Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Tobacco smoking in Egypt: a scoping literature review of its epidemiology and control measures.

BACKGROUND: According to World Health Organization (WHO) reports, the prevalence of smoking is increasing in many developing countries, including Egypt. The aim of this study is to summarize the published data in the literature about tobacco smoking in Egypt. METHODS: A computerized literature search of PubMed and relevant Egyptian journals was conducted using the relevant keywords. The findings of retrieved studies were extracted and discussed in a narrative approach. RESULTS: Our search retrieved 44 relevant studies. The most updated prevalence of tobacco smoking in Egypt is 22% in 2010 and is increasing. Highly significant odds ratios were reported for sibling, parent, and peer smoking as risk factors for smoking. Cardiovascular disorders, malignant tumors, and erectile dysfunction are common complications of smoking in the Egyptian population. Efforts to control tobacco smoking are available, but inadequate. CONCLUSIONS: Tobacco smoking is a prevalent health problem in Egypt, associated with cardiovascular disorders and malignant tumors. Health education programmes should be delivered through mass media and school-based programmes to reach a large section of the Egyptian population.

Bapineuzumab for mild to moderate Alzheimer's disease: a meta-analysis of randomized controlled trials.

BACKGROUND: Alzheimer's disease (AD) is a globally prevalent neurodegenerative condition, clinically characterized by progressive memory loss and gradual impairment of cognitive functions. Bapineuzumab is a fully humanized monoclonal antibody that binds to neurotoxic amyloid proteins in the brain, enhancing their clearance. We performed this systematic review and meta-analysis to evaluate the safety and efficacy of bapineuzumab in patients with mild to moderate Alzheimer's disease. METHODS: We performed a web-based literature search of PubMed, Ovid, EBSCO, Scopus, Embase, Cochrane CENTRAL, and web of science using the relevant keywords. Data were extracted from eligible records and pooled as mean difference (MD) or risk ratio (RR) values with their 95% confidence interval (CI), using Review Manager software (version 5.3 for windows). Heterogeneity was measured by Chi-square and I-square tests. RESULT: The pooled effect estimate from six randomized clinical trials (n = 2380) showed that bapineuzumab significantly reduced the cerebrospinal fluid concentration of phosphorylated tau proteins (Standardized MD = -5.53, 95% CI [-8.29, -2.76]). However, the bapineuzumab group was not superior to the placebo group in terms of change from baseline in Alzheimer's disease assessment scale (ADAS)-Cog11 (MD = 0.14, 95% CI [-0.72, 0.99]), disability assessment for dementia (DAD) scale (MD = 1.35, 95% CI [-1.74, 4.43]), and mini-mental state examination (MMSE) scores (MD = 0.08, 95% CI [-0.31, 0.47]). Regarding safety, bapineuzumab increased the risk of serious treatment-emergent adverse events (RR = 1.18, 95% CI [1.02, 1.37]) and cerebral vasogenic edema (RR = 40.88, 95% CI [11.94, 135.95]). All bapineuzumab doses (0.15, 0.5, 1, and 2 mg/kg) were similar to placebo in terms of change from baseline in ADAS-cog11, DAD, and MMSE scores, except for the 0.15 mg/kg dose, which caused a significant worsening on the ADAS-cog11 scale (MD = 5.6, 95% CI [0.22, 10.98]). CONCLUSIONS: Considering the lack of clinical efficacy, combined with the significant association with serious adverse events, bapineuzumab should not be used to treat patients with mild to moderate AD. Future studies should investigate the effect of combining bapineuzumab with other therapeutic strategies and reevaluate the efficacy of targeting amyloid ß proteins in AD therapy.

Findings of PTSD-specific deficits in default mode network strength following a mild experimental stressor.

Reductions in default mode (DMN) connectivity strength have been reported in posttraumatic stress disorder (PTSD). However, the specificity of DMN connectivity deficits in PTSD compared to major depressive disorder (MDD), and the sensitivity of these alterations to acute stressors are not yet known. 52 participants with a primary diagnosis of PTSD (n = 28) or MDD (n = 24) completed resting-state functional magnetic resonance imaging immediately before and after a mild affective stressor. A 2 × 2 design was conducted to determine the effects of group, stress, and group*stress on DMN connectivity strength. Exploratory analyses were completed to identify the brain region(s) underlying the DMN alterations. There was significant group*stress interaction (p = 0.03), reflecting stress-induced reduction in DMN strength in PTSD (p = 0.02), but not MDD (p = 0.50). Nodal exploration of connectivity strength in the DMN identified regions of the ventromedial prefrontal cortex and the precuneus potentially contributing to DMN connectivity deficits. The findings indicate the possibility of distinct, disease-specific, patterns of connectivity strength reduction in the DMN in PTSD, especially following an experimental stressor. The identified dynamic shift in functional connectivity, which was perhaps induced by the stressor task, underscores the potential utility of the DMN connectivity and raises the question whether these disruptions may be inversely affected by antidepressants known to treat both MDD and PTSD psychopathology.

To study any differences between PTSD and depression in the way the brain talks with itself in its default mode when not doing any particular thing, we did MRI brain scans with 52 people with Depression, but only some had PTSD. We found that mild emotional stress may briefly reduce default mode strength in PTSD, but not in depression. This might help researchers better understand the impact of stress and trauma on the brain.

mTORC1 inhibitor effects on rapid ketamine-induced reductions in suicidal ideation in patients with treatment-resistant depression.

Suicide is a public health crisis with limited treatment options. Ketamine has demonstrated rapid and robust improvements in suicidal ideation (SI). The parent study for the secondary pilot analyses presented here was a double-blind, cross-over trial that found pretreatment with the mechanistic target of rapamycin complex 1 (mTORC1) prolonged the antidepressant effects of ketamine. Here we examined the effect of mTORC1 inhibition on ketamine's antisuicidal effects. Twenty patients in a major depressive episode were randomized to pretreatment with oral rapamycin (6 mg) or placebo prior to IV ketamine (0.5 mg/kg). We found ketamine administration resulted in significant improvements across all measures with the largest effect at 24 h with only the Beck Scale for Suicide remaining significant at the two-week follow-up. There were no significant main effects of pretreatment. While these analyses are pilot in nature and overall severity of SI was relatively low, the antisuicidal findings (no effect of rapamycin) being in contrast to the antidepressant effects (prolonged effect with rapamycin), suggest the rapid-acting antisuicidal and antidepressant effects of ketamine may be mechanistically distinct and the trajectories of response, recovery, and relapse may be independent. These findings provide additional evidence of ketamine's antisuicidal effects and highlight the importance of future studies that continue to examine potential differences in mechanisms and trajectory of outcomes.

A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants.

Over the past decade, various N-methyl-D-aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In this longitudinal functional magnetic resonance imaging study of data from 265 participants, we used a validated predictive model approach that allows the full assessment of brain functional connectivity, without the need for seed selection or connectivity summaries. First, we identified a connectome fingerprint (CFP) in healthy participants (Cohort A, n = 25) during intravenous infusion of a subanesthetic dose of ketamine, compared to normal saline. We then demonstrated the robustness and reproducibility of the discovered ketamine CFP in two separate healthy samples (Cohort B, n = 22; Cohort C, n = 18). Finally, we investigated the ketamine CFP connectivity at 1-week post treatment in major depressive disorder patients randomized to 8 weeks of sertraline or placebo (Cohort D, n = 200). We found a significant, robust, and reproducible ketamine CFP, consistent with reduced connectivity within the primary cortices and within the executive network, but increased connectivity between the executive network and the rest of the brain. Compared to placebo, the ketamine CFP connectivity changes at 1 week predicted response to sertraline at 8 weeks. In each of Cohorts A-C, ketamine significantly increased connectivity in a previously identified antidepressant CFP. Investigating the brain connectivity networks, we successfully identified a robust and reproducible ketamine biomarker that is related to the mechanisms of antidepressants.

Chronic stress pathology and ketamine-induced alterations in functional connectivity in major depressive disorder: An abridged review of the clinical evidence.

A paradigm shift in the conceptualization of the neurobiology of depression and the serendipitous discovery of ketamine's rapid-acting antidepressant (RAAD) effects has ushered in a new era of innovative research and novel drug development. Since the initial discovery of ketamine's RAAD effects, multiple studies have supported its short-term efficacy for fast-tracked improvements in treatment-resistant depression. Evidence from MRI studies have repeatedly demonstrated functional connectivity alterations in stress- and trauma-related disorders suggesting this may be a viable biomarker of chronic stress pathology (CSP). Human mechanistic studies further support this by coupling functional connectivity to ketamine's RAAD effects including connectivity to glutamate neurotransmission, ketamine to normalized connectivity, and these advantageous normalizations to symptom improvement/ketamine response. This review provides an abridged discussion of the suspected neurobiological underpinnings of ketamine's RAAD effects, highlighting ketamine-induced alterations in prefrontal, striatal, and anterior cingulate cortex functional connectivity in major depressive disorder. We present a model of CSP underscoring the role of synaptic loss and dysconnectivity and discuss how ketamine may be used both as (1) a treatment to restore and normalize these stress-induced neural alterations and (2) a tool to study potential biomarkers of CSP and treatment response. We conclude by noting challenges and future directions including heterogeneity, sex differences, the role of early life stress, and the need for proliferation of new methods, paradigms, and tools that will optimize signal and allow analyses at different levels of complexity, according to the needs of the question at hand, perhaps by thinking hierarchically about both clinical and biological phenotypes.

Pretreatment Brain Connectome Fingerprint Predicts Treatment Response in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) treatment is characterized by low remission rate and often involves weeks to months of treatment. Identification of pretreatment biomarkers of response may play a critical role in novel drug development, in enhanced prognostic predictions, and perhaps in providing more personalized medicine. Using a network restricted strength predictive modeling (NRS-PM) approach, the goal of the current study was to identify pretreatment functional connectome fingerprints (CFPs) that (1) predict symptom improvement regardless of treatment modality and (2) predict treatment specific improvement. METHODS: Functional magnetic resonance imaging and behavioral data from unmedicated patients with MDD (n = 200) were investigated. Participants were randomized to daily treatment of sertraline or placebo for 8 weeks. NRS-PM with 1000 iterations of 10 cross-validation were implemented to identify brain connectivity signatures that predict percent improvement in depression severity at week-8. RESULTS: The study identified a pretreatment CFP that significantly predicts symptom improvement independent of treatment modality but failed to identify a treatment specific CFP. Regardless of treatment modality, improved antidepressant response was predicted by high pretreatment connectivity between modules in the default mode network and the rest of the brain, but low external connectivity in the executive network. Moreover, high pretreatment internal nodal connectivity in the bilateral caudate predicted better response. CONCLUSIONS: The identified CFP may contribute to drug development and ultimately to enhanced prognostic predictions. However, the results do not assist with providing personalized medicine, as pretreatment functional connectivity failed to predict treatment specific response.

A Unique Brain Connectome Fingerprint Predates and Predicts Response to Antidepressants.

More than six decades have passed since the discovery of monoaminergic antidepressants. Yet, it remains a mystery why these drugs take weeks to months to achieve therapeutic effects, although their monoaminergic actions are present rapidly after treatment. In an attempt to solve this mystery, rather than studying the acute neurochemical effects of antidepressants, here we propose focusing on the early changes in the brain functional connectome using traditional statistics and machine learning approaches. Capitalizing on three independent datasets (n = 1,261) and recent developments in data and network science, we identified a specific connectome fingerprint that predates and predicts response to monoaminergic antidepressants. The discovered fingerprint appears to generalize to antidepressants with differing mechanism of action. We also established a consensus whole-brain hierarchical connectivity architecture and provided a set of model-based features engineering approaches suitable for identifying connectomic signatures of brain function in health and disease.

Coenzyme Q10 for Patients with Parkinson's Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Coenzyme Q10 (CoQ10) is an antioxidant that enhances the activity of complex I and II in the Electron Transport Chain. Many preclinical and clinical studies evaluated CoQ10 for neuroprotection against Parkinson's disease (PD). The aim of this study is to synthesize evidence from published randomized controlled trials (RCTs) about the benefit of CoQ10 supplementation for patients with Parkinson's disease. METHODS: We followed the PRISMA statement guidelines during the preparation of this systematic review and metaanalysis. A computer literature search for (PubMed, EBSCO, Web of science and Ovid Midline) was carried out. We included RCTs comparing CoQ10 with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, UPDRS III and Schwab and England scores were pooled as standardized mean difference (SMD) between two groups from baseline to the endpoint. RESULTS: Five RCTs (981 patients) were included in this study. The overall effect did not favor either of the two groups in terms of: total UPDRS score (SMD -0.05, 95%CI [-0.10, 0.15]), UPDRS I (SMD -0.03, 95% CI [-0.23, 0.17]), UPDRS II (SMD -0.10, 95%CI [-0.35, 0.15]), UPDRS III (SMD -0.05, 95%CI [-0.07, 0.17]) or Schwab and England score (SMD 0.08, 95%CI [-0.13, 0.29]). CONCLUSION: CoQ10 supplementation does not slow functional decline nor provide any symptomatic benefit for patients with Parkinson's disease.

Tobacco smoking in Egypt: a scoping literature review of its epidemiology and control measures

Background: According to World Health Organization [WHO] reports, the prevalence of smoking is increasing in many developing countries, including Egypt. The aim of this study is to summarize the published data in the literature about tobacco smoking in Egypt. Methods: A computerized literature search of PubMed and relevant Egyptian journals was conducted using the relevant keywords. The findings of retrieved studies were extracted and discussed in a narrative approach. Results: Our search retrieved 44 relevant studies. The most updated prevalence of tobacco smoking in Egypt is 22% in 2010 and is increasing. Highly significant odds ratios were reported for sibling, parent, and peer smoking as risk factors for smoking. Cardiovascular disorders, malignant tumors, and erectile dysfunction are common complications of smoking in the Egyptian population. Efforts to control tobacco smoking are available, but inadequate. Conclusions: Tobacco smoking is a prevalent health problem in Egypt, associated with cardiovascular disorders and malignant tumors. Health education programmes should be delivered through mass media and school-based programmes to reach a large section of the Egyptian population

Contexte : Selon les rapports de l'OMS, la prévalence du tabagisme est en augmentation dans de nombreux pays en développement, dont l'Égypte. La présente étude avait pour objectif de synthétiser l'ensemble des données publiées dans la littérature sur le tabagisme en Égypte. Méthodes : Une recherche documentaire sur ordinateur dans PubMed et d'autres revues égyptiennes pertinentes a été effectuée à l'aide de mots-clés. Les résultats des études extraites ont été compilés et discutés. Résultats : Notre recherche a permis d'extraire 44 études pertinentes. Des odds ratios hautement significatifs ont été rapportés pour le fait d'avoir des frères et sœurs, des parents et des amis fumeurs en tant que facteurs de risque. Les troubles cardio-vasculaires, les tumeurs malignes, et les dysfonctionnements érectiles sont des complications courantes du tabagisme dans la population égyptienne. Des mesures pour lutter contre le tabagisme sont disponibles, mais ne sont pas adaptées. Conclusions : Le tabagisme constitue un problème de santé prévalent en Égypte, associé aux troubles cardio-vasculaires et aux tumeurs malignes. Une éducation sanitaire devrait être dispensée à travers les médias de masse et dans le cadre de programmes menés dans les écoles afin d'atteindre une frange importante de la population égyptienne

معلومات أساسية: تشير تقارير منظمة الصحة العالمية إلى تزايد معدل انتشار التدخين في كثير من البلدان النامية، بما فيها مصر. وتهدف هذه الدراسةإلى تلخيص جميع البيانات المنشورة في الدراسات السابقة حول تدخين التبغ في مصر.والمجلات المصرية ذات الصلة باستخدام الكلمات PubMed طرق البحث: أُجري بحث باستخدام الحاسوب في الدراسات السابقة في موقعالرئيسية في هذا المجال. واستخلصت نتائج الدراسات المستخرجة ونوقشت بأسلوب سردي.النتائج: اعتمد البحث الذي أجريناه على 44 دراسة ذات صلة. وتبيّ وجود نسب أرجحية كبيرة للغاية لتدخين الأشقاء والآباء والأقران باعتبارهاعوامل خطر للتدخين. وتعدّ الاضطرابات القلبية الوعائية والأورام الخبيثة واضطراب الانتصاب من المضاعفات الشائعة للتدخين بين المصريين.وثمة جهود حالية لمكافحة تدخين التبغ، لكنها ليست كافية.الاستنتاجات: يمثل تدخين التبغ مشكلة صحية واسعة الانتشار في مصر، ترتبط بالاضطرابات القلبية الوعائية والأورام الخبيثة. وينبغي تقديمبرامج للتثقيف الصحي عبر وسائل الإعلام وفي المدارس للوصول إلى قطاع أوسع من المصريين