Quantitative variations in the pathology of 11 cases of variant Creutzfeldt–Jakob disease (vCJD)

Quantitative variations in the density and distribution of the vacuolation (‘spongiform change’), surviving neurons, and prion protein (PrP) deposits were studied in eight brain regions from 11 cases of variant Creutzfeldt–Jakob disease (vCJD). Principal components analysis (PCA) was used to study the similarities and differences between cases and to identify the neuropathological variables which could best account for these variations. Two principal components (PC) were extracted from the data accounting in total for 93.4% of the variance; the majority of the variance (90%) being associated with PC1. Some clustering of the 11 cases in relation to PC1 and PC2 was evident. The densities of the vacuolation in the occipital cortex and the molecular layer of the cerebellum were positively and negatively correlated, respectively, with PC1. No significant variation between cases was associated with PrP deposition. These data suggest that vCJD cases have a consistent neuropathological profile characterised by the presence of vacuolation, neuronal loss and PrP deposition in the form of florid and non-florid deposits. However, there are quantitative variations between cases in the development of the vacuolation especially affecting the occipital cortex and cerebellum.     

Tau pathology in Creutzfeldt‐Jakob disease revisited

Creutzfeldt‐Jakob disease (CJD) is a human prion disease with different etiologies. To determine the spectrum of tau pathologies in CJD, we assessed phospho‐Tau (pTau) immunoreactivities in 75 sporadic CJD cases including an evaluation of the entorhinal cortex and six hippocampal subregions. Twelve cases (16%) showed only small tau‐immunoreactive neuritic profiles. Fifty‐two (69.3%) showed additional tau pathology in the medial temporal lobe compatible with primary age related tauopathy (PART). In 22/52 cases the lower pTau immunoreactivity load in the entorhinal cortex as compared to subiculum, dentate gyrus or CA4 region of the hippocampus was significantly different from the typical distribution of the Braak staging. A further 11 cases (14.7%) showed widespread tau pathologies compatible with features of primary tauopathies or the gray matter type of ageing‐related tau astrogliopathy (ARTAG). Prominent gray matter ARTAG was also observed in two out of three additionally examined V203I genetic CJD cases. Analysis of cerebrospinal fluid revealed prominent increase of total tau protein in cases with widespread tau pathology, while pTau (T181) level was increased only in four. This correlated with immunohistochemical observations showing less pathology with anti‐pTau T181 antibody when compared to anti‐pTau S202/T205, T212/S214 and T231. The frequency of tau pathologies is not unusually high in sporadic CJD and does not precisely relate to PrP deposition. However, the pattern of hippocampal tau pathology often deviates from the stages of Braak. Currently applied examination of cerebrospinal fluid pTau (T181) level does not reliably reflect primary tauopathies, PART and ARTAG seen in CJD brains.     

Mutation of the PRNP gene at codon 211 in familial Creutzfeldt‐Jakob disease

Creutzfeldt‐Jakob disease (CJD) belongs to a group of chronic, progressive, neurodegenerative disorders that may be hereditary, infectious, or sporadic. Hereditary CJDs are associated with mutations in the PRNP gene on chromosome 20p12‐pter. We report a family in which four patients developed classical clinical signs of CJD, including severe cognitive decline, cerebellar signs, myoclonic jerks, and synchronic periodic discharges on electroencephalogram. The E211Q mutation has been identified in family members, but not in 97 sporadic CJD patients referred to the Italian registry of CJD nor in 205 healthy normal subjects, suggesting a pathogenic role for this mutation. © 2001 Wiley‐Liss, Inc.     

Comparison of apnoea–hypopnoea index and oxygen desaturation index when identifying obstructive sleep apnoea using type‐4 sleep studies

The concordance of different indices from type‐4 sleep studies in diagnosing and categorising the severity of obstructive sleep apnoea is not known. This is a critical gap as type‐4 sleep studies are used to diagnose obstructive sleep apnoea in some settings. Therefore, we aimed to determine the concordance between flow‐based apnoea–hypopnoea index (AHI_flow50%) and oxygen desaturation index (ODI_3%) by measuring them concurrently. Using a random sub‐sample of 296 from a population‐based cohort who underwent two‐channel type‐4 sleep studies, we assessed the concordance between AHI_flow50% and ODI_3%. We compared the prevalence of obstructive sleep apnoea of various severities as identified by the two methods, and determined their concordance using coefficient Kappa(κ). Participants were aged (mean ± SD) 53 ± 0.9 years (48% male). The body mass index was 28.8 ± 5.2 kg m^?2 and neck circumference was 37.4 ± 3.9 cm. The median AHI_flow50% was 5 (inter‐quartile range 2, 10) and median ODI_3% was 9 (inter‐quartile range 4, 15). The obstructive sleep apnoea prevalence reported using AHI_flow50% was significantly lower than that reported using ODI_3% at all severity thresholds. Although 90% of those with moderate–severe obstructive sleep apnoea classified using AHI_flow50% were identified by using ODI_3%, only 46% of those with moderate–severe obstructive sleep apnoea classified using ODI_3% were identified by AHI_flow50%. The overall concordance between AHI_flow50% and ODI_3% in diagnosing and classifying the severity of obstructive sleep apnoea was only fair (κ = 0.32), better for males (κ = 0.42 [95% confidence interval 0.32–0.57] versus 0.22 [95% confidence interval 0.09–0.31]), and lowest for those with a body mass index ≥ 35 (κ = 0.11). In conclusion, ODI_3% and AHI_flow50% from type‐4 sleep studies are at least moderately discordant. Until further evidence is available, the use of ODI_3% as the measure of choice for type‐4 sleep studies is recommended cautiously.     

Misdiagnosis of familial Mediterranean fever in patients with Anderson–Fabry disease

Fabry disease (FD) is an underdiagnosed pathology due to its symptomatology that overlaps with various systemic and rheumatic disorders, including familial Mediterranean fever (FMF). We examined the Mediterranean fever (MEFV) and α‐galactosidase A (GLA) genes, whose mutations are responsible for FMF and FD, respectively, in 42 unrelated patients diagnosed with FMF, which revealed significant ambiguity regarding some of the symptoms which are also present in FD. The objective of this study was to determine the spectrum of mutations present in these genes, in order to identify cases of mistaken diagnosis of FMF and/or missed diagnosis of FD. Ten out of 42 patients had one mutation in homozygosis or two different mutations in heterozygosis in the MEFV gene; 20/42 had a single heterozygous mutation, and 12/42 did not have genetic alterations in MEFV. The analysis of the GLA gene conducted on all the samples revealed that three subjects, and some members of their families, had two different exonic mutations associated with FD. Family studies allowed us to identify eight other cases of FD, bringing the total undiagnosed subjects to 11/53. Analyzing the MEFV and GLA genes in patients with clinical diagnoses of FMF proved to be fundamentally important for the reduction of diagnostic errors.     

Sporadic Creutzfeldt–Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties

The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt–Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these “pure” cases, “mixed” cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co‐occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft‐associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1.     

Incremental shuttle walk test in the assessment of patients with obstructive sleep apnea–hypopnea syndrome

Obstructive sleep apnea–hypopnea syndrome is associated independently with an increase in cardiovascular risk factors and is associated with self‐reported lack of exercise. We aimed to investigate the utility of the incremental shuttle walk test in routine clinical practice to monitor physical capacity of patients with obstructive sleep apnea–hypopnea syndrome and explore whether continuous positive airway pressure therapy alters exercise capacity. Participants with symptomatic moderate/severe obstructive sleep apnea–hypopnea syndrome attending for a trial of continuous positive airway pressure therapy completed questionnaires assessing sleepiness and physical activity and underwent an incremental shuttle walk test. Subjects compliant or partially compliant with continuous positive airway pressure therapy underwent reassessment at 2 weeks, 3 months and 6 months post‐initiation of therapy. Participants unable to tolerate continuous positive airway pressure therapy completed a single reassessment 6 months after their initial visit. Continuous positive airway pressure therapy resulted in an increased distance walked during the incremental shuttle walk test. Improvements in cardiovascular responses to exercise were identified. Compliant patients reported increased daily activity. The incremental shuttle walk test is a simple, reproducible and safe test that is responsive to continuous positive airway pressure treatment. Our findings support the use of the incremental shuttle walk test for monitoring the effects of continuous positive airway pressure treatment and may suggest its use in rehabilitation programmes designed to reduce obesity and cardiovascular risk factors in patients with obstructive sleep apnea–hypopnea syndrome.     

Temporal association between sleep apnea–hypopnea and sleep bruxism events

There is some evidence suggesting that obstructive sleep apnea–hypopnea syndrome is concomitant with sleep bruxism. The aim of this study was to investigate the temporal association between sleep apnea–hypopnea events and sleep bruxism events. In an open observational study, data were gathered from 10 male subjects with confirmed obstructive sleep apnea–hypopnea syndrome and concomitant sleep bruxism. Polysomnography and audio‐video recordings were performed for 1 night in a sleep laboratory. Breathing, brain, heart and masticatory muscle activity signals were analysed to quantify sleep and sleep stage duration, and number and temporal distribution of apnea–hypopnea events and sleep bruxism events. Apnea–hypopnea events were collected within a 5‐min time window before and after sleep bruxism events, with the sleep bruxism events as the pivotal reference point. Two temporal patterns were analysed: (i) the interval between apnea–hypopnea events termination and sleep bruxism events onset, called T1; and (ii) the interval between sleep bruxism events termination and apnea–hypopnea events onset, called T2. Of the intervals between sleep bruxism events and the nearest apnea–hypopnea event, 80.5% were scored within 5 min. Most intervals were distributed within a period of <30 s, with peak at 0–10 s. The T1 interval had a mean length of 33.4 s and was significantly shorter than the T2 interval (64.0 s; P < 0.05). Significantly more sleep bruxism events were scored in association with the T1 than the T2 pattern (P < 0.05). Thus, in patients with concomitant obstructive sleep apnea–hypopnea syndrome and sleep bruxism, most sleep bruxism events occurred after sleep apnea–hypopnea events, suggesting that sleep bruxism events occurring close to sleep apnea–hypopnea events is a secondary form of sleep bruxism.     

Subjective–objective sleep discrepancy in patients with insomnia during and after cognitive behavioural therapy: An actigraphy study

Although patients with insomnia often show a discrepancy between self‐reported and objective sleep parameters, the role of and change in this phenomenon during treatment remain unclear. The present study aimed to assess the effect of cognitive behavioural therapy for insomnia on subjective and objective sleep discrepancy of total sleep time, sleep‐onset latency and wake after sleep onset. The total sleep time discrepancy was also assessed across the entire therapy. The second aim was to examine the treatment outcome of two insomnia groups differing in sleep perception. Thirty‐six adults with insomnia (mean age = 46.7 years, SD = 13.9; 22 females) were enrolled in the final analyses. Patients underwent a 6‐week group cognitive behavioural therapy for insomnia programme. Sleep diary and actigraphy measurements were obtained during the therapy. Patients who underestimated total sleep time (n = 16; underestimating group) were compared with patients who accurately perceived or overestimated total sleep time (n = 20; accurate/overestimating group). After cognitive behavioural therapy for insomnia, a significant decrease of total sleep time and sleep‐onset latency discrepancy was observed without a change in wake after sleep onset discrepancy in the total sample. Only the underestimating group reported decreased sleep‐onset latency discrepancy after the treatment, whereas total sleep time discrepancy significantly changed in both groups. The underestimating group showed a significant decrease of total sleep time discrepancy from Week 1 to Week 2 when the sleep restriction was implemented, whereas the accurate/overestimating group showed the first significant change at Week 4. In conclusion, both groups differing in sleep perception responded similarly to cognitive behavioural therapy for insomnia, although different In conclusion, both groups differing in sleep perception responded similarly to cognitive behavioural therapy for insomnia, although different therapeutic components could play important roles in each group. components could play important roles in each group.     

The Sleep Disorders Inventory: an instrument for studies of sleep disturbance in persons with Alzheimer's disease

The Sleep Disorders Inventory (SDI) is an expanded version of one item of the Neuropsychiatric Inventory (NPI). It describes the frequency, severity, and caregiver burden of sleep-disturbed behaviors during a period prior to its administration. We carried out post hoc analyses on baseline responses to the SDI in 104 persons with Alzheimer's disease (AD) and live-in caregivers who had been recruited for a trial of melatonin in the treatment of sleep disturbance. These patient-participants averaged <7 h of sleep per night, measured by actigraph (sleep disturbance), for the 2-3-week period prior to administration of SDI. Data were from the 2 weeks prior to the baseline visit (SDI, NPI) including actigraph-derived sleep variables and 2 weeks' worth of sleep quality ratings (SQR) kept in a diary by caregivers, plus Mini-Mental State Examination and activities of daily living assessment at baseline. The prevalence of sleep disorder symptoms ranged from 34% (waking up at night thinking it is daytime) and 82% (getting up during the night). Worse SDI scores were associated with worse cognitive, functional, and behavioral status, but not with sex, age, education or duration of dementia. SDI scores were significantly worse in individuals meeting independently established criteria for a diagnosis of 'sleep disturbance' (<6 h total sleep time per night) whereas demographic variables and scores reflecting cognition and function were not significantly different across this grouping. The SDI covers a wide range of sleep behaviors and provides information independent of sleep time and SQR.     

Subjective poor sleep quality in Chinese patients with Parkinson's disease without dementia

Parkinson''s disease (PD) is a common progressive neurological disorder and is composed of motor and non-motor symptoms. Sleep disturbances are frequent problems for patients with PD. The relationship between sleep disturbances with Hoehn and Yahr (H&Y) staging have been demonstrated. However, the relationship between sleep disorders and H&Y is still unclear in patients with PD without dementia in Chinese PD patients. In this study, we interviewed 487 non-demented PD patients of Chinese Han descents by H&Y classification. We found that night sleep quality was significantly associated with the severity of PD (P = 0.008). Panic disorder severity scale (PDSS) total scores were correlated with PD non-motor symptoms scale (PDNMS) scores (r = -0.528, P < 0.001), the Hamilton depression scale (HAMD) scores (r = -0.545, P < 0.001) and the Hamilton anxiety scale (HAMA) scores (r = -0.498, P < 0.001). Our results indicated that sleep quality deteriorated with the advancing of PD in Chinese non-demented patients with PD. Depression and anxiety may partly explain sleep disturbances in non-demented patients with PD.     

Pain and sleep quality in children with non‐vascular Ehlers–Danlos syndromes

The objective of this study was to explore the factors contributing to quality of life in pediatric patients with non‐vascular Ehlers–Danlos syndromes (EDS). Data were analyzed on 41 children with a diagnosis of non‐vascular EDS from the de‐identified data available from the National Institute on Aging (NIA) study of heritable disorders of connective tissue. Children under age 19 years were seen as part of a long‐term evaluation project from 2003 to 2013 on a larger natural history of patients with heritable disorders of connective tissue. Data collected included medical history, physical examination findings, diagnostic study results, and responses on validated questionnaires. We reviewed a sub‐cohort of children with a diagnosis of non‐vascular EDS and explored pain severity and interference via the Brief Pain Inventory, and sleep quality via the Pittsburgh Sleep Quality Index. Pain severity had a strong correlation with pain interference, and both were similar to other disorders that include chronic pain reported in the literature. Sleep quality did not correlate with pain severity or interference, but all patients had poor sleep quality in comparison to historical controls. We conclude that pain and sleep are significant issues in the pediatric non‐vascular EDS population, and future research may be directed toward these issues.     

Objective measures of sleep disturbances in children with Potocki–Lupski syndrome

Potocki–Lupski syndrome (PTLS; MIM 610883) is a neurodevelopmental disorder caused by a microduplication, a 3.7 Mb copy number variant, mapping within chromosome 17p11.2, encompassing the dosage‐sensitive RAI1 gene. Whereas RAI1 triplosensitivity causes PTLS, haploinsufficiency of RAI1 due to 17p11.2 microdeletion causes the clinically distinct Smith–Magenis syndrome (SMS; MIM 182290). Most individuals with SMS have an inversion of the melatonin cycle. Subjects with PTLS have mild sleep disturbances such as sleep apnea with no melatonin abnormalities described. Sleep patterns and potential disturbances in subjects with PTLS have not been objectively characterized. We delineated sleep characteristics in 23 subjects with PTLS who underwent a polysomnogram at Texas Children's Hospital. Eleven of these subjects (58%) completed the Child's Sleep Habits Questionnaire (CSHQ). Urinary melatonin was measured in one patient and published previously. While the circadian rhythm of melatonin in PTLS appears not to be disrupted, we identified significant differences in sleep efficiency, percentage of rapid eye movement sleep, oxygen nadir, obstructive apnea hypopnea index, and periodic limb movements between prepubertal subjects with PTLS and previously published normative data. Data from the CSHQ indicate that 64% (7/11) of parents do not identify a sleep disturbance in their children. Our data indicate that younger individuals, <10 years, with PTLS have statistically significant abnormalities in five components of sleep despite lack of recognition of substantial sleep disturbances by parents. Our data support the contention that patients with PTLS should undergo clinical evaluations for sleep disordered breathing and periodic limb movement disorder, both of which are treatable conditions.     

Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy

This post hoc analysis evaluated the dose‐related effects of sodium oxybate on sleep continuity and nocturnal sleep quality in patients with narcolepsy–cataplexy. Polysomnography data, including shifts to Stage N1/Wake, were from a randomized, placebo‐controlled trial of sodium oxybate. Patients were ≥16 years old with a diagnosis of narcolepsy including symptoms of cataplexy and excessive daytime sleepiness. Treatment was for 8 weeks with placebo or sodium oxybate 4.5, 6 or 9 g administered as two equally divided nightly doses. Relative to baseline, significant dose‐dependent reductions in the number of shifts per hour from Stages N2/3/rapid eye movement and Stages N2/3 to Stage N1/Wake were observed at week 8 with sodium oxybate (P < 0.05); sodium oxybate 6‐ and 9‐g doses also resulted in similar reductions in shifts per hour of rapid eye movement to Stage N1/Wake (both P < 0.05). Across all shift categories, the shift reductions with sodium oxybate 9 g were significantly greater than those observed with placebo (P < 0.05). Improvements from baseline in reported sleep quality were significantly greater with sodium oxybate 4.5 and 9 g at week 8 (P < 0.05). Correlations between change from baseline in number of shifts per hour to Stage N1/Wake and cataplexy frequency, patient‐reported nocturnal sleep quality, and excessive daytime sleepiness assessed using the Epworth Sleepiness Scale were numerically highest for the sodium oxybate 9‐g dose across all sleep stage shift categories. In these patients with narcolepsy, sodium oxybate showed improvements in the sleep continuity and nocturnal sleep quality that are characteristic of disrupted nighttime sleep ( ClinicalTrials.gov identifier NCT00049803).     

Genetic factors in evolution of sleep length – a longitudinal twin study in Finnish adults

Genetic factors affect many aspects of sleep, such as sleep length. We investigated the contribution of genetic factors to stability and change of sleep length among adults over a 15‐year period. In this representative follow‐up study we used the Finnish Twin Cohort as the study population. Questionnaire surveys were performed in 1975 (response rate 89%, 11 041 twin pairs; age ≥18 years), 1981 (84%, 9323; ≥24 years) and 1990 (77%, 4507; 33–60 years). Sleep was categorized as short (<7 h), average or long (>8 h). Pairwise similarity in monozygotic and dizygotic pairs was examined at each survey by age group and sex. Quantitative genetic modelling was used to estimate cross‐sectional and longitudinal genetic effects. The proportion of variance in sleep length at one point in time that was accounted for by genetic effects was very stable over the study period, being 0.31 in 1975, 0.32 in 1981 and 0.30 in 1990. Longitudinal genetic modelling indicated that the correlations of genetic effects between the three measurement points were high: 0.85 between 1975 and 1981; 0.93 between 1981 and 1990; and 0.76 between 1975 and 1990. Despite a high contribution of environmental effects, their correlations over time were modest: 0.31 between 1975 and 1981; 0.33 between 1981 and 1990; and 0.18 between 1975 and 1990. In conclusion, genetic factors have a modest but stable effect on the evolution of sleep length over a long time span in adults. Multiple measures are a more robust basis for genetic analyses than a single cross‐sectional measure.     

Cortico-motoneurone excitability in patients with obstructive sleep apnoea

A disordered neuromotor control of pharynx muscles may play a role in the genesis of obstructive sleep apnoea syndrome (OSAS). This raises the possibility of a dysfunction of projections descending from the cortex to segmental nuclei. With single pulse transcranial magnetic stimulation (TMS) we studied the physiology of the corticospinal projection to hand muscles in seven OSAS patients. At first, we compared them with nine age- and sex-matched normal controls in the wake state. The only abnormality was a lengthening of the central silent period (P < 0.001). This supports a steady imbalance of motor cortical interneurone activities towards a state of enhanced inhibition. Then we looked at changes of the motor-evoked potential (MEP) size and latency, according to whether patients were awake, or in a non-rapid eye movement (REM) 2 sleep stage, or during a typical apnoea. During non-REM 2 sleep, the average MEP amplitude was significantly (P < 0.05) smaller than in the awake state. The MEP latency was, in turn, significantly longer (P < 0.05). During apnoeas, the MEP size decreased, and the latency increased further (P < 0.05), indicating an extra depression of the cortico-motoneuronal activity. All TMS changes were detected outside the pharyngeal district, suggesting a widespread dysfunction of the cortico-motoneuronal system in the OSAS, which is more evident during apnoeas.     

Prolactin secretion during sleep in obstructive sleep apnoea patients

SUMMARY  Plasma prolactin (PRL) concentration exhibits a sleep-dependent pattern, with highest levels during sleep and lowest levels during the waking period. The syndrome of obstructive sleep apnoea (OSA) is associated with severe hypoxaemia and chronic sleep fragmentation, both of which could affect the sleep-entrained PRL rhythm. Treatment with nasal continuous positive airway pressure (CPAP) immediately restores a normal sleep structure by successful abolition of the apnoeas. In the present study, seven OSA patients underwent two night studies, once when no treatment was given and once during the first night of CPAP treatment. Sleep was recorded polygraphically in all experiments. Plasma PRL was measured at 10 min intervals and secretory rates were calculated by a deconvolution procedure. CPAP treatment greatly reduced hypoxaemia and improved sleep quality. The secretory pulse amplitude and the total amount of PRL secreted during the night remained constant regardless of whether patients were treated or not. The only difference found was a lower pulse frequency in untreated OSA patients as compared to treated patients, which may be attributed either to hypoxaemia or to sleep disturbance or to the combined action of both. Treatment may be considered to normalize PRL release by restoring pulse frequency to values similar to those observed for normal subjects.     

Symptoms of sleep disturbance in persons with Alzheimer's disease and normal elderly

We retrospectively analyzed sleep time and sleep disturbance symptoms in 399 healthy, non-demented elderly (NDE) and 263 persons with a diagnosis of possible (n = 53) or probable (n = 210) Alzheimer's disease (AD). Our primary objective was to determine differences in subjective sleep disturbance between these samples. Secondary objectives were to determine if subjects with time in bed (TIB) < or =6 h per night reported more sleep disturbance and whether sleep complaints were associated with more severe cognitive and/or functional impairment. The prevalence of 'sleep problems' (a single item) was significantly lower in NDE (18.3%) than AD (27.6%), and the proportions of each cohort reporting TIB < or =6 h per night were very low (NDE: 6.0%; AD: 3.5%) and not significantly different. Less TIB was correlated with better cognitive function for AD (P < 0.01), and cognition and function were significantly worse for AD subjects with estimates of >6 h of TIB compared with those with estimates of < or =6 h (P < 0.05). Greater sleep disturbance was correlated with greater functional impairment in both cohorts; but only in AD did greater estimated TIB also correlate with greater functional impairment (all P < 0.05). In general, estimated TIB was not associated with mood in either cohort; however, in both cohorts depression was significantly associated with sleep disturbance symptoms and was significantly worse in those who reported having 'sleep problems'. There was no association between subjective perception of 'sleep problems', the number and frequency of sleep disturbance symptoms, and estimated TIB in either group.