Theranostic Biomarkers for Schizophrenia Perkovic, Matea Nikolac; Erjavec, Gordana Nedic; Strac, Dubravka Svob ...
International journal of molecular sciences,
04/2017, Letnik:
18, Številka:
4
Journal Article
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Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To ...allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.
Nowadays depression is considered as a systemic illness with different biological mechanisms involved in its etiology, including inflammatory response, hypothalamic-pituitary-adrenal (HPA) axis ...dysregulation and neurotransmitter and neurotrophic systems imbalance. Novel “omics” approaches, such as metabolomics and glycomics provide information about altered metabolic pathways and metabolites, as well as disturbances in glycosylation processes affected by or causing the development of depression. The clinical diagnosis of depression continues to be established based on the presence of the specific symptoms, but due to its heterogeneous underlying biological background, that differs according to the disease stage, there is an unmet need for treatment response biomarkers which would facilitate the process of appropriate treatment selection. This paper provides an overview of the role of major stress response system, the HPA axis, and its dysregulation in depression, possible involvement of neurotrophins, especially brain-derived neurotrophic factor, glial cell line–derived neurotrophic factor and insulin-like growth factor-1, in the development of depression. Article discusses how activated inflammation processes and increased cytokine levels, as well as disturbed neurotransmitter systems can contribute to different stages of depression and could specific metabolomic and glycomic species be considered as potential biomarkers of depression. The second part of the paper includes the most recent findings about available medical treatment of depression. The described biological factors impose an optimistic conclusion that they could represent easy obtainable biomarkers potentially predicting more personalized treatment and diagnostic options.
•Depression is characterized by elevated levels of stress and proinflammatory factors.•Decreased neurotrophins indicate the pathophysiological processes in depression.•Antidepressants normalize 5-HT neurotransmission which is decreased in depression.•Products of amino and fatty acid metabolisms reflect the pathogenesis of depression.•Increased N-glycan sialyation is associated with the severity of depression.
•PTSD veterans had lower plasma BDNF and worse cognitive decline vs. healthy subjects.•PTSD veterans had similarly decreased plasma BDNF as MCI subjects.•PTSD veterans had similar cognitive ...deterioration as MCI subjects.•Reduced plasma BDNF was found in cognitively impaired subjects.•PTSD veterans should be monitored to predict cognitive worsening.
Post-traumatic stress disorder (PTSD) is a trauma and stress related disorder frequently associated with cognitive decline. War veterans with PTSD have a higher risk of developing dementia than healthy subjects. Brain derived neurotrophic factor (BDNF) is an important protein that modulates plasticity, memory consolidation and cognitive processes. Lower circulating BDNF levels were related to memory impairment and cognitive deterioration. The aim of this study was to evaluate cognitive deterioration and plasma BDNF concentration in 120 veterans with combat related PTSD, 120 healthy controls, 47 subjects with mild cognitive impairment (MCI) and 76 patients with Alzheimer's disease (AD), and to assess if plasma BDNF concentration might be used as biomarker of cognitive deterioration. Veterans with PTSD had significantly decreased plasma BDNF concentration and worse cognitive performances (assessed using the Mini Mental State Examination, Clock Drawing test and Montreal Cognitive Assessment scores/categories) than healthy subjects, and similarly reduced plasma BDNF and cognitive decline as MCI subjects. Reduced plasma BDNF was found in cognitively impaired subjects. These results suggest that veterans with PTSD should be closely monitored in order to early detect and predict cognitive worsening and promote interventions that might help restore blood BDNF levels and cognitive functions.
There are currently no validated biomarkers which can be used to accurately diagnose Alzheimer's disease (AD) or to distinguish it from other dementia-causing neuropathologies. Moreover, to date, ...only symptomatic treatments exist for this progressive neurodegenerative disorder. In the search for new, more reliable biomarkers and potential therapeutic options, epigenetic modifications have emerged as important players in the pathogenesis of AD. The aim of the article was to provide a brief overview of the current knowledge regarding the role of epigenetics (including mitoepigenetics) in AD, and the possibility of applying these advances for future AD therapy. Extensive research has suggested an important role of DNA methylation and hydroxymethylation, histone posttranslational modifications, and non-coding RNA regulation (with the emphasis on microRNAs) in the course and development of AD. Recent studies also indicated mitochondrial DNA (mtDNA) as an interesting biomarker of AD, since dysfunctions in the mitochondria and lower mtDNA copy number have been associated with AD pathophysiology. The current evidence suggests that epigenetic changes can be successfully detected, not only in the central nervous system, but also in the cerebrospinal fluid and on the periphery, contributing further to their potential as both biomarkers and therapeutic targets in AD.
The molecular underpinnings of post-traumatic stress disorder (PTSD) are still unclear due to the complex interactions of genetic, psychological, and environmental factors. Glycosylation is a common ...post-translational modification of proteins, and different pathophysiological states, such as inflammation, autoimmune diseases, and mental disorders including PTSD, show altered N-glycome. Fucosyltransferase 8 (FUT8) is the enzyme that catalyzes the addition of core fucose on glycoproteins, and mutations in the
gene are associated with defects in glycosylation and functional abnormalities. This is the first study that investigated the associations of plasma N-glycan levels with
-related rs6573604, rs11621121, rs10483776, and rs4073416 polymorphisms and their haplotypes in 541 PTSD patients and control participants. The results demonstrated that the rs6573604 T allele was more frequent in the PTSD than in the control participants. Significant associations of plasma N-glycan levels with PTSD and
-related polymorphisms were observed. We also detected associations of rs11621121 and rs10483776 polymorphisms and their haplotypes with plasma levels of specific N-glycan species in both the control and PTSD groups. In carriers of different rs6573604 and rs4073416 genotypes and alleles, differences in plasma N-glycan levels were only found in the control group. These molecular findings suggest a possible regulatory role of
-related polymorphisms in glycosylation, the alternations of which could partially explain the development and clinical manifestation of PTSD.
Posttraumatic stress disorder (PTSD) is a stressor-related disorder that develops in a subset of individuals exposed to a traumatic experience. Factors associated with vulnerability to PTSD are still ...not fully understood. PTSD is frequently comorbid with various psychiatric and somatic disorders, moderate response to treatment and remission rates. The term “theranostics” combines diagnosis, prognosis, and therapy and offers targeted therapy based on specific analyses. Theranostics, combined with novel techniques and approaches called “omics”, which integrate genomics, transcriptomic, proteomics and metabolomics, might improve knowledge about biological underpinning of PTSD, and offer novel therapeutic strategies. The focus of this review is on metabolomic and glycomic data in PTSD. Metabolomics evaluates changes in the metabolome of an organism by exploring the set of small molecules (metabolites), while glycomics studies the glycome, a complete repertoire of glycan structures with their functional roles in biological systems. Both metabolome and glycome reflect the physiological and pathological conditions in individuals. Only a few studies evaluated metabolic and glycomic changes in patients with PTSD. The metabolomics studies in PTSD patients uncovered different metabolites that might be associated with psychopathological alterations in PTSD. The glycomics study in PTSD patients determined nine N-glycan structures and found accelerated and premature aging in traumatized subjects and subjects with PTSD based on a GlycoAge index. Therefore, further larger studies and replications are needed. Better understanding of the biological basis of PTSD, including metabolomic and glycomic data, and their integration with other “omics” approaches, might identify new molecular targets and might provide improved therapeutic approaches.
•Factors associated with vulnerability to develop PTSD are still not fully understood.•Combination of “omics” approaches might improve knowledge about PTSD.•Metabolomics and glycomics data in patients with PTSD are scarce.•Metabolomics and glycomics might identify novel diagnostics, prognostics, and possibly theranostics biomarkers in PTSD.
Posttraumatic stress disorder (PTSD) is complex neuropsychiatric disorder triggered by a traumatic event and characterized by the symptoms that represent large burden to patients, as well as to ...society. Lipidomic approach can be applied as a useful tool for discovery of novel diagnostic, prognostic and therapeutic lipid biomarkers of various disorders, whose etiology is complex and still unknown, including PTSD. Since changes in the levels of lipid metabolites might indicate impairments in various metabolic pathways and cellular processes, the aim of this lipidomic study was to determine altered levels of lipid compounds in PTSD. The study enrolled 235 male patients with combat PTSD and 241 healthy male control subjects. Targeted lipidomic analysis of plasma samples was conducted using reverse-phase liquid chromatography coupled with mass spectrometry. Lipids that have been analyzed belong to the group of ceramides, cholesterol esters, diacylglycerols, lysophosphatidylcholines, lysophosphatidylethanolamines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The levels of fifteen lipid compounds were found to be significantly different between PTSD patients and healthy control subjects, including four phosphatidylcholines, two phosphatidylethanolamines, five sphingomyelins, two cholesterol esters and two ceramides. The lipid metabolites whose levels significantly differed between patients with PTSD and control subjects are associated with various biological processes, including impairments of membrane integrity and function, mitochondrial dysfunction, inflammation and oxidative stress. As these processes might be associated with development and progression of PTSD, altered lipid compounds represent potential biomarkers that could facilitate the diagnosis of PTSD, prediction of the disease, as well as identification of novel treatment approaches in PTSD.
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•Targeted lipidomic analysis of PTSD patients compared to healthy controls.•The concentration of 11 lipid metabolites was significantly decreased in PTSD.•The concentration of 4 lipid metabolites was significantly increased in PTSD.•The altered lipid metabolites are associated with various biological processes.•The lipid compounds might represent potential biomarkers of PTSD.
Antipsychotic drugs target primarily dopaminergic system which makes catechol-O-methyltransferase (COMT) an interesting target in studies searching for treatment response predictors in schizophrenia. ...The study assessed the association of the COMT rs4680 and rs4818 polymorphisms with therapeutic response to olanzapine, risperidone, clozapine or other antipsychotic medication after 8 weeks of monotherapy in patients with schizophrenia. 521 Caucasian patients with schizophrenia received a monotherapy with olanzapine (10-20 mg/day; N = 190), risperidone (3-6 mg/day; N = 99), or clozapine (100-500 mg/day; N = 102). The fourth group (N = 130) consisted of patients receiving haloperidol (3-15 mg/day), fluphenazine (4-25 mg/day) or quetiapine (50-800 mg/day). Treatment response was defined as a 50% reduction from the baseline positive and negative syndrome scale (PANSS) total and subscale scores, but also as an observed percentage reduction from the initial PANSS
total and subscale scores. Carriers of the COMT rs4680 A allele and carriers of the COMT rs4680-rs4818 C-A haplotype block had greater reduction in the PANSS total scores following olanzapine treatment, compared to carriers of the COMT rs4680 GG genotype and other COMT rs4680-rs4818 haplotypes. The COMT rs4680 A allele, and COMT rs4680-rs4818 C-A haplotype, were significantly associated with therapeutic response in patients treated with olanzapine, but not in patients treated with other antipsychotics.
Reduced brain derived neurotrophic factor (BDNF) concentration is reported to be associated with a cognitive decline in schizophrenia, depending on the stage of the disease. Aim of the study was to ...examine the possible association between plasma BDNF and cognitive decline in chronic stable schizophrenia and mild cognitive impairment (MCI). The study included 123 inpatients of both sexes with schizophrenia, 123 patients with MCI and 208 healthy control subjects. Cognitive abilities were assessed using mini mental state examination (MMSE), Clock Drawing test (CDT) and cognitive subscale of the Positive and Negative Syndrome Scale (PANSS). Plasma BDNF concentration was determined using ELISA. BDNF concentration was lower in patients with schizophrenia and MCI compared to age-matched healthy controls and was similar in carriers of different BDNF Val/66Met genotypes. The MMSE and CDT scores were lower in patients with schizophrenia compared to healthy controls and subjects with MCI. Reduced plasma BDNF was significantly associated with lower MMSE scores in all subjects. BDNF concentration in patients with schizophrenia was not affected by clinical and demographic factors. BDNF Val66Met polymorphism was not associated with the MMSE scores in all participants. Further studies should include longitudinal follow-up and other cognitive scales to confirm these results and offer cognition-improving strategies to prevent cognitive decline in chronic schizophrenia.
Recent evidence from the studies evaluating the association between brain-derived neurotrophic factor (BDNF) concentration/levels, BDNF Val66Met (rs6265) polymorphism, and major depressive disorders, ...referred as depression, and the association between BDNF levels and/or BDNF Val66Met with the treatment response in depression is presented.
This mini review focuses on the changes in the peripheral BDNF levels in blood (serum, plasma, platelets) in patients with depression before or after treatment with antidepressant drugs or different therapeutic strategies. In addition, this review describes the recent data on the possible association between different antidepressants/therapeutic strategies and the particular BDNF Val66Met genotypes, evaluating the risk alleles associated with the response in patients with depression.
BDNF has an important role in the pathophysiology and treatment response in depression. Most data reveal that peripheral BDNF levels are lower before than after antidepressant treatment and might be used as potential biomarkers of therapeutic response. Novel therapeutic strategies should target restoring/increasing BDNF levels.
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