Treatment Implications of Sleep-Related Problems in Pediatric Anxiety Disorders: A Narrative Review of the Literature.

Pediatric anxiety disorders and sleep-related problems (SRPs) are highly prevalent and are associated with serious health or psychopathological consequences. This narrative review aims to provide an overview of the current evidence of the associations between anxiety disorders and SRPs, to examine how this relationship may affect treatment, and to evaluate future directions for the field. Despite their strong bi-directional relationship, SRPs are often neglected in pediatric anxiety literature. There is little consensus on the conceptualization and related measurements of SRPs, which has led to methodological limitations and difficulties. Furthermore, available research suggests that anxiety treatment alone may be inadequate as clinically impairing SRPs were still present post-treatment, which may, in turn, diminish effects of therapy. Understanding the implications of the relationship between anxiety and SRPs on treatment outcomes may be helpful in recognizing opportunities for high impact and enduring interventions.

Functional mobility decline and incident mild cognitive impairment and early dementia in community-dwelling older adults: the Singapore Longitudinal Ageing Study.

BACKGROUND: Motor and gait disturbances are evident in early Alzheimer and non-Alzheimer dementias and may predict the likelihood of mild cognitive impairment (MCI) or progression to dementia. OBJECTIVE: We investigated the Timed-Up-and-Go (TUG) measure of functional mobility in predicting cognitive decline and incident MCI or early dementia (MCI-dementia). DESIGN: Prospective cohort study with 4.5 years follow-up. SETTING: Population based. PARTICIPANTS: 2,544 community-dwelling older adults aged 55+ years. METHODS: Participants with baseline data on TUG, fast gait speed (GS), knee extension strength (KES) and performance-oriented mobility assessment (POMA) gait and balance were followed up for cognitive decline (Mini-Mental State Exam; MMSE drop of ≥2, among 1,336 dementia-free participants) and incident MCI-dementia (among 1,208 cognitively normal participants). Odds ratio (OR) and 95% confidence intervals (95% CI) were adjusted for age, sex, education, smoking, physical, social and productive activity, multi-morbidity, metabolic syndrome and MMSE. RESULTS: Per standard deviation increase in TUG, POMA, GS and KES were significantly associated with incident MCI-dementia: TUG (OR = 2.84, 95% CI = 2.02-3.99), GS (OR = 2.17, 95% CI = 1.62-2.91), POMA (OR = 1.88, 95% CI = 1.22-2.92) and KES (OR = 1.52, 95% CI = 1.15-2.02). Adjusted OR remained significant only for TUG (OR = 1.52, 95% CI = 1.01-2.31) and GS (OR = 1.53, 95% CI = 1.08-2.16). Areas under the curve (AUC) for TUG (AUC = 0.729, 95% CI = 0.671-0.787) were significantly greater than GS (AUC = 0.683, 95% CI = 0.619-0.746), KES (AUC = 0.624, 95% CI = 0.558-0.689) and POMA (AUC = 0.561, 95% CI = 0.485-0.637). Similar associations with cognitive decline were significant though less pronounced, and adjusted ORs remained significant for TUG, GS and POMA. CONCLUSION: Functional mobility decline precedes incident MCI and early dementia. The TUG appears to be especially accurate in predicting the future risks of adverse cognitive outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03405675. Registered 23 January 2018 (retrospectively registered).

Cardiometabolic and Vascular Disease Factors and Mild Cognitive Impairment and Dementia.

INTRODUCTION: There is empirical evidence that cardiovascular risk factors and vascular pathology contribute to cognitive impairment and dementia. METHODS: We profiled cardiometabolic and vascular disease (CMVD) and CMVD burden in community-living older adults in the Singapore Longitudinal Ageing Study cohort and examined the association of CMVD risk markers with the prevalence and incidence of mild cognitive impairment (MCI) and dementia from a median 3.8 years of follow-up. RESULTS: Prevalent MCI and dementia, compared with normal cognition, was associated with higher proportions of persons with any CMVD, hypertension, diabetes, coronary heart disease, atrial fibrillation, or stroke. Diabetes, stroke, and the number of CMVD risk markers remained significantly associated with dementia or MCI after adjusting for age, sex, formal education level, APOE-ε4 genotype, and level of physical, social, or productive activities, with odds ratios ranging from 1.3 to 5.7. Among cognitively normal participants who were followed up, any CMVD risk factor, dyslipidemia, diabetes, or heart failure at baseline predicted incident MCI or its progression to dementia after adjusting for potential confounders. CONCLUSION: Older adults with higher burden of CMVD, driven especially by diabetes, are likely to increase the risk of prevalent and incident MCI and dementia.

Older adult psychopathology: international comparisons of self-reports, collateral reports, and cross-informant agreement.

OBJECTIVES: To conduct international comparisons of self-reports, collateral reports, and cross-informant agreement regarding older adult psychopathology. PARTICIPANTS: We compared self-ratings of problems (e.g. I cry a lot) and personal strengths (e.g. I like to help others) for 10,686 adults aged 60-102 years from 19 societies and collateral ratings for 7,065 of these adults from 12 societies. MEASUREMENTS: Data were obtained via the Older Adult Self-Report (OASR) and the Older Adult Behavior Checklist (OABCL; Achenbach et al., ). RESULTS: Cronbach's alphas were .76 (OASR) and .80 (OABCL) averaged across societies. Across societies, 27 of the 30 problem items with the highest mean ratings and 28 of the 30 items with the lowest mean ratings were the same on the OASR and the OABCL. Q correlations between the means of the 0-1-2 ratings for the 113 problem items averaged across all pairs of societies yielded means of .77 (OASR) and .78 (OABCL). For the OASR and OABCL, respectively, analyses of variance (ANOVAs) yielded effect sizes (ESs) for society of 15% and 18% for Total Problems and 42% and 31% for Personal Strengths, respectively. For 5,584 cross-informant dyads in 12 societies, cross-informant correlations averaged across societies were .68 for Total Problems and .58 for Personal Strengths. Mixed-model ANOVAs yielded large effects for society on both Total Problems (ES = 17%) and Personal Strengths (ES = 36%). CONCLUSIONS: The OASR and OABCL are efficient, low-cost, easily administered mental health assessments that can be used internationally to screen for many problems and strengths.

Gene expression in the epileptic (EL) mouse hippocampus.

The neuropathology of hippocampal seizure foci in human temporal lobe epilepsy (TLE) and several animal models of epilepsy reveal extensive neuronal loss along with astrocyte and microglial activation. Studies of these models have advanced hypotheses that propose both pathological changes are essential for seizure generation. However, some seizure foci in human TLE show an extreme loss of neurons in all hippocampal fields, giving weight to hypotheses that favor neuroglia as major players. The epileptic (EL) mouse is a seizure model in which there is no observable neuron loss but associated proliferation of microglia and astrocytes and provides a good model to study the role of activated neuroglia in the presence of an apparently normal population of neurons. While many studies have been carried out on the EL mouse, there is a paucity of studies on the molecular changes in the EL mouse hippocampus, which may provide insight on the role of neuroglia in epileptogenesis. In this paper we have applied high throughput gene expression analysis to identify the molecular changes in the hippocampus that may explain the pathological processes. We have observed several classes of genes whose expression levels are changed. It is hypothesized that the upregulation of heat shock proteins (HSP70, HSP72, FOSL2 (HSP40), and their molecular chaperones BAG3 and DNAJB5 along with the down regulated gene MALAT1 may contribute to the neuroprotection observed. The increased expression of BDNF along with immediate early gene expression (FosB, JunB, ERG4, NR4A1, NR4A2, FBXO3) and the down regulation of GABRD, DBP and MALAT1 it is hypothesized may contribute to the hyperexcitability of the hippocampal neurons in this model. Activated astrocytes and microglia may also contribute to excitability pathomechanisms. Activated astrocytes in the ELS mouse are deficient in glutamine synthetase and thus reduce the clearance of extracellular glutamate. Activated microglia which may be associated with C1Q and MHC class I molecules we propose may mediate a process of selective removal of defective GABAergic synapses through a process akin to trogocytosis that may reduce neuronal inhibition and favor hyperexcitability.

Insomnia Disorders: Nosology and Classification Past, Present, and Future.

Insomnia is the most common sleep disorder in the adult population. However, the definition of insomnia disorder has varied across major classification systems and changed over time. In the present study, the investigators traced the evolution of insomnia disorder across classification systems, contemplated the empirical basis for its current definitions, and surveyed ongoing research efforts that may clarify insomnia nosology in the future. Three major classification systems for insomnia are the International Classification of Sleep Disorders, the International Classification of Diseases, and DSM. Despite their divergent origins, these classification systems have converged to nearly identical contemporary insomnia definitions. Over time, the emphasis in classification approaches has shifted from symptomatology to etiology to treatment implications. Additionally, the historical multitude of insomnia subtypes has gradually consolidated into a few core diagnoses, reflecting inadequate evidence with which to support subtyping. Current insomnia definitions include frequency and duration criteria to operationalize these diagnoses, while the diagnostic criterion of nonrestorative sleep has been eliminated (with some controversy). In ongoing research efforts, the quest for insomnia biomarkers has not thus far yielded clinically deployable breakthroughs. Data-driven insomnia subtyping suggests a promising new approach in deriving empirically based subtypes; conversely, the transdiagnostic perspective proposes the elimination of categorical distinctions in favor of finding common processes underlying all psychiatric disorders. The continual evolution of insomnia nosology highlights that much remains to be learned about these conditions; all current diagnostic classification systems are best regarded as "works in progress." Nevertheless, refinement and convergence of classification approaches is essential to standardizing insomnia research, diagnosis, and treatment.

Randomised prospective phase II trial in multiple brain metastases comparing outcomes between hippocampal avoidance whole brain radiotherapy with or without simultaneous integrated boost: HA-SIB-WBRT study protocol.

BACKGROUND: Recent evidence supports hippocampal avoidance with whole brain radiotherapy (HA-WBRT) as the recommended treatment option in patients with good prognosis and multiple brain metastases as this results in better neurocognitive preservation compared to whole brain radiotherapy. However, there is often poor tumour control with this technique due to the low doses given. Stereotactic Radiosurgery (SRS), a form of focused radiotherapy which is given to patients who have a limited number of brain metastases, delivers a higher radiation dose to the metastases resulting in better target lesion control. With improvements in radiation technology, advanced dose-painting techniques now allow a simultaneous integrated boost (SIB) dose to lesions whilst minimising doses to the hippocampus to potentially improve brain tumour control and preserve cognitive outcomes. This technique is abbreviated to HA-SIB-WBRT or HA-WBRT+SIB. METHODS: We hypothesise that the SIB in HA-SIB-WBRT (experimental arm) will result in better tumour control compared to HA-WBRT (control arm). This may also lead to better intracranial disease control as well as functional and survival outcomes. We aim to conduct a prospective randomised phase II trial in patients who have good performance status, multiple brain metastases (4-25 lesions) and a reasonable life expectancy (> 6 months). These patients will be stratified according to the number of brain metastases and randomised between the 2 arms. We aim for a recruitment of 100 patients from a single centre over a period of 2 years. Our primary endpoint is target lesion control. These patients will be followed up over the following year and data on imaging, toxicity, quality of life, activities of daily living and cognitive measurements will be collected at set time points. The results will then be compared across the 2 arms and analysed. DISCUSSION: Patients with brain metastases are living longer. Maintaining functional independence and intracranial disease control is thus increasingly important. Improving radiotherapy treatment techniques could provide better control and survival outcomes whilst maintaining quality of life, cognition and functional capacity. This trial will assess the benefits and possible toxicities of giving a SIB to HA-WBRT. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04452084 . Date of registration 30th June 2020.

The generalizability of Older Adult Self-Report (OASR) syndromes of psychopathology across 20 societies.

OBJECTIVES: As the world population ages, psychiatrists will increasingly need instruments for measuring constructs of psychopathology that are generalizable to diverse elders. The study tested whether syndromes of co-occurring problems derived from self-ratings of psychopathology by US elders would fit self-ratings by elders in 19 other societies. METHODS/DESIGN: The Older Adult Self-Report (OASR) was completed by 12 826 adults who were 60 to 102 years old in 19 societies from North and South America, Asia, and Eastern, Northern, Southern, and Western Europe, plus the United States. Individual and multigroup confirmatory factor analyses (CFAs) tested the fit of the seven-syndrome OASR model, consisting of the Anxious/Depressed, Worries, Somatic Complaints, Functional Impairment, Memory/Cognition Problems, Thought Problems, and Irritable/Disinhibited syndromes. RESULTS: In individual CFAs, the primary model fit index showed good fit for all societies, while the secondary model fit indices showed acceptable to good fit. The items loaded strongly on their respective factors, with a median item loading of .63 across 20 societies, and 98.7% of the loadings were statistically significant. In multigroup CFAs, 98% of items demonstrated approximate or full metric invariance. Fifteen percent of items demonstrated approximate or full scalar invariance, and another 59% demonstrated scalar invariance across more than half of societies. CONCLUSIONS: The findings supported the generalizability of OASR syndromes across societies. The seven syndromes offer empirically based clinical constructs that are relevant for elders of different backgrounds. They can be used to assess diverse elders and as a taxonomic framework to facilitate communication, services, research, and training in geriatric psychiatry.

Early Detection of Mild Cognitive Impairment With In-Home Sensors to Monitor Behavior Patterns in Community-Dwelling Senior Citizens in Singapore: Cross-Sectional Feasibility Study.

BACKGROUND: Dementia is a global epidemic and incurs substantial burden on the affected families and the health care system. A window of opportunity for intervention is the predementia stage known as mild cognitive impairment (MCI). Individuals often present to services late in the course of their disease and more needs to be done for early detection; sensor technology is a potential method for detection. OBJECTIVE: The aim of this cross-sectional study was to establish the feasibility and acceptability of utilizing sensors in the homes of senior citizens to detect changes in behaviors unobtrusively. METHODS: We recruited 59 community-dwelling seniors (aged >65 years who live alone) with and without MCI and observed them over the course of 2 months. The frequency of forgetfulness was monitored by tagging personal items and tracking missed doses of medication. Activities such as step count, time spent away from home, television use, sleep duration, and quality were tracked with passive infrared motion sensors, smart plugs, bed sensors, and a wearable activity band. Measures of cognition, depression, sleep, and social connectedness were also administered. RESULTS: Of the 49 participants who completed the study, 28 had MCI and 21 had healthy cognition (HC). Frequencies of various sensor-derived behavior metrics were computed and compared between MCI and HC groups. MCI participants were less active than their HC counterparts and had more sleep interruptions per night. MCI participants had forgotten their medications more times per month compared with HC participants. The sensor system was acceptable to over 80% (40/49) of study participants, with many requesting for permanent installation of the system. CONCLUSIONS: We demonstrated that it was both feasible and acceptable to set up these sensors in the community and unobtrusively collect data. Further studies evaluating such digital biomarkers in the homes in the community are needed to improve the ecological validity of sensor technology. We need to refine the system to yield more clinically impactful information.

Astrocytes and Glutamine Synthetase in Epileptogenesis.

The cellular, molecular, and metabolic mechanisms that underlie the development of mesial temporal lobe epilepsy are incompletely understood. Here we review the role of astrocytes in epilepsy development (a.k.a. epileptogenesis), particularly astrocyte pathologies related to: aquaporin 4, the inwardly rectifying potassium channel Kir4.1, monocarboxylate transporters MCT1 and MCT2, excitatory amino acid transporters EAAT1 and EAAT2, and glutamine synthetase. We propose that inhibition, dysfunction or loss of astrocytic glutamine synthetase is an important causative factor for some epilepsies, particularly mesial temporal lobe epilepsy and glioblastoma-associated epilepsy. We postulate that the regulatory mechanisms of glutamine synthetase as well as the downstream effects of glutamine synthetase dysfunction, represent attractive, new targets for antiepileptogenic interventions. Currently, no antiepileptogenic therapies are available for human use. The discovery of such interventions is important as it will fundamentally change the way we approach epilepsy by preventing the disease from ever becoming manifest after an epileptogenic insult to the brain.