Venous thromboembolism (VTE) which includes deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) is a moderately common disease especially in elderly population with high rate of recurrence ...and complications. Evidence is accumulating that VTE is not restricted to coagulation system and immune system appears to be involved in formation and resolution of thrombus. The present study was aimed at reviewing current evidences on immune system abnormalities such as alterations in cytokines, chemokines and immune cells. Also, current evidences suggest that; a, inflammation in general functions as a double-edged sword, b, inflammation can be both a cause and a consequence of VTE, and c, current anti-coagulation therapies are not well-equipped with the capacity to selectively inhibit inflammatory cells and pathways. Applying such inferences for selective pharmacological targeting of immune mediators in VTE and thereby for adoption of higher effective anti-thromboinflammatory strategies, either therapeutic or prophylactic, is henceforth to be considered as the line of research for future.
•Inflammation can cause venous thromboembolism (VTE).•VTE leads to immune abnormalities and inflammation.•VTE-induced inflammation exacerbates clinical status of patients.•Certain VTE-induced inflammatory markers are required in thrombus resolution.•Selective targeting of inflammatory elements results in more effective therapeutic/preventive strategies.
Although our understanding of psychotic disorders has advanced substantially in the past few decades, very little has changed in the standard of care for these illnesses since the development of ...atypical anti-psychotics in the 1990s. Here, we integrate new insights into the pathophysiology with the increasing interest in early detection and prevention. First, we explore the role of
-methyl-d-aspartate receptors in a subpopulation of cortical parvalbumin-containing interneurons (PVIs). Postmortem and preclinical data has implicated these neurons in the positive and negative symptoms, as well as the cognitive dysfunction present in schizophrenia. These neurons also appear to be sensitive to inflammation and oxidative stress during the perinatal and peripubertal periods, which may be mediated in large part by aberrant synaptic pruning. After exploring some of the molecular mechanisms through which neuroinflammation and oxidative stress are thought to exert their effects, we highlight the progress that has been made in identifying psychosis prior to onset through the identification of individuals at clinical high risk for psychosis (CHR). By combining our understanding of psychosis pathogenesis with the increasing characterization of endophenotypes that precede frank psychosis, it may be possible to identify patients before they present with psychosis and intervene to reduce the burden of the disease to both patients and families.
Immune dysfunction and abnormal immune response may be associated with certain mechanisms underlying autism spectrum disorder (ASD). The early evidence for this link was based on the increased ...incidence of ASD in children with a history of maternal infection during pregnancy. Observational studies show increased prevalence of immune-related disorders-ranging from atopy, food allergy, viral infections, asthma, primary immunodeficiency, to autoimmune disorders-in individuals with ASD and their families. Evidence of neuroglial activation and focal brain inflammation in individuals with ASD implies that the central nervous system immunity may also be atypical in some individuals with ASD. Also, both peripheral and central inflammatory responses are suggested to be associated with ASD-related behavioral symptoms. Atypical immune responses may be evident in specific ASD subgroups, such as those with significant gastrointestinal symptoms. The present review aimed to evaluate current literature of potential interventions that target inflammatory pathways for individuals with ASD and to summarize whether these interventions were associated with improvement in autism symptoms and adaptation. We found that the current literature on the efficacy of anti-inflammatory interventions in ASD is still limited and large-scale randomized controlled trials are needed to provide robust evidence. We concluded that the role of immune-mediated mechanisms in the emergence of ASD or related challenges may be specific to subsets of individuals (e.g. those with concurrent immunological disorders, developmental regression, or high irritability). These subsets of individuals of ASD might be more likely to benefit from interventions that target immune-mediated mechanisms and with whom next-stage immune-mediated clinical trials could be conducted.
Alterations in glutamate neurotransmission have been implicated in the pathophysiology of schizophrenia, as well as in symptom severity and cognitive deficits. The hippocampus, in particular, is a ...site of key functional and structural abnormalities in schizophrenia. Yet few studies have investigated hippocampal glutamate in antipsychotic-naïve first episode psychosis patients or in individuals at clinical high risk (CHR) of developing psychosis. Using proton magnetic resonance spectroscopy (
H-MRS), we investigated glutamate metabolite levels in the left hippocampus of 25 CHR (19 antipsychotic-naïve), 16 patients with first-episode psychosis (13 antipsychotic-naïve) and 31 healthy volunteers. We also explored associations between hippocampal glutamate metabolites and glial activation, as indexed by
FFEPPA positron emission tomography (PET); symptom severity; and cognitive function. Groups differed significantly in glutamate plus glutamine (Glx) levels (F
= 6.39, p = 0.003). Post-hoc analysis revealed that CHR had significantly lower Glx levels than both healthy volunteers (p = 0.003) and first-episode psychosis patients (p = 0.050). No associations were found between glutamate metabolites and glial activation. Our findings suggest that glutamate metabolites are altered in CHR.
This study aimed to evaluate the effectiveness of a selected group exercise known as Sports, Play and Active Recreation for Kids (SPARK) on the motor and behavioral skills of children with autism ...spectrum disorder (ASD) using a quasi-experimental design with repeated measures.
Twenty-eight children with ASD (age range of 5e12 years) participated in this study. The participants were examined at baseline, pre-test, and post-test using Bruininks-Oseretsky Test of Motor Proficiency (BOTMP), Autism treatment evaluation checklist (ATEC), and Gilliam Autism Rating Scale-second edition (GARS-2).
The results showed that the SPARK program significantly improved balance (static and dynamic), bilateral coordination and social interaction (p < 0.05) in children with ASD.
The results of this study suggest that the SPARK's training can be considered as a therapeutic option not only for motor enhancement but also for improving social skills in children with ASD.
Altered neuroimmune response and oxidative stress have both been implicated in the pathophysiology of schizophrenia. While preclinical studies have proposed several pathways regarding potential ...interactions between oxidative stress and neuroimmune imbalance in the development of psychosis, the molecular mechanisms underlying this interaction are not yet understood. To date, no study has investigated this link in vivo in the human brain. We conducted the first in vivo study linking translocator protein 18 kDa (TSPO) expression and glutathione (a major brain antioxidant and a marker for redox status) in the medial prefrontal cortex (mPFC) of a relatively large sample of participants (N = 48) including 27 antipsychotic-naïve individuals at clinical high risk for psychosis and 21 matched healthy volunteers using high-resolution PET with TSPO radioligand,
FFEPPA, and 3T proton magnetic resonance spectroscopy (
H MRS). The omnibus model (including TSPO genotype as covariate) was significant (F
= 10.01, p < 0.001), with a significant group interaction (t = -2.10, p = 0.04), suggesting a different relation between
FFEPPA V
and glutathione in each clinical group. In healthy volunteers, but not in individuals at clinical high risk for psychosis, we found a significant negative association between glutathione levels and
FFEPPA V
(r = -0.60, p = 0.006). We observed no significant group differences with respect to
FFEPPA V
or glutathione levels. These findings suggest an abnormal interaction between TSPO expression and redox status in the clinical high risk states for psychosis.
γ-Aminobutyric acidergic (GABAergic) dysfunction and immune activation have been implicated in the pathophysiology of schizophrenia. Preclinical evidence suggests that inflammation-related ...abnormalities may contribute to GABAergic alterations in the brain, but this has never been investigated in vivo in humans. In this multimodal imaging study, we quantified cerebral GABA plus macromolecule (GABA+) levels in antipsychotic-naive people at clinical high risk for psychosis and in healthy volunteers. We investigated for the first time the association between GABA+ levels and expression of translocator protein 18 kDa (TSPO; a marker of microglial activation) using positron emission tomography (PET).
Thirty-five people at clinical high risk for psychosis and 18 healthy volunteers underwent 3 T proton magnetic resonance spectroscopy to obtain GABA+ levels in the medial prefrontal cortex (mPFC). A subset (29 people at clinical high risk for psychosis and 15 healthy volunteers) also underwent a high-resolution 18FFEPPA PET scan to quantify TSPO expression. Each participant was genotyped for the TSPO
polymorphism.
We found that GABA+ levels were significantly associated with TSPO expression in the mPFC (
= 10.45,
= 0.002). We found no significant differences in GABA+ levels in the mPFC (
= 0.00,
> 0.99) between people at clinical high risk for psychosis and healthy volunteers. We found no significant correlations between GABA+ levels or residuals of the association with TSPO expression and the severity of prodromal symptoms or cognition.
Given the cross-sectional nature of this study, we could determine no cause-and-effect relationships for GABA alterations and TSPO expression.
Our findings suggest that TSPO expression is negatively associated with GABA+ levels in the prefrontal cortex, independent of disease status.
Abstract
Introduction
Oxidative stress and glutathione dysregulation have been implicated in the etiology of schizophrenia. To date, most in vivo studies have investigated alterations in cerebral ...glutathione levels in patients in which the disorder is already established; however, whether oxidative stress actually predates the onset of psychosis remains unknown. In the current study, we investigated cerebral glutathione levels of antipsychotic-naïve individuals at clinical high risk for psychosis. As exploratory analyses, we also investigated the associations between cerebral glutathione levels and peripheral glutathione peroxidase activity and clinical and neuropsychological measures.
Methods
Glutathione levels were measured in the medial prefrontal cortex of 30 clinical high risk (n=26 antipsychotic naïve) and 26 healthy volunteers using 3T proton magnetic resonance spectroscopy. Each participant was assessed for glutathione peroxidase activity in plasma and genotyped for the glutamate cysteine ligase catalytic subunit polymorphism.
Results
No significant differences were observed in glutathione levels between clinical high risk and healthy volunteers in the medial prefrontal cortex (F(1,54)=0.001, P =0.98). There were no significant correlations between cerebral glutathione levels and clinical and neuropsychological measures. Similarly, no significant differences were found in peripheral glutathione peroxidase activity between clinical high risk and healthy volunteers (F(1,37)=0.15, P =0.70). However, in clinical high risk, we observed a significant effect of lifetime history of cannabis use on glutathione peroxidase activity (F(1,23)=7.41, P =0.01).
Discussion
The lack of significant differences between antipsychotic naïve clinical high risk and healthy volunteers suggests that alterations in glutathione levels in medial prefrontal cortex are not present in the clinical high risk state.
Evidence of elevated peripheral Neurofilament light-chain (NfL) as a biomarker of neuronal injury can be utilized to reveal nonspecific axonal damage, which could reflect altered neuroimmune ...function. To date, only a few studies have investigated NfL as a fluid biomarker in schizophrenia primarily, though none in its putative prodrome (Clinical High-Risk, CHR) or in untreated first-episode psychosis (FEP). Further, it is unknown whether peripheral NfL is associated with 18 kDa translocator protein (TSPO), a validated neuroimmune marker. In this secondary study, we investigated for the first time (1) serum NfL in early stages of psychosis including CHR and FEP as compared to healthy controls, and (2) examined its association with brain TSPO, using 18FFEPPA positron emission tomography (PET). Further, in the exploratory analyses, we aimed to assess associations between serum NfL and symptom severity in patient group and cognitive impairment in the combined cohort. A large cohort of 84 participants including 27 FEP (24 antipsychotic-naive), 41 CHR (34 antipsychotic-naive) and 16 healthy controls underwent structural brain MRI and 18FFEPPA PET scan and their blood samples were obtained and assessed for serum NfL concentrations. We found no significant differences in serum NfL levels across clinical groups, controlling for age. We also found no significant association between NfL levels and brain TSPO in the entire cohort. We observed a negative association between serum NfL and negative symptom severity in CHR. Our findings suggest that neither active neuroaxonal deterioration as measured with NfL nor associated neuroimmune activation (TSPO) is clearly identifiable in an early mostly untreated psychosis sample including its putative high-risk.
•Serum NfL levels did not differ between clinical groups (FEP and CHR vs. HC).•No significant association between serum NfL and brain TSPO levels.•Negative association between NfL levels and negative symptom severity in CHR.•Neuro-axonal damage and immune activation are non-identifiable in early psychosis.
Neuroinflammatory events prior to the diagnosis of schizophrenia may play a role in transition to illness. To date only one in-vivo study has investigated this association between peripheral ...proinflammatory cytokines and brain markers of inflammation (e.g., mitochondrial 18 kDa translocator protein, TSPO) in schizophrenia, but none in its putative prodrome.
In this study, we primarily aimed to (Barron et al., 2017) test study group (clinical high-risk (CHR) and healthy controls) differences in peripheral inflammatory markers and test for any associations with symptom measures, (Hafizi et al., 2017a) investigate the interaction between brain TSPO levels (dorsolateral prefrontal cortex (DLPFC) and hippocampus) and peripheral inflammatory clusters (entire cohort and (CHR) group independently) within a relatively large group of individuals at CHR for psychosis (N = 38) and healthy controls (N = 20). Participants underwent structural brain magnetic resonance imaging (MRI) and TSPO 18FFEPPA positron emission tomography (PET) scans. Serum samples were assessed for peripheral inflammatory markers (i.e., CRP and interleukins). For exploratory analysis, we aimed to examine cluster differences for symptom measures and identify independent peripheral predictors of brain TSPO expression.
Here, we report increased IL-8 levels that are positively correlated with prodromal general symptom severity and showed trend-level association with apathy in CHR. We identified distinct inflammatory clusters characterized by inflammatory markers (IL-1 β, IL-2, IFN-γ) that were comparable between entire cohort and CHR. TSPO levels did not differ between inflammatory clusters (entire cohort or CHR). Finally, we show that CRP, IL-1 β, TNF-α, and IFN-γ levels were the independent peripheral predictors of brain TSPO expression.
Thus, alterations in brain TSPO expression in response to inflammatory processes are not evident in CHR. Taken together, clustering by inflammatory status is a promising strategy to characterize the interaction between brain TSPO and peripheral markers of inflammation.
•Serum IL-8 levels are elevated in individuals at CHR for psychosis.•Positive association between elevated IL-8 and prodromal general symptom severity.•Inflammatory clusters (IL-1β, IL-2, IFN-γ) are identified (entire cohort and CHR).•TSPO levels did not differ between inflammatory clusters (entire cohort or CHR).•CRP, IL-1β, TNF-α and IFN-γ levels are the independent predictors of brain TSPO.
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