Clinical utility of plasma Aß42/40 ratio by LC-MS/MS in Alzheimer's disease assessment.

Introduction: Plasma Aß42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear. Methods: Aß42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and for 6,192 consecutive clinical specimens submitted for Aß42/40 testing. Results: High diagnostic sensitivity and negative predictive value (NPV) for Aß-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aß42/40 values for individuals with positive vs. negative Aß-PET results. Assuming a moderate prevalence of Aß-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%. Conclusion: High-throughput plasma Aß42/40 LC-MS/MS assays can help identify patients with low likelihood of AD pathology, which can reduce PET evaluations, allowing for cost savings.

New plasma LC-MS/MS assays for the quantitation of beta-amyloid peptides and identification of apolipoprotein E proteoforms for Alzheimer's disease risk assessment.

Early detection of Alzheimer's disease (AD) represents an unmet clinical need. Beta-amyloid (Aß) plays an important role in AD pathology, and the Aß42/40 peptide ratio is a good indicator for amyloid deposition. In addition, variants of the apolipoprotein E (APOE) gene are associated with variable AD risk. Here, we describe the development and validation of high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for plasma Aß40 and Aß42 quantitation, as well as apolipoprotein E (ApoE) proteotype determination as a surrogate for APOE genotype. Aß40 and Aß42 were simultaneously immunoprecipitated from plasma, proteolytically digested, and quantitated by LC-MS/MS. ApoE proteotype status was qualitatively assessed by targeting tryptic peptides from the ApoE2, ApoE3, and ApoE4 proteoforms. Both assays were validated according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Within-run precision was 1.8%-4.2% (Aß40), 1.9%-7.2% (Aß42), and 2.6%-8.3% (Aß42/40 ratio). Between-run precision was 3.5%-5.9% (Aß40), 3.8%-8.0% (Aß42), and 3.3%-8.7% (Aß42/40 ratio). Both Aß40 and Aß42 were linear from 10 to 2500 pg/mL. Identified ApoE proteotypes had 100% concordance with APOE genotypes. We have developed a precise, accurate, and sensitive high-throughput LC-MS/MS assay for plasma Aß40, Aß42, and proteoforms of ApoE.

Diffusion MRI relates to plasma Aß42/40 in PET negative participants without dementia.

INTRODUCTION: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-ß (Aß42/40) positivity in Aß positron emission tomography (PET) negative individuals. METHODS: Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aß plasma-/PET- (NC = 22, MCI = 60), plasma+/PET- (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. RESULTS: Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aß42/40 and p-tau181. DISCUSSION: FW imaging changes distinguish plasma Aß42/40 positive and negative groups, independent of group differences in cognitive status, Aß PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light). HIGHLIGHTS: Plasma Aß42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aß42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.

Clinical utility of plasma Aß42/40 ratio by LC-MS/MS in Alzheimer's disease assessment.

INTRODUCTION: Plasma Aß42/40 ratio can be used to help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear. METHODS: Aß42/40 ratio was measured by LC-MS/MS in 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and 6,192 consecutive clinical specimens submitted for Aß42/40 testing. RESULTS: High diagnostic sensitivity and negative predictive value (NPV) for Aß-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aß42/40 values for individuals with positive vs negative Aß-PET results. Assuming a moderate prevalence of Aß-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%. DISCUSSION: Using high-throughput plasma Aß42/40 LC-MS/MS assays can help reduce PET evaluations in patients with low likelihood of AD pathology, allowing for cost savings.

Antibody-Free Quantification of Serum Chromogranin A by Targeted Mass Spectrometry.

BACKGROUND: Chromogranin A (CgA) is a 48 kDa protein that serves as a diagnostically sensitive, but nonspecific, serum biomarker for neuroendocrine tumors. Immunoassays for CgA are not standardized and have a narrow dynamic range, which requires dilution of concentrated specimens. We developed and validated an antibody-free, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method for CgA without these limitations. METHODS: CgA was extracted from serum using a mixed-mode anion exchange solid-phase extraction plate, digested with trypsin, and analyzed by LC-MS/MS using well-characterized CgA calibration standards. After validation, the mass spectrometry method was compared with the CISBIO immunoassay using 200 serum specimens previously submitted for CgA analysis. Specimens with discordant results were reanalyzed by high-resolution mass spectrometry- (HRMS) -based methods to assess the contribution of truncated and post-translationally modified forms of CgA. RESULTS: The assay had a linear range of 50 to 50 000 ng/mL, recoveries between 89% and 115%, and intra- and interassay imprecision <10%. LC-MS/MS assay results showed a Pearson's correlation of r = 0.953 with the CISBIO immunoassay, with CgA values being a mean 2- to 4-fold higher. Concordance for CgA between the 2 assays was 80.9% (95% CI 72.8%-89.2%), showing substantial agreement. Truncation and posttranslational modification, including 2 phosphorylation sites that had not been previously observed or predicted to our knowledge, did not appear to contribute directly to discordance between the 2 assays. CONCLUSION: Quantification of CgA by LC-MS/MS provides an analytically sensitive and reproducible alternative to commercially available immunoassays.

High-Throughput Mass Spectrometry Assay for Quantifying ß-Amyloid 40 and 42 in Cerebrospinal Fluid.

BACKGROUND: The ratio of ß-amyloid 1-42 (Aß42) to Aß40 in cerebrospinal fluid (CSF) may be useful for evaluating Alzheimer disease (AD), but quantification is limited by factors including preanalytical analyte loss. We developed an LC-MS/MS assay that limits analyte loss. Here we describe the analytical characteristics of the assay and its performance in differentiating patients with AD from non-AD dementia and healthy controls. METHODS: To measure Aß42/Aß40, we used unique proteolytically derived C-terminal peptides as surrogate markers of Aß40 and Aß42, which were analyzed and quantified by LC-MS/MS. The assay was analytically validated and applied to specimens from individuals with clinically diagnosed AD (n = 102), mild cognitive impairment (n = 37), and non-AD dementias (n = 22), as well as from healthy controls (n = 130). Aß42/Aß40 values were compared with APOE genotype inferred from phenotype, also measured by LC-MS/MS. RESULTS: The assay had a reportable range of 100 to 25000 pg/mL, a limit of quantification of 100 pg/mL, recoveries between 93% and 111%, and intraassay and interassay CV <15% for both peptides. An Aß42/Aß40 ratio cutoff of <0.16 had a clinical sensitivity of 78% for distinguishing patients with AD from non-AD dementia (clinical specificity, 91%) and from healthy controls (clinical specificity, 81%). The Aß42/Aß40 ratio decreased significantly (P < 0.001) with increasing dose of APOE4 alleles. CONCLUSIONS: This assay can be used to determine Aß42/Aß40 ratios, which correlate with the presence of AD.

Profiling of proteins secreted in the bovine oviduct reveals diverse functions of this luminal microenvironment.

The oviductal microenvironment is a site for key events that involve gamete maturation, fertilization and early embryo development. Secretions into the oviductal lumen by either the lining epithelium or by transudation of plasma constituents are known to contain elements conducive for reproductive success. Although previous studies have identified some of these factors involved in reproduction, knowledge of secreted proteins in the oviductal fluid remains rudimentary with limited definition of function even in extensively studied species like cattle. In this study, we used a shotgun proteomics approach followed by bioinformatics sequence prediction to identify secreted proteins present in the bovine oviductal fluid (ex vivo) and secretions from the bovine oviductal epithelial cells (in vitro). From a total of 2087 proteins identified, 266 proteins could be classified as secreted, 109 (41%) of which were common for both in vivo and in vitro conditions. Pathway analysis indicated different classes of proteins that included growth factors, metabolic regulators, immune modulators, enzymes, and extracellular matrix components. Functional analysis revealed mechanisms in the oviductal lumen linked to immune homeostasis, gamete maturation, fertilization and early embryo development. These results point to several novel components that work together with known elements mediating functional homeostasis, and highlight the diversity of machinery associated with oviductal physiology and early events in cattle fertility.

Absolute Quantification of Human Milk Caseins and the Whey/Casein Ratio during the First Year of Lactation.

Whey proteins and caseins in breast milk provide bioactivities and also have different amino acid composition. Accurate determination of these two major protein classes provides a better understanding of human milk composition and function, and further aids in developing improved infant formulas based on bovine whey proteins and caseins. In this study, we implemented a LC-MS/MS quantitative analysis based on iBAQ label-free quantitation, to estimate absolute concentrations of α-casein, ß-casein, and κ-casein in human milk samples (n = 88) collected between day 1 and day 360 postpartum. Total protein concentration ranged from 2.03 to 17.52 with a mean of 9.37 ± 3.65 g/L. Casein subunits ranged from 0.04 to 1.68 g/L (α-), 0.04 to 4.42 g/L (ß-), and 0.10 to 1.72 g/L (α-), with ß-casein having the highest average concentration among the three subunits. Calculated whey/casein ratio ranged from 45:55 to 97:3. Linear regression analyses show significant decreases in total protein, ß-casein, κ-casein, total casein, and a significant increase of whey/casein ratio during the course of lactation. Our study presents a novel and accurate quantitative analysis of human milk casein content, demonstrating a lower casein content than earlier believed, which has implications for improved infants formulas.

In vivo digestomics of milk proteins in human milk and infant formula using a suckling rat pup model.

Human milk is the optimal mode of infant feeding for the first several months of life, and infant formulas serve as an alternative when breast-feeding is not possible. Milk proteins have a balanced amino acid composition and some of them provide beneficial bioactivities in their intact forms. They also encrypt a variety of bioactive peptides, possibly contributing to infant health and growth. However, there is limited knowledge of how milk proteins are digested in the gastrointestinal tract and bioactive peptides are released in infants. A peptidomic analysis was conducted to identify peptides released from milk proteins in human milk and infant formula, using a suckling rat pup model. Among the major milk proteins targeted, α-lactalbumin and ß-casein in human milk, and ß-lactoglobulin and ß-casein in infant formula were the main sources of peptides, and these peptides covered large parts of the parental proteins' sequences. Release of peptides was concentrated to specific regions, such as residues 70-92 of ß-casein in human milk, residues 39-55 of ß-lactoglobulin in infant formula, and residues 57-96 and 145-161 of ß-CN in infant formula, where resistance to gastrointestinal digestion was suggested. In the context of bioactive peptides, release of fragments containing known bioactive peptides was confirmed, such as ß-CN-derived opioid and antihypertensive peptides. It is therefore likely that these fragments are of biological significance in neonatal health and development.

Dexamethasone Stiffens Trabecular Meshwork, Trabecular Meshwork Cells, and Matrix.

PURPOSE: Treatment with corticosteroids can result in ocular hypertension and may lead to the development of steroid-induced glaucoma. The extent to which biomechanical changes in trabecular meshwork (TM) cells and extracellular matrix (ECM) contribute toward this dysfunction is poorly understood. METHODS: Primary human TM (HTM) cells were cultured for either 3 days or 4 weeks in the presence or absence of dexamethasone (DEX), and cell mechanics, matrix mechanics and proteomics were determined, respectively. Adult rabbits were treated topically with either 0.1% DEX or vehicle over 3 weeks, and mechanics of the TM were determined. RESULTS: Treatment with DEX for 3 days resulted in a 2-fold increase in HTM cell stiffness, and this correlated with activation of extracellular signal-related kinase 1/2 (ERK1/2) and overexpression of α-smooth muscle actin (αSMA). Further, the matrix deposited by HTM cells chronically treated with DEX is approximately 4-fold stiffer, more organized, and has elevated expression of matrix proteins commonly implicated in glaucoma (decorin, myocilin, fibrillin, secreted frizzle-related protein [SFRP1], matrix-gla). Also, DEX treatment resulted in a 3.5-fold increase in stiffness of the rabbit TM. DISCUSSION: This integrated approach clearly demonstrates that DEX treatment increases TM cell stiffness concurrent with elevated αSMA expression and activation of the mitogen-activated protein kinase (MAPK) pathway, stiffens the ECM in vitro along with upregulation of Wnt antagonists and fibrotic markers embedded in a more organized matrix, and increases the stiffness of TM tissues in vivo. These results demonstrate glucocorticoid treatment can initiate the biophysical alteration associated with increased resistance to aqueous humor outflow and the resultant increase in IOP.

CaMKII Phosphorylation of Na(V)1.5: Novel in Vitro Sites Identified by Mass Spectrometry and Reduced S516 Phosphorylation in Human Heart Failure.

The cardiac voltage-gated sodium channel, Na(V)1.5, drives the upstroke of the cardiac action potential and is a critical determinant of myocyte excitability. Recently, calcium (Ca(2+))/calmodulin(CaM)-dependent protein kinase II (CaMKII) has emerged as a critical regulator of Na(V)1.5 function through phosphorylation of multiple residues including S516, T594, and S571, and these phosphorylation events may be important for the genesis of acquired arrhythmias, which occur in heart failure. However, phosphorylation of full-length human Na(V)1.5 has not been systematically analyzed and Na(V)1.5 phosphorylation in human heart failure is incompletely understood. In the present study, we used label-free mass spectrometry to assess phosphorylation of human Na(V)1.5 purified from HEK293 cells with full coverage of phosphorylatable sites and identified 23 sites that were phosphorylated by CaMKII in vitro. We confirmed phosphorylation of S516 and S571 by LC-MS/MS and found a decrease in S516 phosphorylation in human heart failure, using a novel phospho-specific antibody. This work furthers our understanding of the phosphorylation of Na(V)1.5 by CaMKII under normal and disease conditions, provides novel CaMKII target sites for functional validation, and provides the first phospho-proteomic map of full-length human Na(V)1.5.

Comparative Proteomics of Human and Macaque Milk Reveals Species-Specific Nutrition during Postnatal Development.

Milk has been well established as the optimal nutrition source for infants, yet there is still much to be understood about its molecular composition. Therefore, our objective was to develop and compare comprehensive milk proteomes for human and rhesus macaques to highlight differences in neonatal nutrition. We developed a milk proteomics technique that overcomes previous technical barriers including pervasive post-translational modifications and limited sample volume. We identified 1606 and 518 proteins in human and macaque milk, respectively. During analysis of detected protein orthologs, we identified 88 differentially abundant proteins. Of these, 93% exhibited increased abundance in human milk relative to macaque and include lactoferrin, polymeric immunoglobulin receptor, alpha-1 antichymotrypsin, vitamin D-binding protein, and haptocorrin. Furthermore, proteins more abundant in human milk compared with macaque are associated with development of the gastrointestinal tract, the immune system, and the brain. Overall, our novel proteomics method reveals the first comprehensive macaque milk proteome and 524 newly identified human milk proteins. The differentially abundant proteins observed are consistent with the perspective that human infants, compared with nonhuman primates, are born at a slightly earlier stage of somatic development and require additional support through higher quantities of specific proteins to nurture human infant maturation.

Transforming Growth Factor Beta 3 Modifies Mechanics and Composition of Extracellular Matrix Deposited by Human Trabecular Meshwork Cells.

Pseudoexfoliation syndrome is a systemic disorder of the extracellular matrix (ECM) with ocular manifestations in the form of chronic open angle glaucoma. Elevated levels of TGFß3 in the aqueous humor of individuals with pseudoexfoliation glaucoma (PEX) have been reported. The influence of TGFß3 on the biochemical composition and biomechanics of ECM of human trabecular meshwork (HTM) cells was investigated. HTM cells from eye bank donor eyes were isolated, plated on aminosilane functionalized glass substrates and cultured in the presence or absence of 1 ng/mL TGFß3 for 4 weeks. After incubation, samples were decellularized and decellularization was verified by immunostaining. The mechanics of the remaining ECM that was deposited by the treated or the control cells were measured by atomic force microscopy (AFM). Imaged by AFM, the surface features of the ECM from both sets of samples had a similar roughness/topography (as determined by RMS values) suggesting surface features of the ECM were similar in both cases; however, the ECM from the HTM cells treated with TGFß3 was between 3- and 5-fold stiffer than that produced by the control HTM cells. Proteins present in the ECM were solubilized and analyzed using liquid chromatography tandem mass spectroscopy (LC-MS/MS). Data indicate that multiple proteins previously reported to be altered in glaucoma were changed in the ECM as a result of the presence of TGFß3, including inhibitors of the BMP and Wnt signaling pathways. Gremlin1and 4, SERPINE1 and 2, periostin, secreted frizzled related protein (SFRP) 1 and 4, and ANGPTL4 were among those proteins that were overexpressed in the ECM after TGFß3 treatment.

The human colostrum whey proteome is altered in gestational diabetes mellitus.

Proteomics of human milk has been used to identify the comprehensive cargo of proteins involved in immune and cellular function. Very little is known about the effects of gestational diabetes mellitus (GDM) on lactation and breast milk components. The objective of the current study was to examine the effect of GDM on the expression of proteins in the whey fraction of human colostrum. Colostrum was collected from women who were diagnosed with (n = 6) or without (n = 12) GDM at weeks 24-28 in pregnancy. Colostral whey was analyzed for protein abundances using high-resolution, high-mass accuracy liquid chromatography tandem mass spectrometry. A total of 601 proteins were identified, of which 260 were quantified using label free spectral counting. Orthogonal partial least-squares discriminant analysis identified 27 proteins that best predict GDM. The power law global error model corrected for multiple testing was used to confirm that 10 of the 27 proteins were also statistically significantly different between women with versus without GDM. The identified changes in protein expression suggest that diabetes mellitus during pregnancy has consequences on human colostral proteins involved in immunity and nutrition.

Dynamic activation of frontal, parietal, and sensory regions underlying anticipatory visual spatial attention.

Although it is well established that multiple frontal, parietal, and occipital regions in humans are involved in anticipatory deployment of visual spatial attention, less is known about the electrophysiological signals in each region across multiple subsecond periods of attentional deployment. We used MEG measures of cortical stimulus-locked, signal-averaged (event-related field) activity during a task in which a symbolic cue directed covert attention to the relevant location on each trial. Direction-specific attention effects occurred in different cortical regions for each of multiple time periods during the delay between the cue and imperative stimulus. A sequence of activation from V1/V2 to extrastriate, parietal, and frontal regions occurred within 110 ms after cue, possibly related to extraction of cue meaning. Direction-specific activations ∼300 ms after cue in frontal eye field (FEF), lateral intraparietal area (LIP), and cuneus support early covert targeting of the cued location. This was followed by coactivation of a frontal-parietal system [superior frontal gyrus (SFG), middle frontal gyrus (MFG), LIP, anterior intraparietal sulcus (IPSa)] that may coordinate the transition from targeting the cued location to sustained deployment of attention to both space and feature in the last period. The last period involved direction-specific activity in parietal regions and both dorsal and ventral sensory regions [LIP, IPSa, ventral IPS, lateral occipital region, and fusiform gyrus], which was accompanied by activation that was not direction specific in right hemisphere frontal regions (FEF, SFG, MFG). Behavioral performance corresponded with the magnitude of attention-related activity in different brain regions at each time period during deployment. The results add to the emerging electrophysiological characterization of different cortical networks that operate during anticipatory deployment of visual spatial attention.

Loss of intestinal nuclei and intestinal integrity in aging C. elegans.

The roundworm C. elegans is widely used as an aging model, with hundreds of genes identified that modulate aging (Kaeberlein et al., 2002. Mech. Ageing Dev.123, 1115-1119). The development and bodyplan of the 959 cells comprising the adult have been well described and established for more than 25 years (Sulston & Horvitz, 1977. Dev. Biol.56, 110-156; Sulston et al., 1983. Dev. Biol.100, 64-119.). However, morphological changes with age in this optically transparent animal are less well understood, with only a handful of studies investigating the pathobiology of aging. Age-related changes in muscle (Herndon et al., 2002. Nature419, 808-814), neurons (Herndon et al., 2002), intestine and yolk granules (Garigan et al., 2002. Genetics161, 1101-1112; Herndon et al., 2002), nuclear architecture (Haithcock et al., 2005. Proc. Natl Acad. Sci. USA102, 16690-16695), tail nuclei (Golden et al., 2007. Aging Cell6, 179-188), and the germline (Golden et al., 2007) have been observed via a variety of traditional relatively low-throughput methods. We report here a number of novel approaches to study the pathobiology of aging C. elegans. We combined histological staining of serial-sectioned tissues, transmission electron microscopy, and confocal microscopy with 3D volumetric reconstructions and characterized age-related morphological changes in multiple wild-type individuals at different ages. This enabled us to identify several novel pathologies with age in the C. elegans intestine, including the loss of critical nuclei, the degradation of intestinal microvilli, changes in the size, shape, and cytoplasmic contents of the intestine, and altered morphologies caused by ingested bacteria. The three-dimensional models we have created of tissues and cellular components from multiple individuals of different ages represent a unique resource to demonstrate global heterogeneity of a multicellular organism.

A novel ANCOVA design for analysis of MEG data with application to a visual attention study.

Statistical inference from MEG-based distributed activation maps is well suited to the general linear modeling framework, a standard approach to the analysis of fMRI and PET neuroimaging studies. However, there are important differences from the other neuroimaging modalities related to how observations are created and fitted in GLM models, as well as how subsequent statistical inference is performed. In this paper, we demonstrate how MEG oscillatory components can be analyzed in this framework based on a custom ANCOVA model that takes into account baseline and inter-hemispheric effects, rather than a simpler ANOVA design. We present the methodology using as an example an MEG study of visual spatial attention, since the model design depends on the specific experiment and neuroscience hypotheses being tested. However, the techniques presented here can be readily adapted to accommodate other experimental paradigms. We create statistics that estimate the temporal evolution of attention effects on alpha power in several cortical regions. We present evidence for direction-specific attention effects on alpha activity in occipital and parietal regions and demonstrate the sub-second timing of these effects in each region. The results support a mechanism for anticipatory attentional deployment that dynamically modulates the local alpha synchrony in a network of parietal control and occipital sensory regions.

Information Processing Bias in Post-traumatic Stress Disorder.

This review considers theory and evidence for abnormal information processing in post-traumatic stress disorder (PTSD). Cognitive studies have indicated sensitivity in PTSD for traumatic information, more so than general emotional information. These findings were supported by neuroimaging studies that identify increased brain activity during traumatic cognition, especially in affective networks (including the amygdala, orbitofrontal and anterior cingulate cortex). In theory, it is proposed that traumatic cognition may interfere with neutral cognition and there is evidence of abnormal neutral stimulus processing in PTSD. Firstly, PTSD patients perform poorly on a variety of neuropsychology tasks that involve attention and memory for neutral information. The evidence from event-related potentials and functional neuroimaging also indicates abnormal results in PTSD during neutral stimulus processing. The research evidence generally provides support for theories of trauma sensitivity and abnormal neutral stimulus processing in PTSD. However, there is only tentative evidence that trauma cognition concurrently interferes with neutral cognition. There is even some evidence that traumatic or novelty arousal processes can increase the capacity for attentive processing, thereby enhancing cognition for neutral stimulus information. Research on this topic has not yet fully explored the mechanisms of interaction between traumatic and neutral content in the cognitive dynamics of PTSD.

Abnormal frontal and parietal activity during working memory updating in post-traumatic stress disorder.

This study used event-related potentials (ERPs) to investigate the timing and scalp topography of working memory in post-traumatic stress disorder (PTSD). This study was designed to investigate ERPs associated with a specific working memory updating process. ERPs were recorded from 10 patients and 10 controls during two visual tasks where (a) targets were a specific word or (b) targets were consecutive matching words. In the first task, nontarget words are not retained in working memory. In the second task, as in delay-match-to-sample tasks, a non-target word defines a new target identity, so these words are retained in working memory. This working memory updating process was related to large positive ERPs over frontal and parietal areas at 400-800 ms, which were smaller in PTSD. Estimation of cortical source activity indicated abnormal patterns of frontal and parietal activity in PTSD, which were also observed in regional cerebral blood flow [Clark, C.R., McFarlane, A.C., Morris, P., Weber, D.L., Sonkkilla, C., Shaw, M., Marcina, J., Tochon-Danguy, H., Egan, G., 2003. Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study. Biological Psychiatry 53, 474-481]. Frontal and parietal cortex are known to be involved in distributed networks for working memory processes, interacting with medial temporal areas during episodic memory processes. Abnormal function in these brain networks helps to explain everyday concentration and memory difficulties in PTSD.

Cerebral function in posttraumatic stress disorder during verbal working memory updating: a positron emission tomography study.

BACKGROUND: This study examined cerebral function in posttraumatic stress disorder (PTSD) during the updating of working memory to trauma-neutral, verbal information. METHODS: Ten PTSD and matched control subjects completed a visuoverbal target detection task involving continuous updating (Variable target condition) or no updating (Fixed target condition) of target identity, with updating activity estimated by condition comparison. RESULTS: Normal updating activity using this paradigm involved bilateral activation of the dorsolateral prefrontal cortex (DLPFC) and inferior parietal lobe. The PTSD group lacked this activation in the left hemisphere and was significantly different from control subjects in this regard, but showed additional activation in the superior parietal lobe, bilaterally. CONCLUSIONS: The pattern of parietal activation suggests a dependence on visuospatial coding for working memory representation of trauma-neutral, verbal information. Group differences in the relative involvement of the DLPFC indicate less dependence in PTSD on the executive role normally attributed to the left DLPFC for monitoring and manipulation of working memory content in posterior regions of the brain.