Analysis of striatal connectivity corresponding to striosomes and matrix in de novo Parkinson's disease and isolated REM behavior disorder.

Striosomes and matrix are two compartments that comprise the striatum, each having its own distinct immunohistochemical properties, function, and connectivity. It is currently not clear whether prodromal or early manifest Parkinson's disease (PD) is associated with any striatal matrix or striosomal abnormality. Recently, a method of striatal parcellation using probabilistic tractography has been described and validated, using the distinct connectivity of these two compartments to identify voxels with striosome- and matrix-like connectivity. The goal of this study was to use this approach in tandem with DAT-SPECT, a method used to quantify the level of nigrostriatal denervation, to analyze the striatum in populations of de novo diagnosed, treatment-naïve patients with PD, isolated REM behavioral disorder (iRBD) patients, and healthy controls. We discovered a shift in striatal connectivity, which showed correlation with nigrostriatal denervation. Patients with PD exhibited a significantly higher matrix-like volume and associated connectivity than healthy controls and higher matrix-associated connectivity than iRBD patients. In contrast, the side with less pronounced nigrostriatal denervation in PD and iRBD patients showed a decrease in striosome-like volume and associated connectivity indices. These findings could point to a compensatory neuroplastic mechanism in the context of nigrostriatal denervation and open a new avenue in the investigation of the pathophysiology of Parkinson's disease.

Sleep disorders in Wilson's disease.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive inherited disease with copper accumulation; neurodegeneration is associated with dopaminergic deficit. The aim of the study is to verify sleep co-morbidity by questionnaire and objective sleep examinations (polysomnography, multiple sleep latency test). METHODS: fifty-five patients with WD (22 hepatic, 28 neurological, five asymptomatic form) and 55 age- and sex-matched control subjects completed a questionnaire concerning their sleep habits, sleep co-morbidity, Epworth sleepiness scale (ESS), and answered screening questions for rapid eye movement (REM) behaviour disorder (RBD-SQ). Twenty-four patients with WD and control subjects underwent polysomnographic examination. RESULTS: unlike the controls, patients with WD were more prone to daytime napping accompanied by tiredness and excessive daytime sleepiness, cataplexy-like episodes and poor nocturnal sleep. Their mean ESS as well as RBD-SQ was higher than that of the controls. Total sleep time was lower, accompanied by decreased sleep efficiency and increased wakefulness. Patients with WD had lower latency of stage 1 and stage 2 of non-rapid eye movement (NREM) sleep and less amount of NREM sleep stage 2. One-third of the patients with WD were found to have short or borderline multiple sleep latency test (MSLT) values independent of nocturnal pathology (sleep apnoea, periodic leg movements and/or restless leg syndrome). CONCLUSIONS: patients with WD often suffer from sleep disturbances (regardless of the clinical form). The spectrum of sleep/wake symptoms raises the suspicion that altered REM sleep function may also be involved.

Replication of restless legs syndrome loci in three European populations.

BACKGROUND: Restless legs syndrome (RLS) is associated with common variants in three intronic and intergenic regions in MEIS1, BTBD9, and MAP2K5/LBXCOR1 on chromosomes 2p, 6p and 15q. METHODS: Our study investigated these variants in 649 RLS patients and 1230 controls from the Czech Republic (290 cases and 450 controls), Austria (269 cases and 611 controls) and Finland (90 cases and 169 controls). Ten single nucleotide polymorphisms (SNPs) within the three genomic regions were selected according to the results of previous genome-wide scans. Samples were genotyped using Sequenom platforms. RESULTS: We replicated associations for all loci in the combined samples set (rs2300478 in MEIS1, p = 1.26 x 10(-5), odds ratio (OR) = 1.47, rs3923809 in BTBD9, p = 4.11 x 10(-5), OR = 1.58 and rs6494696 in MAP2K5/LBXCOR1, p = 0.04764, OR = 1.27). Analysing only familial cases against all controls, all three loci were significantly associated. Using sporadic cases only, we could confirm the association only with BTBD9. CONCLUSION: Our study shows that variants in these three loci confer consistent disease risks in patients of European descent. Among the known loci, BTBD9 seems to be the most consistent in its effect on RLS across populations and is also most independent of familial clustering.

Comparative study of the substantia nigra echogenicity and 123I-Ioflupane SPECT in patients with synucleinopathies with and without REM sleep behavior disorder.

OBJECTIVES: Hyperechogenicity of the substantia nigra (SN) and abnormal dopamine transporter-single-photon emission computed tomography (DAT-SPECT) are biomarkers commonly used in the assessment of prodromal synucleinopathy. Our goals were as follows: (1) to compare echogenicity of SN in idiopathic rapid eye movement (REM) behavior disorder (iRBD), Parkinson's disease (PD) without RBD (PD-noRBD), PD with RBD (PD + RBD), and control subjects; and (2) to examine association between SN degeneration assessed by DAT-SPECT and SN echogenicity. PATIENTS/METHODS: A total of 61 subjects with confirmed iRBD were examined using Movement Disorders Society-unified PD rating scale (MDS-UPDRS), TCS (transcranial sonography) and DAT-SPECT. The results were compared with 44 patients with PD (25% PD + RBD) and with 120 age-matched healthy subjects. RESULTS AND CONCLUSION: The abnormal SN area was found in 75.5% PD, 23% iRBD and 7.3% controls. Median SN echogenicity area in PD (0.27 ± 0.22 cm2) was higher compared to iRBD (0.07 ± 0.07 cm2; p < 0.0001) and controls (0.05 ± 0.03 cm2; p < 0.0001). SN echogenicity in PD + RBD was not significantly different from PD-noRBD (0.30 vs. 0.22, p = 0.15). Abnormal DAT-SPECT was found in 16 iRBD (25.4%) and 44 PD subjects (100%). No correlation between the larger SN area and corresponding putaminal binding index was found in iRBD (r = -0.13, p = 0.29), nor in PD (r = -0.19, p = 0.22). The results of our study showed that: (1) SN echogenicity area in iRBD was higher compared to controls, but the hyperechogenicity was present only in a minority of iRBD patients; (2) SN echogenicity and DAT-SPECT binding index did not correlate in either group; and (3) SN echogenicity does not differ between PD with/without RBD.

Automatic substantia nigra segmentation in neuromelanin-sensitive MRI by deep neural network in patients with prodromal and manifest synucleinopathy.

Neuromelanin (NM) is a black pigment located in the brain in substantia nigra pars compacta (SN) and locus coeruleus. Its loss is directly connected to the loss of nerve cells in this part of the brain, which plays a role in Parkinson's Disease. Magnetic resonance imaging (MRI) is an ideal tool to monitor the amount of NM in the brain in vivo. The aim of the study was the development of tools and methodology for the quantification of NM in a special neuromelanin-sensitive MRI images. The first approach was done by creating regions of interest, corresponding to the anatomical position of SN based on an anatomical atlas and determining signal intensity threshold. By linking the anatomical and signal intensity information, we were able to segment the SN. As a second approach, the neural network U-Net was used for the segmentation of SN. Subsequently, the volume characterizing the amount of NM in the SN region was calculated. To verify the method and the assumptions, data available from various patient groups were correlated. The main benefit of this approach is the observer-independency of quantification and facilitation of the image processing process and subsequent quantification compared to the manual approach. It is ideal for automatic processing many image sets in one batch.

The effects of sleep and sleep deprivation on metabolic, endocrine and immune parameters.

Sleep curtailment is becoming widespread in modern society. In parallel with this, more and more studies are dealing with the health consequences of sleep deprivation. This short review focuses on the main results of studies examining the effects of sleep and sleep deprivation on metabolism with extra emphasis on appetite regulation, and on the endocrine and immune system.

Advanced oxidation protein products in obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a risk factor of hypertension, coronary artery disease and stroke. OSA is also considered a cause of accelerated atherogenesis. Advanced oxidation protein products (AOPP) are among the biochemical indicators of higher risk of atherogenesis as an independent risk factor for coronary artery disease. 20 men suffering from OSA were examined using night polygraphy, the AOPP were determined from their morning blood samples. The mean AOPP concentration in the patients group was 91.8 (SD=42.3) micromol/l, in the control group 76.2 (SD=35.3) pmol/l, the difference was not significant. The AOPP were found correlated with the AHI (apnoe/hypopnoe index) (R=0.485, P=0.030). The results support the hypothesis that OSA increases the oxidative stress and atherogenesis.

Sleep apnoea in patients with nocturnal hypertension - a multicenter study in the Czech Republic.

Sleep apnoea (SA) is common in patients with hypertension. Nowadays, limited data on the prevalence of SA in nocturnal hypertension (NH) exist. Therefore, we studied the occurrence of SA in Czech patients and its association with 24-h ambulatory blood pressure monitoring (ABPM), breathing disturbances in sleep, anthropometric data, Mallampati score and Epworth sleepiness scale (ESS) using the Apnea Link device. Undiagnosed SA was found in 72.9 % patients (29.3 % mild, 26.6 % moderate, 17.0 % severe) of 188 patients with NH measured by ABPM. The median of the apnoea-hypopnoea index (AHI) was 12.0 (25th-75th percentile 5.0-23.8). Moderate/severe SA (AHI>/=15) was associated with BMI, waist circumference, mean night saturation (SpO(2)), t90, oxygen desaturation index (ODI), ESS (daytime BP only) (p0.09). A likelihood of moderate/severe SA was enhanced by ODI>14.5 events/h (odds ratio=57.49, 95 % CI=22.79-145.01), t90>6.5 % (8.07, 4.09-15.92), mean night SpO(2)<93.5 % (3.55, 1.92-6.59), BMI>29.05 kg/m(2) (6.22, 3.10-12.49), circum waist>105.5 cm (3.73, 1.57-8.83), but not by any ABPM parameter. In conclusion, a high incidence of SA (72.9 %) was observed in Czech patients with NH. SA severity was associated with body characteristics and oxygenation parameters, but not with ABMP parameters and Mallampati score.

Spontaneous improvement in both obstructive sleep apnea and cognitive impairment after stroke.

BACKGROUND: Knowledge available about the relationship between obstructive sleep apnea (OSA) and cognitive impairment after stroke is limited. The evolution of OSA and cognitive performance after stroke is not sufficiently described. METHODS: We prospectively enrolled and examined acute stroke patients without previously diagnosed OSA. The following information was collected: (1) demographics, (2) sleep cardio-respiratory polygraphy (PG) at 72 h, day seven, month three, and month 12 after stroke, (3) post-stroke functional disability tests at entry and at months three and 12, and (4) cognition (attention and orientation, memory, verbal fluency, language, and visual-spatial abilities) using the revised Addenbrooke's Cognitive Examination (ACE-R) at months three and 12. RESULTS: Of 68 patients completing the study, OSA was diagnosed in 42 (61.8%) patients. The mean apnea/hypopnea index (AHI) at study entry of 21.0 ± 13.7 spontaneously declined to 11.6 ± 11.2 at month 12 in the OSA group (p < 0.0005). The total ACE-R score was significantly reduced at months three (p = 0.005) and 12 (p = 0.004) in the OSA group. Poorer performance on the subtests of memory at months 3 (p = 0.039) and 12 (p = 0.040) and verbal fluency at months 3 (p < 0.005) and 12 (p < 0.005) were observed in the OSA group compared to non-OSA group. Visual-spatial abilities in both the OSA (p = 0.001) and non-OSA (p = 0.046) groups and the total ACE-R score in the OSA (p = 0.005) and non-OSA (p = 0.002) groups improved. CONCLUSIONS: A high prevalence of OSA and cognitive decline were present in patients after an acute stroke. Spontaneous improvements in both OSA and cognitive impairment were observed.

EFNS guidelines on management of narcolepsy.

Management of narcolepsy with or without cataplexy relies on several classes of drugs, namely stimulants for excessive daytime sleepiness and irresistible episodes of sleep, antidepressants for cataplexy and hypnosedative drugs for disturbed nocturnal sleep. In addition, behavioral measures can be of notable value. Guidelines on the management of narcolepsy have already been published. However contemporary guidelines are necessary given the growing use of modafinil to treat excessive daytime sleepiness in Europe within the last 5-10 years, and the decreasing need for amphetamines and amphetamine-like stimulants; the extensive use of new antidepressants in the treatment of cataplexy, apart from consistent randomized placebo-controlled clinical trials; and the present re-emergence of gamma-hydroxybutyrate under the name sodium oxybate, as a treatment of all major symptoms of narcolepsy. A task force composed of the leading specialists of narcolepsy in Europe has been appointed. This task force conducted an extensive review of pharmacological and behavioral trials available in the literature. All trials were analyzed according to their class evidence. Recommendations concerning the treatment of each single symptom of narcolepsy as well as general recommendations were made. Modafinil is the first-line pharmacological treatment of excessive daytime sleepiness and irresistible episodes of sleep in association with behavioral measures. However, based on several large randomized controlled trials showing the activity of sodium oxybate, not only on cataplexy but also on excessive daytime sleepiness and irresistible episodes of sleep, there is a growing practice in the USA to use it for the later indications. Given the availability of modafinil and methylphenidate, and the forseen registration of sodium oxybate for narcolepsy (including excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep) in Europe, the place of other compounds will become fairly limited. Since its recent registration cataplexy sodium oxybate has now become the first-line treatment of cataplexy. Second-line treatments are antidepressants, either tricyclics or newer antidepressants, the later being increasingly used these past years despite few or no randomized placebo-controlled clinical trials. As for disturbed nocturnal sleep the best option is still hypnotics until sodium oxybate is registered for narcolepsy. The treatments used for narcolepsy, either pharmacological or behavioral, are diverse. However the quality of the published clinical evidences supporting them varies widely and studies comparing the efficacy of different substances are lacking. Several treatments are used on an empirical basis, specially antidepressants for cataplexy, due to the fact that these medications are already used widely in depressed patients, leaving little motivation from the manufacturers to investigate efficacy in relatively rare indications. Others, in particular the more recently developed substances, such as modafinil or sodium oxybate, are evaluated in large randomized placebo-controlled trials. Our objective was to reinforce the use of those drugs evaluated in randomized placebo-controlled trials and to reach a consensus, as much as possible, on the use of other available medications.

Reduced hypothalamic gray matter in narcolepsy with cataplexy.

OBJECTIVES: Narcolepsy with cataplexy is associated with a loss of hypocretin. The question is, if there is an autoimmune or neurodegenerative process selectively killing the hypothalamic hypocretin-containing neurons or if these cells survive but fail to produce hypocretin. To support one of these hypothesis we aimed to detect structural changes in the hypothalamus of narcoletic patients. MATERIALS AND METHODS: Nineteen narcoleptic patients were compared to 16 healthy controls. We used voxel-based morphometry (VBM), an unbiased MRI morphometric method with a high sensitivity for subtle changes in gray and white matter volumes to investigate hypothalamic region in this condition. RESULTS: Classical MRI protocol revealed no structural abnormalities, but using VBM we found significant reduction in hypothalamic gray matter volumes between patients and controls. CONCLUSIONS: VBM showed hypothalamic gray matter loss in narcolepsy with cataplexy. This suggest that functional abnormalities of hypocretin neurons in narcolepsy are associated with structural changes of hypothalamus.

Medical factors of falling asleep behind the wheel.

Drivers' sleepiness and falling asleep while driving account for a considerable proportion of vehicle accidents (studies show different results from 1% to 30%). Sleepiness is rarely well recognised as a causing factor of traffic accidents. 2.5% up to 20% people suffer from excessive daytime sleepiness (EDS) with sleep deprivation as its most frequent cause. There is a strong association between sleep deprivation and medical problems--especially sleep disturbances. The sleep apnoea syndrome (SAS) has been identified as the most common cause of habitual drowsy driving. Patients with SAS (apart from other health problems) are 6 times more likely to have accidents. After adequate treatment of severe SAS with continuous positive airway pressure the risk of accident lowered 5 x. Other important sleep disturbances include chronic insomnia, narcolepsy, restless legs syndrome and periodic limb movement in sleep. Sleepiness was described in Parkinson's disease, dementia, epilepsy, in chronic cardiacs and in people with complex internal health problems. Regular or single intake of drugs (benzodiazepines, antidepressants, antihistaminics, antipsychotics and others) can itself induce sleep problems. Sleepiness in persons without sleep disorder may occur due to preventable causes such as poor sleep habits which lead to sleep deprivation.

Decreased perception of high frequency sound in severe obstructive sleep apnea.

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of upper airway obstruction during sleep, which is manifested by apnea or hypopnea. Decreased blood oxygen saturation, changes in heart rate, fluctuations in brain perfusion, changes in intracranial pressure, snoring and vibration are factors that may potentially affect hearing in patients with OSA. The aim of the present study was to test the hypothesis that hearing is affected in OSA. 43 males aged 34-74 years (mean 48.2) with suspected sleep-disordered breathing without other comorbidity or medication that may affect sleep or hearing were included. Nocturnal polysomnography, pure tone audiometry (PTA), transient evoked otoacoustic emissions (TEOAE) and brainstem auditory evoked potentials (BAEP) were evaluated. The severity of OSA was indicated by the number of apneas and hypopneas per hour of sleep (apnoe/hypopnoe index - AHI). OSA (AHI>/=5) was detected in 28 patients by polysomnography. Mild OSA (AHI 5-15) was confirmed in 11 patients, severe OSA (AHI>/=30) in 17 patients. Simple snoring (AHI<5) was diagnosed in 15 males. In patients suffering from severe OSA, tone audiometry demonstrated higher auditory threshold at frequencies of 4000 and 8000 Hz than in patients with AHI<15 (p<0.005). Auditory threshold values correlated with age in all groups. At a frequency of 8000 Hz, auditory threshold additionally correlated with BMI, AHI, oxygen desaturation index and decreased oxygen saturation. No differences were detected in TEOAE and BAEP between subjects with OSA and snoring. PTA and TEOAE decreased with increasing age. The present results show decreased perception of high frequency sound in severe OSA.

Changing of facial skeleton for treatment of obstructive sleep apnoea syndrome.

Obstructive sleep apnoea syndrome (OSAS) is a potentially life-threatening disorder. It is characterized by at least five episodes of apnoea or hypopnoea during sleep lasting for more than 10 seconds. Apnoea or hypopnoea are accompanied by respiratory efforts. Changes of the facial skeleton by mandibular or maxillo-mandibular advancement belong to surgical techniques which might affect moderate and severe OSAS. In the surgical procedure mandible alone or the upper and lower jaws are moved forward by at least 10 mm. Thus also muscles fixed to the facial skeleton and upper airway dilatators are moved forward. The discussion also mentions possible complications and limitations of this surgical technique.

[Periodic limb movements in sleep: polysomnographic and actigraphic methods for their detection]. / Periodické pohyby koncetinami ve spáinku a jejich vysetrování pomocí polygrafie a aktigrafie.

BACKGROUND: The aim of our study was to compare the results obtained by simultaneous polysomnographic and actigraphic recording and thus to estimate the specificity and sensitivity of actigraphic evaluation of periodic leg movements in sleep (PLMS). As a standard method, PLMS are detected by means of polysomnography, including superficial EMG of anterior tibial muscles. Since 1995, there have been efforts to detect PLMS by means of actigraphy, which is more convenient for both patient and investigator. METHODS AND RESULTS: Recordings were done during 44 nights in 42 patients (10 women, mean age 49.2, SD 13.1 years) in our sleep laboratory. The same criteria for periodic leg movements and the cut-off periodic leg movements index (PLMI > 5) were used in both methods. For the actigraphic way of PLMS detection, we found a specificity of 90%, sensitivity 60%, positive predictive value 88.2%, negative predictive value 64.3 % and total diagnostic accuracy of 73.3%. A close correlation (Spearman's coefficient rho > 0.64, p < 0.0001) between PLMI resulting from either method of recording was observed, though the PLMI actigraph proved to be significantly lower (Sign test--p < 0.01). CONCLUSIONS: Our study has proven good specificity a negative predictive value of the actigraphic recording. To improve its sensitivity, we suggest to reduce the threshold of significant presence PLMS, as expressed by PLMI, from 5 to 3. Actigraphy seems to be a suitable method from PLMS screening in the general population for both clinical and research purposes.

Kleine-Levin syndrome: an autoimmune hypothesis based on clinical and genetic analyses.

BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities in the central serotonin and dopamine metabolism. Several clinical symptoms also suggest an underlying autoimmune process. OBJECTIVE: To systematically investigate patients with KLS with reference to the available hypotheses. METHODS: The authors collected clinical, polysomnographic, CSF, CT, and MRI records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS and their families. The genotype data were contrasted with data from a normal control population. RESULTS: Only human leukocyte antigen (HLA)-DQB1*0201 allele frequency was significantly increased in patients with KLS. Three patients with KLS but none of the control subjects were DQB1*0201 homozygous. Two affected subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201 heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a preferential transmission. CONCLUSION: These findings, together with the young age at onset, the recurrence of symptoms, and the frequent infectious precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome.

An alternative to the multiple sleep latency test for determining sleepiness in narcolepsy and hypersomnia: polygraphic score of sleepiness.

This article describes a quantitative assessment of pathological diurnal sleepiness in three groups of patients with excessive daytime sleepiness: narcoleptic patients, idiopathic hypersomniac patients, hypersomniac patients with sleep apnea syndrome. We analyzed polygraphic diurnal recordings of 45 min duration obtained under standardized conditions. We called the percentage of total sleep time during the 45-min recording the polygraphic index of sleepiness. The polygraphic score of sleepiness is determined by the latencies and total durations of the individual sleep stages. Because deeper sleep stages correspond to more pronounced sleepiness than do superficial sleep stages, we introduced coefficients for each sleep stage. We present a formula for calculating a score in a single figure that gives a good indication of the patient's sleepiness and makes inter- and intraindividual comparison possible. Separate REM and NREM sleep scores are also given.

Familial aspects of narcolepsy-cataplexy in the Czech Republic.

A group of 153 probands with narcolepsy included 38 subjects (24.8%) with a familial incidence of excessive daytime sleepiness (EDS). In 15 cases (9.8%), at least one additional family member suffered from narcolepsy-cataplexy; only EDS was present in the remaining 23 cases (15.0%). One thousand eighty-two relatives were evaluated. The percentage of first degree relatives affected with narcolepsy-cataplexy was 2.28% (1.20% if only clinically confirmed cases were accounted); the adequate value for second degree relatives was 1.49%. The occurrence of EDS exceeded these values several times (4.28% in first degree relatives, 6.57% in second degree relatives). The vertical mode of transmission was found in most families. Human leukocyte antigen (HLA) typing was performed in six families with multiple-case incidence of narcolepsy. Forty-one blood samples were analyzed (12 patients with narcolepsy, 7 with only EDS, 2 with sleep apnea syndrome, and 20 healthy relatives). HLA DR2+ and DQB1*0602+ were found in only 8 out of 12 narcoleptic patients with cataplexy and in six out of seven patients with isolated attacks of sleepiness. These findings support the hypothesis that there is a common genetic basis for narcolepsy associated with cataplexy and "monosymptomatic" forms of narcolepsy and suggest the existence of non-major histocompatibility complex (MHC) susceptibility factors for narcolepsy.