Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from ?0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to ?0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.     

Efficacy and safety of acupuncture treatment on primary insomnia: a randomized controlled trial

ObjectiveThe objective of this study was to evaluate the efficacy and safety of acupuncture treatment for primary insomnia.MethodsWe conducted a single-center, single-blinded, and randomized controlled clinical trial. Seventy-two patients with primary insomnia were randomly assigned into two groups – the acupuncture group, who received acupuncture treatment, and the control group, who received sham acupuncture treatment. The treatment was given three times a week for four weeks. Patients were asked to wear sleep monitors and complete questionnaires every two weeks for a total of eight weeks. The primary outcome was the Insomnia Severity Index (ISI). The secondary outcomes were sleep parameters including sleep efficiency (SE), sleep awakenings (SA) and total sleep time (TST) recorded by the Actigraphy, as well as scores of the Self-Rating Anxiety Scale (SAS) and the Self-Rating Depression Scale (SDS).ResultsCompared with pretreatment baseline, patients in both groups had varying degrees of improvements in their sleep conditions. Paired t-test showed that there was a significant difference in all indicators in the acupuncture group before and after acupuncture treatment. One-way analysis of covariance adjusted for baseline scores indicated that the ISI improved dramatically in the acupuncture group at two weeks post-treatment (F = 11.3, p = 0.001), four weeks post-treatment (F = 33.6, p < 0.001), 2 weeks follow-up (F = 39.4, p < 0.001) and four weeks follow-up (F = 34.1, p < 0.001). Similar significant improvements can also be observed in the SE, TST and SDS scores. Although no differences in SA and SAS were shown between the two groups until the end of the treatment, remarkable decrements in SA and SAS were found in the acupuncture treatment group after the two-week and four-week follow-ups.ConclusionAcupuncture treatment is more effective than sham acupuncture treatment in increasing insomnia patients' sleep quality and improving their psychological health.Trial RegistrationChinese Clinical Trial Registry: Chi CTR-TRC-14004859.     

Treatment response and cognitive impairment in major depression: association with C-reactive protein

Levels of inflammatory markers have been found to be significantly associated with major depressive disorder (MDD) and cognitive impairment. The aim of this study was to investigate whether the level of C-reactive protein (CRP) is correlated with depressive mood and cognitive impairment in MDD patients. In 149 subjects with MDD, the 21-item Hamilton Rating Scale for Depression (HAM-D), Continuous Performance Test (CPT), Finger-Tapping Test (FTT), and Wisconsin Card-Sorting Test (WCST) were administered before and after antidepressant treatment. Besides, the level of CRP was measured. After 6 weeks of treatment, the total HAM-D scores decreased significantly. In addition, the subjects’ performance in the masked CPT and the WCST with completed categories significantly improved (p < 0.001 and p = 0.027, respectively) after the reliable change indices were corrected for practice effects. The CRP levels had increased significantly after six weeks of treatment after adjustment for age and gender (p < 0.001). In addition, the CRP levels remained significantly high after six weeks of treatment in patients with a higher baseline level (r = 0.657, p < 0.001). Although the association between baseline CRP level and HAM-D score was not significant, the baseline CRP level was significantly correlated with treatment response at week 2 (r = 0.327, p = 0.020). The baseline CRP level was also negatively correlated with performance in the FTT before treatment (r = −0.580, p = 0.006). Moreover, the baseline CRP level was significantly correlated with performance in the FTT (r = −0.501, p = 0.021) and WCST with completed categories (r = −0.521, p = 0.015) at week 6. The cognitive function of patients with high baseline CRP levels might remain impaired even if their mood symptoms improve after antidepressant treatment. Whether adjunctive anti-inflammatory medication may help to preserve cognitive function merits further investigation.     

The relationship between plasma serotonin and kynurenine pathway metabolite levels and the treatment response to escitalopram and desvenlafaxine

IntroductionThe response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels.MethodsThe levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤7.ResultsResponse to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p = 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047).ConclusionsIn MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.     

Effects of adjunctive inflammatory modulation on IL-1β in treatment resistant bipolar depression

BackgroundAdjunctive inflammatory modulation improved remission rates in treatment-resistant bipolar depression (TRBDD), but reliable biomarkers must be established to characterize the biosignature of TRBDD and the mechanisms underlying treatment response. In this molecular profiling study, we describe TRBDD and treatment response from the standpoint of interleukin-1 Beta (IL-1β) and KYN/TRP.Methods47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg–40 mg daily dose range) + celecoxib (CBX) (200 mg twice daily), or ESC (10 mg–40 mg daily dose range) + placebo (PBO) (twice daily). Plasma cytokine levels were measured in both treatment arms at baseline and week 8, and in a healthy control (HC) group of subjects (N = 43) once. A linear mixed model (LMM) was applied to evaluate whether clinical outcome is related to CBX and changes to biomarkers throughout treatment. A binary logistic regression model was formulated from this series to predict both the primary outcome of treatment response to CBX, and the secondary outcome of diagnosis of TRBDD using age, BMI, gender, and IL-1β at baseline.ResultsPatients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT = 3, and 15.300 times more likely to remit (p < 0.001) with NNT = 2, compared with ESC + PBO patients. Patient BMI (p = 0.003), baseline IL-1β (p = 0.004), and baseline KYN/TRP (p = 0.001) were most predictive of TRBDD diagnosis. By Week 8, responders showed a downtrend in IL-1β compared to non-responders in the ESC + CBX treatment arm. However, there was no statistical difference in the IL-1β or KYN/TRP change after treatment between placebo and ESC + CBX group responders/non-responders (p = 0.239, and p = 0.146, respectively). While baseline IL-1β was elevated in TRBDD compared to HC (p < 0.001), there was no difference in IL-1β between treatment responders at Week 8 compared to HC (p = 0.067).ConclusionsElevated IL-1β and low KYN/TRP at baseline are components of the TRBDD molecular signature. CBX but not baseline IL-1β or KYN/TRP predict treatment response. Change in IL-1β and KYN/TRP did not predict treatment response.     

Hippocampal volume and white matter disease in the prediction of dementia in Parkinson's disease

BackgroundLongitudinal neuroimaging studies could provide insights into pathophysiology of cognitive impairment in PD. We examined the role of hippocampal atrophy and cerebral white matter disease as risk factors for mild cognitive impairment and dementia in PD.MethodsProspective longitudinal study of patients with mild PD in a tertiary neurology center. All subjects underwent baseline MRI brain and had baseline and 6 monthly cognitive evaluations. Cognitive impairment was diagnosed based on the Movement Disorder Society Criteria. The predictive role of hippocampal volume and white matter hyperintensity at baseline on progression of cognitive impairment was studied.Results97 subjects with mean age 65.3 years, mean education of 10.3 years and mean Hoehn & Yahr of 1.9 were studied. Over 2 years, 16 subjects developed mild cognitive impairment and 8 subjects with mild cognitive impairment progressed to dementia. After adjusting for age and vascular risk factors, hippocampal volume was a significant predictor for mild cognitive impairment (OR 7.05, CI 1.5–34.1; p = 0.015) and dementia (OR 7.03, CI 2.39–25.2; p = 0.001). With Cox regression, hippocampal volume was a significant predictor for “time to cognitive impairment” (HR 7.67; CI 3.47–16.95, p < 0.001). Difference between survival curves based on volume of white matter hyperintensity in predicting “time to mild cognitive impairment” was significant (p = 0.0295).ConclusionsHippocampal volume is a major factor predicting the development of mild cognitive impairment and dementia in PD. White matter hyperintensity also contributes to the longitudinal cognitive status in PD.     

Social dysfunction predicts two years clinical outcome in people at ultra high risk for psychosis

The experience of a first psychotic episode is associated with a marked impairment in psychosocial functioning. However, the decline may be already evident in the pre-psychotic phases and play a significant role in the etiopathology of the disease onset. A sample of subjects at ultra high clinical risk for psychosis (“At Risk Mental State”, ARMS, n = 152) was compared with a demographically-matched general population (n = 98,072) on different measures of psychosocial functioning. The proportion of subjects with an ARMS living in communal establishments or living at home with their parents was significantly higher than that of the local population (p < 0.001). Subjects with an ARMS showed also higher rates of unemployment as compared to the general population (p < 0.001). GAF scores at baseline were significantly lower in unemployed ARMS as compared to students and employed ARMS (p = 0.002). ARMS subjects living in communal establishments presented higher rates of co-morbid psychiatric conditions (p = 0.007) and lower GAF scores at baseline (p = 0.017). Finally, baseline unemployment and living in a communal establishment were associated with an increased risk of developing a psychotic episode within the following two years (p < 0.05). We concluded that the “At Risk Mental State” is a clinical condition which is characterized by marked psychosocial impairment and by an increased vulnerability to psychosis. Unemployment at the first contact with the prodromal service may be a risk factor for the development of a psychotic episode.     

Facial emotional expression in schizophrenia adolescents during verbal interaction with a parent

Research on emotional expression in adult schizophrenia patients has indicated an impairment of the patients’ facial expressions during social interaction. However, it is unclear whether schizophrenia adolescent-onset patients show comparable disturbances in facial expression. Our aim was to analyze facial emotions in adolescents with schizophrenia spectrum psychoses compared with non-patient controls during a problem-solving discussion with their primary caregivers. We assessed facial expressions of emotions and speaker position (speaking vs. listening) in schizophrenia and non-patient adolescents matched for age and gender. The facial emotions were coded with the Emotional Facial Action Coding System. Schizophrenia adolescents showed significantly lower rates per minute of expressions indicating positive emotions compared with non-patient adolescents (β = ?0.95, 95 % CI [?1.34, ?0.57], t _(37.92) = ?5.00, p ≤ 0.001). In contrast, there was no lower rate of expressions indicating negative emotions of schizophrenia adolescents (β = 0.10, CI [?0.42, 0.61], t _(35.03) = 0.38, p = 0.709). While the negative facial expressions of non-patient adolescents were related to speaking (β = 0.63, CI [0.34, 0.92], t ₍₂₆₎ = 4.50, p = < 0.001), this relationship was not observed in schizophrenia adolescents. Our results indicated an emotion-specific impairment of positive facial expressions in schizophrenia adolescents early in the course of illness and a deviant relation between facial emotional expressions and speech.     

The effect of spirituality and religious attendance on the relationship between psychological distress and negative life events

Purpose

The aim of this study was to assess the effect of religious attendance and spirituality on the relationship between negative life events and psychological distress.

Methods

This was a cross-sectional study of 1,071 community dwelling adults from East Baltimore, Maryland who participated in the fourth (2004–2005) wave of the Baltimore Epidemiologic Catchment Area study. The 20-item General Health Questionnaire (GHQ-20) was used to measure psychological distress. Multiple regression models were used to assess the association between negative life events and distress as well as to measure the effect of religious attendance and spirituality on the association between psychological distress and negative events while adjusting for demographic variables, past distress and social support from friends and relatives.

Results

In pooled analysis, negative events were significant predictors of distress, b = 1.00, β = 0.072, p < 0.05. Religious attendance and spirituality did not affect or modify the association between negative events and distress. However, religious attendance was inversely associated with distress with higher frequency of attendance associated with lower distress after controlling for demographic and social support factors, b = ?2.10, β = ?.110, p < 0.01 for attending 1–3 times a month; b = ?2.39, β = ?0.156, p < 0.01 for attending weekly; and b = ?3.13, β = ?0.160, p < 0.001 for attending more than once per week. In stratified analysis, negative events were associated with distress for those who were low on spirituality, b = 1.23, β = 0.092, p < .05, but not for those who were high on spirituality; the association between religious attendance and decreased distress was true only for those scoring high in spirituality. Social support accounted for some of the inverse association between religious and distress.

Conclusion

Religious attendance and spirituality may play a role in how people experience and deal with difficult life situations.     

Common carotid intima media thickness as a marker of clinical severity in patients with symptomatic extracranial carotid artery stenosis

Objectives

Increased common carotid artery intima-media thickness (CCA-IMT) is a risk factor for ischemic stroke and especially large vessel atherothrombotic infarction. However, the potential association of stroke severity with the intima-media thickening has not been previously studied. We sought to investigate the association between CCA-IMT and clinical severity of ischemic stroke in patients with symptomatic extracranial carotid artery stenosis (SCAS).

Patients and methods

Consecutive patients with acute, first-ever ischemic stroke and SCAS (50%–99%) were prospectively evaluated. All subjects underwent IMT measurements at the far wall of CCA. Stroke severity was assessed using the National Institute of Health Stroke Scale (NIHSS) on hospital admission and Barthel Ambulatory Index (BI) at hospital discharge.

Results

CCA-IMT was strongly correlated to NIH (Spearman's correlation coefficient: r = 0.546, p < 0.001) and BI (r = −0.450, p < 0.001) in the study population (n = 102). A 0.1 mm increase in CCA-IMT was independently associated with increasing NIHSS-scores on hospital admission (β: 0.510; p < 0.001) and decreasing BI-scores at hospital discharge (β: −0.483; p < 0.001) even after adjustment for demographic characteristics and cardiovascular risk factors. After including baseline stroke severity (NIHSS) in the multivariate linear regressions models evaluating early functional outcome, only NIHSS was independently related to BI (standardized linear regression coefficient: −0.776, p < 0.001), while the initial association between IMT and BI did not retain its statistical significance (β: −0.074, p = 0.276).

Conclusions

Increased CCA-IMT is independently associated with more severe stroke on admission in patients with SCAS.     

Associations Between Fatigue and Disability,Depression, Health-Related Hardiness and Quality of Life in People with Stroke

BackgroundStroke is a common cause of mortality and morbidity which affects approximately 17 million people globally each year. Common symptoms associated with stroke are physical disabilities, impaired cognitive functions, depression, and fatigue, all of which can significantly impact health-related quality of life (HRQoL). To date, no research has explored the inter-relationship among fatigue, disability, depression, health-related hardiness, and quality of life in stroke survivors.MethodsData was obtained from a sub-study of the 45 and Up Study; including 576 Australian adults who had been diagnosed with a stroke. The cross-sectional questionnaire obtained demographic and health status information, as well as clinical measures and stroke-related measures. Associations among fatigue and disability, depression, health-related hardiness and quality of life were analysed using a linear regression model.ResultsIn comparison to those participants with no stroke-related disability, those with slight (β = 1.141; p = 0.008), moderate (β = 3.250; p < 0.001) or severe (β = 3.526; p < 0.001) disability had significantly higher fatigue scores. For every one unit increase in the depression score, the fatigue score increased by 1.502 points (p < 0.001). For every one unit increase in the health-related hardiness score, the fatigue score decreased by 0.054 points (p = 0.044). For every one unit increase in the quality of life score, the fatigue score decreased by 0.068 points (p < 0.001).ConclusionThis study found significant associations among fatigue and disability, depression, health-related hardiness, and quality of life in stroke survivors. Accurate detection and management of fatigue may help improve the rehabilitation of stroke survivors.     

Influence of multisystemic affection on health-related quality of life in patients with myotonic dystrophy type 1

Aim

To assess health-related quality of life (HRQoL) in patients with DM1, to identify muscular, multisystemic, central and social factors that may affect QoL and to define a DM1 patient in risk of poor QoL.

Patients and method

This cross-sectional study comprised 120 DM1 consecutive patients. The following scales were used: Multidimensional Scale of Perceived Social Support (MSPSS), Muscular Impairment Rating Scale (MIRS), battery of neuropsychological tests, acceptance of illness scale (AIS), Hamilton rating scale for depression (Ham-D), Krupp's Fatigue Severity Scale (FSS), Daytime Sleepiness Scale (DSS) and SF-36 questionnaire.

Results

HRQoL was impaired in DM1 patients in both physical and mental domains (PCS was 41.8 ± 23.5, MCS 47.0 ± 24.3 and total SF-36 score 45.6 ± 24.0). The most significant factors correlating with better SF-36 total score were younger age (β = −0.45, p < 0.001), shorter duration of disease (β = −0.27, p = 0.001), higher education (β = 0.20, p = 0.009), less severe muscular weakness (β = −0.52, p < 0.001), normal swallowing (β = 0.22, p = 0.005), absence of fainting (β = 0.31, p = 0.002), absence of snoring (β = 0.21, p = 0.036), better acceptance of disease (β = −0.17, p = 0.036), lower depressiveness (β = −0.46, p = 0.001), lower fatigue (β = −0.32, p = 0.001), absence of cataract (β = −0.21, p = 0.034), absence of kyphosis (β = 0.31, p = 0.004) and absence of constipation (β = 0.24, p = 0.016). Second linear regression analysis revealed that depressed (β = −0.38, p < 0.001) and elder patients (β = −0.27, p = 0.007) and as well as those with poor acceptance of illness (β = −0.21, p = 0.006) were in especially higher risk of having poor HRQoL (R² = 0.68).

Conclusion

We identified different central, social, muscular, cardiorespiratory and other factors correlating with HRQoL. It is of great importance that most of these factors are amenable to treatment.     

A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder

The efficacy, tolerability, and safety of LY2216684, a highly selective norepinephrine reuptake inhibitor, were studied in adult patients with major depressive disorder (MDD). This randomized, double-blind study compared flexible-dose LY2216684 6-18 mg once daily (N = 250) with placebo (N = 245) for 10 weeks acute therapy followed by 1 year LY2216684 treatment (results not reported here). Primary inclusion criteria consisted of GRID 17-item Hamilton Rating Scale for Depression total score ≥18 and Clinical Global Impressions-Severity score ≥4. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Response was defined as a ≥50% reduction in MADRS score and remission as MADRS total score ≤10. Global functioning was assessed using the Sheehan Disability Scale (SDS). LY2216684-treated patients showed significant improvement from baseline on the MADRS total score compared with placebo-treated patients (−13.3 vs. −9.8, p < .001), and they had a significantly higher probability of achieving response (49.5%) and remission (29.7%) compared with placebo-treated patients (29.3% and 18.8%, respectively). For the SDS global functional impairment score, LY2216684 treatment resulted in significantly greater improvement compared with placebo treatment (p < .001). More LY2216684-treated than placebo-treated patients discontinued from the study because of an adverse event or death (9.6% vs. 1.6%, p ≤ .001). LY2216684 was associated with significant increases (p < .01) from baseline in systolic (3 mm Hg) and diastolic (4 mm Hg) blood pressure and pulse (10 bpm) compared with placebo. LY2216684 6-18 mg demonstrated significant efficacy and was tolerated in the treatment of MDD.     

Association of early-onset dementia with activities of daily living (ADL) in middle-aged adults with intellectual disabilities: The caregiver's perspective

Few studies have investigated in detail which factors influence activities of daily living (ADL) in adults with intellectual disabilities (ID) comorbid with/without dementia conditions. The objective of the present study was to describe the relation between early onset dementia conditions and progressive loss of ADL capabilities and to examine the influence of dementia conditions and other possible factors toward ADL scores in adults with ID. This study was part of the “Healthy Aging Initiatives for Persons with an Intellectual Disability in Taiwan: A Social Ecological Approach” project. We analyzed data from 459 adults aged 45 years or older with an ID regarding their early onset symptoms of dementia and their ADL profile based on the perspective of the primary caregivers. Results show that a significant negative correlation was found between dementia score and ADL score in a Pearson's correlation test (r = −0.28, p < 0.001). The multiple linear regression model reported that factors of male gender (β = 4.187, p < 0.05), marital status (β = 4.79, p < 0.05), education level (primary: β = 5.544, p < 0.05; junior high or more: β = 8.147, p < 0.01), Down's syndrome (β = −9.290, p < 0.05), severe or profound disability level (β = −6.725, p < 0.05; β = −15.773, p < 0.001), comorbid condition (β = −4.853, p < 0.05) and dementia conditions (β = −9.245, p < 0.001) were variables that were able to significantly predict the ADL score (R² = 0.241) after controlling for age. Disability level and comorbidity can explain 10% of the ADL score variation, whereas dementia conditions can only explain 3% of the ADL score variation in the study. The present study highlights that future studies should scrutinize in detail the reasons for the low explanatory power of dementia for ADL, particularly in examining the appropriateness of the measurement scales for dementia and ADL in aging adults with ID.     

Associations between sleep,daytime sleepiness and functional outcomes in adolescents with ADHD

Objective/backgroundAdolescents with attention-deficit/hyperactivity disorder (ADHD) experience greater difficulties in the domains of sleep, daytime sleepiness, and functioning compared to their peers. However, the relationship between these domains has not been fully elucidated. This study aimed to examine the relationship between sleep problems (including daytime sleepiness), ADHD severity, and functional outcomes (irritability, sluggish cognitive tempo, homework difficulties, and substance use) in a sample of adolescents with ADHD.Patients/methodsEighty-two adolescents (13–17 years) and their families participated in the study. Sleep was measured by both adolescent and parent-report. Adolescent irritability and sluggish cognitive tempo were reported by both adolescents and parents, while other variables were reported by a single reporter (homework difficulties – parent; ADHD severity – parent; substance use – adolescent). Analyses controlled for demographic factors and internalising and externalising comorbidities.ResultsA weak relationship was found between adolescent-reported sleep problems and daytime sleepiness, which became non-significant in adjusted analyses (β = −0.19, p = 0.115). In adjusted analyses, there was an association between adolescent-reported sleep problems and adolescent-reported irritability (β = −0.27, p = 0.023) as well as between adolescent-reported daytime sleepiness and parent-reported sluggish cognitive tempo (β = 0.28, p = 0.033). In adjusted analyses, parent-reported adolescent sleep problems were associated with ADHD severity (β = 0.54, p = <0.001), parent-reported sluggish cognitive tempo (β = 0.64, p = <0.001), both reporters of irritability (parent-report: β = 0.32, p = 0.004; adolescent-report: β = 0.29, p = 0.022), and homework problems (β = 0.37, p = 0.003). Parent-reported daytime sleepiness was associated with parent-reported sluggish cognitive tempo (β = 0.34, p = 0.024).ConclusionsThis study demonstrates the importance of a holistic assessment of adolescents with ADHD, not only focusing on symptomatology but also on sleep problems and functional outcomes. The importance of multi-informant assessment of sleep problems is also reinforced.     

Cognitive impairment in Parkinson's disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aβ

IntroductionTo identify clinically implementable biomarkers of cognitive impairment in Parkinson's Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis.MethodsIn this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aβ-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments.ResultsLHC-RHC (F_3,67 = 3.41,p=0.023) and CSF Aβ-42:40 (χ²(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment.ConclusionWe used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD.     

The short and long of adolescent sleep: the unique impact of day length

Study objectivesVariation in day length is proposed to impact sleep, yet it is unknown whether this is above the influence of behavioural factors. Day length, sleep hygiene, and parent-set bedtime were simultaneously explored, to investigate the relative importance of each on adolescents’ sleep.MethodsAn online survey was distributed in four countries at varying latitudes/longitudes (Australia, The Netherlands, Canada, Norway).ResultsOverall, 711 (242 male; age M = 15.7 ± 1.6, range = 12–19 yrs) adolescents contributed data. Hierarchical regression analyses showed good sleep hygiene was associated with earlier bedtime, shorter sleep latency, and longer sleep (β = −0.34; −0.30; 0.32, p < 0.05, respectively). Shorter day length predicted later bedtime (β = 0.11, p = 0.009), decreased sleep latency (β = −0.21, p < 0.001), and total sleep (β = −0.14, p = 0.001). Longer day length predicted earlier bedtimes (β = −0.11, p = 0.004), and longer sleep (β = 0.10, p = 0.011).ConclusionsSleep hygiene had the most clinical relevance for improving sleep, thus should be considered when implementing adolescent sleep interventions, particularly as small negative effects of shorter day length may be minimised through sleep hygiene techniques.     

The risk of reduced physical activity in children with probable Developmental Coordination Disorder: a prospective longitudinal study

The aim of the current study was to test the hypothesis that children with probable Developmental Coordination Disorder have an increased risk of reduced moderate to vigorous physical activity (MVPA), using data from a large population based study. Prospectively collected data from 4331 children (boys = 2065, girls = 2266) who had completed motor coordination testing at 7 years and accelerometry at 12 years were analysed from the Avon Longitudinal Study of Parents and Children (ALSPAC). Probable DCD (p-DCD) was defined, using criteria based on the DSM IV classification, as those children below the 15th centile of the ALSPAC Coordination Test at seven years who had a functional impairment in activities of daily living or handwriting, excluding children with a known neurological diagnosis or IQ < 70. Secondary exposure variables consisted of subtests from the ALSPAC Coordination test (manual dexterity, ball skills and balance). Objective measurement of the average daily minutes of MVPA was recorded as ≥3600 counts per minute (cpm) using actigraph accelerometry. Boys with p-DCD were less physically active than boys without DCD (mean difference in MVPA 4.36 cpm, t = 2.69; p = 0.007). For boys, targeting skill (bean bag toss) was related to increased MVPA, after adjustment for confounding factors including neonatal, family and environmental factors as well as Body Mass Index at age seven and 12 years (β = 0.76, t = 3.37, p < 0.001, CI 0.32-1.20). There was no difference in level of MVPA in girls with and without p-DCD (mean difference 1.35 min, t = 0.97, p = 0.31), which may reflect the low levels of MVPA of girls in this cohort. Our findings suggest that the presence of movement difficulties, particularly poor targeting (bean bag toss/ball skills), at a young age is a potential risk factor for reduced MVPA in boys.