Associations between sleep-related symptoms, obesity, cardiometabolic conditions, brain structural alterations and cognition in the UK biobank.

OBJECTIVES: Sleep disturbances are increasingly recognized as adversely affecting brain health in aging. Our aim was to investigate interrelations between subjective sleep-related symptoms, obesity, cardiometabolic disorders, brain structure and cognitive decline in a population-based aging sample. METHODS: Data were extracted from the UK Biobank for anthropometric and demographic information, self-reported sleep behaviours, cardiometabolic measures, structural brain magnetic resonance imaging and cognitive test scores. "Sleep-related symptoms" (SRS) were measured using four questionnaire items: loud snoring, daytime sleepiness, likelihood to nap and difficulty getting up in the morning. Associations were tested using a structural equation model (SEM), adjusted for confounders. Further, multiple regression analysis was used to test for direct relationships between SRS and specific cognitive domains. RESULTS: Among 36,468 participants with an average age of 63.6 (SD 7.5) years and 46.7% male, we found that SRS were associated with obesity and several pre-existing cardiometabolic disturbances. In turn, cardiometabolic disorders were associated with increased white matter hyperintensities and cortical thinning, which were related to cognitive dysfunction. SRS were also directly related to several structural brain changes and to cognitive dysfunction. Regression analyses showed that SRS were directly associated with slower reaction times, and lower scores in fluid intelligence, working memory and executive function. CONCLUSIONS: Self-reported sleep-related symptoms were associated with cognitive dysfunction directly and through pre-existing cardiometabolic disorders and brain structural alterations. These findings provide evidence that symptoms of sleep disturbances, here defined primarily by hypersomnolence and snoring, are important risk factors or markers for cognitive dysfunction in an aging population.

Is REM sleep a paradoxical state?: Different neurons are activated in the cingulate cortices and the claustrum during wakefulness and paradoxical sleep hypersomnia.

Michel Jouvet proposed in 1959 that REM sleep is a paradoxical state since it was characterized by the association of a cortical activation similar to wakefulness (W) with muscle atonia. Recently, we showed using cFos as a marker of activity that cortical activation during paradoxical sleep (PS) was limited to a few limbic cortical structures in contrast to W during which all cortices were strongly activated. However, we were not able to demonstrate whether the same neurons are activated during PS and W and to rule out that the activation observed was not linked with stress induced by the flowerpot method of PS deprivation. In the present study, we answered to these two questions by combining tdTomato and cFos immunostaining in the innovative TRAP2 transgenic mice exposed one week apart to two periods of W (W-W mice), PS rebound (PSR-PSR) or a period of W followed by a period of PSR (W-PSR mice). Using such method, we showed that different neurons are activated during W and PSR in the anterior cingulate (ACA) and rostral and caudal retrosplenial (rRSP and cRSP) cortices as well as the claustrum (CLA) previously shown to contain a large number of activated neurons after PSR. Further, the distribution of the neurons during PSR in the rRSP and cRSP was limited to the superficial layers while it was widespread across all layers during W. Our results clearly show at the cellular level that PS and W are two completely different states in term of neocortical activation.

Excessive daytime sleepiness in sleep apnea: any role of testosterone or vitamin D?

Recent studies reported association of sleep-disordered breathing (SDB) with testosterone and vitamin D deficiency. Low testosterone and vitamin D levels have been linked to fatigue and excessive daytime sleepiness (EDS). However, the impact of testosterone and vitamin D deficiency on EDS in subjects with SDB remains unknown. The aim of this study was to explore the predictors of EDS in habitual snorers. Role of testosterone, and vitamin D was studied in detail. We also looked for associations between testosterone, vitamin D, and sleep-related indices. We prospectively enrolled 291 consecutive male patients with habitual snoring. Baseline clinical characteristics were recorded on admission. Standard overnight polysomnography was performed to detect SDB, and Epworth Sleepiness Scale (ESS) was used to assess EDS. Blood samples were obtained in a fasting condition in the morning after polysomnography to determine levels of testosterone and vitamin D. Respiratory disturbance index (RDI) (95 % CI: 1.004-1.024, p=0.005) and the use of antihistamines (95 % CI: 1.083-11.901, p=0.037) were the only independent variables significantly associated with EDS in binary logistic regression analysis. In linear multiple regression analysis, body mass index (BMI) (Beta=-0.282, p<0.001) and oxygen desaturation index (Beta=-0.150, p=0.043) were the only independent variables significantly associated with testosterone levels, and BMI (Beta=-0.142, p=0.016) was the only independent variable significantly associated with vitamin D. We failed to find any independent association of testosterone and vitamin D with subjectively rated EDS among habitual snorers. Our results suggest an independent association between the magnitude of nocturnal desaturation and testosterone levels.

Secondary hypersomnia as an initial manifestation of neuromyelitis optica spectrum disorders.

The identification of AQP4-IgG, a specific and pathogenic antibody of NMO/SD has led to a broadening of the clinical spectrum of manifestations of NMO/SD including the presence of encephalic symptoms. Lesions are often distributed on peri­ependymal area and sometimes affected the diencephalon leading to sleep disorders. We report a case of hypersomnia with polysomnographic documentation during the first attack of NMO/SD. Brain MRI revealed bilateral hypothalamic lesions around the third ventricle, whereas optic nerves and spinal cord were intact. The record of the nocturnal video-polysomnography followed by multiple sleep latency tests (MSLT) revealed an abnormal shortened sleep period with a single sleep onset in REM allowing secondary central hypersomnia diagnosis. The recovery of hypersomnia was complete within few months without psychostimulant treatment and the diencephalic lesion disappeared. Thus, diencephalic form of NMO/SD seems to cause narcolepsy or non-narcoleptic central hypersomnia and have a good recovery.

Excessive daytime sleepiness and topographic expansion of Lewy pathology.

OBJECTIVE: While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up. METHODS: Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years. RESULTS: Although EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies. CONCLUSIONS: The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.

Sleepiness, fatigue, anxiety and depression in Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea - Overlap - Syndrome, before and after continuous positive airways pressure therapy.

Patients with Chronic Obstructive Pulmonary Disease (COPD) and / or Obstructive Sleep Apnea (OSA) often complain about sleepiness, fatigue, anxiety and depression. However, common screening questionnaires, like Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS) and Hospital Anxiety and Depression Scale (HADS) have not been previous evaluated in patients with overlap-coexisting COPD and OSA-syndrome versus patients with OSA alone. Our study compared ESS, FSS and HADS between patients with overlap syndrome and patients with OSA, before and after treatment with Continuous Positive Airways Pressure (CPAP). We examined 38 patients with coexisting COPD and OSA versus 38 patients with OSA-only and 28 subjects without respiratory disease, serving as controls. All patients underwent pulmonary function tests (PFTs), oximetry and overnight polysomnography and completed the questionnaires, before and after 3 months of CPAP therapy. The two patient groups did not differ significantly in terms of age, Body Mass Index (BMI), neck, waist and hip circumferences, and arterial blood pressure values. They also had similar comorbidities. They differed significantly, as expected, in PFTs (Forced Vital Capacity-FVC, 2.53±0.73 vs 3.08±0.85 lt, p = 0.005, Forced Expiratory Volume in 1sec-FEV1, 1.78±0.53 vs 2.60±0.73 lt/min, p<0.001) and in daytime oximetry (94.75±2.37 vs 96.13±1.56%, p = 0.007). ESS, HADS-Anxiety and HADS-Depression scores did not differ statistically significant between these two groups, whereas overlap syndrome patients expressed significantly more fatigue (FSS) than OSA-only patients, a finding that persisted even after 3 months of CPAP therapy. We conclude that sleepiness, anxiety and depression were similar in both groups, whereas fatigue was more prominent in patients with overlap syndrome than in sleep apneic patients and did not ameliorate after treatment.

Daytime sleepiness in dementia with Lewy bodies is associated with neuronal depletion of the nucleus basalis of Meynert.

INTRODUCTION: Excessive daytime sleepiness is a commonly reported clinical feature of dementia with Lewy bodies (DLB) that can occur early in the disease. Cholinergic depletion is known to be severe in DLB, even when dementia severity is mild. The nucleus basalis of Meynert serves as a primary source of cortical acetylcholine, and has a role in facilitating cortical activation and arousal. We sought to determine whether daytime sleepiness at the initial evaluation of patients with DLB was associated with neuronal loss in the nucleus basalis of Meynert. METHODS: Autopsy-confirmed patients who met clinical criteria for probable DLB at their initial evaluation and who were administered the informant-completed Epworth Sleepiness Scale were included in the study (n = 40). Each patient had a dementia at baseline (80% with mild severity) and two or more features of parkinsonism, visual hallucinations, fluctuations, or probable REM sleep behavior disorder. Quantitative digital pathology of the nucleus basalis of Meynert was performed in the DLB group and in 20 non-DLB autopsy controls. RESULTS: DLB had greater neuronal depletion in the nucleus basalis of Meynert (p < 0.0001) than pathologic controls. Sleepiness was present in 58% of the DLB group and those with daytime sleepiness had significantly lower neuron counts in the nucleus basalis of Meynert than their non-sleepy counterparts (p = 0.001). Regression modeling revealed that sleepiness was a stronger predictor of neuronal loss in the nucleus basalis of Meynert than visual hallucinations, fluctuations or dementia severity (p = 0.003). CONCLUSIONS: Excessive daytime sleepiness in early DLB is indicative of a more profound loss of basal forebrain cholinergic integrity.

Excessive daytime sleepiness and fatigue may indicate accelerated brain aging in cognitively normal late middle-aged and older adults.

Excessive daytime sleepiness (EDS) and fatigue increases with age. The aim of this study was to investigate the association between EDS and fatigue with cortical thickness and hippocampal volume in cognitively normal, late middle-aged and older adults. We performed a cross-sectional observational study of 1374 cognitively-normal subjects aged 50 years and older who had a structural MRI. Regional cortical thickness and hippocampal volume were measured. Multiple linear regression models were fit to explore associations between EDS and fatigue and structural MRI measures in different brain regions, adjusting for multiple covariates. EDS was defined as Epworth Sleepiness Scale ≥10. Fatigue severity was assessed with the Beck Depression Inventory-2. 208 participants had EDS, 27 had significant fatigue, and 11 had both. Participants with EDS or fatigue had significantly lower cognitive scores, more disturbed sleep, and medical comorbidities. The presence of EDS was associated with both global and regional atrophy, whereas fatigue was more associated with frontal and temporal changes. Cortical thinning predicted by EDS and fatigue was maximal in the temporal region with average reduction of 34.2 µm (95% CI, -54.1, -14.3; P = 0.001) and 90.2 µm (95% CI, -142.1, -38.2; P = 0.001), respectively. Fatigue was also associated with hippocampal volume reduction of -374.2 mm3 (95% CI, -670.8, -77.7; P = 0.013). Temporal cortical thinning predicted by presence of EDS and fatigue was equivalent to more than 3.5 and 9 additional years of aging, respectively. EDS and fatigue were associated with cortical thickness reduction primarily in regions with increased age-susceptibility, which may indicate accelerated brain aging.

[Metal implant sensitivity: clinical and histological presentation]. / Klinik und Histologie Metallimplantat-assoziierter Hauterscheinungen.

Metal implant sensitivity (intolerance) can cause pain, reduced mobility, loosening of the implant and skin rashes. Knowledge of differential diagnoses, histology and appropriate diagnostics are essential for proper diagnosis. To outline typical clinical signs and histology in metal-implant-associated skin lesions we present three exemplary patients from our implant allergy outpatient department and give an overview of the current literature regarding metal implant sensitivity. In patients with a negative patch test the lymphocyte transformation test may reveal metal sensitization. Even "pure" titanium alloys may contain traces of nickel. The histology of implant-associated skin reactions goes from teleangiectatic postimplantation erythema to eczema and vasculitis. Based on the synopsis of history, clinical picture, allergological testing and histology, metal implant sensitivity can be diagnosed more precisely.

Mitochondrial defects associated with ß-alanine toxicity: relevance to hyper-beta-alaninemia.

Hyper-beta-alaninemia is a rare metabolic condition that results in elevated plasma and urinary ß-alanine levels and is characterized by neurotoxicity, hypotonia, and respiratory distress. It has been proposed that at least some of the symptoms are caused by oxidative stress; however, only limited information is available on the mechanism of reactive oxygen species generation. The present study examines the hypothesis that ß-alanine reduces cellular levels of taurine, which are required for normal respiratory chain function; cellular taurine depletion is known to reduce respiratory function and elevate mitochondrial superoxide generation. To test the taurine hypothesis, isolated neonatal rat cardiomyocytes and mouse embryonic fibroblasts were incubated with medium lacking or containing ß-alanine. ß-alanine treatment led to mitochondrial superoxide accumulation in conjunction with a decrease in oxygen consumption. The defect in ß-alanine-mediated respiratory function was detected in permeabilized cells exposed to glutamate/malate but not in cells utilizing succinate, suggesting that ß-alanine leads to impaired complex I activity. Taurine treatment limited mitochondrial superoxide generation, supporting a role for taurine in maintaining complex I activity. Also affected by taurine is mitochondrial morphology, as ß-alanine-treated fibroblasts undergo fragmentation, a sign of unhealthy mitochondria that is reversed by taurine treatment. If left unaltered, ß-alanine-treated fibroblasts also undergo mitochondrial apoptosis, as evidenced by activation of caspases 3 and 9 and the initiation of the mitochondrial permeability transition. Together, these data show that ß-alanine mediates changes that reduce ATP generation and enhance oxidative stress, factors that contribute to heart failure.

Multimodal imaging evaluation of excessive daytime sleepiness in Parkinson's disease.

PURPOSE OF THE STUDY: The multimodal imaging investigation of excessive daytime sleepiness (EDS) in Parkinson's disease (PD). The role of dopaminergic treatment and other clinical parameters was also evaluated. MATERIALS AND METHODS: Seventeen non-demented PD patients with EDS (PD-EDS) and 17 PD patients without EDS were enrolled. Clinical, treatment and MRI data were acquired. Gray matter (GM) volume was examined with voxel-based morphometry, while white matter (WM) integrity was assessed with diffusion tensor imaging by means of fractional anisotropy, mean diffusivity, axial diffusivity (AD) and radial diffusivity measures. RESULTS: Increased regional GM volume was found in the PD-EDS group bilaterally in the hippocampus and parahippocampal gyri. Increased AD values were also shown in the PD-EDS group, in the left anterior thalamic radiation and the corticospinal tract and bilaterally in the superior corona radiata and the superior longitudinal fasciculus. Levodopa equivalent dose differed significantly between the groups and was the only predictor of EDS, while the only predictor of the Epworth sleepiness scale score in the PD-EDS group was the dopamine-agonist dose. Increased frequency of gamblers was also observed in the PD-EDS group. CONCLUSIONS: Regional GM increases and increased AD values in certain WM tracts were found in the PD-EDS group. The changes could result from disinhibited signaling pathways or represent compensatory changes in response to anatomical or functional deficits elsewhere. The study findings support also the contribution of the total dopaminergic load in the development of EDS, while the dose of dopamine agonists was found to predict the severity of the disorder.

Central Hypersomnia.

Sleepiness is not uncommon in the pediatric population. Although the etiology can be multifactorial, sleepiness due to increased sleep drive, also called central hypersomnia, is a common cause. The third edition of the International Classification of Sleep Disorders updated the diagnostic criteria for several of the central disorders of hypersomnolence, most notably narcolepsy. Although the International Classification Of Sleep Disorders-3 is not specific to pediatric patients, the peak incidence for many of the included disorders occurs during childhood or adolescence. As a result, recognition of these lifelong and potentially debilitating disorders is imperative for providers who evaluate pediatric patients. This review provides an update on recent advances in the field and highlights some of the diagnostic dilemmas, unique clinical features, and variable presentations associated with central disorders of hypersomnolence within the pediatric population.

Unusual presentation of hypothalamic hamartoma with hypersomnia in an adult patient.

We report a patient with polysomnography findings related to hypersomnia, as a primary presenting symptom, who was shown to have stereotypical gelastic seizures. Her cranial magnetic resonance imaging revealed a hypothalamic hamartoma in the posterior region of the hypothalamus. The patient had no previous history of gelastic seizures. We suggest that patients who present with hypersomnia should be investigated for gelastic seizures in order to avoid misdiagnosis and receive appropriate treatment.

Correlation between hippocampal volume and excessive daytime sleepiness in obstructive sleep apnea syndrome.

BACKGROUND/AIM: The limbic system, specifically the hippocampus, plays a key role in controlling the sleep-wake cycle. Changes in these particular structures of the central nervous system have been suggested to be related to obstructive sleep apnea syndrome (OSAS). We hypothesized that reduced hippocampal volume is a risk factor for excessive daytime sleepiness (EDS) in OSAS. PATIENTS AND METHODS: Twenty-two patients with newly diagnosed OSAS and 20 healthy controls were included in the present study. Polysomnography was performed for each participant to determine the presence of OSAS. EDS was defined based on the Epworth sleepiness scale (ESS) score, and patients were grouped as sleepy or non-sleepy according to this score. The hippocampal volume was calculated by MR volumetry using a manual tracing technique. RESULTS: There was no significant difference between groups in demographic variables. The hippocampus was markedly smaller in the OSAS groups than in controls (p < 0.001 Hippocampal volume was negatively correlated with the ESS score (r = -0.631, p = 0.002). CONCLUSIONS: Our findings suggest that EDS is associated with reduced hippocampal volume in OSAS.

Cognitive decline and hypersomnolence: thalamic manifestations of a tentorial dural arteriovenous fistula (dAVF).

BACKGROUND: Intracranial dural arteriovenous fistulas (dAVFs) often present with pulsatile tinnitus, orbital congestion, and headache. Occasionally, they present with focal neurologic deficits, a dementia-like syndrome, hemorrhage, or ischemic infarction. METHODS: This study is based on the case of a 71-year-old gentleman who presented with 6 months of progressive forgetfulness, inattention, and hypersomnolence. Four weeks prior to presentation, he developed symptoms of left-sided pain, numbness, and worsening weakness. Neurologic examination demonstrated hypersomnolence, a score of 30/38 on the Kokmen Short Test of Mental Status, and left hemiparesis. MRI brain revealed bilateral thalamic T2 hyperintensities with associated enhancement. MR venogram (MRV) showed a vascular malformation in the posterior fossa and occlusion of the straight sinus. Conventional cerebral angiogram confirmed a tentorial dAVF. The dAVF was definitively treated with transarterial embolization, followed by clip ligation of the arterialized draining vein. Twelve weeks later, there was clinical resolution of left hemiparesis and improvement in cognitive status. MRI revealed complete resolution of the thalamic hyperintensities. MRV demonstrated recanalization of the straight sinus. RESULTS: Intracranial dAVFs are uncommon but potentially life-threatening acquired vascular malformations. The initiating factor is venous hypertension, causing retrograde flow, venous congestion, ischemia, and sometimes infarction. The spectrum of clinical manifestations in dAVFs reflects the degree of venous congestion present. If retrograde venous flow is surgically obliterated, then venous hypertension may be reversible. Bilateral thalamic venous congestion can present as a thalamic dementia. CONCLUSION: We conclude that intracranial dAVFs with thalamic venous congestion should be considered in the diagnostic differential for patients who present with subacute cognitive decline and T2 hyperintense thalamic signal change.

Hypothermia, hypotension, hypersomnia, and obesity associated with hypothalamic lesions in a patient positive for the anti-aquaporin 4 antibody: a case report and literature review.

OBJECTIVE: To describe a patient positive for the anti-aquaporin 4 antibody with hypothalamic lesions showing hypothermia, hypotension, hypersomnia, and obesity. DESIGN: Case report. SETTING: University hospital. PATIENT: We describe a 21-year-old woman who was positive for anti-aquaporin 4 antibody and presented with hypothermia, hypotension, and hypersomnia owing to bilateral hypothalamic lesions as the only abnormal clinical finding. RESULTS: Immediate steroid administration resulted in significant improvement of the patient's vital signs and imaging findings; however, her cognitive impairment and sleepiness persisted, and she subsequently developed obesity. Decreased cerebrospinal fluid orexin levels and sleep studies confirmed the diagnosis of narcolepsy due to medical condition. Physicians should be aware that neuromyelitis optica spectrum disorders can initially involve the hypothalamus. CONCLUSIONS: We emphasize that measurement of anti-aquaporin 4 antibody is of clinical importance in the differential diagnosis of hypothalamic lesions.

Altered slow wave activity in major depressive disorder with hypersomnia: a high density EEG pilot study.

Hypersomnolence in major depressive disorder (MDD) plays an important role in the natural history of the disorder, but the basis of hypersomnia in MDD is poorly understood. Slow wave activity (SWA) has been associated with sleep homeostasis, as well as sleep restoration and maintenance, and may be altered in MDD. Therefore, we conducted a post-hoc study that utilized high density electroencephalography (hdEEG) to test the hypothesis that MDD subjects with hypersomnia (HYS+) would have decreased SWA relative to age- and sex-matched MDD subjects without hypersomnia (HYS-) and healthy controls (n=7 for each group). After correction for multiple comparisons using statistical non-parametric mapping, HYS+ subjects demonstrated significantly reduced parieto-occipital all-night SWA relative to HYS- subjects. Our results suggest hypersomnolence may be associated with topographic reductions in SWA in MDD. Further research using an adequately powered prospective design is indicated to confirm these findings.

Role of the lateral paragigantocellular nucleus in the network of paradoxical (REM) sleep: an electrophysiological and anatomical study in the rat.

The lateral paragigantocellular nucleus (LPGi) is located in the ventrolateral medulla and is known as a sympathoexcitatory area involved in the control of blood pressure. In recent experiments, we showed that the LPGi contains a large number of neurons activated during PS hypersomnia following a selective deprivation. Among these neurons, more than two-thirds are GABAergic and more than one fourth send efferent fibers to the wake-active locus coeruleus nucleus. To get more insight into the role of the LPGi in PS regulation, we combined an electrophysiological and anatomical approach in the rat, using extracellular recordings in the head-restrained model and injections of tracers followed by the immunohistochemical detection of Fos in control, PS-deprived and PS-recovery animals. With the head-restrained preparation, we showed that the LPGi contains neurons specifically active during PS (PS-On neurons), neurons inactive during PS (PS-Off neurons) and neurons indifferent to the sleep-waking cycle. After injection of CTb in the facial nucleus, the neurons of which are hyperpolarized during PS, the largest population of Fos/CTb neurons visualized in the medulla in the PS-recovery condition was observed in the LPGi. After injection of CTb in the LPGi itself and PS-recovery, the nucleus containing the highest number of Fos/CTb neurons, moreover bilaterally, was the sublaterodorsal nucleus (SLD). The SLD is known as the pontine executive PS area and triggers PS through glutamatergic neurons. We propose that, during PS, the LPGi is strongly excited by the SLD and hyperpolarizes the motoneurons of the facial nucleus in addition to local and locus coeruleus PS-Off neurons, and by this means contributes to PS genesis.