Olli Polo

Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1

Restless legs syndrome (RLS) is a sensorimotor disorder with an age-dependent prevalence of up to 10% in the general population above 65 years of age. Affected individuals suffer from uncomfortable sensations and an urge to move in the lower limbs that occurs mainly in resting situations during the evening or at night. Moving the legs or walking leads to an improvement of symptoms. Concomitantly, patients report sleep disturbances with consequences such as reduced daytime functioning. We conducted a genome-wide association study (GWA) for RLS in 922 cases and 1,526 controls (using 301,406 SNPs) followed by a replication of 76 candidate SNPs in 3,935 cases and 5,754 controls, all of European ancestry. Herein, we identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972, Pu200a=u200a9.03 × 10−11, ORu200a=u200a1.23) and a locus on 16q12.1 (rs3104767, Pu200a=u200a9.4 × 10−19, ORu200a=u200a1.35) in a linkage disequilibrium block of 140 kb containing the 5′-end of TOX3 and the adjacent non-coding RNA BC034767.

Comparison of Pregabalin with Pramipexole for Restless Legs Syndrome

BACKGROUNDnDopaminergic medications relieve symptoms of the restless legs syndrome (RLS) but have the potential to cause iatrogenic worsening (augmentation) of RLS with long-term treatment. Pregabalin may be an effective alternative.nnnMETHODSnIn this 52-week, randomized, double-blind trial, we assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. Patients were randomly assigned to receive 52 weeks of treatment with pregabalin at a dose of 300 mg per day or pramipexole at a dose of 0.25 mg or 0.5 mg per day or 12 weeks of placebo followed by 40 weeks of randomly assigned active treatment. The primary analyses involved a comparison of pregabalin and placebo over a period of 12 weeks with use of the International RLS (IRLS) Study Group Rating Scale (on which the score ranges from 0 to 40, with a higher score indicating more severe symptoms), the Clinical Global Impression of Improvement scale (which was used to assess the proportion of patients with symptoms that were very much improved or much improved), and a comparison of rates of augmentation with pregabalin and pramipexole over a period of 40 or 52 weeks of treatment.nnnRESULTSnA total of 719 participants received daily treatment, 182 with 300 mg of pregabalin, 178 with 0.25 mg of pramipexole, 180 with 0.5 mg of pramipexole, and 179 with placebo. Over a period of 12 weeks, the improvement (reduction) in mean scores on the IRLS scale was greater, by 4.5 points, among participants receiving pregabalin than among those receiving placebo (P<0.001), and the proportion of patients with symptoms that were very much improved or much improved was also greater with pregabalin than with placebo (71.4% vs. 46.8%, P<0.001). The rate of augmentation over a period of 40 or 52 weeks was significantly lower with pregabalin than with pramipexole at a dose of 0.5 mg (2.1% vs. 7.7%, P=0.001) but not at a dose of 0.25 mg (2.1% vs. 5.3%, P=0.08). There were six cases of suicidal ideation in the group receiving pregabalin, three in the group receiving 0.25 mg of pramipexole, and two in the group receiving 0.5 mg of pramipexole.nnnCONCLUSIONSnPregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole. (Funded by Pfizer; ClinicalTrials.gov number, NCT00806026.).

Sleep in midlife women: effects of menopause, vasomotor symptoms, and depressive symptoms.

ObjectiveThis study aims to evaluate subjective sleep quality in premenopausal and postmenopausal women and to study its association with night sweats, hot flashes, and depressive symptoms. MethodsA total of 158 healthy women were recruited; 107 were premenopausal (44-48 y) and 51 were postmenopausal (53-58 y). Sleep quality was evaluated with the Basic Nordic Sleep Questionnaire, night sweats and hot flashes were evaluated with a specific symptom questionnaire, and depressive symptoms were evaluated with the Beck Depression Inventory. ResultsPostmenopausal women had poorer general sleep quality (P < 0.001), slept more restlessly (P = 0.020), and had more nocturnal awakenings (P = 0.015). However, the frequency of difficulty falling asleep, snoring, witnessed apnea, or use of sleep medication was similar between the groups. Furthermore, sleep latency, morning tiredness, or daytime tiredness did not differ between the groups. Postmenopausal women did not report more unintentional falling asleep at work or during leisure time; however, when not active, they dozed off more easily than premenopausal women (P < 0.001). Postmenopausal women had more night sweats (P < 0.001), hot flashes (P < 0.001), and depressive symptoms (P < 0.001). Even a low frequency of night sweats disturbed sleep in postmenopausal women, whereas only frequent night sweats were disturbing in premenopausal women. Depressive symptoms disturbed sleep regardless of menopause status. ConclusionsMaintenance insomnia, most evidently because of night sweats and hot flashes, seems to be the major type of insomnia in postmenopausal women and has to be considered when choosing insomnia treatment for this group. Initiation of sleep and daytime vitality are not, in general, affected by menopause.

Visual Dysfunction and Computational Sleep Depth Changes in Obstructive Sleep Apnea Syndrome

The aims of this study are to clarify whether patients with obstructive sleep apnea syndrome (OSAS) have a decline in verbally or visually-based cognitive abilities and whether the possible decline is related to particular sleep depth changes. In addition, the effect of continuous positive airway pressure (CPAP) on the possible changes is investigated. Fifteen OSAS patients and 15 healthy controls joined two full-night polysomnographies, including a computational measure of deep sleep percentage (DS%) bilaterally from the frontal, central and occipital channels, and a neuropsychological assessment. After a 6-month CPAP the patients underwent one more full-night polysomnography with computational DS% analysis and a neuropsychological assessment. At the baseline, the OSAS patients had poorer performance in the Picture Completion, in the Digit Symbol and in copying the Rey-Osterrieth Complex Figure Test (ROCFT) compared to the controls. The patients also showed reduced DS% in all 6 electrographic (EEG) channels compared to controls. The patients had an inter-hemispheric difference showing less deep sleep in the right hemisphere than in the left hemisphere both frontopolarly and centrally, while the controls showed this inter-hemispheric difference only frontopolarly. After CPAP the patients still had poorer performance in the Picture Completion and in the ROCFT. The patients continued to show reduced DS% in all 3 channels of the right hemisphere and occipitally in the left hemisphere, also the inter-hemispheric difference frontopolarly and centrally remained. OSAS patients have mild visually based cognitive dysfunction and reduced amount of deep sleep in the right hemisphere even after CPAP.

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

Summary Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15u2008126 cases and 95u2008725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5u2008×u200810−8) were tested for replication in an independent GWAS of 30u2008770 cases and 286u2008913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. Funding Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

Subjective sleep in premenopausal and postmenopausal women during workdays and leisure days: a sleep diary study.

ObjectiveThis study aims to evaluate subjective sleep in premenopausal and postmenopausal women by assessing differences between workdays and leisure days. MethodsNinety-one regularly working women—of which 58 were premenopausal (aged 44-48 y) and 33 were postmenopausal (aged 53-58 y)—were recruited. A 14-day sleep diary was used to investigate total sleep time (TST), nocturnal sleep time (ST), sleep latency, and number of awakenings after workdays and leisure days. ResultsTST (P = 0.002 during the 14-d period, P < 0.001 during workdays) and ST (P < 0.001 and P < 0.001) were shorter, and the number of awakenings (P = 0.033 and P = 0.043) during the entire 14-day period and after workdays was higher in postmenopausal women than in premenopausal women. No differences were observed during leisure days. Falling asleep took longer in postmenopausal women during the entire 14-day period (P = 0.011), during workdays (P = 0.040), and during leisure days (P = 0.010). After adjustment for the depression score, TST and ST during the 14-day period (P = 0.006 for TST, P = 0.004 for ST) and during workdays (P < 0.001 and P < 0.001) remained shorter in postmenopausal women. ConclusionsSelf-reported sleep problems are more common in postmenopausal women than in premenopausal women, and the difference is more pronounced during workdays than during leisure days. These observations suggest that postmenopausal women have the capacity for good sleep but are more vulnerable to sleep problems related to work-related stress.

Short-term medroxyprogesterone acetate in postmenopausal women with sleep-disordered breathing: a placebo-controlled, randomized, double-blind, parallel-group study.

ObjectiveMenopause predisposes women to sleep-disordered breathing (SDB) and sleep disturbances. Progestin has a potential to stimulate breathing and to induce sleep. Our goal was to test these effects objectively and to compare them with the effects of nasal continuous positive airway pressure (CPAP), which is the standard treatment of SDB. MethodsIn a placebo-controlled, double-blind, parallel-group trial, we investigated 34 postmenopausal women (17 in the placebo group and 17 in the medroxyprogesterone acetate [MPA] group) whose SDB had been treated with nasal CPAP for 6 months to 8 years prior to study entry. The 6-week trial included measurements with CPAP at baseline, after 14 days of placebo or MPA (60 mg daily), and after a 3-week washout. The participants discontinued their nasal CPAP therapy 1 week after baseline measurements and went on with study medication. ResultsTwo weeks after discontinuation of CPAP therapy, nightly oxygen saturation was sustained higher (P = 0.004) and arterial carbon dioxide tension was lower (P < 0.001) with MPA than with placebo. Carbon dioxide was also lower than during CPAP (P < 0.001), and this effect was sustained beyond 3 weeks after the cessation of MPA (P < 0.001). However, the apnea-hypopnea index of CPAP increased and sleep deteriorated similarly on MPA and placebo after withdrawal of CPAP therapy. ConclusionsIn postmenopausal women with SDB, MPA induces a long-lasting stimulatory effect on breathing without improving sleep quality or the apnea-hypopnea index.

Women with partial upper airway obstruction are not less sleepy than those with obstructive sleep apnea

PurposeSleep-disordered breathing (SDB) differs between genders in terms of the type, signs, and symptoms of the disease. Partial upper airway obstruction is underdiagnosed and undertreated.MethodsIn this study, we retrospectively investigated respiratory sleep recordings of 601 women, ending up with 240 women for the final statistical analyses. We hypothesized that there are differences between the signs and symptoms of sleep-disordered breathing whether women had partial upper airway obstruction or obstructive sleep apnea.ResultsThe results showed no difference in sleepiness between women with partial upper airway obstruction or obstructive sleep apnea. Also, the other main symptoms of SDB were the same between the groups. Micrognathia was more common in women with partial upper airway obstruction than with obstructive sleep apnea.ConclusionThese results indicate that partial upper airway obstruction in women should be clinically recognized like obstructive sleep apnea.

Transcutaneous CO2 plateau as set-point for respiratory drive during upper airway flow-limitation

Upper airway flow-limitation is often but not always associated with prolonged gradually increasing respiratory effort. We investigated the changes in transcutaneous carbon dioxide tension (tcCO(2)) during episodes of upper airway flow limitation during sleep with or without respiratory effort response. Seventy-seven episodes of progressive flow-limitation were analyzed in 36 patients with sleep-disordered breathing. TcCO(2) and arterial oxyhaemoglobin saturation (SaO2) were measured during steady breathing and during episodes of flow-limitation with and without effort response. After lights-off tcCO(2) increased and leveled-off at plateau, when breathing stabilized. During flow-limitation tcCO(2) increased at rate of 4.0kPa/h. Flow-limitation with increasing respiratory effort associated with tcCO(2) increase above the plateau (terminating at 105.2%, p<0.001), whereas flow-limitation without effort response associated with tcCO(2) increase starting below the plateau (95.8%, p<0.001). We conclude that the nocturnal tcCO(2) plateau indicates the level above which the increasing respiratory effort is triggered as response to upper airway flow-limitation. We propose that flow-limitation below the tcCO(2) plateau is an event related to stabilization of sleep and breathing.

Is ‘MILD’ sleep-disordered breathing in women really mild?

Sleep‐disordered breathing (SDB) consists of episodes of periodic obstructive or central sleep apnea and partial upper airway obstruction. The first two are well recognized and diagnosed, although still underdiagnosed. Traditionally, research in SDB has focused mainly on male patients with obstructive sleep apnea using apnea/hypopnea index (AHI) as a measure of severity. This has led to overrating of AHI as the only marker of SDB and underestimating of SDB in women. However, recently, partial upper airway obstruction has been acknowledged to be pathological and it may cause symptoms of SDB. There is a growing body of evidence that women suffer from SDB more than thought before and they especially have partial upper airway obstruction. Co‐morbidities such as cardiovascular diseases seem to be more prevalent in patients with SDB. This commentary points out some differences of SDB between genders in terms of symptoms and findings and emphasizes the clinical relevance of partial upper airway obstruction, especially in women.