Hallucinations and sleep–wake cycle in Alzheimer's disease: a questionnaire-based study in 218 patients

Abstract The aim was to evaluate the relationship between hallucinations and the sleep-wake cycle in a sample of Alzheimer's disease (AD) patients in the early-moderate stage. Two hundred and eighteen AD patients (66 males, 152 females, mean age 74.3±6.85) were administered a sleep questionnaire in the presence of a care-giver. Twenty-six out of 218 (12%) reported the occurrence of hallucinations, mainly visual. In 18/28 (69%) hallucinations occurred when the patient was awake and in 8 (31%) hallucinations were reported to occur close to a specific phase of the sleep-wake cycle. Vivid dreams were reported in 25/218 (11%) and violent sleep-related and dream-related behaviours (probable REM behaviour episodes) in 22/218 (10%). Both REM phenomena were more frequent in AD hallucinators than in AD non-hallucinators (26.9% vs. 9.3%, and 26.9% vs. 7.8%, p<0.007). Our data indicate a lower incidence of hallucinations and presumable REM behaviour disorder (RBD) in AD, at least in the early-moderate phase, than that observed in synucleinopathies. However, the higher occurrence of vivid dreams and RBD in AD patients with hallucinations compared to those without hallucinations indicates a potential role of disordered REM sleep in influencing the occurrence of hallucinations in AD, similar to what has been observed in synucleinopathies.     

Diurnal and sleep/wake patterns of epileptic spasms in different age groups

Purpose: Epileptic spasms are seizures that occur predominantly in children and are characterized by clusters of brief axial movements. Epileptic spasms may occur in the context of a variety of syndromes. Previous research has found that epileptic spasms occur in a sleep/wake and diurnal rhythm. The purpose of this study was to identify these patterns in different age groups. Methods: Charts of 2,021 patients with epilepsy undergoing video–electroencephalography (EEG) monitoring over a 10‐year period were reviewed for presence of epileptic spasms and analyzed for their occurrence during the day (6 a.m. to 6 p.m.) or night, out of wake or sleep, and in 3‐h time‐blocks throughout the day. Exact epileptic spasm time, EEG localization, and the presence or absence of magnetic resonance imaging lesion were also recorded. Patients were separated into two age groups: A ages 3 and under, and over age 3. Statistical analysis of seizure occurrence in time bins was carried out using binomial calculations. p‐Values <0.05 were taken as significant. Using exact seizure times, a generalized linear mixed model of the Poisson‐family with a square root link function was used to calculate mean seizure times. Age, as a binary variable, and time, as a categorical variable, was treated as fixed effect predictors, and individual effects were modeled as random effects. For comparison between the two age groups, over age 3 and under age 3, seizure times were transformed into circular variables. A circular analysis of variance test was used to assess for the difference in mean seizure time, assuming a von Mises distribution of the circle. Key Findings: We analyzed 219 clusters of epileptic spasms in 51 patients (15 girls; mean age 2.15 ± 2.22 years). Forty‐two patients younger than 3 years of age had 163 seizures and nine patients older than 3 years had 56 seizures. Epileptic spasms occurred predominantly during wakefulness (p < 0.001) and during daytime (p < 0.001). Epileptic spasms occurred most frequently between 9 a.m. and noon (p < 0.05) and between 3 p.m. and 6 p.m. (p < 0.001). Patients without magnetic resonance imaging lesions had most seizures between 9 a.m. and noon (p < 0.01) and 3 p.m. and 6 p.m. (p < 0.001). Thirty‐seven patients had 157 epileptic spasms (71.2%) with generalized EEG patterns and 14 patients had 62 epileptic spasms (28.8%) with focal EEG patterns. Generalized EEG seizures occurred more frequently than focal EEG seizures (p < 0.001). Following age stratification, patients younger than 3 years had most epileptic spasms between 9 a.m. and noon (p < 0.05) and 3 p.m. and –6 p.m. (p < 0.01) and patients older than 3 years had most epileptic spasms between 6 a.m. and –9 a.m. (p < 0.05) and a second peak between 3 p.m. and 6 p.m., although the difference was not statistically significant due to insufficient numbers. Using continuous time analysis, the mean seizure time in the under age 3 and the over age 3 groups was 2:24 p.m. and 11:40 a.m. Using a circular analysis of variance test, the difference between mean seizure times in these groups was found to be statistically significant (p = 0.038). Significance: Epileptic spasms occur more frequently in the waking state and daytime. Younger patients have epileptic spasms mostly between 9 a.m. and noon and 3 p.m. and –6 p.m., and older patients have epileptic spasms mostly between 6 a.m. and 9 a.m. These findings emphasize age‐related changes in epileptic spasm pathophysiology or potentially evolution of disease with age.     

Risperidone augmentation decreases rapid eye movement sleep and decreases wake in treatment-resistant depressed patients

BACKGROUND: The atypical antipsychotic agent risperidone has beneficial effects on mood in patients with schizophrenia. This study aimed to assess whether risperidone produced typical antidepressant-like effects in the polysomnogram of healthy subjects and in depressed patients unresponsive to antidepressant medication. METHOD: We measured the effect of a single dose of risperidone (1 mg) on the polysomnogram of 8 healthy volunteers in a placebo-controlled, double-blind, crossover design. We also measured the effects of open-label risperidone treatment (0.5-1.0 mg daily) on the polysomnogram of 8 patients meeting DSM-IV criteria for major depressive disorder who had received therapeutic doses of an antidepressant with an unsatisfactory response. Sleep was recorded at baseline and following 2 weeks of risperidone addition. RESULTS: In the healthy volunteers, risperidone significantly decreased rapid eye movement (REM) sleep (p =.04). After 2 weeks of risperidone treatment, depressed patients had significantly less wake (p =.02) and REM sleep (p =.02). Scores on depression rating scales for the depressed patients showed a significant decline (p <.05). CONCLUSION: Risperidone administration decreases REM sleep in both healthy volunteers and medication-resistant depressed patients, an action characteristic of conventional antidepressant medication. In depressed patients, risperidone also decreased wake. The utility of risperidone as an augmentation agent in depressed patients merits controlled study.     

A SPECT study of wandering behavior in Alzheimer's disease

BACKGROUND: Among behavior disturbance during Alzheimer's disease (AD), wandering is one of the most common. Different psychological processes have been suggested to explain the wandering behavior. The aim of this study was to examine whether wandering during AD was associated with cerebral perfusion patterns measured by (99 m)Tc-labeled bicisate (ECD) brain SPECT. METHODS: We compared SPECT scans of 13 AD subjects with wandering behavior (sex ratio M/F, 4/9; age, 73.1 years, SD 7.4; Mini Mental Status Examination score, median 20 interquartile range [16-23]), 13 AD subjects without wandering behavior (matched for age [ +/- 2 years], sex and MMSE score [ +/- 2 points]) and 13 healthy controls (matched for age [ +/- 2 years] and sex) without cognitive impairment. Wandering was defined on the Neuro-Psychiatric Inventory. Score of leukoaraiosis, assessed with the scale of Blennow and number of lacuna infarction were compared on CT scan. SPECT imaging was compared using statistical parametric mapping (SPM 2). RESULTS: There were no significant differences between the groups in term of educational level and CT scan analysis. SPECT imaging was consistent with the diagnosis of AD in both wanderers and AD subjects without wandering behavior. Despite similar clinical dementia severity, wanderers had more severely reduced regional cerebral blood flow (rCBF) in the left parietal-temporal lobe than AD subjects without wandering behavior. CONCLUSION: Wandering behavior could be facilitated by a specific patterns of cerebral blood flow. Wandering, as a physical activity, could also enhance the recruitment of the cortical network.     

Predicting diurnal and sleep/wake seizure patterns in paediatric patients of different ages

Aim. To identify factors that influence diurnal and sleep/wake seizure timing in children undergoing tapered drug withdrawal in an epilepsy monitoring unit. Methods. Medical charts of patients that underwent video‐EEG were reviewed. Seizures were evaluated based on their occurrence in three‐hour time intervals (bins) and between wakefulness and sleep. Patients were classified according to EEG localisation and age: infants (≤3 years), children (3–12 years), and adolescents (>12–21 years). Analysis utilising generalised estimating equations with a negative binomial distribution was performed. Results. A total of 390 patients (188 girls; mean age: 9.2 years; SD: 6.0) had 1,754 seizures. Generalised seizures (109 patients; 490 seizures) occurred more during wakefulness (p<0.001) and during the day (p<0.001). Modelling revealed a greater occurrence of seizures at night with increasing age (p=0.046). Temporal lobe seizures (62 patients; 271 seizures) occurred overall more frequently during wakefulness (p=0.03). Frontal lobe seizures (41 patients; 184 seizures) occurred more frequently during wakefulness in infants (p<0.05) and more frequently during sleep in adolescents (p<0.0001). Adolescents with frontal lobe seizures were 3.6 times more likely to have seizures during sleep compared to other children (95% CI: 1.8–7.2). Conclusion. These findings are suggestive of changes in circadian rhythmicity that may alter seizure susceptibility in different age groups. The results may assist in prediction of periods of greatest seizure propensity.     

Sleep/wake disruption in Alzheimer's disease: APOE status and longitudinal course

Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele.     

Fingerprint patterns in Alzheimer's disease

Fingerprint dermatoglyphic patterns in 50 patients with presumed senile dementia of the Alzheimer type (SDAT) were compared with a control group of 50 patients with other neurologic diseases and with population norms. Patients with SDAT showed a significantly increased frequency of ulnar loops on their fingertips and a concomitantly decreased frequency of whorls and arches. A pattern of eight or more ulnar loops was found significantly more often in patients with SDAT (72%) than in the control group (26%). Fourteen patients with SDAT had ulnar loops on all ten fingers; this occurred in four patients in the control group. Radial loops on the fourth and fifth digits were more prevalent in patients with SDAT. The fingerprint patterns observed in patients with SDAT are congruent with patterns repeatedly found in Down's syndrome, and support the known associations between these two diseases at a further level.     

Shift work and disturbed sleep/wakefulness

This paper reviews the effects of shift work and finds strong, acute effects on sleep and alertness in relation to night and morning work. The effects seem, however, to linger and also affect days off. The level of the disturbances is similar to that seen in clinical insomnia and may be responsible for considerable human and economical costs due to fatigue related accidents and reduced productivity. The mechanism behind the disturbances is the sleep interfering properties of the circadian system during day sleep and the corresponding sleep promoting properties during night work. Various strategies may be used to counteract the effects of shift work, such as napping, sufficient recovery time between shifts, clockwise rotation, etc. Still it does not seem possible to more eliminate the effects-only to reduce them.     

Prostaglandin D2 and sleep/wake regulation

Prostaglandin (PG) D₂ is the most potent endogenous sleep-promoting substance. PGD₂ is produced by lipocalin-type PGD synthase localized in the leptomeninges, choroid plexus, and oligodendrocytes in the brain, and is secreted into the cerebrospinal fluid as a sleep hormone. PGD₂ stimulates DP₁ receptors localized in the leptomeninges under the basal forebrain and the hypothalamus. As a consequence, adenosine is released as a paracrine sleep-promoting molecule to activate adenosine A_2A receptor-expressing sleep-promoting neurons and to inhibit adenosine A₁ receptor-possessing arousal neurons. PGD₂ activates a center of non-rapid eye movement (NREM) sleep regulation in the ventrolateral preoptic area, probably mediated by adenosine signaling, which activation inhibits the histaminergic arousal center in the tuberomammillary nucleus via descending GABAergic and galaninergic projections. The administration of a lipocalin-type PGD synthase inhibitor (SeCl₄), DP₁ antagonist (ONO-4127Na) or adenosine A_2A receptor antagonist (caffeine) suppresses both NREM and rapid eye movement (REM) sleep, indicating that the PGD₂-adenosine system is crucial for the maintenance of physiological sleep.     

Treatment of sleep disturbance in Alzheimer's disease

The prevalence of Alzheimer's disease (AD) is rapidly increasing as growing numbers of people around the world are living to old age. Sleep disturbances are a common, and often highly disruptive, behavioral symptom associated with AD. Nevertheless, the study of sleep in AD is relatively new. Little is known about the moderating factors that may alter a given patient's risk for developing sleep problems, or that may influence severity of presentation and persistence. Current treatments for improving sleep in AD fall into three broad categories: (i) pharmacological; (ii) cognitive-behavioral or psycho-educational strategies; and (iii) biological/circadian therapies. There are few studies demonstrating the efficacy of these treatments with community-dwelling AD patients, although studies with persons in institutional settings are promising. In this review, it is suggested that sleep problems in AD are multi-factorial, and influenced by a variety of demographic, physical, psychiatric and situational factors. These factors vary in how readily they can be modified and in how relevant they are to any individual case. Thus, when developing a treatment plan for sleep problems in a dementia patient, it is important to evaluate the underlying causes as well as the context in which the problems are occurring, and to target the intervention accordingly.     

Stage-dependent patterns of disturbed neural synchrony in Parkinson's disease

Synchronization of neuronal activity within and across distributed brain regions is a fundamental property of cortical and subcortical networks and serves a variety of functions including motor and cognitive processes. Data will be reviewed here from cross-sectional EEG and MEG studies to suggest that Parkinson's disease is characterized by changing patterns of disturbed neural synchrony that appear to be dependent on the stage of disease. Some of these alterations in neural synchrony may directly account for a number of disease-related impairments in motor and cognitive functions. Future longitudinal studies are required to fully understand the disturbances of functional brain networks in Parkinson's disease and how they evolve throughout the course of the disease.     

Risperidone in the treatment of patients with Alzheimer's disease with negative symptoms

INTRODUCTION: Negative symptoms such as diminished initiative, drive, motivation, and emotional reactivity have been described in patients with Alzheimer's disease (AD). The purpose of this study was to retrospectively analyze the efficacy and tolerability of risperidone for the treatment of clinically significant positive and negative symptoms in AD. METHODS: We reviewed the charts of 50 community-residing AD patients who had been treated in a specialized university-based dementia management clinic. Clinical data comparing baseline and 12 weeks of treatment were obtained by reviewing a series of rating scales that were recorded as part of a comprehensive behavioral assessment. RESULTS: Reviewed subjects had a mean age of 79.7 6 years and a mean of 12 +/- 3.6 years of school. Seventy percent of the subjects were female and the majority was White. The mean dose of risperidone prescribed was 1.3 +/- 0.6 mg per day (range from 0.5 mg to 3.0 mg). After 12 weeks of treatment, the severity of positive and negative symptoms was significantly reduced. Importantly, improvement in negative symptoms with the use of risperidone appeared to be independent of a positive treatment effect on positive symptoms. Risperidone had insignificant effects on both cognitive status and the emergence of extrapyramidal symptoms. CONCLUSION: This retrospective study demonstrates that risperidone appears to be efficacious in the treatment of clinically significant positive and negative symptoms in patients with AD.     

Dietary patterns in Alzheimer's disease and cognitive aging

Much of the attention on diet and Alzheimer's disease (AD) or cognition among the elderly has focused on the role of single nutrients or foods, while available information on dietary pattern (DP) analysis, which better reflects the complexity of the diet, is sparse. In this review, we describe different patterning approaches and present studies performed to date that have assessed the associations between DPs and risk of AD or cognitive function in the elderly. Three patterning approaches have been most commonly used: (i) hypothesis-based that use dietary quality indexes or scores (e.g. Mediterranean pattern), (ii) data-driven that use factor or cluster analysis to derive DPs, (iii) reduced rank regression which combines characteristics of the former two approaches. Despite differences existing among the approaches, DPs characterized by higher intake of fruits, vegetables, fish, nuts and legumes, and lower intake of meats, high fat dairy, and sweets seemed to be associated with lower odds of cognitive deficits or reduced risk of AD. Overall, the inherent advantages as well as the existing evidence of DP analyses strongly suggest that this approach may be valuable in AD and aging research. Further studies are warranted, though, to confirm the findings in different population settings, to address some methodological issues, and possibly utilize the information for future clinical trial design.     

The sleep/wake rhythm in children with autism

The sleep patterns of two groups of children with autism, one with moderate to severe intellectual handicap, and one with mild handicap to normal IQ level, were compared with those of children without autism. Parents completed 14 day sleep diaries and questionnaires. Results suggested that at some stage during childhood, particularly under 8 years of age, the majority of children with autism will experience sleep problems. These problems are likely to be severe in many cases and will generally include one or more of: extreme sleep latencies; lengthy periods of night waking; shortened night sleep; and early morning waking. Such problems may have some specificity for autism as they appear to be rare in non-handicapped children and in children with mild degrees of intellectual handicap. It is likely that sleep problems in early childhood are related to the severe social difficulties present in autism and the consequent inability of these children to use social cues to synchronise their sleep/wake cycle. Continued sleep difficulties at older ages and with higher IQ may also be related to arousal and anxiety factors.

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Zusammenfassung Die Schlafmuster zweier Gruppen von Kindern mit Autismus wurden verglichen mit den Mustern von Kindern ohne Autismus. Die eine Gruppe mit Autismus umfaßte Kinder mit mäßiger bis hin zu schwerer intellektueller Beeinträchtigung, die andere hingegen Kinder mit leichter intellektueller Beeinträchtigung oder einem IQ im Durchschnittsbereich. Die Eltern füllten Schlaftagebücher und Fragebögen über einen Zeitraum von 14 Tagen aus. Die Ergebnisse legen nahe, daß die Mehrzahl der Kinder mit Autismus in irgendeiner Entwicklungsphase während der Kindheit (besonders im Altersbereich von unter 8 Jahren) Schlafstörungen aufweisen. Diese Schlafstörungen sind in vielen Fällen schwerwiegend und umfassen in der Regel eines oder mehrere der folgenden Merkmale: extreme Schlaflatenzen, lang anhaltende Wachperioden, verkürzter Nachtschlaf und frühes morgendliches Erwachen. Solche Störungen könnten in gewisser Weise spezifisch für Autismus sein, da sie nur selten bei nicht-behinderten Kindern bzw. bei Kindern mit leichten intellektuellen Beeinträchtigungen vorzukommen scheinen. Es erscheint wahrscheinlich, daß Schlafstörungen in der frühen Kindheit im Zusammenhang mit den schwerwiegenden sozialen Auffälligkeiten stehen, die beim Autismus vorkommen und mit der Unfähigkeit dieser Kinder, sich bei der Synchronisation ihres Schlaf-Wachzyklus an Hinweisen aus ihrem sozialen Umfeld zu orientieren. Fortbestehende Schlafstörungen bei älteren Individuen, die zugleich einen höheren IQ haben, können auch auf Angst- bzw. Erregungsfaktoren zurückgeführt werden.

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Résumé On a comparé les cycles veille-sommeil de deux groupes d'enfants autistes, l'un avec des handicaps intellectuels de modérés à sévères et l'autre avec des handicaps de léger à un QI normal, avec d'enfants non-autistes. Les parents ont tenu des relevés quotidiens et des questionnaires sur 14 jours de sommeil. Les résultats ont suggéré qu'à certaines périodes de l'enfance, surtout à l'âge de 8 ans, la majorité des enfants autistes souffrent des troubles de sommeil. Ces troubles apparaissent sévères dam de nombreux cas et sont faits le plus souvent d'un ou plusieurs troubles tels que: latences extrêmes du sommeil; périodes de réveils nocturnes prolongées; sommeil nocturne plus bref et réveil matinal très tôt; de tels problèmes peuvent être particuliers à l'autisme, parce qu'ils semblent être rares chez les enfants non-handicapés et chez les enfants avec des handicaps intellectuels légers. Les troubles du sommeil qui apparaissent tôt dans l'enfance sont probablement liés aux difficultés sociales sévères qu'on trouve dans l'autisme et à l'incapacité consécutive de ces enfants à utiliser les signaux sociaux afin de synchroniser leurs cycles veille-sommeil. Les troubles du sommeil continus chez les plus âgés et avec un QI plus élevé peuvent aussi être liés à des facteurs de vigilance et d'anxiété.

     

Counting complex dot patterns in Alzheimer's disease

Patients affected by Alzheimer's disease (DAT) showed considerable difficulties assessing the numerosity of complex dot patterns (up to 30 dots). Patients' and controls' performance was found to be modulated by the spatial array of dot patters. Dots presented in curved lines were easier to count than dots in circle arrays or in random arrays. Highly significant between group differences were found in counting dots in circle arrays, but not in counting curved lines. Patients and controls differed in the choice of counting strategies. While controls efficiently adapted their counting strategies to the respective dot patterns, DAT patients were not able to adapt counting strategies to the requirements of the spatial arrays. Analysis of error types further evidenced the particular difficulties of patients. Several recounts in counting circle arrays reflected difficulties to stop counting, while omissions in random patterns suggested deficits in monitoring already counted items. Results of this study suggest that deficits in executive functions prevented patients from selecting and adapting counting strategies in order to keep track of already counted items, to enhance accuracy and to reduce demands on cognitive resources.