital Anxiety and Depression Scale, HADS). The expanded disability status scale (EDSS) reflected physical disability in MS. RESULTS: The Russian versions of the three FIS subscales (cognitive, physical, and psychosocial) and FSS had excellent internal consistencies (Cronbach's α coefficients 0.88-0.96), and good test-retest stability with intraclass coefficients between 0.78 and 0.89. Both convergent and discriminant validity of the Russian FIS and FSS appeared to be good, as expressed by strong inter-correlations between FIS subscales and FSS, and by absent associations between fatigue scales and BMI. Principal components analysis and scree plots indicated unidimensional structures of the physical and cognitive FIS subscales and FSS, but a multidimensional structure of the psychosocial subscale. We identified EDSS and anxiety scores as independent predictors of more severe fatigue in MS. SIGNIFICANCE: The Russian FIS and FSS represent reliable and valid tools for efficient quantification and monitoring of fatigue severity and its clinical impact in MS. EDSS and anxiety are important contributors to fatigue severity in MS.

Damage to histaminergic tuberomammillary neurons and other hypothalamic neurons with traumatic brain injury.

The need for increased sleep after traumatic brain injury is a common and disabling complaint, yet its etiology is unknown. Previous studies have demonstrated diffuse damage to various hypothalamic systems, but the integrity of the histaminergic tuberomammillary nucleus, a major arousal-promoting system located in the posterior hypothalamus, has never been examined in head trauma patients. Here, we demonstrate that severe head trauma is associated with a marked loss (41%) of histaminergic neurons. Reduced histamine signaling may contribute to increased sleep need, and therapies that enhance histaminergic tone may improve arousal after head trauma or other conditions.

Diagnostic delay in narcolepsy type 1: combining the patients' and the doctors' perspectives.

Narcolepsy type 1 is a neurological disorder characterized by a unique syndrome, including the pathognomonic symptom of cataplexy. The diagnosis can be confirmed by objective measures, such as typical findings in the multiple sleep latency test, reduced or undetectable levels of orexin (hypocretin) in the cerebrospinal fluid, and linkage to a specific HLA haplotype. Nevertheless, the mean time that elapses from symptom onset to the correct diagnosis ranges between 10 and 20 years, and the causes and correlates of this delay are poorly understood. Diagnostic delay was assessed on 52 well-defined patients with narcolepsy type 1, evaluating clinical, electrophysiological and neurochemical parameters and the results of a 41-item questionnaire developed to obtain the patients' perspective on various aspects of the diagnostic process. The mean time gap between disease onset and first medical consultation was 3.2 ± 5.1 years; the mean diagnostic delay was 8.9 ± 11.0 years. Prior to correct diagnosis, patients received a wide variety of misdiagnoses. The self-ratings of the patients revealed that the undiagnosed symptoms caused high levels of anxiety and unjustified criticism by family, friends and employers. Multiple regression analysis identified higher cerebrospinal fluid orexin levels (ß = 0.311, P = 0.01), and a longer interval between the onset of excessive daytime sleepiness and cataplexy (ß = 0.368, P = 0.002) as independent associates of longer diagnostic delay. The diagnostic delay decreased over the last decades (ß = -0.672, P < 0.001). In conclusion, delayed diagnosis of narcolepsy type 1 is very common, associated with many adverse consequences, and requires educational efforts to improve awareness on narcolepsy among healthcare providers and the general population.

Increased sleep need and daytime sleepiness 6 months after traumatic brain injury: a prospective controlled clinical trial.

Post-traumatic sleep-wake disturbances are common after acute traumatic brain injury. Increased sleep need per 24 h and excessive daytime sleepiness are among the most prevalent post-traumatic sleep disorders and impair quality of life of trauma patients. Nevertheless, the relation between traumatic brain injury and sleep outcome, but also the link between post-traumatic sleep problems and clinical measures in the acute phase after traumatic brain injury has so far not been addressed in a controlled and prospective approach. We therefore performed a prospective controlled clinical study to examine (i) sleep-wake outcome after traumatic brain injury; and (ii) to screen for clinical and laboratory predictors of poor sleep-wake outcome after acute traumatic brain injury. Forty-two of 60 included patients with first-ever traumatic brain injury were available for follow-up examinations. Six months after trauma, the average sleep need per 24 h as assessed by actigraphy was markedly increased in patients as compared to controls (8.3 ± 1.1 h versus 7.1 ± 0.8 h, P < 0.0001). Objective daytime sleepiness was found in 57% of trauma patients and 19% of healthy subjects, and the average sleep latency in patients was reduced to 8.7 ± 4.6 min (12.1 ± 4.7 min in controls, P = 0.0009). Patients, but not controls, markedly underestimated both excessive sleep need and excessive daytime sleepiness when assessed only by subjective means, emphasizing the unreliability of self-assessment of increased sleep propensity in traumatic brain injury patients. At polysomnography, slow wave sleep after traumatic brain injury was more consolidated. The most important risk factor for developing increased sleep need after traumatic brain injury was the presence of an intracranial haemorrhage. In conclusion, we provide controlled and objective evidence for a direct relation between sleep-wake disturbances and traumatic brain injury, and for clinically significant underestimation of post-traumatic sleep-wake disturbances by trauma patients.

Diminished event-related cortical arousals and altered heart rate response in Parkinson's disease.

OBJECTIVES: In Parkinson's disease (PD), partial neuronal loss occurs in several arousal-promoting structures, but the effects on arousability have not yet been studied. METHODS: Polysomnographic analysis of 70 PD patients and 70 control subjects matched for age, sex, body mass index, apnea-hypopnea index (AHI), and periodic limb movements in sleep index (PLMSI). RESULTS: In PD patients, arousal frequency was diminished by 50% compared with controls (9.1 ± 7.6 vs. 18.6 ± 22.9/h; P < 0.001), and the correlations with AHI (rho = 0.266 vs. 0.503, P = 0.004) and PLMSI (rho = 0.082 vs. 0.354, P = 0.006) were weaker. Hoehn & Yahr stage was an independent negative predictor of arousal index (ß = -0.297, P = 0.015). Normalization of heart rate increase after cortical arousals was prolonged in PD patients compared with controls (P = 0.003). CONCLUSION: Our findings indicate that the neurodegenerative process in PD is associated with an attenuated arousability to respiratory and motor events, and with an alteration of the heart rate pattern accompanying arousals.

Increase of histaminergic tuberomammillary neurons in narcolepsy.

OBJECTIVE: Narcolepsy is caused by loss of the hypothalamic neurons producing the orexin/hypocretin neuropeptides. One key target of the orexin system is the histaminergic neurons of the tuberomammillary nucleus (TMN), an essential wake-promoting system. As cerebrospinal fluid histamine levels may be low in patients with narcolepsy, we examined histaminergic neurons in patients with narcolepsy and in 2 mouse models of narcolepsy. METHODS: We counted the number of hypothalamic neurons producing orexin, melanin-concentrating hormone, and histamine in 7 narcolepsy patients and 12 control subjects using stereological techniques. We identified histaminergic neurons using immunostaining for histidine decarboxylase. We also examined these systems in 6 wild-type mice, 6 orexin/ataxin-3 transgenic mice, and 5 orexin ligand knockout mice. RESULTS: Compared to controls, narcolepsy patients had 94% more histaminergic TMN neurons (233,572 ± 49,476 vs 120,455 ± 10,665, p < 0.001). This increase was higher in 5 narcolepsy patients with >90% orexin neuron loss than in 2 patients with ≤75% orexin neuron loss (252,279 ± 46,264 vs 186,804 ± 1,256, p = 0.03). Similarly, the number of histaminergic TMN neurons was increased 53% in orexin ligand knockout mice compared to wild-type mice, whereas orexin/ataxin-3 transgenic mice showed an intermediate 28% increase. INTERPRETATION: This surprising increase in histaminergic neurons in narcolepsy may be a compensatory response to loss of excitatory drive from the orexin neurons and may contribute to some of the symptoms of narcolepsy such as preserved consciousness during cataplexy and fragmented nighttime sleep. In addition, this finding may have therapeutic implications, as medications that enhance histamine signaling are now under development.

Body side and predominant motor features at the onset of Parkinson's disease are linked to motor and nonmotor progression.

Patients with Parkinson's disease most often have asymmetric motor features at onset, and specific motor signs (ie, tremor versus bradykinesia and rigidity) frequently characterize the first few years of disease evolution. Some previous clinical evidence has suggested that body side and a predominance of motor manifestations at disease onset are linked to long-term evolution and disease progression. We prospectively analyzed 206 patients with Parkinson's disease according to the most affected side and predominant motor signs at onset. Patients were divided into left-side rigid-akinetic (n = 71), right-side rigid-akinetic (n = 59), left-side tremor (n = 41), and right-side tremor (n = 35) subgroups. These subgroups were compared in terms of motor and cognitive functions, mean motor deterioration per year (calculated as the motor score divided by disease duration), total equivalent doses of dopaminergic drugs, and the presence of hallucinations and rapid eye movement sleep behavior disorder. Disease duration was similar in all groups. Motor fluctuations were more likely to occur in rigid-akinetic patients. In a multiple model analysis adjusted for potential confounders, faster disease progression was associated with right-side (P = 0.045) and rigid-akinetic onset (P = 0.001). With respect to nonmotor symptoms, the rigid-akinetic type was associated with increased risk of cognitive decline (P = 0.004) compared with the tremor type. A trend was noticed toward an increased risk of developing visual hallucinations in rigid-akinetic patients and toward an increased frequency of rapid eye movement sleep behavior disorder in those who had left-sided onset of symptoms. Our findings corroborate that body side and type of motor signs at the time of diagnosis affect the evolution of motor severity and may also have an impact on some nonmotor manifestations.

Excessive sleep need following traumatic brain injury: a case-control study of 36 patients.

Increased sleep need following traumatic brain injury, referred to in this study as post-traumatic pleiosomnia, is common, but so far its clinical impact and therapeutic implications have not been characterized. We present a case-control study of 36 patients with post-traumatic pleiosomnia, defined by an increased sleep need of at least 2 h per 24 h after traumatic brain injury, compared to 36 controls. We assessed detailed history, sleep-activity patterns with sleep logs and actigraphy, nocturnal sleep with polysomnography and daytime sleep propensity with multiple sleep latency tests. Actigraphy recordings revealed that traumatic brain injury (TBI) patients had longer estimated sleep durations than controls (10.8 h per 24 h, compared to 7.3 h). When using sleep logs, TBI patients underestimated their sleep need. During nocturnal sleep, patients had higher amounts of slow-wave sleep than controls (20 versus 13.8%). Multiple sleep latency tests revealed excessive daytime sleepiness in 15 patients (42%), and 10 of them had signs of chronic sleep deprivation. We conclude that post-traumatic pleiosomnia may be even more frequent than reported previously, because affected patients often underestimate their actual sleep need. Furthermore, these patients exhibit an increase in slow-wave sleep which may reflect recovery mechanisms, intrinsic consequences of diffuse brain damage or relative sleep deprivation.

Sleep spindle and slow wave activity in Parkinson disease with excessive daytime sleepiness.

STUDY OBJECTIVES: Excessive daytime sleepiness (EDS) is a common and devastating symptom in Parkinson disease (PD), but surprisingly most studies showed that EDS is independent from nocturnal sleep disturbance measured with polysomnography. Quantitative electroencephalography (EEG) may reveal additional insights by measuring the EEG hallmarks of non-rapid eye movement (NREM) sleep, namely slow waves and spindles. Here, we tested the hypothesis that EDS in PD is associated with nocturnal sleep disturbance revealed by quantitative NREM sleep EEG markers. METHODS: Patients with PD (n = 130) underwent polysomnography followed by spectral analysis to calculate spindle frequency activity, slow-wave activity (SWA), and overnight SWA decline, which reflects the dissipation of homeostatic sleep pressure. We used the Epworth Sleepiness Scale (ESS) to assess subjective daytime sleepiness and define EDS (ESS > 10). All examinations were part of an evaluation for deep brain stimulation. RESULTS: Patients with EDS (n = 46) showed reduced overnight decline of SWA (p = 0.036) and reduced spindle frequency activity (p = 0.032) compared with patients without EDS. Likewise, more severe daytime sleepiness was associated with reduced SWA decline (ß= -0.24 p = 0.008) and reduced spindle frequency activity (ß= -0.42, p < 0.001) across all patients. Reduced SWA decline, but not daytime sleepiness, was associated with poor sleep quality and continuity at polysomnography. CONCLUSIONS: Our data suggest that daytime sleepiness in PD patients is associated with sleep disturbance revealed by quantitative EEG, namely reduced overnight SWA decline and reduced spindle frequency activity. These findings could indicate that poor sleep quality, with incomplete dissipation of homeostatic sleep pressure, may contribute to EDS in PD.

Cerebrospinal fluid hypocretin-1 levels during the active period of cluster headache.

BACKGROUND: Hypocretins (orexins) are hypothalamic neuropeptides which are involved in a wide range of physiological processes in mammals including central pain processing. Genetic studies in humans evidenced a role for the hypocretinergic system in cluster headache (CH). PATIENTS AND METHODS: We tested cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) levels in 10 CH patients during an active cluster period. CSF hypocretin-1 levels were measured by radioimmunoassay. RESULTS: CSF hypocretin-1 levels were within the normal range (mean 457.3±104.98 pg/ml, range 304-639) in our 10 patients, with a slight reduction in one case (304 pg/ml). There were no associations between CSF hypocretin-1 levels and the clinical features of CH. A trend towards higher hypocretin-1 levels was disclosed in patients with chronic CH compared to episodic CH. CONCLUSIONS: CSF hypocretin-1 levels seem not to influence the clinical course of CH, but our results cannot completely exclude a functional involvement of the hypothalamic hypocretinergic system in the pathogenesis of CH.

Sleep-wake misperception. A comprehensive analysis of a large sleep lab cohort.

OBJECTIVES: Sleep-wake misperception has mainly been reported in insomnia patients. Conversely, the present study aimed to assess the prevalence and correlates of sleep-wake misperception in a large cohort of patients with various sleep-wake disorders, all diagnosed along the third version of the International Classification of Sleep Disorders. METHODS: We retrospectively included 2738 patients examined by polysomnography, who in addition estimated upon awakening their total sleep time, sleep onset latency and Wake after sleep onset (WASO). We computed subjective-objective mismatch by the formula (subjective - objective value)/objective value ×100; negative and positive values indicated under- and overestimation, respectively. RESULTS: In the entire sample, the magnitude of under- and overestimation of total sleep time was similar, but varied significantly between diagnostic groups, with insomnia and insufficient sleep syndrome showing the most pronounced underestimation and REM parasomnia and circadian rhythm disorders showing the most pronounced overestimation of total sleep time. In all diagnostic categories, a majority tended to overestimate their sleep onset latency and to underestimate the amount of WASO. Younger age was independently correlated with underestimation of total sleep time and WASO, and with overestimation of sleep onset latency. Overestimation of sleep onset latency independently correlated to an increased latency to N3 sleep stage on polysomnography. CONCLUSIONS: While sleep-wake misperception is highly prevalent in all sleep-wake disorders, significant differences exist in magnitude of under- and overestimation between distinct diagnostic groups.

Reduced Regional NREM Sleep Slow-Wave Activity Is Associated With Cognitive Impairment in Parkinson Disease.

Growing evidence implicates a distinct role of disturbed slow-wave sleep in neurodegenerative diseases. Reduced non-rapid eye movement (NREM) sleep slow-wave activity (SWA), a marker of slow-wave sleep intensity, has been linked with age-related cognitive impairment and Alzheimer disease pathology. However, it remains debated if SWA is associated with cognition in Parkinson disease (PD). Here, we investigated the relationship of regional SWA with cognitive performance in PD. In the present study, 140 non-demented PD patients underwent polysomnography and were administered the Montréal Cognitive Assessment (MoCA) to screen for cognitive impairment. We performed spectral analysis of frontal, central, and occipital sleep electroencephalography (EEG) derivations to measure SWA, and spectral power in other frequency bands, which we compared to cognition using linear mixed models. We found that worse MoCA performance was associated with reduced 1-4 Hz SWA in a region-dependent manner (F 2, 687 =11.67, p < 0.001). This effect was driven by reduced regional SWA in the lower delta frequencies, with a strong association of worse MoCA performance with reduced 1-2 Hz SWA (F 2, 687 =18.0, p < 0.001). The association of MoCA with 1-2 Hz SWA (and 1-4 Hz SWA) followed an antero-posterior gradient, with strongest, weaker, and absent associations over frontal (rho = 0.33, p < 0.001), central (rho = 0.28, p < 0.001), and occipital derivations, respectively. Our study shows that cognitive impairment in PD is associated with reduced NREM sleep SWA, predominantly in lower delta frequencies (1-2 Hz) and over frontal regions. This finding suggests a potential role of reduced frontal slow-wave sleep intensity in cognitive impairment in PD.

Fatigue in inflammatory bowel disease and its impact on daily activities.

BACKGROUND: Fatigue is a common symptom of chronic inflammation, including inflammatory bowel disease (IBD), resulting in significant impairment in quality of life. AIMS: To identify the prevalence of fatigue in a large IBD cohort compared to the general population, address risk factors, and evaluate its impact on daily life. METHODS: We evaluated 1208 IBD patients from the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS) and 414 healthy controls. Significant fatigue was defined as a visual analogue scale (VAS-F, range 0-10) score ≥ 4. Secondary endpoints were severity of fatigue and its impact on daily activities with the Fatigue Severity Scale (FSS), with a score ≥ 4 indicative of fatigue. Demographic, IBD-related and psychiatric symptoms were assessed with a multivariate analysis of variance (MANOVA) model optimised for prediction of VAS-F (primary outcome) and FSS scores. RESULTS: Overall, 672 IBD patients (55.6%) reported significant fatigue compared to 145 (35%) controls (OR 2.71; 95% CI 2.08-3.54; P < 0.001). In IBD, fatigue also significantly affected daily activities (FSS ≥ 4; 405 (33.5%) IBD patients vs 81 (19.6%) controls, P < 0.001). In the MANOVA model, fatigue levels were associated with female gender (coefficient 0.839; 0.556 - 1.123; P < 0.001), younger age at diagnosis (-0.031 per year; -0.042- -0.019; P < 0.001), shorter disease duration (-0.036 per year; -0.050- -0.022; P < 0.001), nocturnal diarrhoea (0.718; 0.295-1.141; P = 0.001), low educational level (P = 0.034) and symptoms of depression and anxiety. CONCLUSIONS: Fatigue is both more frequent and more severe in patients with IBD than in the general population.

Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson's disease.

Slow-wave sleep (SWS) modulation in rodent models of Alzheimer's disease alters extracellular amyloid burden. In Parkinson's disease (PD), SWS appears to be closely linked with disease symptoms and progression. PD is characterized by damaging intracellular α-synuclein (αSyn) deposition that propagates extracellularly, contributing to disease spread. Intracellular αSyn is sensitive to degradation, whereas extracellular αSyn may be eliminated by glymphatic clearance, a process increased during SWS. Here, we explored whether long-term slow-wave modulation in murine models of PD presenting αSyn aggregation alters pathological protein burden and, thus, might constitute a valuable therapeutic target. Sleep-modulating treatments showed that enhancing slow waves in both VMAT2-deficient and A53T mouse models of PD reduced pathological αSyn accumulation compared to control animals. Nonpharmacological sleep deprivation had the opposite effect in VMAT2-deficient mice, severely increasing the pathological burden. We also found that SWS enhancement was associated with increased recruitment of aquaporin-4 to perivascular sites, suggesting a possible increase of glymphatic function. Furthermore, mass spectrometry data revealed differential and specific up-regulation of functional protein clusters linked to proteostasis upon slow wave­enhancing interventions. Overall, the beneficial effect of SWS enhancement on neuropathological outcome in murine synucleinopathy models mirrors findings in models of Alzheimer. Modulating SWS might constitute an effective strategy for modulating PD pathology in patients.

Loss of hypocretin (orexin) neurons with traumatic brain injury.

Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson disease and other disorders. We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI. This observation highlights the often overlooked hypothalamic injury in TBI and provides new insights into the causes of chronic sleepiness in patients with TBI.

Cerebellum and source memory.

We report the case of a 40-year-old right-handed German-speaking man who presented with ischemic stroke in the territories of the right superior cerebellar artery and posterior inferior cerebellar artery. The objective of the present study was to investigate the consequences of this cerebellar damage with regard to higher cognitive functions. On admission to the stroke unit, the patient presented with dysarthria, right-sided appendicular ataxia, gait ataxia, and right-sided horizontal nystagmus (National Institutes of Health Stroke Scale, NIHSS, score 4). When examined 10 days after his stroke using a set of neuropsychological tests, he showed a marked deficit in the ability to remember when and in which context he had previously encountered verbal material. This aspect of memory, so-called 'source memory', is known to be mediated mainly by frontal and medial temporal structures. The present case suggests the existence of a strong functional connectivity between cerebellum and cortical regions underlying specific memory processes.