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, P = 9.03 × 10(-11), OR = 1.23) and a locus on 16q12.1 (rs3104767, P = 9.4 × 10(-19), OR = 1.35) in a linkage disequilibrium block of 140 kb containing the 5'-end of TOX3 and the adjacent non-coding RNA BC034767.

Anatomy of disturbed sleep in pallido-ponto-nigral degeneration.

OBJECTIVE: Pallido-ponto-nigral degeneration (PPND), caused by an N279K mutation of the MAPT gene, is 1 of a family of disorders collectively referred to as frontotemporal dementia and parkinsonism linked to chromosome 17. This study aims to characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Pathological findings are also provided. METHODS: Ten subjects were recruited from the PPND kindred; 5 affected and 5 unaffected. The subjects underwent clinical assessment, polysomnography, and wrist actigraphy. Available sleep-relevant areas (pedunculopontine/laterodorsal tegmentum, nucleus basalis of Meynert, thalamus, and locus ceruleus) of affected subjects were analyzed postmortem. RESULTS: The affected group's total sleep time was an average of 130.8 minutes compared to 403.6 minutes in the control group (p < 0.01). Initial sleep latency was significantly longer in affected subjects (range, 58-260 minutes vs 3-34 minutes). Affected subjects also had an increase in stage I sleep (8.5% vs 1%), and less stage III/IV sleep (8.5% vs 17%). At the time of autopsy, all cases had severe neuronal tau pathology in wake-promoting nuclei, as well as decreases in thalamic cholinergic innervations. There was no difference in orexinergic fiber density in nucleus basalis of Meynert or locus ceruleus compared to controls. INTERPRETATION: The PPND kindred showed severe sleep disturbance. Sleep abnormalities are common in neurodegenerative illnesses, but this is the first study of sleep disorders in PPND. Unlike most neurodegenerative conditions, PPND is characterized by decreased total sleep time, increased sleep latency, and decreased sleep efficiency, without daytime hypersomnolence.

Prevalence of restless legs syndrome in blood donors.

Iron deficiency anemia has been linked to restless legs syndrome (RLS) and regular blood donation may lead to iron deficiency. It has been reported that blood donations may be associated with RLS. A recent study from Sweden found that 25% of the women donors were affected by RLS. However, this type of study has not been replicated in the United States. We conducted a study in our blood donation unit between September and October 2008. To identify those with RLS, we used the RLS diagnostic index questionnaire by Benes et al. The proportion of blood donors with RLS was estimated and the number of blood donations and hemoglobin levels were compared according to RLS status. One hundred and fifty one patients were interviewed; 7 patients who donated only platelets were excluded, leaving 144 patients for analysis. There were 13 (9.0%, 95% confidence interval [CI]: 4.9-14.9%) patients with RLS. Of these, 7 (4.9%, 95% CI: 2.0-9.8%) had possible RLS and 6 (4.2%, 95% CI: 1.5-8.9%) had major or clinically relevant RLS. There was no dramatic association between RLS and number of blood donations or hemoglobin level (all P >or= 0.21). In our sample of blood donors in the United States, the prevalence of major RLS was 4%. We could not demonstrate an association between RLS and the frequency of blood donation or hemoglobin level in our relatively small sample; a larger sample is needed to better identify any associations.

Clinical-pathologic study of biomarkers in FTDP-17 (PPND family with N279K tau mutation).

The objective of this clinical-pathologic study was to identify biomarkers for a pallidopontonigral degeneration (PPND) kindred of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) harboring the N279K tau mutation. Five affected subjects, one at-risk who later became symptomatic, and one at-risk asymptomatic mutation carrier, had abnormal (18)fluorodeoxyglucose PET demonstrating asymmetric temporal lobe hypometabolism. All except the asymptomatic mutation carrier had abnormal brain MRI. Parkinsonism, myoclonus, anosmia, insomnia, speech, and autonomic dysfunction were identified. Autopsy of six affected subjects showed frontotemporal degeneration with extensive tauopathy. Further studies of FTDP-17 patients are needed to replicate these findings.

Absence of rapid eye movement sleep behavior disorder in 11 members of the pallidopontonigral degeneration kindred.

BACKGROUND: Rapid eye movement sleep behavior disorder (RBD) is a parasomnia that is manifested by dream enactment behavior. The electrophysiologic substrate for RBD on polysomnography is rapid eye movement sleep without atonia. Rapid eye movement sleep behavior disorder likely stems from neuronal network dysfunction in the brainstem, although it is not yet clear which specific networks are involved. Rapid eye movement sleep behavior disorder is often associated with the sporadic synucleinopathies but rarely associated with the sporadic tauopathies. There are no reports on the possible association of rapid eye movement sleep without atonia and RBD with any familial tauopathy. OBJECTIVE: To characterize the clinical sleep and polysomnography features in a kindred with a familial tauopathy. METHODS: We performed standard polysomnography in 11 members of the pallidopontonigral degeneration kindred irrespective of any sleep-related complaints. Neuropathologic findings were analyzed in those who subsequently underwent autopsy. RESULTS: Six affected and 5 genealogically at-risk family members were studied. None of the 11 had a history of dream enactment behavior. Nine of the 11 members attained sufficient rapid eye movement sleep on polysomnography, and the electrophysiologic features of rapid eye movement sleep without atonia and behavioral manifestations of RBD were absent in all subjects. Neuropathologic examination of 4 affected individuals revealed marked nigral degeneration in 3 along with mild degenerative changes in the locus coeruleus, pontine nuclei and tegmentum, and medullary tegmentum. CONCLUSIONS: These findings argue against nigral degeneration being the primary cause of RBD. The absence of the historical, electrophysiologic, and behavioral manifestations of RBD in this kindred provides further evidence that RBD is rare in the sporadic and familial tauopathies. The difference in frequencies of RBD associated with the synucleinopathies compared with the tauopathies suggests differences in the selective vulnerability of brainstem circuits between the synucleinopathies and tauopathies.

Prevalence of restless legs syndrome among native South Americans residing in coastal and mountainous areas.

OBJECTIVE: To determine the prevalence of restless legs syndrome (RLS) in native South Americans and identify the impact of geographic location. PARTICIPANTS AND METHODS: An epidemiological telephone survey of RLS symptoms involving natives from coastal and mountainous areas was performed during July 2, 2004, through September 28, 2004. The process consisted of 2 phases: the creation of the epidemiological instrument and the telephone survey. RESULTS: Five hundred adults, 250 from the mountainous regions and 250 from the coastal region (190 men and 310 women; age range, 25-85 years) were interviewed and subsequently divided on the basis of International Restless Legs Syndrome Study Group criteria into those who had RLS (RLS+ group) and those who did not (RLS- group). Ten (2.0%) had RLS. The overall rate of RLS in adults living in the mountainous region at 2816 m above sea level (3.2% [8/250]) was significantly higher than that for adults living in the coastal region at 4 m above sea level (0.80% [2/250]; P = .002). The mean age of the RLS+ group was 49.5 years (SD, 15.20 years; range, 25-85 years). CONCLUSION: Native South American adults have a prevalence of RLS well below that reported in populations with European ancestry but similar to that in Asian and Turkish populations. Furthermore, in Ecuador, geographic differences were identified in areas of similar population density.

Genetics of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder, although under-diagnosed, with a prevalence of up to 15% depending on the population sampled. Familial aggregation has been widely shown since Ekbom formerly described the condition in 1960; twin studies support a genetic contribution in the development of this disorder. Molecular genetic approaches have identified three genomic regions in RLS susceptibility, however no specific mutations have yet been identified. Herein, we review the current status of genetics in RLS, providing some methodological guidelines to help future research.

Neurobiologic basis of nicotine addiction and psychostimulant abuse: a role for neurotensin?

Addiction to psychostimulant drugs such as nicotine, amphetamine, and cocaine is a serious public health problem for which there is a paucity of accepted forms of pharmacotherapy. Nicotine dependence has become more frequently associated with psychiatric illness in recent decades, and patients who have schizophrenia are at highest risk and have the poorest prognosis for stopping their addiction. Possible mechanisms for this association include self-medication, with nicotine attenuating attentional deficits and negative symptoms. Neurotensin has been postulated to be an endogenous neuroleptic, and the performance of neurotensin analogues in animal models of addiction makes such compounds intriguing candidates for treatment of addiction in high-risk psychiatric populations.

Pupillometry in clinically sleepy patients.

OBJECTIVES: Investigators have suggested using pupillometry to assess alertness in hypersomnolent patients. In this study we assessed hypersomnolent patients and normal volunteers by using pupillometry and examined the usefulness of this technique for the diagnosis of pathologic sleepiness in individual patients. METHODS: Forty-nine patients were examined by pupillometry and their sleepiness was assessed by using the multiple sleep latency test (MSLT). Thirty-three normal well-rested volunteers were also examined by pupillometry. The patients were classified as having 'mild', 'moderate', or 'severe' sleepiness, based on their mean MSLT sleep latency. Several dynamic variables of pupil diameter were calculated from the pupillograms and correlated with the mean MSLT sleep latency, and were compared between severity groups of patients and the well-rested normal subjects. RESULTS: All but two pupillometric variables were significantly correlated with sleep latency. All except the same two pupillometric variables of the sleepiest group were significantly different from those of normal subjects. However, only 51% of patients with mean sleep latencies less than 10 min and 35% of patients with mean sleep latencies of less than 5 min could be correctly identified by pupillometry. CONCLUSIONS: Pupillometry is clearly associated with differences in alertness between groups of patients. However, pupillometric assessment cannot substitute for the MSLT in most cases.

Sleep patterns of cyclic parenteral nutrition, a pilot study: are there sleepless nights?

BACKGROUND: Cyclic home parenteral nutrition (HPN) is 1 of the few medical therapies given during normal nocturnal sleep hours, and it is possible that infusion may alter normal sleep patterns. The aim of this pilot study was to evaluate the sleep patterns of 5 patients receiving HPN. METHODS: An Epworth sleep questionnaire was completed and wrist Actigraph data were collected before admission to the sleep laboratory. Formal overnight polysomnography was then preformed for 3 consecutive nights. The first night served as the acclimatization period. On the second and third nights, patients were randomized to receive either no infusion or infusion of their standard parenteral nutrition. Results were reported as the median and range and were compared with historical aged-matched controls. RESULTS: Five patients (3 women and 2 men) with a mean age of 61 years (40 to 73 years) were studied. Patients had been HPN-dependent for a median of 23 months (4 to 60 months). Patients were receiving HPN because of short bowel syndrome (2), chronic pancreatitis (2), and intestinal pseudoobstruction (1). A 1.5-liter HPN formula, infused over 10 hours, included approximately 25 kcal/kg/d with 30% lipid and 1.0 to 1.5 g/kg/d of protein. All solutions included multiple trace elements and standard multivitamins. During total parenteral nutrition (TPN) infusion, the percent of sleep efficiency was higher than without infusion, 81% versus 72%. Sleep efficiency in age-matched controls was approximately 88%. Sleep latency was longer in patients compared with controls, and longer in patients during infusion than without infusion, 35 versus 28 minutes. During TPN infusion, the percent of stage-1 (2%), stage-2 (52%), slow-wave (24%) and random eye movement (REM) sleep (21%) was similar to values during the night without infusion. Controls had lower slow-wave and REM times. The median Epworth sleep score was 3, which is the normal reported range. CONCLUSIONS: Although sleep quality is reduced in patients receiving HPN compared with aged-matched controls, sleep quality does not seem to be negatively effected by cyclic HPN infusion.

Abnormal daytime sleepiness in dementia with Lewy bodies compared to Alzheimer's disease using the Multiple Sleep Latency Test.

INTRODUCTION: Excessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer's disease (AD) dementia. METHODS: A full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime Multiple Sleep Latency Test (MSLT). Neuropathologic examinations of 20 participants with DLB were carried out. RESULTS: Although nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean 6.4 ± 5 minutes vs 11 ± 5 minutes, P <0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (P <0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (P <0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism or rapid eye movement sleep behavior disorder. These data suggest that abnormal daytime sleepiness is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features or sleep variables. CONCLUSIONS: Daytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. Daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep-wake physiology, and further work is needed to better understand the underlying mechanisms.

Analysis of the C9orf72 repeat in Parkinson's disease, essential tremor and restless legs syndrome.

The hexanucleotide expanded repeat (GGGGCC) in intron 1 of the C9orf72 gene is recognized as the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, as part of the clinical phenotype, some patients present with parkinsonism. The present study investigated the potential expansion or association of the C9orf72 repeat length with susceptibility to Parkinson's disease and related disorders, essential tremor and restless legs syndrome. One restless legs syndrome patient was shown to harbor a repeat expansion, however on clinical follow-up this patient was observed to have developed frontotemporal dementia. There was no evidence of association of repeat length on disease risk or age-at-onset for any of the three disorders. Therefore the C9orf72 hexanucleotide repeat expansion appears to be specific to TDP-43 driven amyotrophic lateral sclerosis and dementia.

Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in a community-based sample.

OBJECTIVE: To validate a questionnaire focused on REM sleep behavior disorder (RBD) in a community-based sample. BACKGROUND: RBD is a parasomnia manifested by recurrent dream enactment behavior during REM sleep. While confirmation of RBD requires the presence of REM sleep without atonia on polysomnography (PSG), a screening measure for RBD validated in older adults would be desirable for clinical and research purposes. METHODS: We had previously developed the Mayo Sleep Questionnaire (MSQ) to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of subjects' bed partners with the findings on PSG. All subjects recruited from 10/04 to 12/08 in the Mayo Clinic Study of Aging--a population-based study of aging in Olmsted County, Minnesota--who had also undergone a previous PSG were the focus of this analysis. RESULTS: The study sample included 128 subjects (104 male; median age 77 years [range 67-90]), with the following clinical diagnoses at baseline assessment: normal (n = 95), mild cognitive impairment (n = 30), and mild Alzheimer disease (n = 3). Nine (5%) subjects had RBD based on history and PSG evidence of REM sleep without atonia. The core question on recurrent dream enactment behavior yielded sensitivity (SN) of 100% and specificity (SP) of 95% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD improved specificity. CONCLUSIONS: These data suggest that the MSQ has adequate SN and SP for the diagnosis of RBD among elderly subjects in a community-based sample.

Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in an aging and dementia cohort.

OBJECTIVE: To validate a questionnaire focused on rapid eye movement sleep (REM) sleep behavior disorder (RBD) among participants in an aging and dementia cohort. BACKGROUND: RBD is a parasomnia that can develop in otherwise neurologically-normal adults as well as in those with a neurodegenerative disease. Confirmation of RBD requires polysomnography (PSG). A simple screening measure for RBD is desirable for clinical and research purposes. METHODS: We had previously developed the Mayo Sleep Questionnaire (MSQ), a 16 item measure, to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of patients' bed partners with the findings on PSG. All subjects recruited in the Mayo Alzheimer's Disease Research Center at Mayo Clinic Rochester and Mayo Clinic Jacksonville from 1/00 to 7/08 who had also undergone a PSG were the focus of this analysis. RESULTS: The study sample was comprised of 176 subjects (150 male; median age 71 years (range 39-90)), with the following clinical diagnoses: normal (n = 8), mild cognitive impairment (n = 44), Alzheimer's disease (n = 23), dementia with Lewy bodies (n = 74), as well as other dementia and/or parkinsonian syndromes (n = 27). The core question on recurrent dream enactment behavior yielded a sensitivity (SN) of 98% and specificity (SP) of 74% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD and one on obstructive sleep apnea improved specificity. CONCLUSIONS: These data suggest that among aged subjects with cognitive impairment and/or parkinsonism, the MSQ has adequate SN and SP for the diagnosis of RBD. The utility of this scale in other patient populations will require further study.

Clinical and genetic description of a family with a high prevalence of autosomal dominant restless legs syndrome.

OBJECTIVE: To conduct clinical and molecular genetic analyses of the members of an extended family in Central Indiana with a high prevalence of restless legs syndrome (RLS). PARTICIPANTS AND METHODS: From February 1, 2006, through August 31, 2008, we collected data from members of this family, which is of English descent. Genealogical methods were used to expand the family tree, and family members were screened with an RLS questionnaire. Telephone interviews and personal examinations were performed at Mayo Clinic and during a field trip to Central Indiana. Blood samples were collected for molecular genetic analysis. A follow-up telephone interview was conducted 1 year later. RESULTS: The family tree spans 7 generations with 88 living members, 30 of whom meet the criteria for diagnosis of RLS established by the International Restless Legs Syndrome Study Group. Three affected family members also have Parkinson disease or essential tremor. The mode of RLS inheritance is compatible with an autosomal dominant pattern. The affected family members do not exhibit linkage to the 5 known RLS loci or mutations in the RLS susceptibility genes MEIS1 and BTBD9. CONCLUSION: Of 88 members of this single extended family in Central Indiana, 30 were diagnosed as having RLS. Because our analysis shows that the disease is not linked to any of the known RLS loci or risk-associated genes, we postulate that members of this family may carry a gene mutation in a novel genetic locus.