Biomarker Commons

Proteomic approaches to unravel the complexity of schizophrenia.

Expert Rev Proteomics. 2012;9(1):97-108

Authors: Martins-de-Souza D, Guest PC, Rahmoune H, Bahn S

Abstract
Schizophrenia is a debilitating mental disorder that affects approximately 30 million people worldwide. The development and progression of this disease is now thought to be precipitated through a complex interaction between altered gene function and environmental factors. Proteomic analyses have been applied extensively over the past 10 years in studies of several tissues from schizophrenic patients, resulting in increased insight into the affected molecular pathways. In addition, these proteomic approaches have led to the identification of a set of molecular biomarker assays as the first blood-based test to aid in the diagnosis of schizophrenia. Here, we discuss the main outcome of these investigations and suggest a practical means of integrating and translating the findings between the brain and peripheral blood to increase our understanding of schizophrenia pathophysiology.

PMID: 22292827 [PubMed - indexed for MEDLINE]

Altered resting state complexity in schizophrenia.

Neuroimage. 2012 Feb 1;59(3):2196-207

Authors: Bassett DS, Nelson BG, Mueller BA, Camchong J, Lim KO

Abstract
The complexity of the human brain's activity and connectivity varies over temporal scales and is altered in disease states such as schizophrenia. Using a multi-level analysis of spontaneous low-frequency fMRI data stretching from the activity of individual brain regions to the coordinated connectivity pattern of the whole brain, we investigate the role of brain signal complexity in schizophrenia. Specifically, we quantitatively characterize the univariate wavelet entropy of regional activity, the bivariate pairwise functional connectivity between regions, and the multivariate network organization of connectivity patterns. Our results indicate that univariate measures of complexity are less sensitive to disease state than higher level bivariate and multivariate measures. While wavelet entropy is unaffected by disease state, the magnitude of pairwise functional connectivity is significantly decreased in schizophrenia and the variance is increased. Furthermore, by considering the network structure as a function of correlation strength, we find that network organization specifically of weak connections is strongly correlated with attention, memory, and negative symptom scores and displays potential as a clinical biomarker, providing up to 75% classification accuracy and 85% sensitivity. We also develop a general statistical framework for the testing of group differences in network properties, which is broadly applicable to studies where changes in network organization are crucial to the understanding of brain function.

PMID: 22008374 [PubMed - indexed for MEDLINE]

CNTRICS imaging biomarker selections: Executive control paradigms.

Schizophr Bull. 2012 Jan;38(1):34-42

Authors: Carter CS, Minzenberg M, West R, Macdonald A

Abstract
In this article, we describe results of the 5th Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia meeting which identified candidate imaging biomarkers for used in measuring neural activity associated with specific component processes of cognition that are targeted for treatment development in schizophrenia and other disorders. This manuscript describes the process by which measures related to executive control were selected, along with the specific measures recommended for further development. Two paradigms were recommended for measurement of the cognitive and neural mechanisms underlying 2 core component processes of executive control, rule generation and selection, and dynamic adjustments of Control. The 2 paradigms are the AX continuous performance task task (letter and dot forms), implemented as an functional magnetic resonance imaging (fMRI) paradigm to engage neural systems supporting rule generation and selection, and the switching Stroop task, implemented as either fMRI or electroencephalography that may be used as a measure of both rule generation and selection as well as dynamic adjustment in control. A detailed description of each paradigm, together with a review of the relevant literature related to their cognitive and neural validity and measurement properties is provided. These 2 paradigms are recommended for further development, including further validation at the cognitive and neural level and optimization with respect to subject tolerability, psychometric, and neurometric features.

PMID: 22114099 [PubMed - indexed for MEDLINE]

CNTRICS imaging biomarkers selection: Working memory.

Schizophr Bull. 2012 Jan;38(1):43-52

Authors: Barch DM, Moore H, Nee DE, Manoach DS, Luck SJ

Abstract
The sixth meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) consortium was focused on selecting promising imaging biomarker measures for each of the cognitive constructs selected in the first CNTRICS meeting. In the domain of working memory (WM), the 2 constructs of interest were "goal maintenance" and "interference control." CNTRICS received 7 task nominations for goal maintenance and 3 task nominations for interference control. For goal maintenance, the breakout group for WM recommended the AX Continuous Performance Test/Dot Pattern Expectancy (DPX) and the Switching Stroop task for translation and further development for use in clinical trial contexts in schizophrenia research. Notably, these same 2 paradigms were recommended for "rule generation and selection" in executive control, a highly related construct. For interference control, the breakout group recommended the Suppress Task and the Sternberg Item Recognition Paradigm for translation for use in clinical trials. This manuscript describes the ways in which each of these tasks met the criteria used by the breakout group to recommend tasks for further development. In addition, the group revisited the construct of WM capacity. Since the initial CNTRICS meeting, a growing body of work has emerged on the neurobiological substrates of WM capacity, making measure of this construct ready for translation. The group suggested a promising imaging biomarker measure for capacity, a version of the change detection task that measures delay activity over posterior parietal and occipital cortex.

PMID: 22080498 [PubMed - indexed for MEDLINE]

Imaging biomarkers for treatment development for impaired cognition: report of the sixth CNTRICS meeting: Biomarkers recommended for further development.

Schizophr Bull. 2012 Jan;38(1):26-33

Authors: Carter CS, Barch DM,

Abstract
The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia initiative, funded by an R13 conference grant from the National Institute of Mental Health, has sought to facilitate the translation of measures from the basic science of cognition into practical brain-based tools to measure treatment effects on cognition in schizophrenia. In this overview article, we summarize the process and products of the sixth meeting in this series, which focused on the identification of promising imaging paradigms, based on the measurement of cognitive evoked potentials (event-related potential) of cognition-related time-frequency analyses of the electroencephalography as well as functional magnetic resonance imaging. A total of 23 well-specified paradigms from cognitive neuroscience that measure cognitive functions previously identified as targets for treatment development were identified at the meeting as being recommended for the further developmental work needed in order to validate and optimize them as biomarker measures. Individual paradigms are discussed in detail in 6 domain-based articles in this volume. Ongoing issues related to the development of these and other measures as valid, sensitive and reliable measurement, and assessment tools, as well as the steps necessary for the development of specific measures for use as biomarkers for treatment development and personalized medicine, are discussed.

PMID: 21914642 [PubMed - indexed for MEDLINE]

CNTRICS final biomarker selection: Control of attention.

Schizophr Bull. 2012 Jan;38(1):53-61

Authors: Luck SJ, Ford JM, Sarter M, Lustig C

Abstract
Attention is widely believed to be dysfunctional in schizophrenia. The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) group previously concluded that the processes involved in the top-down control of attention are particularly impaired in schizophrenia and should be the focus of future research. These processes determine which sources of input should be attended, linking goal representations in prefrontal cortex with more posterior regions that implement the actual selection of attended information. A more recent meeting of the CNTRICS group assessed several paradigms that might be useful for identifying biomarkers of attentional control and that could be used for treatment development and assessment. Two types of paradigms were identified as being particularly promising. In one approach, neural activity is measured (using electroencephalography or functional magnetic resonance imaging) during the period between an attention-directing cue and a target. In a second approach, neural activity is measured under low- and high-distraction conditions. These approaches make it possible to identify the goal representations that guide attention and the interactions between these goal representations and the implementation of selection. Although more basic science research with healthy volunteers and preclinical research with schizophrenia patients is needed before these paradigms will be ready to provide clinically useful biomarkers, they hold substantial promise for aiding in the development and assessment of new treatments.

PMID: 21765166 [PubMed - indexed for MEDLINE]

An integrative functional genomics approach for discovering biomarkers in schizophrenia.

Brief Funct Genomics. 2011 Nov;10(6):387-99

Authors: Vawter MP, Mamdani F, Macciardi F

Abstract
Schizophrenia (SZ) is a complex disorder resulting from both genetic and environmental causes with a lifetime prevalence world-wide of 1%; however, there are no specific, sensitive and validated biomarkers for SZ. A general unifying hypothesis has been put forward that disease-associated single nucleotide polymorphisms (SNPs) from genome-wide association study (GWAS) are more likely to be associated with gene expression quantitative trait loci (eQTL). We will describe this hypothesis and review primary methodology with refinements for testing this paradigmatic approach in SZ. We will describe biomarker studies of SZ and testing enrichment of SNPs that are associated both with eQTLs and existing GWAS of SZ. SZ-associated SNPs that overlap with eQTLs can be placed into gene-gene expression, protein-protein and protein-DNA interaction networks. Further, those networks can be tested by reducing/silencing the gene expression levels of critical nodes. We present pilot data to support these methods of investigation such as the use of eQTLs to annotate GWASs of SZ, which could be applied to the field of biomarker discovery. Those networks that have association with SNP markers, especially cis-regulated expression, might lead to a more clear understanding of important candidate genes that predispose to disease and alter expression. This method has general application to many complex disorders.

PMID: 22155586 [PubMed - indexed for MEDLINE]

Anatomical insights into disrupted small-world networks in schizophrenia.

Neuroimage. 2012 Jan 16;59(2):1085-93

Authors: Wang Q, Su TP, Zhou Y, Chou KH, Chen IY, Jiang T, Lin CP

Abstract
Schizophrenia is characterized by lowered efficiency in distributed information processing, as indicated by research that identified a disrupted small-world functional network. However, whether the dysconnection manifested by the disrupted small-world functional network is reflected in underlying anatomical disruption in schizophrenia remains unresolved. This study examined the topological properties of human brain anatomical networks derived from diffusion tensor imaging in patients with schizophrenia and in healthy controls. We constructed the weighted brain anatomical network for each of 79 schizophrenia patients and for 96 age and gender matched healthy subjects using diffusion tensor tractography and calculated the topological properties of the networks using a graph theoretical method. The topological properties of the patients' anatomical networks were altered, in that global efficiency decreased but local efficiency remained unchanged. The deleterious effects of schizophrenia on network performance appear to be localized as reduced regional efficiency in hubs such as the frontal associative cortices, the paralimbic/limbic regions and a subcortical structure (the left putamen). Additionally, scores on the Positive and Negative Symptom Scale correlated negatively with efficient network properties in schizophrenia. These findings suggest that complex brain network analysis may potentially be used to detect an imaging biomarker for schizophrenia.

PMID: 21963918 [PubMed - indexed for MEDLINE]

Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia.

Schizophr Res. 2011 Dec;133(1-3):150-5

Authors: Okusaga O, Langenberg P, Sleemi A, Vaswani D, Giegling I, Hartmann AM, Konte B, Friedl M, Groer MW, Yolken RH, Rujescu D, Postolache TT

Abstract
Toxoplasma gondii (T. gondii) a widespread neurotropic parasite, has been previously associated with schizophrenia and more recently with suicidal behavior. However, no previous study has examined the association of T. gondii with suicidal behavior in schizophrenia patients. 950 individuals diagnosed with schizophrenia by SCID were recruited from the Munich area of Germany. Solid-enzyme immunoassay methods were used to measure IgG plasma antibodies to T. gondii, other neurotropic pathogens and gliadin. Logistic regression models were developed to analyze the association of T. gondii seropositivity or serointensity with history of suicidal behavior. In those younger than the median age of the sample, 38, T. gondii serointensity was associated with history of suicidal behavior (p = 0.02), while in the older patients the relationship was not significant (p = 0.21). Seropositivity was also associated with history of suicide attempt in younger patients, odds ratio 1.59 (95% CI 1.06 to 2.40), p = 0.03. Seropositivity for CMV (p = 0.22), HSV-1 (p = 0.36) and gliadin (p = 0.92) was not related to history of suicide attempt in the entire sample or any age subgroup. T. gondii serology might become, with interaction with vulnerability genes, a candidate biomarker for a subgroup of schizophrenia patients prone to attempting suicide.

PMID: 21890329 [PubMed - indexed for MEDLINE]

Discovery and development of integrative biological markers for schizophrenia.

Prog Neurobiol. 2011 Dec;95(4):686-702

Authors: Oertel-Knöchel V, Bittner RA, Knöchel C, Prvulovic D, Hampel H

Abstract
Schizophrenia is one of the most disabling forms of mental illness. One of the most important challenges is to establish biological markers which can accurately identify at-risk individuals in preclinical stages and thus improve the effects of early intervention strategies. Here, we review recent findings in the field of molecular genetics, CSF (cerebrospinal fluid) based markers as well as structural and functional neuroimaging in the light of their relevance for schizophrenia biomarker research. We also examine evidence supporting the hypothesis that schizophrenia and neurodegenerative disorders such as Alzheimer's disease may share certain pathophysiological features, e.g. chronic inflammation and oxidative stress, and discuss their possible role in schizophrenia. The heterogeneous, multifaceted and multifactorial nature of the traditionally clinically operationalized entity "schizophrenia" presents an enormous challenge towards the identification of single diagnostic or surrogate markers. We propose that abnormal neural coordination is a major point of convergence of a number of crucial pathophysiological pathways. Therefore, functional markers reflecting disturbed neural coordination might be particularly attractive biomarker candidates, because of their ability to integrate the influence of diverse pathophysiological mechanisms. Similarly, combinatorial and multimodal approaches may be a promising way to more accurately capture the complex biological underpinnings schizophrenia. We consider the development of such integrative biomarkers to be essential in order to facilitate a timely diagnosis of schizophrenia. They should also advance our understanding of the subtle and intricate biological nature of schizophrenia.

PMID: 21664943 [PubMed - indexed for MEDLINE]

Biomarker profile of minor physical anomalies in schizophrenia patients.

Folia Med (Plovdiv). 2011 Jul-Sep;53(3):45-51

Authors: Akabaliev VH, Sivkov ST, Mantarkov MJ, Ahmed-Popova FM

Abstract
AIM: The aim of this study was to determine the frequency and topographical distribution of minor physical anomalies (MPAs) in schizophrenia patients and control subjects, and the ability of the items of the Waldrop scale to predict the patient-control status.
MATERIAL AND METHODS: 128 schizophrenic patients (66 men, 62 women) and 103 normal controls (49 men, 54 women) were evaluated for MPAs with a modified version of the Waldrop scale.
RESULTS: Compared with controls, schizophrenia patients showed a higher incidence of almost all studied MPAs, differences being statistically significant for 12 items: fine electric hair, abnormal hair whorls, epicanthus, adherent ear-lobes, lower edges of the ears extending backward/upward, malformed ears, asymmetrical ears, high/arched palate, furrowed tongue, smooth/rough spots on the tongue, III toe > or = II toe, big gap between I and II toe. Some anomalies occurred with almost equal frequency in schizophrenic patients and controls, while others were more than 10 times more common in patients (odds ratio: 0.62 - 10.55). The distribution frequency of MPAs in schizophrenia tended to increase in the cranial direction. Nine predictor MPA biomarkers successfully distinguished 81.10% of patients, 81.55% of controls, and 81.30% of all examined subjects.
CONCLUSIONS: The elevated incidence of MPA biomarkers in schizophrenia patients implies impaired neurodevelopment that increases the risk for the development of schizophrenia. The pattern of changes in the morphological characteristics suggests they may be a random outcome of a general neurodevelopmental defect or may reflect different neurodevelopmental defects that allow better characterization of schizophrenia patients subgroups.

PMID: 22359982 [PubMed - indexed for MEDLINE]

DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder.

J Psychiatr Res. 2011 Nov;45(11):1432-8

Authors: Nohesara S, Ghadirivasfi M, Mostafavi S, Eskandari MR, Ahmadkhaniha H, Thiagalingam S, Abdolmaleky HM

Abstract
The failure in the discovery of etiology of psychiatric diseases, despite extensive genetic studies, has directed the attention of neuroscientists to the contribution of epigenetic modulations, which play important roles in fine-tuning of gene expression in response to environmental factors. Previously, we analyzed 115 human post-mortem brain samples from the frontal lobe and reported DNA hypo methylation of the membrane-bound catechol-O-methyltransferase (MB-COMT) gene promoter, associated with an increased gene expression, as a risk factor for schizophrenia (SCZ) and bipolar disorder (BD). Since most epigenetic modifications are tissue specific and the availability of brain tissue to identify epigenetic aberrations in living subjects is limited, detection of epigenetic abnormalities in other tissues that represent the brain epigenetic marks is one of the critical steps to develop diagnostic and therapeutic biomarkers for mental diseases. Here, hypothesizing that; those factors that lead to the brain MB-COMT promoter DNA hypo-methylation may also cause concurrent epigenetic aberrations in peripheral tissues, we analyzed MB-COMT promoter methylation in DNA derived from the saliva in SCZ, BD and their first-degree relatives (20 cases each) as well as 25 control subjects. Using bisulfite DNA sequencing and quantitative methylation specific PCR (qMSP), we found that similar to the brain, MB-COMT promoter was hypo-methylated (∼50%) in DNA derived from the saliva in SCZ and BD compared to the control subjects (p = 0.02 and 0.037, respectively). These studies suggest that DNA methylation analysis of MB-COMT promoter in saliva can potentially be used as an available epigenetic biomarker for disease state in SCZ and BD.

PMID: 21820670 [PubMed - indexed for MEDLINE]

Adjunct treatments for schizophrenia and bipolar disorder: what to try when you are out of ideas.

Clin Schizophr Relat Psychoses. 2012 Jan;5(4):208-216

Authors: Torrey EF, Davis JM

Abstract
The pharmacologic treatment of schizophrenia and bipolar disorder leaves much to be desired. Repurposed drugs, which are approved for other medical conditions, represent an underutilized therapeutic resource for patients who have not responded to other drugs. Using experience gained from a decade of repurposed drug studies by the Stanley Medical Research Institute and search of the literature, we have identified nine such drugs for which there is some evidence of efficacy for schizophrenia and/or bipolar disorder. These include: aspirin; celecoxib; estrogen/raloxifene; folate; minocycline; mirtazapine; omega-3 fatty acids; pramipexole; and, pregnenolone. The evidence of efficacy is reviewed for each drug. Because there is little or no financial incentive for pharmaceutical companies to promote such drugs, there is a paucity of definitive trials, and these drugs are less widely known than they deserve to be. Biomarker studies should also be carried out to identify subgroups of patients who do respond to these drugs.

PMID: 22182458 [PubMed - indexed for MEDLINE]

Evaluation of state and trait biomarkers in healthy volunteers for the development of novel drug treatments in schizophrenia.

J Psychopharmacol. 2011 Sep;25(9):1207-25

Authors: Koychev I, Barkus E, Ettinger U, Killcross S, Roiser JP, Wilkinson L, Deakin B

Abstract
Antipsychotic drugs are the mainstay of treatment for schizophrenia but they have little effect on core negative symptoms or cognitive impairment. To meet the deficiencies of current treatments, novel potential compounds are emerging from preclinical research but translation to clinical success has been poor. This article evaluates the possibility that cognitive and physiological abnormalities in schizophrenia can be used as central nervous system biomarkers to predict, in healthy volunteers, the likely efficacy of entirely new pharmacological approaches to treatment. Early detection of efficacy would focus resource on rapidly developing, effective drugs. We review the relevance of selected cognitive and physiological abnormalities as biomarkers in schizophrenia and three of its surrogate populations: (i) healthy volunteers with high trait schizotypy; (ii) unaffected relatives of patients; and (iii) healthy volunteers in a state of cortical glutamate disinhibition induced by low-dose ketamine. Several biomarkers are abnormal in these groups and in some instances there has been exploratory work to determine their sensitivity to drug action. They are generally insensitive to current antipsychotics and therefore their predictive validity cannot be established until novel, therapeutically useful drugs are discovered. Until then such biomarker studies can provide evidence of drugs engaging with the mechanism of interest and encouragement of the concept.

PMID: 21994315 [PubMed - indexed for MEDLINE]

Translating potential biomarker candidates for schizophrenia and depression to animal models of psychiatric disorders.

Expert Rev Mol Diagn. 2011 Sep;11(7):721-33

Authors: Kluge W, Alsaif M, Guest PC, Schwarz E, Bahn S

Abstract
Schizophrenia and major depressive disorder are severe mental illnesses, which are diagnosed based on patient interviews. Despite many years of extensive research, scientists have not yet fully deciphered how genetic and environmental factors interact to cause these illnesses. Biomarker tests that can confirm diagnoses of schizophrenia or depression are only now beginning to emerge, and could result in a paradigm shift in this field. These tests will help to evaluate the validity of animal models of psychiatric disorders, which are currently characterized based on behavioral measures. In this article, we explore the utility of translating both behavioral and molecular phenotypes of such models to the corresponding human disorders. This approach may help to provide construct validity to animal models and could lead to the identification of models corresponding to defined subtypes of neuropsychiatric disorders based on molecular profiles. Here, we review the molecular and biological pathway alterations that have been found in animal models of schizophrenia and depression and focus on those that are mirrored by similar abnormalities in human patients. Such parallels may provide insight into the validity of specific animal models and therefore help to provide more valuable and accurate tools for the discovery and development of improved psychiatric medications.

PMID: 21902534 [PubMed - indexed for MEDLINE]