PET/MRI of hypoxia and vascular function in ER-positive breast cancer: correlations with immunohistochemistry.

OBJECTIVES: To explore the relationship between indices of hypoxia and vascular function from 18F-fluoromisonidazole ([18F]-FMISO)-PET/MRI with immunohistochemical markers of hypoxia and vascularity in oestrogen receptor-positive (ER +) breast cancer. METHODS: Women aged > 18 years with biopsy-confirmed, treatment-naïve primary ER + breast cancer underwent [18F]-FMISO-PET/MRI prior to surgery. Parameters of vascular function were derived from DCE-MRI using the extended Tofts model, whilst hypoxia was assessed using the [18F]-FMISO influx rate constant, Ki. Histological tumour sections were stained with CD31, hypoxia-inducible factor (HIF)-1α, and carbonic anhydrase IX (CAIX). The number of tumour microvessels, median vessel diameter, and microvessel density (MVD) were obtained from CD31 immunohistochemistry. HIF-1α and CAIX expression were assessed using histoscores obtained by multiplying the percentage of positive cells stained by the staining intensity. Regression analysis was used to study associations between imaging and immunohistochemistry variables. RESULTS: Of the lesions examined, 14/22 (64%) were ductal cancers, grade 2 or 3 (19/22; 86%), with 17/22 (77%) HER2-negative. [18F]-FMISO Ki associated negatively with vessel diameter (p = 0.03), MVD (p = 0.02), and CAIX expression (p = 0.002), whilst no significant relationships were found between DCE-MRI pharmacokinetic parameters and immunohistochemical variables. HIF-1α did not significantly associate with any PET/MR imaging indices. CONCLUSION: Hypoxia measured by [18F]-FMISO-PET was associated with increased CAIX expression, low MVD, and smaller vessel diameters in ER + breast cancer, further corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. KEY POINTS: • Hypoxia, measured by [18F]-FMISO-PET, was associated with low microvessel density and small vessel diameters, corroborating the link between inadequate vascularity and hypoxia in ER + breast cancer. • Increased CAIX expression was associated with higher levels of hypoxia measured by [18F]-FMISO-PET. • Morphologic and functional abnormalities of the tumour microvasculature are the major determinants of hypoxia in cancers and support the previously reported perfusion-driven character of hypoxia in breast carcinomas.

Dabigatran Treatment of Acute Noncardioembolic Ischemic Stroke.

Background and Purpose- Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated. Methods- DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization. Results- A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0-2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778-6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03-1.12]; P=0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]). Conclusions- Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02295826.

Metabolic imaging across scales reveals distinct prostate cancer phenotypes.

Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.

Risk of hemorrhagic transformation with early use of direct oral anticoagulants after acute ischemic stroke: A pooled analysis of prospective studies and randomized trials.

INTRODUCTION: Precise risk of hemorrhagic transformation (HT) in acute ischemic stroke (AIS) remains unknown, leading to delays in anticoagulation initiation for secondary stroke prevention. We sought to assess the rate of HT associated with direct oral anticoagulant (DOAC) initiation within and beyond 48 h post-AIS. METHODS: A pooled analysis of DOAC initiation within 14 days of AIS or transient ischemic attack (TIA) was conducted with six studies (four prospective open label treatment, blinded outcome studies and two randomized trials; NCT02295826 and NCT02283294). The primary endpoint was incident radiographic HT on follow-up imaging (days 7-30). Secondary endpoints included symptomatic HT, new parenchymal hemorrhage, recurrent ischemic events, extracranial hemorrhage, study period mortality, and follow-up modified Rankin Scale score. The results were reported as odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI). RESULTS: We evaluated 509 patients; median infarct volume was 1.5 (0.1-7.8) ml, and median National Institutes of Health Stroke Scale was 2 (0-3). Incident radiographic HT was seen on follow-up scan in 34 (6.8%) patients. DOAC initiation within 48 h from index event was not associated with incident HT (adjusted OR 0.67, [0.30-1.50] P = 0.32). No patients developed symptomatic HT. Conversely, 31 (6.1%) patients developed recurrent ischemic events, 64% of which occurred within 14 days. Initiating a DOAC within 48 h of onset was associated with similar recurrent ischemic event rates compared with those in which treatment was delayed (HR: 0.42, [0.17-1.008] P = 0.052). In contrast to HT, recurrent ischemic events were associated with poor functional outcomes (OR = 6.8, [2.84-16.24], p < 0.001). CONCLUSIONS: In this pooled analysis, initiation of DOAC within 48 h post-stroke was not associated with increased incident risk of HT, and none developed symptomatic HT. The analysis was underpowered to determine the effect of early DOAC use upon recurrent ischemic events.

Designing a safer radiology department.

OBJECTIVE: Patients presume safety in radiologic services, but the potential to do harm exists in every area of imaging. Radiology department personnel need to understand basic regulatory requirements for safety and how to promote and improve safety in the future. CONCLUSION: This article reviews key safety metrics that we think are relevant to radiology and discusses how to define the measures and how we are attempting to translate the metrics into a culture of safety.

Progressive membrane phospholipid changes in first episode schizophrenia with high field magnetic resonance spectroscopy.

Patients with a first episode of schizophrenia generally have increased phospholipid membrane breakdown products within the brain, while findings in chronic patients have been inconsistent. In this study we examine progressive changes in phosphorus membrane metabolites in the same patient group through the early years of schizophrenia in brain regions associated with the disease. Sixteen never-treated and medicated first episode schizophrenic patients were assessed at 10 months and 52 months after diagnosis. Sixteen matched volunteers were assessed at baseline and after 35 months. Phospholipid membrane metabolism was assessed with phosphorous magnetic resonance spectroscopy in the thalamus, cerebellum, hippocampus, anterior/posterior cingulate, prefrontal cortex, parieto-occipital cortex, superior temporal gyrus and temporal pole. At 10 months, glycerophosphocholine was increased in the anterior cingulate in patients as compared to controls. Glycerophosphocholine was decreased in the anterior cingulate and increased in the posterior cingulate and left superior temporal gyrus; glycerophosphoethanolamine was decreased in the left thalamus and increased in the left hippocampus within patients over time. At 52 months, compared to controls phosphocholine was increased in the left thalamus and glycerophosphoethanolamine was increased in the left hippocampus. These results imply a gradual inclusion of brain regions in schizophrenia where an initial increase, followed by a decrease in phospholipid membrane metabolites was observed. This pattern, observed in the early years of schizophrenia, is consistent with excitotoxic neural membrane breakdown in these regions.

Divinylpyrimidine reagents generate antibody-drug conjugates with excellent in vivo efficacy and tolerability.

The development of divinylpyrimidine (DVP) reagents for the synthesis of antibody-drug conjugates (ADCs) with in vivo efficacy and tolerability is reported. Detailed structural characterisation of the synthesised ADCs was first conducted followed by in vitro and in vivo evaluation of the ADCs' ability to safely and selectively eradicate target-positive tumours.

Hyperpolarised 13C-MRI identifies the emergence of a glycolytic cell population within intermediate-risk human prostate cancer.

Hyperpolarised magnetic resonance imaging (HP 13C-MRI) is an emerging clinical technique to detect [1-13C]lactate production in prostate cancer (PCa) following intravenous injection of hyperpolarised [1-13C]pyruvate. Here we differentiate clinically significant PCa from indolent disease in a low/intermediate-risk population by correlating [1-13C]lactate labelling on MRI with the percentage of Gleason pattern 4 (%GP4) disease. Using immunohistochemistry and spatial transcriptomics, we show that HP 13C-MRI predominantly measures metabolism in the epithelial compartment of the tumour, rather than the stroma. MRI-derived tumour [1-13C]lactate labelling correlated with epithelial mRNA expression of the enzyme lactate dehydrogenase (LDHA and LDHB combined), and the ratio of lactate transporter expression between the epithelial and stromal compartments (epithelium-to-stroma MCT4). We observe similar changes in MCT4, LDHA, and LDHB between tumours with primary Gleason patterns 3 and 4 in an independent TCGA cohort. Therefore, HP 13C-MRI can metabolically phenotype clinically significant disease based on underlying metabolic differences in the epithelial and stromal tumour compartments.

Getting mixed messages: the impact of conflicting social signals on the brain's target emotional response.

Amidst a barrage of sensory information in the environment, the impact that individual stimuli have on our behaviour is thought to depend on the outcome of competition that occurs within and between multiple brain regions. Although biased competition models of attention have been tested in visual cortices and to a lesser extent in auditory cortex, little is known about the nature of stimulus competition outside of sensory areas. Given the hypothesized role of multiple pathways (cortical and subcortical) and specialized brain regions for processing valence information, studies involving conflicting basic emotional stimuli provide a unique opportunity to examine whether the principles of biased competition apply outside of sensory cortex. We used fMRI to examine the neural representation and resolution of emotional conflict in a sample of healthy individuals. Participants made explicit judgments about the valence of happy or fearful target facial expressions in the context of emotionally congruent, neutral, or incongruent distracters. The results suggest that emotional conflict is reflected in a dissociable manner across distinct neural regions. Posterior areas of visual cortex showed enhanced responding to congruent relative to neutral or incongruent stimuli. Orbitofrontal cortex remained sensitive to positive affect in the context of conflicting emotional stimuli. In contrast, within the amygdala, activity associated with identifying positive target expressions declined with the introduction of neutral and incongruent expressions; however, activity associated with fearful target expressions was less susceptible to the influence of emotional context. Enhanced functional connectivity was observed between medial prefrontal cortex and the amygdala during incongruent trials; the degree of connectivity was correlated with reaction time costs incurred during incongruent trials. The results are interpreted with reference to current models of emotional attention and regulation.

Retrosplenial cortex connectivity in schizophrenia.

In this paper, we build on our previous analysis [Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., et al., 2007 Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophrenia Bulletin 33, 1004-1012] of resting state connectivity in schizophrenia by examining alterations in connectivity of the retrosplenial cortex. We have previously demonstrated altered connectivity of the posterior cingulate/precuneus, particularly with other regions of the "default network" (which includes the medial prefrontal cortex and bilateral lateral parietal cortex). It was hypothesized that the retrosplenial cortex would show aberrant patterns of connectivity with regions of the default network and regions associated with memory. Patients with schizophrenia (N=17) and healthy controls (N=17) underwent a 5.5-min resting functional magnetic resonance imaging scan. Lower correlations were observed in patients with schizophrenia than in healthy controls between the retrosplenial cortex and both the temporal lobe and regions of the default network. In patients with schizophrenia, activity in the retrosplenial cortex correlated negatively with activity in bilateral anterior cingulate gyrus/medial prefrontal cortex (BA 32/10), despite the fact that these regions, as part of the default network, were expected to show positive correlations in activity. Connectivity of the retrosplenial cortex was greater in patients with more positive symptoms with areas previously associated with hallucinations, particularly the left superior temporal gyrus. These results suggest that spontaneous activity in the retrosplenial cortex during rest is altered in patients with schizophrenia. These alterations may help to explain alterations in self-oriented processing in this patient population.

Longitudinal 4.0 Tesla (31)P magnetic resonance spectroscopy changes in the anterior cingulate and left thalamus in first episode schizophrenia.

Progressive volumetric losses in schizophrenia may be preceded by abnormal cell membrane metabolism. Longitudinal changes in membrane metabolites were quantified with (31)P MRS in the anterior cingulate and left thalamus of 13 first episode schizophrenic patients and 13 healthy volunteers at baseline and 30 months. Glycerophosphocholine was higher in patients at baseline in the anterior cingulate and glycerophosphoethanolamine was lower in the left thalamus at 30 months compared with patients at baseline and volunteers at 30 months. These observations suggest longitudinal changes in membrane metabolites consistent with a neurodegenerative process in certain cases of schizophrenia.

Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death-Dependent Changes in Glycolysis.

Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [18F]FDG uptake and MRI measurement of hyperpolarized [1-13C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6-13C2]glucose and measuring 13C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1-13C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [18F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [18F]FDG uptake by infiltrating immune cells. Quantification of [18F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b+/CD45+ macrophages as the most [18F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [18F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1-13C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [18F]FDG uptake. SIGNIFICANCE: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1-13C]pyruvate metabolism versus PET measurement of 18F-FDG uptake for detecting early changes in glycolysis following treatment-induced tumor cell death.

Transmission of equine influenza virus to English foxhounds.

We retrospectively demonstrated that an outbreak of severe respiratory disease in a pack of English foxhounds in the United Kingdom in September 2002 was caused by an equine influenza A virus (H3N8). We also demonstrated that canine respiratory tissue possesses the relevant receptors for infection with equine influenza virus.

Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study.

STUDY OBJECTIVE: To evaluate the pharmacokinetics of haloperidol after intranasal administration compared with intravenous and intramuscular administration, and to evaluate systemic and local tolerance of intranasal administration. DESIGN: Randomized, open-label, three-way crossover study. SETTING: Academic medical center. SUBJECTS: Four healthy volunteers (two men, two women; aged 24-37 yrs). INTERVENTION: Each subject received in a randomized order the following three treatments, with a 2-week washout period between treatments: intravenous haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml) infused over 15 minutes, intramuscular haloperidol 2.5 mg (0.5 ml of 5.0 mg/ml), and intranasal haloperidol 2.5 mg (2.5 mg/0.1-ml spray into a single naris). MEASUREMENTS AND MAIN RESULTS: Blood samples were obtained serially and plasma levels determined. Noncompartmental analysis was used to estimate pharmacokinetic parameters. Physical and nasal examinations and adverse-effect profiles were obtained to assess tolerance. Mean (percent coefficient of variation) haloperidol bioavailability after intranasal administration was 63.8% (24.4%) compared with intravenous administration and 48.6% (29.4%) compared with intramuscular administration. Intranasal administration achieved higher peak levels that occurred more quickly compared with intramuscular administration. Median time to maximum concentration was 15 minutes after the intranasal dose compared with 37.5 and 15 minutes after the intramuscular and intravenous doses, respectively. Subjects had mild-to-moderate systemic adverse effects, all related to an extension of haloperidol's pharmacologic actions. Two of the four subjects complained of mild-tomoderate nasal irritation after the intranasal doses. CONCLUSION: Our results suggest that additional research studies are warranted for further evaluation of intranasal administration of haloperidol. The product provides rapid therapeutic plasma levels and sedation, with only minor and short-lived nasal irritation. These data suggest that intranasal administration of haloperidol, or other antipsychotics with similar potency, could play a role in treating psychiatric emergencies.

Expression of cyclooxygenase-2 by equine ocular and adnexal squamous cell carcinomas.

OBJECTIVE: To investigate whether cyclooxygenase-2 (COX-2) is expressed by equine ocular and adnexal squamous cell carcinomas (SCC). METHODS: Forty-three samples of histologically confirmed cases of ocular SCC or carcinoma in situ (CIS) from 34 horses presented to the Animal Health Trust between 1992 and 2004 were subjected to a standard, two-layered, indirect immunohistochemical method using a rabbit polyclonal antihuman COX-2 antibody. Ten formalin-fixed, paraffin-embedded tissue samples taken from recognized predilection sites for SCC, from the grossly normal eyes of 10 horses euthanized for reasons unrelated to this study, were used as negative controls. Samples of equine fetal kidney were used as positive controls. Following immunolabeling, the number of normal and neoplastic epithelial cells exhibiting positive COX-2 expression was recorded along with staining intensity and distribution. RESULTS: Of 43 tumors, 34 were defined as first presentation tumors. When compared with control tissue, in which 0% (0/10) of samples expressed COX-2, significantly more of these samples with SCC (58.6%, 17/29: P = 0.002), CIS (60%, 3/5: P = 0.022) or either tumor type (58.8%, 20/34: P = 0.001) exhibited positive cytoplasmic and perinuclear immunohistochemical staining for COX-2. Of the samples exhibiting positive immunohistochemical staining, only 10% (2/20) showed staining in 2%-10% of neoplastic cells, while 90% (18/20) showed staining in 1% of neoplastic cells. About 70% (14/20) of those positively immunolabeled samples exhibited an intensity of staining greater than or equal to the staining exhibited by the equine fetal kidney positive control. CONCLUSION: Neoplastic tissue from both equine ocular SCC and CIS exhibit COX-2 expression at significantly higher levels than normal control ocular tissue. However, the percentage of cells expressing positive immunohistochemical staining is consistently low. On the basis of this study, it is unlikely that anti-COX-2 therapy would be of benefit in the treatment of equine ocular and adnexal SCC.

Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network.

Spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (MRI) signal have been shown to reflect neural synchrony between brain regions. A "default network" of spontaneous low-frequency fluctuations has been described in healthy volunteers during stimulus-independent thought. Negatively correlated with this network are regions activated during attention-demanding tasks. Both these networks involve brain regions and functions that have been linked with schizophrenia in previous research. The present study examined spontaneous slow fluctuations in the BOLD signal at rest, as measured by correlation with low-frequency oscillations in the posterior cingulate, in 17 schizophrenic patients, and 17 comparable healthy volunteers. Healthy volunteers demonstrated correlation between spontaneous low-frequency fluctuations of the BOLD signal in the posterior cingulate and fluctuations in the lateral parietal, medial prefrontal, and cerebellar regions, similar to previous reports. Schizophrenic patients had significantly less correlation between spontaneous slow activity in the posterior cingulate and that in the lateral parietal, medial prefrontal, and cerebellar regions. Connectivity of the posterior cingulate was found to vary with both positive and negative symptoms in schizophrenic patients. Because these data suggest significant abnormalities in resting-state neural networks in schizophrenia, further investigations of spontaneous slow fluctuations of the BOLD signal seem warranted in this population.

Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity.

Estrogen Receptor-ß (ERß) has been implicated in many cancers. In prostate and breast cancer its function is controversial, but genetic studies implicate a role in cancer progression. Much of the confusion around ERß stems from antibodies that are inadequately validated, yet have become standard tools for deciphering its role. Using an ERß-inducible cell system we assessed commonly utilized ERß antibodies and show that one of the most commonly used antibodies, NCL-ER-BETA, is non-specific for ERß. Other antibodies have limited ERß specificity or are only specific in one experimental modality. ERß is commonly studied in MCF-7 (breast) and LNCaP (prostate) cancer cell lines, but we found no ERß expression in either, using validated antibodies and independent mass spectrometry-based approaches. Our findings question conclusions made about ERß using the NCL-ER-BETA antibody, or LNCaP and MCF-7 cell lines. We describe robust reagents, which detect ERß across multiple experimental approaches and in clinical samples.

Rapid Imaging of Tumor Cell Death In Vivo Using the C2A Domain of Synaptotagmin-I.

Cell death is an important target for imaging the early response of tumors to treatment. We describe here the validation of a phosphatidylserine-binding agent for detecting tumor cell death in vivo based on the C2A domain of synaptotagmin-I. Methods: The capability of near-infrared fluorophore-labeled and 99mTc- and 111In-labeled derivatives of C2Am for imaging tumor cell death, using planar near-infrared fluorescence imaging and SPECT, respectively, was evaluated in implanted and genetically engineered mouse models of lymphoma and in a human colorectal xenograft. Results: The fluorophore-labeled C2Am derivative showed predominantly renal clearance and high specificity and sensitivity for detecting low levels of tumor cell death (2%-5%). There was a significant correlation (R > 0.9, P < 0.05) between fluorescently labeled C2Am binding and histologic markers of cell death, including cleaved caspase-3, whereas there was no such correlation with a site-directed mutant of C2Am (iC2Am) that does not bind phosphatidylserine. 99mTc-C2Am and 111In-C2Am also showed favorable biodistribution profiles, with predominantly renal clearance and low nonspecific retention in the liver and spleen at 24 h after probe administration. 99mTc-C2Am and 111In-C2Am generated tumor-to-muscle ratios in drug-treated tumors of 4.3× and 2.2×, respectively, at 2 h and 7.3× and 4.1×, respectively, at 24 h after administration. Conclusion: Given the favorable biodistribution profile of 99mTc- and 111In-labeled C2Am, and their ability to produce rapid and cell death-specific image contrast, these agents have potential for clinical translation.

Grey and white matter differences in brain energy metabolism in first episode schizophrenia: 31P-MRS chemical shift imaging at 4 Tesla.

Altered high energy and membrane metabolism, measured with phosphorus magnetic resonance spectroscopy (31P-MRS), has been inconsistently reported in schizophrenic patients in several anatomical brain regions implicated in the pathophysiology of this illness, with little attention to the effects of brain tissue type on the results. Tissue regression analysis correlates brain tissue type to measured metabolite levels, allowing for the extraction of "pure" estimated grey and white matter compartment metabolite levels. We use this tissue analysis technique on a clinical dataset of first episode schizophrenic patients and matched controls to investigate the effect of brain tissue specificity on altered energy and membrane metabolism. In vivo brain spectra from two regions, (a) the fronto-temporal-striatal region and (b) the frontal-lobes, were analyzed from 12 first episode schizophrenic patients and 11 matched controls from a (31)P chemical shift imaging (CSI) study at 4 Tesla (T) field strength. Tissue regression analyses using voxels from each region were performed relating metabolite levels to tissue content, examining phosphorus metabolite levels in grey and white matter compartments. Compared with controls, the first episode schizophrenic patient group showed significantly increased adenosine triphosphate levels (B-ATP) in white matter and decreased B-ATP levels in grey matter in the fronto-temporal-striatal region. No significant metabolite level differences were found in grey or white matter compartments in the frontal cortex. Tissue regression analysis reveals grey and white matter specific aberrations in high-energy phosphates in first episode schizophrenia. Although past studies report inconsistent regional differences in high-energy phosphate levels in schizophrenia, the present analysis suggests more widespread differences that seem to be strongly related to tissue type. Our data suggest that differences in grey and white matter tissue content between past studies may account for some of the variance in the literature.