Biomarker Commons

Understanding epileptogenesis in calcified neurocysticercosis with perfusion MRI.

Neurology. 2012 Feb 28;78(9):618-25

Authors: Gupta RK, Awasthi R, Rathore RK, Verma A, Sahoo P, Paliwal VK, Prasad KN, Pandey CM, Narayana PA

Abstract
OBJECTIVES: Calcified cysticercus larva with perilesional abnormality is thought to be responsible for seizures in patients with neurocysticercosis (NCC). However, it is not well understood why some calcified cysts are associated with seizures even without perilesional abnormality.
METHODS: The study group consists of 30 subjects from an ongoing survey for disease burden estimation of a swine farming community who had a single calcified lesion without any perilesional abnormality with or without presentation of seizures. Each group consisted of 15 patients with calcified cysts and was labeled as asymptomatic and symptomatic. We performed dynamic contrast-enhanced (DCE) MRI on all these subjects and determined serum matrix metalloproteinase-9 (MMP-9) levels and MMP-9 gene polymorphisms.
RESULTS: DCE-MRI-derived rate transfer constant (k(ep)) and serum MMP-9 levels showed significant differences between symptomatic and asymptomatic subjects. We observed an increase in the MMP-9 levels, k(ep), and the volume transfer coefficient (k(trans)) in these lesions. We also observed a significant increase in MMP-9 (R279Q) gene polymorphism in symptomatic subjects compared with asymptomatic and control subjects.
CONCLUSIONS: Perilesional inflammation, which varies from symptomatic to asymptomatic subjects, can be quantified using DCE-MRI in calcified cysticercosis and may help distinguish these 2 groups with similar imaging findings. The observed increase in k(ep) with serum MMP-9 levels suggests that the former may serve as a biomarker of MMP-9 levels in these subjects. The significant MMP-9 (R279Q) gene polymorphism in symptomatic subjects might explain the differences in the observed DCE-MRI indices between symptomatic and asymptomatic subjects.

PMID: 22302547 [PubMed - indexed for MEDLINE]

Hyperhomocysteinemia among Omani autistic children: a case-control study.

Acta Biochim Pol. 2011;58(4):547-51

Authors: Ali A, Waly MI, Al-Farsi YM, Essa MM, Al-Sharbati MM, Deth RC

Abstract
High serum homocysteine (Hcy) level is regarded as an indicator for impairment of folate-dependent methionine cycle and is associated with oxidative stress. In a case control study, we evaluated eighty 3-5 years old Omani children (40 diagnosed with Autism Spectrum Disorder and 40 their age and gender matched controls) for their fasting serum homocysteine levels as a biomarker of Autism Spectrum Disorder (ASD). Serum folate and vitamin B(12) status were also evaluated. The serum homocysteine was measured using an enzyme immunoassay (EIA) technique whereas folate and vitamin B(12) were measured using an automated random access immune-assay system. The results indicated that mean serum Hcy levels were significantly (P < 0.05) higher in autistic children (20.1 ± 3.3 µmol/L) as compared to controls (9.64 ± 2.1 µmol/L). Significantly (P < 0.05) lower serum folate (1.8 ± 0.4 µg/L) and vitamin B(12) (191.1 ± 0.9 pg/mL) levels were observed in autistic children as compared to controls (6.1 ± 0.6 µg/L and 288.9 ± 1.3 pg/mL, respectively). The levels of homocysteine in autistic children were also much higher as compared to normal reference values (5-15 µmol/L). The results suggest that high fasting serum homocysteine and low folate and vitamin B(12) levels could be used as clinical biomarkers for an early diagnosis and management of ASD.

PMID: 22187679 [PubMed - indexed for MEDLINE]

Stability of resting fMRI interregional correlations analyzed in subject-native space: a one-year longitudinal study in healthy adults and premanifest Huntington's disease.

Neuroimage. 2012 Feb 1;59(3):2452-63

Authors: Seibert TM, Majid DS, Aron AR, Corey-Bloom J, Brewer JB

Abstract
The pattern of interregional functional MRI correlations at rest is being actively considered as a potential noninvasive biomarker in multiple diseases. Before such methods can be used in clinical studies it is important to establish their usefulness in three ways. First, the long-term stability of resting correlation patterns should be characterized, but there have been very few such studies. Second, analysis of resting correlations should account for the unique neuroanatomy of each subject by taking measurements in native space and avoiding transformation of functional data to a standard volume space (e.g., Talairach-Tournox or Montreal Neurological Institute atlases). Transformation to a standard volume space has been shown to variably influence the measurement of functional correlations, and this is a particular concern in diseases which may cause structural changes in the brain. Third, comparisons within the patient population of interest and comparisons between patients and age-matched controls, should demonstrate sensitivity to any disease-related disruption of resting functional correlations. Here we examine the test-retest stability of resting fMRI correlations over a period of one year in a group of healthy adults and in a group of cognitively intact individuals who are gene-positive for Huntington's disease. A recently-developed method is used to measure functional correlations in the native space of individual subjects. The utility of resting functional correlations as a biomarker in premanifest Huntington's disease is also investigated. Results in control and premanifest Huntington's populations were both highly consistent at the group level over one year. We thus show that when resting fMRI analysis is performed in native space (to reduce confounds in registration between subjects and groups) it has good long-term stability at the group level. Individual-subject level results were less consistent between visit 1 and visit 2, suggesting further work is required before resting fMRI correlations can be useful diagnostically for individual patients. No significant effect of premanifest Huntington's disease on prespecified interregional fMRI correlations was observed relative to the control group using either baseline or longitudinal measures. Within the premanifest Huntington's group, though, there was evidence that decreased striatal functional correlations might be associated with disease severity, as gauged by estimated years to symptom onset or by striatal volume.

PMID: 21945695 [PubMed - indexed for MEDLINE]

Decreased sAβPPβ, Aβ38, and Aβ40 cerebrospinal fluid levels in frontotemporal dementia.

J Alzheimers Dis. 2011;26(3):553-63

Authors: Gabelle A, Roche S, Gény C, Bennys K, Labauge P, Tholance Y, Quadrio I, Tiers L, Gor B, Boulanghien J, Chaulet C, Vighetto A, Croisile B, Krolak-Salmon P, Perret-Liaudet A, Touchon J, Lehmann S

Abstract
To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38, and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.

PMID: 21709372 [PubMed - indexed for MEDLINE]

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]

Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy.

Circulation. 2012 Apr 3;125(13):1605-16

Authors: Hijazi Z, Oldgren J, Andersson U, Connolly SJ, Ezekowitz MD, Hohnloser SH, Reilly PA, Vinereanu D, Siegbahn A, Yusuf S, Wallentin L

Abstract
BACKGROUND: Cardiac biomarkers are strong predictors of adverse outcomes in several patient populations. We evaluated the prevalence of elevated troponin I and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and their association to cardiovascular events in atrial fibrillation (AF) patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.
METHODS AND RESULTS: Biomarkers at randomization were analyzed in 6189 patients. Outcomes were evaluated by Cox proportional hazards models adjusting for established cardiovascular risk factors and the CHADS(2) and CHA(2)DS(2)-VASc risk scores. Patients were stratified based on troponin I concentrations: <0.010 μg/L, n=2663; 0.010 to 0.019 μg/L, n=2006; 0.020 to 0.039 μg/L, n=1023; ≥0.040 μg/L, n=497; and on NT-proBNP concentration quartiles: <387; 387 to 800; 801 to 1402; >1402 ng/L. Rates of stroke were independently related to levels of troponin I with 2.09%/year in the highest and 0.84%/year in the lowest troponin I group (hazard ratio [HR], 1.99 [95% CI, 1.17-3.39]; P=0.0040), and to NT-proBNP with 2.30%/year versus 0.92% in the highest versus lowest NT-proBNP quartile groups, (HR, 2.40 [95% CI, 1.41-4.07]; P=0.0014). Vascular mortality was also independently related to biomarker levels with 6.56%/year in the highest and 1.04%/year the lowest troponin I group (HR, 4.38 [95% CI, 3.05-6.29]; P<0.0001), and 5.00%/year in the highest and 0.61%/year in the lowest NT-proBNP quartile groups (HR, 6.73 [3.95-11.49]; P<0.0001). Biomarkers increased the C-statistic from 0.68 to 0.72, P<0.0001, for a composite of thromboembolic events.
CONCLUSIONS: Elevations of troponin I and NT-proBNP are common in patients with AF and independently related to increased risks of stroke and mortality. Cardiac biomarkers seem useful for improving risk prediction in AF beyond currently used clinical variables.

PMID: 22374183 [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]

Massive astrocyte destruction in neuromyelitis optica despite natalizumab therapy.

Mult Scler. 2012 Jan;18(1):108-12

Authors: Barnett MH, Prineas JW, Buckland ME, Parratt JD, Pollard JD

Abstract
Auto-antibody mediated astrocyte injury is implicated as a primary event in neuromyelitis optica (NMO) by biomarker, post-mortem and experimental studies that differentiate the condition from multiple sclerosis. We describe the clinical, radiological and neuropathological features of a severe cerebral attack in a natalizumab-treated patient with relapsing myelitis and serum aquaporin-4 antibodies. Our findings support autopsy evidence that abrupt astrocyte destruction precedes demyelination in NMO, and emphasize the importance of serological testing in patients with limited disease. Adherence to current NMO diagnostic criteria may delay treatment, or lead to inappropriate therapy with beta-interferon or natalizumab.

PMID: 21868485 [PubMed - indexed for MEDLINE]

The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception.

Alzheimers Dement. 2012 Feb;8(1 Suppl):S1-68

Authors: Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ,

Abstract
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects, and are leading candidates for the detection of AD in its preclinical stages; (5) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.

PMID: 22047634 [PubMed - indexed for MEDLINE]

Human serum transthyretin levels correlate inversely with Alzheimer's disease.

J Alzheimers Dis. 2011;25(1):77-84

Authors: Han SH, Jung ES, Sohn JH, Hong HJ, Hong HS, Kim JW, Na DL, Kim M, Kim H, Ha HJ, Kim YH, Huh N, Jung MW, Mook-Jung I

Abstract
Alzheimer's disease (AD) is the fastest growing neurodegenerative disease in the elderly population, and the search for therapeutic targets and diagnostic AD biomarkers is an exigent issue. Because amyloid-β (Aβ) aggregation constitutes the epicenter of AD pathology, Aβ-binding proteins that regulate Aβ aggregation, such as transthyretin (TTR), have attracted much attention. TTR binds to Aβ, prevents its aggregation, and consequently inhibits Aβ-induced cellular toxicity. Decreased TTR levels in cerebrospinal fluid (CSF) from AD patients suggest that TTR is a biomarker of AD. But, studies on TTR as a biomarker have focused on CSF; no study has evaluated peripheral levels of TTR in AD. Here, we examined the relationship between serum TTR levels and AD. We measured TTR levels in serum samples from 90 nondemented controls and 111 AD patients and observed significantly lower serum TTR levels in AD (p < 0.001). Notably, females in the control group had lower serum TTR levels compared with male in the control (p = 0.006), while no difference in gender was noted in the AD group. There were no age-related changes in serum TTR levels. Thus, this study demonstrates a clear negative correlation between serum TTR levels and AD, suggesting that TTR is not only involved in AD pathological process but also suggested as possible peripheral biomarker for AD diagnosis in serum level.

PMID: 21335655 [PubMed - indexed for MEDLINE]

Reduced levels of IgM autoantibodies against N-truncated pyroglutamate Aβ in plasma of patients with Alzheimer's disease.

Neurobiol Aging. 2011 Aug;32(8):1379-87

Authors: Marcello A, Wirths O, Schneider-Axmann T, Degerman-Gunnarsson M, Lannfelt L, Bayer TA

Abstract
In the present work, we investigated the level of IgM autoantibodies directed against different Aβ epitopes as potential diagnostic biomarker for Alzheimer's disease (AD). Anti-Aβ autoantibody levels were measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To validate the presence of anti-Aβ IgMs, pooled plasma samples were subjected to gel-filtration analysis. The mean level of pGluAβ-IgM (N-terminal truncated starting at position three with pyroglutamate) was significantly decreased in AD patients as compared to HC. In the group of MCI patients there was a significant positive correlation between pGluAβ-IgM and cognitive decline analyzed by MMSE (rho = 0.58, d.f. = 13, p = 0.022). These observations indicate that the level of IgM autoantibodies against pGluAβ is a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk to develop AD.

PMID: 19781815 [PubMed - indexed for MEDLINE]

Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics.

J Neural Transm. 2012 Jan;119(1):39-52

Authors: Gerlach M, Maetzler W, Broich K, Hampel H, Rems L, Reum T, Riederer P, Stöffler A, Streffer J, Berg D

Abstract
Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson's disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies.

PMID: 21755462 [PubMed - indexed for MEDLINE]

Evolving role of biomarkers in acute cerebrovascular disease.

Ann Neurol. 2012 Mar;71(3):289-303

Authors: Kernagis DN, Laskowitz DT

Abstract
The development of a clinically validated biomarker of acute cerebral ischemia would have the potential to facilitate the use of time-sensitive reperfusion strategies, allow for individualization of patient care by predicting relative risk of hemorrhage and volume of penumbral tissue, and add valuable prognostic information for patients presenting with acute stroke. Additionally, a stroke biomarker might benefit early stage clinical research by serving as a surrogate measure of ischemic injury. Although at present there are no clinically validated biomarkers of acute stroke, previous studies have focused on markers associated with different components of the ischemic cascade, including microglial activation, inflammation, oxidative stress, neuronal injury, hemostasis, and endothelial dysfunction. Evolving technologies have provided high throughput approaches to investigate potential gene and protein signatures, and methods to measure newly discovered markers of cell death and immune responses. Prior to defining the clinical utility of stroke biomarkers, it is critical to understand the inherent limitations of a biomarker-based approach and define its potential value for providing adjunctive diagnostic and prognostic information. The identification and validation of a clinically relevant biomarker, or panel of markers, of stroke will ultimately require incorporation of both stringent research design and assessment in the clinical context in which the marker will be used.

PMID: 22451199 [PubMed - indexed for MEDLINE]

MRI biomarkers in Huntington's disease.

Front Biosci (Elite Ed). 2012;4:1910-25

Authors: van den Bogaard S, Dumas E, van der Grond J, van Buchem M, Roos R

Abstract
Huntington's disease (HD) is a devastating neurodegenerative disease affecting the brain resulting in neuronal dysfunction and neuronal loss. Since the identification of the gene responsible for HD, genetic testing has become widely available, allowing for genetic status of persons at risk for HD to be determined. For the effective evaluation of future therapeutic trials a great need exists for sensitive biomarkers. In (premanifest) HD, MRI of the brain is one of the most logical candidates as a biomarker, as opposed to clinical measures, since brain neurons are the main target of the disease. These biomarkers can facilitate early detection of disease related changes, but are also needed to monitor disease progression from the premanifest phase of HD onwards. MRI derived parameters have this biomarker potential as they have been shown to identify brain abnormalities before symptom onset. In this review the available MRI techniques of conventional MRI, Diffusion Tensor Imaging, Magnetization Transfer Imaging, Magnetic Resonance Spectroscopy and Functional MRI will be discussed and the findings will be placed into context of different HD stages.

PMID: 22202007 [PubMed - indexed for MEDLINE]

Shape analysis of subcortical nuclei in Huntington's disease, global versus local atrophy--results from the TRACK-HD study.

J Neurol Sci. 2011 Aug 15;307(1-2):60-8

Authors: van den Bogaard SJ, Dumas EM, Ferrarini L, Milles J, van Buchem MA, van der Grond J, Roos RA

Abstract
Huntington's disease (HD) is characterized by brain atrophy. Localized atrophy of a specific structure could potentially be a more sensitive biomarker reflecting neuropathologic changes rather than global volume variation. We examined 90 TRACK-HD participants of which 30 were premanifest HD, 30 were manifest HD and 30 were controls. Using FMRIB's Integrated Registration and Segmentation Tool, segmentations were obtained for the pallidum, caudate nucleus, putamen, thalamus, accumbens nucleus, amygdala, and hippocampus and overall volumes were calculated. A point distribution model of each structure was obtained using Growing and Adaptive Meshes. Permutation testing between groups was performed to detect local displacement in shape between groups. In premanifest HD overall volume loss occurred in the putamen, accumbens and caudate nucleus. Overall volume reductions in manifest HD were found in all subcortical structures, except the amygdala, as compared to controls. In premanifest HD shape analysis showed small areas of displacement in the putamen, pallidum, accumbens and caudate nucleus. When the premanifest group was split into two groups according to predicted disease onset, the premanifest HD group close to expected disease onset showed more pronounced displacements in caudate nucleus and putamen compared to premanifest HD far from disease onset or the total premanifest group. Analysis of shape in manifest HD showed widespread shape differences, most prominently in the caudal part of the accumbens nucleus, body of the caudate nucleus, putamen and dorsal part of the pallidum. We conclude that shape analysis provides new insights in localized intrastructural atrophy patterns in HD, but can also potentially serve as specific target areas for disease tracking.

PMID: 21624624 [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]

Antigen microarrays identify CNS-produced autoantibodies in RRMS.

Neurology. 2012 Feb 21;78(8):532-9

Authors: Quintana FJ, Farez MF, Izquierdo G, Lucas M, Cohen IR, Weiner HL

Abstract
OBJECTIVE: Multiple sclerosis (MS) is characterized by the local production of antibodies in the CNS and the presence of oligoclonal bands in the CSF. Antigen arrays allow the study of antibody reactivity against a large number of antigens using small volumes of fluid with greater sensitivity than ELISA. We investigated whether there were unique autoantibodies in the CSF of patients with MS as measured by antigen arrays and whether these antibodies differed from those in serum.
METHODS: We used antigen arrays to analyze the reactivity of antibodies in matched serum and CSF samples of 20 patients with untreated relapsing-remitting MS (RRMS), 26 methylprednisolone-treated patients with RRMS, and 20 control patients with other noninflammatory neurologic conditions (ONDs) against 334 different antigens including heat shock proteins, lipids, and myelin antigens.
RESULTS: We found different antibody signatures in matched CSF and serum samples The targets of these antibodies included epitopes of the myelin antigens CNP, MBP, MOBP, MOG, and PLP (59%), HSP60 and HSP70 (38%), and the 68-kD neurofilament (3%). The antibody response in patients with MS was heterogeneous; CSF antibodies in individual patients reacted with different autoantigens. These autoantibodies were locally synthesized in the CNS and were of the immunoglobulin G class. Finally, we found that treatment with steroids decreased autoantibody reactivity, epitope spreading, and intrathecal autoantibody synthesis.
CONCLUSIONS: These studies provide a new avenue to investigate the local antibody response in the CNS, which may serve as a biomarker to monitor both disease progression and response to therapy in MS.

PMID: 22262743 [PubMed - indexed for MEDLINE]