Hepatic LRP-1 plays an important role in amyloidosis in Alzheimer's disease mice: Potential role in chronic heavy alcohol feeding.

BACKGROUND: Hepatic lipoprotein receptor-related protein 1 (LRP-1) plays a central role in peripheral amyloid beta (Aß) clearance, but its importance in Alzheimer's disease (AD) pathology is understudied. Our previous work showed that intragastric alcohol feeding to C57BL/6 J mice reduced hepatic LRP-1 expression which correlated with significant AD-relevant brain changes. Herein, we examined the role of hepatic LRP-1 in AD pathogenesis in APP/PS1 AD mice using two approaches to modulate hepatic LRP-1, intragastric alcohol feeding to model chronic heavy drinking shown by us to reduce hepatic LRP-1, and hepato-specific LRP-1 silencing. METHODS: Eight-month-old male APP/PS1 mice were fed ethanol or control diet intragastrically for 5 weeks (n = 7-11/group). Brain and liver Aß were assessed using immunoassays. Three important mechanisms of brain amyloidosis were investigated: hepatic LRP-1 (major peripheral Aß regulator), blood-brain barrier (BBB) function (vascular Aß regulator), and microglia (major brain Aß regulator) using immunoassays. Spatial LRP-1 gene expression in the periportal versus pericentral hepatic regions was confirmed using NanoString GeoMx Digital Spatial Profiler. Further, hepatic LRP-1 was silenced by injecting LRP-1 microRNA delivered by the adeno-associated virus 8 (AAV8) and the hepato-specific thyroxine-binding globulin (TBG) promoter to 4-month-old male APP/PS1 mice (n = 6). Control male APP/PS1 mice received control AAV8 (n = 6). Spatial memory and locomotion were assessed 12 weeks after LRP-1 silencing using Y-maze and open-field test, respectively, and brain and liver Aß were measured. RESULTS: Alcohol feeding reduced plaque-associated microglia in APP/PS1 mice brains and increased aggregated Aß (p < 0.05) by ELISA and 6E10-positive Aß load by immunostaining (p < 0.05). Increased brain Aß corresponded with a significant downregulation of hepatic LRP-1 (p < 0.01) at the protein and transcript level, primarily in pericentral hepatocytes (zone 3) where alcohol-induced injury occurs. Hepato-specific LRP-1 silencing significantly increased brain Aß and locomotion hyperactivity (p < 0.05) in APP/PS1 mice. CONCLUSION: Chronic heavy alcohol intake reduced hepatic LRP-1 expression and increased brain Aß. The hepato-specific LRP-1 silencing similarly increased brain Aß which was associated with behavioral deficits in APP/PS1 mice. Collectively, our results suggest that hepatic LRP-1 is a key regulator of brain amyloidosis in alcohol-dependent AD.

Anxiety symptoms and disorders during the COVID-19 pandemic in children and adolescents: Systematic review and meta-analysis

Background and Objectives The COVID-19 pandemic and its associated factors have been shown to affect anxiety levels of young people. We meta-analytically assessed the prevalence of anxiety symptoms and anxiety disorders in children and adolescents during the pandemic, and the predictors and moderating factors influencing anxiety. Methods Multiple databases and registers were searched in this PRISMA and MOOSE-compliant systematic review and meta-analysis (PROSPERO:CRD42021266695) until 27/06/2021. We included individual studies evaluating the prevalence and characteristics of anxiety symptoms or anxiety disorders in children and adolescents (mean age ≤18 years), during the COVID-19 pandemic. Data extraction and quality assessment were carried out by independent authors. Random-effects meta-analyses of the prevalence of anxiety symptoms and anxiety disorders were conducted using Comprehensive Meta-Analysis (CMA) V3. Results 74 articles (total participant sample=478,882) were included (mean age=13.4 years, 52.3% female). The pooled rate of children and adolescents fulfilling diagnostic criteria for anxiety disorders was 13.0% (95%CI=4.9–30.1); the pooled prevalence of anxiety symptoms was 26.5% (95%CI=20.3–33.9). Anxiety symptoms were significantly more prevalent in females than males (B = 0.103, p<.001), significantly higher during the second wave of COVID-19, following July 2020, than during the first wave, prior to June 2020, (Q= 8.136, p=.017), and during school closure (Q= 8.100, p=.014). Quality of included studies was overall moderate. Conclusions There is a high prevalence of anxiety symptoms in children and adolescents during the COVID-19 pandemic, especially amongst females. This study identifies vulnerable groups, risk, and protective factors, which is crucial to developing clinical practice to prevent further mental health deterioration in young people. (AU)

The impact of COVID-19 lockdown on child and adolescent mental health: systematic review.

COVID-19 was declared a pandemic in March 2020, resulting in many countries worldwide calling for lockdowns. This study aimed to review the existing literature on the effects of the lockdown measures established as a response to the COVID-19 pandemic on the mental health of children and adolescents. Embase, Ovid, Global Health, PsycINFO, Web of Science, and pre-print databases were searched in this PRISMA-compliant systematic review (PROSPERO: CRD42021225604). We included individual studies reporting on a wide range of mental health outcomes, including risk and protective factors, conducted in children and adolescents (aged ≤ 19 years), exposed to COVID-19 lockdown. Data extraction and quality appraisal were conducted by independent researchers, and results were synthesised by core themes. 61 articles with 54,999 children and adolescents were included (mean age = 11.3 years, 49.7% female). Anxiety symptoms and depression symptoms were common in the included studies and ranged 1.8-49.5% and 2.2-63.8%, respectively. Irritability (range = 16.7-73.2%) and anger (range = 30.0-51.3%), were also frequently reported by children and adolescents. Special needs and the presence of mental disorders before the lockdown, alongside excessive media exposure, were significant risk factors for anxiety. Parent-child communication was protective for anxiety and depression. The COVID-19 lockdown has resulted in psychological distress and highlighted vulnerable groups such as those with previous or current mental health difficulties. Supporting the mental health needs of children and adolescents at risk is key. Clinical guidelines to alleviate the negative effects of COVID-19 lockdown and public health strategies to support this population need to be developed.

Efficacy of remotely-delivered cognitive behavioural therapy for obsessive-compulsive disorder: An updated meta-analysis of randomised controlled trials.

INTRODUCTION: Despite remotely-delivered cognitive behavioural therapy (CBT) being an emerging field, the evidence of its efficacy in obsessive-compulsive disorder (OCD) is limited. We aimed to estimate the efficacy of remotely-delivered CBT for OCD, compared to face-to-face CBT and non-CBT control conditions. METHODS: Randomised clinical trials (RCTs) identified through a systematic literature search of PubMed, Ovid/PsychINFO and Web of Science until 21/06/2021. Eligible studies included individuals with OCD evaluating at least one form of remotely-delivered CBT versus a control condition. Random-effects meta-analyses, sub-analyses, meta-regressions, heterogeneity analyses, publication bias assessment and quality assessment. RESULTS: Twenty-two RCTs were included (n = 1796, mean age = 27.7 years, females = 59.1 %). Remotely-delivered CBT was more efficacious than non-CBT control conditions for OCD symptoms (g = 0.936 95 % CI = 0.597-1.275, p < .001), depressive symptoms (g = 0.358, 95 % CI = 0.125-0.590, p = .003) and anxiety symptoms (g = 0.468, 95 % CI = 0.135-0.800, p = .006). There were no significant differences in efficacy between remotely-delivered CBT and face-to-face CBT for OCD symptoms (g = -0.104 95 % CI = -0.391-0.184, p = .479), depressive symptoms (g = 0.138, 95 % CI = -0.044-0.320, p = .138), anxiety symptoms (g = 0.166, 95 % CI = -0.456-0.780, p = .601) or quality of life (g = 0.057, 95 % CI = -0.178-0.292, p = .489). Higher baseline severity of OCD symptoms was associated with a lower efficacy of remotely-delivered CBT compared to face-to-face CBT (ß = -0.092, p = .036). The quality of the included studies was mostly identified as "low risk of bias" (45.5 %) or "some concerns" (45.5 %). LIMITATIONS: Heterogeneity and limited evidence for some outcomes. CONCLUSIONS: Remotely-delivered CBT appears efficacious in reducing OCD symptoms and other relevant outcomes and is therefore a viable option for increasing treatment access. Preliminary evidence suggests some individuals with severe OCD may benefit more from face-to-face than remotely-delivered CBT.