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Summary: The study objective was to explore associations of fetal and infant weight patterns and preterm birth with sleep and 24‐h activity rhythm parameters at school‐age. In our prospective population‐based study, 1327 children were followed from birth to age 10–15 years. Fetal weight was estimated using ultrasound in the second and third trimester of pregnancy. Birth weight and gestational age were available from midwife registries. Infant weight was measured at 6, 12 and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change of >0.67 standard deviation between the corresponding age intervals. At school‐age, sleep duration, sleep efficiency, wake after sleep onset, social jetlag, inter‐daily stability, and intra‐daily variability were assessed using tri‐axial wrist actigraphy for 9 consecutive nights. We observed that low birth weight (<2500 g) was associated with 0.24 standard deviation (95% confidence interval [CI] 0.04; 0.43) longer sleep duration compared to normal weight. Compared to normal growth, growth deceleration in fetal life and infancy was associated with 0.40 standard deviation (95% CI 0.07; 0.73) longer sleep duration, 0.44 standard deviation (95% CI 0.14; 0.73) higher sleep efficiency, and −0.41 standard deviation (95% CI −0.76; ‐0.07) shorter wake after sleep onset. A pattern of normal fetal growth followed by infant growth acceleration was associated with −0.40 standard deviation (95% CI −0.61; −0.19) lower inter‐daily stability. Preterm birth was not associated with any sleep or 24‐h rhythm parameters. Our findings showed that children with fetal and infant growth restriction had longer and more efficient sleep at school‐age, which may be indicative of an increased need for sleep for maturational processes and development after a difficult start in life. [ABSTRACT FROM AUTHOR]

FOXG1 syndrome is a rare neurodevelopmental disorder associated with severe cognitive dysfunction, autistic behavior, and early‐onset hyperkinetic movement disorders. Patients have also been reported to experience sleep disturbances. However, these findings are mainly based on subjective caregivers' reports, and limited by small case numbers. Moreover, no studies using objective evaluation tools, such as actigraphy, have been reported. We analyzed the clinical and sleep manifestations of children with FOXG1 syndrome registered in the FOXG1 Research Foundation Patient Registry database. A total of 258 individuals with FOXG1 syndrome were included in this research. 132 (51.16%) had sleep disturbances. The more impaired of language acquisitions (absence of speech, OR: 3.99, 95%CI = 1.69–9.42, p = 0.002), hyperkinetic movement disorders (OR: 2.64, 95%CI = 1.34‐5.20 p = 0.005) and feeding difficulties (OR: 2.81, 95% CI = 1.52–5.19, p = 0.001) were significantly associated with an increase in odds of sleep disturbance after adjusting for age, sex, and antiepileptic drugs. We also performed sleep studies on six individuals with FOXG1 syndrome using The Children's Sleep Habits Questionnaire (CSHQ), the Sleep Disturbance Scale for Children (SDSC), and 7‐day data from Actiwatch. The Pittsburgh Sleep Quality Index (PSQI) and 7‐day data from Actiwatch were also used to evaluate the sleep condition of their parents. The CSHQ scores revealed bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night‐waking, and parasomnia. Sleep–wake transition disorders and disorders of initiating and maintaining sleep were also suggested by the SDSC scores. The children's actigraphy revealed short sleep durations, impaired sleep efficiency, longer wake after sleep onset, and frequent night‐waking. All caregivers reported significantly higher PSQI scores, mildly declined sleep efficiency, and shorter total sleep duration. Sleep disturbances, especially in initiating and maintaining sleep, are common in individuals with FOXG1 syndrome and their caregivers. Sleep disorders in patients with FOXG1 syndrome and their caregivers should be investigated. Lay Summary: FOXG1 syndrome is a rare disorder with several comorbidities, including sleep disorders. However, studies focusing on sleep conditions in FOXG1 syndrome are scarce. Our studies showed that sleep disturbances occur across different genders, ages, and genotypes in FOXG1 syndrome. Hyperkinetic movements, feeding difficulties, and absence of language acquisition significantly increased the probability of sleep disturbance. Our results also demonstrated greater difficulty in initiating and maintaining sleep, as identified in actigraphy studies, and sleep‐disordered breathing symptoms, as revealed by the report questionnaires submitted by the parents of six children with FOXG1 syndrome. Caregivers of children with this condition also tended to have shorter total sleep durations. [ABSTRACT FROM AUTHOR]

Background and Purpose: Variants in SCN8A, the NaV1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. Experimental Approach: We investigated the therapeutic potential of eslicarbazepine (S‐licarbazepine; S‐lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain‐of‐function (G1475R and M1760I) and one variant with biophysical gain‐of‐function but neuronal loss‐of‐function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV1.6‐associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results: Similar to known effects on NaV1.6 wildtype channels, S‐lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S‐lic exhibits variant‐specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant‐associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S‐lic. Conclusions and Implications: S‐lic has not only substance‐specific effects but also variant‐specific effects. Personalized treatment regimens optimized to achieve such variant‐specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A‐related disease. [ABSTRACT FROM AUTHOR]

Summary: Cyclin‐dependent kinase‐like 5 (CDKL5) gene pathogenic variants result in CDKL5 deficiency disorder (CDD). Early onset intractable epilepsy and severe developmental delays are prominent symptoms of CDD. Comorbid sleep disturbances are a major concerning symptom for families. We aimed to explore the relationship between insomnia, daytime sleepiness, sleep medications and quality of life in children with CDD. Caregivers of 129 children with CDD in the International CDKL5 Disorder Database completed the Quality‐of‐Life Inventory‐Disability (QI‐Disability) questionnaire and "Disorders of Maintaining Sleep" (DIMS) and the "Disorders of Excessive Somnolence" (DOES) items of the Sleep Disturbance Scale for Children. Adjusting for covariates, a unit increase in DOES score was associated with reduced quality of life total (coefficient −3.06, 95% confidence interval [CI] 1.35–7.80), physical health (coefficient −7.20, 95% CI −10.64, −3.76) and negative emotions (coefficient −3.90, 95% CI −7.38, −0.42) scores. Adjusting for covariates, a unit increase in DIMS score was associated with reduced negative emotions (coefficient −6.02, 95% CI −10.18, −2.86). Use of sleep medications had small influences on the effect sizes. This study highlights the importance of sleep problems as a determinant of quality of life in children with CDD, consistent with effects observed for other groups of children with intellectual disability. Excessive daytime sleepiness was particularly associated with detrimental effects on quality of life. Further research in optimal behavioural and pharmaceutical management of sleep problems for this population is required. [ABSTRACT FROM AUTHOR]

SATB2‐associated syndrome (SAS) is a rare disorder characterized by developmental delay, behavioral problems, and craniofacial anomalies in particular dental and palatal abnormalities. We describe the clinical course, genetic and autopsy findings in a Chinese boy with global developmental delay, hypotonia, epilepsy, recurrent fractures and osteopenia. Brain magnetic resonance imaging showed pachygyria, white matter hypoplasia and hypogenesis of the corpus callosum. Whole‐exome sequencing identified a novel heterozygous missense variant c.1555G>A p.(Glu519Lys) in the SATB2 gene. Unfortunately, he died at 26 months of bronchiolitis and pneumonia. Autopsy revealed pachygyria which was more severe anteriorly, dilated lateral and third ventricles and partial agenesis of the corpus callosum. Histology showed features compatible with two‐layered lissencephaly. The bone showed disordered lamination and bone matrix. Although SATB2 has been shown to be involved in the regulation of neuronal migration in the developing brain, lissencephaly has not been reported so far. This could represent a more severe phenotype of SAS. [ABSTRACT FROM AUTHOR]

Autistic children and adults often have sleep disturbances, which may affect their and their family's quality of life. Yet, the relationship between sleep–wake patterns and autism spectrum traits is understudied. Identifying such relationships could lead to future research elucidating common mechanistic underpinnings. Thus, we aimed to determine whether sleep–wake patterns, specifically related to sleep, physical activity, and the daily sleep–wake rhythm (i.e., circadian rhythm), are associated with autism spectrum‐related traits. Accelerometer‐derived sleep–wake parameters were estimated in individuals with autistic spectrum traits and their family members (N = 267). We evaluated autism spectrum traits using the Social Responsiveness Scale (SRS) to assess the presence and severity of social impairment and the Behavior Rating Inventory of Executive Function (BRIEF) to assess executive function. The linear multivariate regression analysis (using SOLAR‐Eclipse) showed that in adults, increased core autism spectrum traits and executive dysfunction were associated with disruption of several sleep–wake parameters, particularly related to the daily sleep–wake rhythm, and that executive dysfunction was associated with disrupted sleep quality and level of physical activity. We highlight the interplay between daytime function and disrupted sleep–wake patterns, specifically related to the daily sleep–wake rhythm, that could guide future research into common mechanisms. Lay Summary: Autistic children and adults often report sleep disturbances. To dissect the relationship between a range of autism spectrum traits and sleep–wake patterns, we assessed social interaction and executive function in participants who also wore actimetry watches on their wrists to assess their sleep–wake patterns. We found that increased impairments in social and executive function occurred with increased sleep–wake disturbances, particularly those related to the circadian rhythm, suggesting that these perturbations/disruptions in the sleep–wake cycle could be connected to autism spectrum traits. [ABSTRACT FROM AUTHOR]

Mutations in the X‐linked CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition mainly characterized by infantile epileptic encephalopathy, intellectual disability, and autistic features. The molecular mechanisms underlying the clinical symptoms remain largely unknown and the identification of reliable biomarkers in animal models will certainly contribute to increase our comprehension of CDD as well as to assess the efficacy of therapeutic strategies. Here, we used different Magnetic Resonance (MR) methods to disclose structural, functional, or metabolic signatures of Cdkl5 deficiency in the brain of adult mice. We found that loss of Cdkl5 does not cause cerebral atrophy but affects distinct brain areas, particularly the hippocampus. By in vivo proton‐MR spectroscopy (MRS), we revealed in the Cdkl5 null brain a metabolic dysregulation indicative of mitochondrial dysfunctions. Accordingly, we unveiled a significant reduction in ATP levels and a decrease in the expression of complex IV of mitochondrial electron transport chain. Conversely, the number of mitochondria appeared preserved. Importantly, we reported a significant defect in the activation of one of the major regulators of cellular energy balance, the adenosine monophosphate‐activated protein kinase (AMPK), that might contribute to the observed metabolic impairment and become an interesting therapeutic target for future preclinical trials. In conclusion, MRS revealed in the Cdkl5 null brain the presence of a metabolic dysregulation suggestive of a mitochondrial dysfunction that permitted to foster our comprehension of Cdkl5 deficiency and brought our interest towards targeting mitochondria as therapeutic strategy for CDD. [ABSTRACT FROM AUTHOR]

We investigated synaptic mechanisms in the hippocampus that could explain how loss of circadian timing leads to impairments in spatial and recognition memory. Experiments were performed in hippocampal slices from Siberian hamsters (Phodopus sungorus) because, unlike mice and rats, their circadian rhythms are easily eliminated without modifications to their genome and without surgical manipulations, thereby leaving neuronal circuits intact. Recordings of excitatory postsynaptic field potentials and population spikes in area CA1 and dentate gyrus granule cells revealed no effect of circadian arrhythmia on basic functions of synaptic circuitry, including long‐term potentiation. However, dentate granule cells from circadian‐arrhythmic animals maintained a more depolarized resting membrane potential than cells from circadian‐intact animals; a significantly greater proportion of these cells depolarized in response to the cholinergic agonist carbachol (10 μM), and did so by increasing their membrane potential three‐fold greater than cells from the control (entrained) group. Dentate granule cells from arrhythmic animals also exhibited higher levels of tonic inhibition, as measured by the frequency of spontaneous inhibitory postsynaptic potentials. Carbachol also decreased stimulus‐evoked synaptic excitation in dentate granule cells from both intact and arrhythmic animals as expected, but reduced stimulus‐evoked synaptic inhibition only in cells from control hamsters. These findings show that loss of circadian timing is accompanied by greater tonic inhibition, and increased synaptic inhibition in response to muscarinic receptor activation in dentate granule cells. Increased inhibition would likely attenuate excitation in dentate‐CA3 microcircuits, which in turn might explain the spatial memory deficits previously observed in circadian‐arrhythmic hamsters. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT, MIM * 312750) is an X‐linked neurodevelopmental disorder caused by pathogenic variants at the Xq28 region involving the gene methyl‐CpG‐binding protein 2 (MECP2, MIM * 300005). The spectrum of MECP2‐related phenotypes is wide and it ranges from asymptomatic female carriers to severe neonatal‐onset encephalopathy in males. Abnormal breathing represents one of the leading features, but today little is known about polysomnographic features in RTT females; no data are available about males. We report the case of a male of Moroccan origins with a MECP2 pathogenic variant and a history of encephalopathy and severe breathing disturbances in the absence of dysmorphic features. For the first time we describe in detail the polysomnographic characteristics of a MECP2‐mutated male and we show the relevance of severe central apneas, which may represent a new clinical clue to suggest the diagnosis. Moreover, we want to highlight the importance to maintain a high index of suspicion for MECP2‐related disorders in the presence of severe hypotonia, apneic crises, and respiratory insufficiency in males to permit an earlier diagnosis and the consequent definition of recurrence risk of the family and to avoid other useless and invasive exams. [ABSTRACT FROM AUTHOR]

Background: To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A‐related developmental epileptic encephalopathy (DEE). Methods: We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole‐cell patch‐clamp recording. Results: The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast‐inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature. Conclusion: These findings provided the insights into the phenotype–genotype–funotype relationships of SCN2A‐related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the cyclin‐dependent kinase‐like 5 (CDKL5) gene cause the neurodevelopmental disorder, the CDKL5 deficiency disorder. Reports of individuals with pathogenic variants in CDKL5 without seizures are exceedingly rare, and in‐depth analyses of their variants have been lacking. Whole‐genome sequencing was performed on a 29‐year‐old female with mild intellectual disability who, in the absence of overt seizures, presented with multiple episodes of altered mental status over a 24‐year period. Clinical history was supplemented by a parent completed questionnaire from the International CDKL5 Disorder Database. We identified a de novo heterozygous variant in CDKL5 (NM_003159.2:c.645T>A;p.Ser215Arg). In‐depth computational analysis performed to predict the impact of the variant on protein structure and function demonstrated that the variant was likely pathogenic. In this light, cell‐based studies showed that the S215R substitution causes a marked reduction in CDKL5 kinase activity. Similarities between our case and one previously reported case are striking. These cases, both without seizures but with apparent behavioral symptomatology, together question whether seizures are mandatory in this neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

Circadian rhythm disorders have been classically associated with disorders of abnormal timing of the sleep–wake cycle, however circadian dysfunction can play a role in a wide range of pathology, ranging from the increased risk for cardiometabolic disease and malignancy in shift workers, prompting the need for a new field focused on the larger concept of circadian medicine. The relationship between circadian disruption and human health is bidirectional, with changes in circadian amplitude often preceding the classical symptoms of neurodegenerative disorders. As our understanding of the importance of circadian dysfunction in disease grows, we need to develop better clinical techniques for identifying circadian rhythms and also develop circadian based strategies for disease management. Overall this review highlights the need to bring the concept of time to all aspects of medicine, emphasizing circadian medicine as a prime example of both personalized and precision medicine. [ABSTRACT FROM AUTHOR]

The circadian system regulates physiology and behavior. Acute challenges to the system, such as those experienced when traveling across time zones, will eventually result in re‐synchronization to local environmental time cues, but this re‐synchronization is oftentimes accompanied by adverse short‐term consequences. When such challenges are experienced chronically, adaptation may not be achieved, as for example in the case of rotating night shift workers. The transient and chronic disturbance of the circadian system is most frequently referred to as "circadian disruption", but many other terms have been proposed and used to refer to similar situations. It is now beyond doubt that the circadian system contributes to health and disease, emphasizing the need for clear terminology when describing challenges to the circadian system and their consequences. The goal of this review is to provide an overview of the terms used to describe disruption of the circadian system, discuss proposed quantifications of disruption in experimental and observational settings with a focus on human research, and highlight limitations and challenges of currently available tools. For circadian research to advance as a translational science, clear, operationalizable, and scalable quantifications of circadian disruption are key, as they will enable improved assessment and reproducibility of results, ideally ranging from mechanistic settings, including animal research, to large‐scale randomized clinical trials. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation (CDG) are an extremely rapidly growing and phenotypically versatile group of disorders. Conserved oligomeric Golgi (COG) complexes are hetero‐octameric proteins involved in retrograde trafficking within the Golgi. Seven of its eight subunits have a causal role in CDG. To date, only three cases of COG8‐CDG have been published but none in the antenatal period. We present the first case of antenatally diagnosed COG8‐CDG with facial dysmorphism and additional features such as Dandy‐Walker malformation and arthrogryposis multiplex congenita, thus expanding the phenotype of this rare disorder. Trio whole exome sequencing revealed a novel homozygous variant in COG8, which creates a new splice site in exon 5 and protein truncation after 12 amino acids downstream to the newly generated splice site. As the mutations of the previous three patients were also identified in exon 5, it is likely to be a potential mutational hotspot in COG8. An association between antenatally increased nuchal translucency and COG8‐CDG is also established, which would alert clinicians to its diagnosis early in gestation. It remains to be seen if this observation can be extended to other COG‐CDGs. [ABSTRACT FROM AUTHOR]

Pathogenic CDKL5 variants cause an X‐linked dominant infantile epileptic encephalopathy, predominantly in females. This condition is characterized by an early‐onset severe mixed seizure disorder. We present a maternally inherited frameshift CDKL5 c.2809_2810insA p.(Cys937Ter) variant in a 13‐year‐old male with severe intellectual disability and late‐onset generalized epilepsy. Interestingly, the variant segregation in the family is consistent with an X‐linked recessive inheritance pattern, which has not previously been described with this gene. This variant is expected to result in truncation of some CDKL5 transcripts, which could potentially account for the later seizure onset and atypical inheritance pattern. Though the possibility of this variant not being causal cannot be completely excluded, this case adds to the variability of the documented phenotypic profile and to the debate around the role of C‐terminus variants in CDKL5‐related disease. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation (CDG) represent an expanding group of conditions that result from defects in protein and lipid glycosylation. Different subgroups of CDG display considerable clinical and genetic heterogeneity due to the highly complex nature of cellular glycosylation. This is further complicated by ethno-geographic differences in the mutational landscape of each of these subgroups. Ten Arab CDG patients from Latifa Hospital in Dubai, United Arab Emirates, were assessed using biochemical (glycosylation status of transferrin) and molecular approaches (next-generation sequencing [NGS] and Sanger sequencing). In silico tools including CADD and PolyPhen-2 were used to predict the functional consequences of uncovered mutations. In our sample of patients, five novel mutations were uncovered in the genes: MPDU1, PMM2, MAN1B1, and RFT1. In total, 9 mutations were harbored by the 10 patients in 7 genes. These are missense and nonsense mutations with deleterious functional consequences. This article integrates a single-center experience within a list of reported CDG mutations in the Arab world, accompanied by full molecular and clinical details pertaining to the studied cases. It also sheds light on potential ethnic differences that were not noted before in regards to CDG in the Arab world. [ABSTRACT FROM AUTHOR]

Background While the medical profession often terms behaviours in individuals with Rett syndrome (RTT) in the second stage as 'autistic-like', parents disagree with this description. The present study focuses on a comparison of parents' experiences with the social-emotional behaviour of the child with RTT in the second and subsequent stages. Method In collaboration with the Dutch Rett Syndrome Organization, 51 parents of children with RTT in the Netherlands took part in the present study. Parents completed an online questionnaire to clarify their experiences of the social-emotional behaviour of their children during and after the second stage of RTT. Both quantitative and qualitative analysis techniques have been used. Results The results of the paired-samples t-test show that parents see significantly less social-emotional behaviour in the children during the second stage of RTT than in the subsequent stages. Parents reported that their children did not seek as much interaction. From the parents' descriptions, it would seem that the children are willing but unable to interact with their environment. Conclusions Like previous research, our study leads to doubts about the appropriateness of the label 'autistic-like' for the behaviour of individuals in the second stage of RTT. While behaviours of individuals with autism and individuals with RTT may resemble each other, quality and intentions may differ. Still, future studies are needed for further clarification. [ABSTRACT FROM AUTHOR]

A recently discovered neurodevelopmental disorder caused by the mutation of the cyclin-dependent kinase-like 5 gene ( CDKL5) entails complex autistic-like behaviours similar to Rett syndrome, but its impact upon physiological functions remains largely unexplored. Sleep-disordered breathing is common and potentially life-threatening in patients with Rett syndrome; however, evidence is limited in children with CDKL5 disorder, and is lacking altogether in adults. The aim of this study was to test whether the breathing pattern during sleep differs between adult Cdkl5 knockout (Cdkl5- KO) and wild-type ( WT) mice. Using whole-body plethysmography, sleep and breathing were recorded non-invasively for 8 h during the light period. Sleep apneas occurred more frequently in Cdkl5- KO than in WT mice. A receiver operating characteristic ( ROC) analysis discriminated Cdkl5- KO significantly from WT mice based on sleep apnea occurrence. These data demonstrate that sleep apneas are a core feature of CDKL5 disorder and a respiratory biomarker of CDKL5 deficiency in mice, and suggest that sleep-disordered breathing should be evaluated routinely in CDKL5 patients. [ABSTRACT FROM AUTHOR]

Congenital disorders of glycosylation (CDG) is a booming class of metabolic diseases. Its number has increased nearly fourfold (to 45) since 2003, the year of the Komrower lecture, entitled 'Congenital disorders of glycosylation CDG): It's all in it!'. This paper presents an overview of recently discovered CDG and CDG phenotypes, of a diagnostic approach, of (the lack of) treatment, of CDG genetics, of a novel CDG nomenclature and classification, and of some future directions in the CDG field. [ABSTRACT FROM AUTHOR]

An author index for the 2009 issue of the periodical "Epilepsia" is presented.

An author index for the Volume 49, Supplement 7, 2008 issue of "Epilepsia" is presented.

Rest-activity rhythm disruption is a prominent clinical feature of Alzheimer's disease (AD). The origin of the altered rest-activity rhythm is believed to be degeneration of the suprachiasmatic nucleus (SCN). In accordance with the ‘use it or lose it’ hypothesis of Swaab [ Neurobiol Aging 1991, 12: 317–324] stimulation of the SCN may prevent age-related loss of neurons and might reactivate nerve cells that are inactive but not lost. Previous studies with relatively small sample sizes have demonstrated positive effects of peripheral electrical nerve stimulation on the rest-activity rhythm in AD patients. The present randomized, placebo-controlled, parallel-group study was meant to replicate prior findings of electrical stimulation in AD in a substantially larger group of AD patients. The experimental group ( n = 31) received peripheral electrical nerve stimulation and the placebo group ( n = 31) received sham stimulation. Effects of the intervention on the rest-activity rhythm were assessed by using wrist-worn actigraphs. Near-significant findings on the rest-activity rhythm partially support the hypothesis that neuronal stimulation enhances the rest-activity rhythm in AD patients. Interestingly, post-hoc analyses revealed significant treatment effects in a group of patients who were not using acetylcholinesterase inhibitors concomitantly. We conclude that more research is needed before firm general conclusions about the effectiveness of electrical stimulation as a symptomatic treatment in AD can be drawn. In addition, the present post-hoc findings indicate that future studies on non-pharmacological interventions should take medication use into account. [ABSTRACT FROM AUTHOR]

We investigated the time-course of nocturnal actigraphic measures, following the termination of bright-light therapy for sleep disturbances in demented nursing home patients. From an earlier study, 11 nursing home patients (86 ± 9 years, Mini-Mental Status Examination score 12 ± 4) with actigraphically measured sleep efficiency <85%, were recruited to morning bright-light treatment (6000–8000 lux) 2 h per day for 14 days. Actigraphic measures were registered at pretreatment, treatment and at four monthly post-treatment periods. Each actigraphic recording period consisted of seven consecutive days. Sleep improved substantially with treatment; sleep efficiency increased from 73% to 86% and total nocturnal wake time was reduced by nearly 2 h. During the 16 weeks post-treatment period, actigraphic measures gradually returned to pretreatment levels. Sleep efficiency remained significantly higher than the pretreatment level 4 weeks after treatment termination. Sleep onset latency remained significantly reduced up until 12 weeks post-treatment. This study supports previous findings of beneficial effects of bright-light therapy for sleep disturbances in demented nursing home patients. Furthermore, these results are the first to suggest that post-treatment effects of short-term bright-light therapy may last longer than previously assumed. [ABSTRACT FROM AUTHOR]

Studies examining levels of illumination in adult populations have demonstrated that the level and amount of light exposure are lower in the elderly compared with younger adults, particularly in institutionalized patients with dementia. Although insufficient light exposure has been implied as a cause of sleep fragmentation, evidence for such a relationship is scant. Sixty-six institutionalized elderly had their activity and light exposure monitored for a 3-day period. Mean and median light levels, minutes spent over 1000 and over 2000 lux, percent sleep and wake, and number of naps were computed for daytime intervals, defined as 07.00–18.59. Percentages of sleep and wake, number of awakenings and mean duration of wake periods were computed for night-time intervals, defined as 22.00–05.59. Mesor, amplitude and acrophase of activity and of light were determined by cosinor analysis. A mixed linear model was used to assess the effects of daytime Actillume measures on subsequent night-time measures, and vice versa. Spearman correlations were computed, and multiple regression analyses were carried out with light variables and dementia level as predictors and sleep–wake and activity measures as dependent variables. The median light level was 54 lux and a median of only 10.5 min were spent over 1000 lux. Higher light levels predicted fewer night-time awakenings, and severe dementia predicted more daytime sleep and lower mean activity. Increased bright light exposure predicted later activity acrophase. There was an association between the acrophases of light and of activity, with maximum illumination preceding peak activity. These results suggest that daytime light exposure has an impact on both night-time sleep consolidation and timing of peak activity level. [ABSTRACT FROM AUTHOR]

This article presents a study on the effect of Alzheimer disease (AD) and the underlying mechanisms on pineal clock gene expression. Certain diurnal rhythmic expression is lost in the pineal gland of preclinical and clinical AD patients. Clock gene alterations similar as the AD pineal is shown in rat pineal deprived of suprachiasmatic nucleus control. Conclusion of the study is given.