Publications by authors named "Jeffry R Alger"

92 Publications

Cortical gyrification in children with attention deficit-hyperactivity disorder and prenatal alcohol exposure.

Drug Alcohol Depend 2021 08 18;225:108817. Epub 2021 Jun 18.

Division of Child & Adolescent Psychiatry, Jane & Terry Semel Institute for Neuroscience, University of California, Los Angeles, CA, USA.

Background: An improved understanding of the neurodevelopmental differences between attention deficit hyperactivity disorder with and without prenatal alcohol exposure (ADHD + PAE and ADHD-PAE, respectively) is needed. Herein, we evaluated gyrification (cortical folding) in children with ADHD + PAE compared to that in children with familial ADHD-PAE and typically developing (TD) children.

Methods: ADHD + PAE (n = 37), ADHD-PAE (n = 25), and TD children (n = 27), aged 8-13 years, were compared on facial morphological, neurobehavioral, and neuroimaging assessments. Local gyrification index (LGI) maps were compared between groups using general linear modelling. Relationships between LGI and clincobehavioral parameters in children with ADHD ± PAE were evaluated using multivariate partial least squares.

Results: ADHD + PAE and ADHD-PAE groups showed significantly lower LGI (relative to TD) in numerous regions, overlapping in medial prefrontal, parietal, and temporo-occipital cortices (p < 0.001). However, LGI in left mid-dorsolateral prefrontal cortex was uniquely lower in the ADHD + PAE group (p < 0.001). Partial least squares analysis identified one significant latent variable (accounting for 59.3 % of the crossblock correlation, p < 0.001), reflecting a significant relationship between a profile of lower LGI in prefrontal (including left mid-dorsolateral), insular, cingulate, temporal, and parietal cortices and a clinicobehavioral profile of PAE, including a flat philtrum and upper vermillion border, lower IQ, poorer behavioral regulation scores, and greater hyperactivity/impulsivity.

Conclusions: Children with ADHD + PAE uniquely demonstrate lower mid-dorsolateral LGI, with widespread lower LGI related to more severe facial dysmorphia and neurobehavioral impairments. These findings add insight into the brain bases of PAE symptoms, potentially informing more targeted ADHD treatments based on an objective differential diagnosis of ADHD + PAE vs. ADHD-PAE.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.108817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445068PMC
August 2021

Analysis of steady-state carbon tracer experiments using akaike information criteria.

Metabolomics 2021 06 19;17(7):61. Epub 2021 Jun 19.

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Introduction: Carbon isotope tracers have been used to determine relative rates of tricarboxylic acid cycle (TCA) cycle pathways since the 1950s. Steady-state experimental data are typically fit to a single mathematical model of metabolism to determine metabolic fluxes. Whether the chosen model is appropriate for the biological system has generally not been evaluated systematically. An overly-simple model omits known pathways while an overly-complex model may produce incorrect results due to overfitting.

Objectives: The objectives were to develop and study a method that systematically evaluates multiple TCA cycle mathematical models as part of the fitting process.

Methods: The problem of choosing overly-simple or overly-complex models was approached by developing software that automatically explores all possible combinations of flux through pyruvate dehydrogenase, pyruvate kinase, pyruvate carboxylase and anaplerosis at propionyl-CoA carboxylase, and equivalent pathways, all relative to TCA cycle flux. Typical TCA cycle metabolic tracer experiments that use C nuclear magnetic resonance for detection and quantification of C-enriched glutamate products were simulated and analyzed. By evaluating the multiple model fits with both the conventional sum-of-squares residual error (SSRE) and the Akaike Information Criterion (AIC), the software helps the investigator understand the interaction between model complexity and goodness of fit.

Results: When fitting alternative models of the TCA cycle metabolism, the SSRE may identify more than one model that fits the data well. Among those models, the AIC provides guidance as to which is the simplest of the candidate models is sufficient to describe the observed data. However under some conditions, AIC used alone inappropriately discriminates against necessary metabolic complexity.

Conclusion: In combination, the SSRE and AIC help the investigator identify the model that best describes the metabolism of a biological system.
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http://dx.doi.org/10.1007/s11306-021-01807-1DOI Listing
June 2021

Combining neuroimaging and behavior to discriminate children with attention deficit-hyperactivity disorder with and without prenatal alcohol exposure.

Brain Imaging Behav 2021 Jun 5. Epub 2021 Jun 5.

Division of Child & Adolescent Psychiatry, Jane & Terry Semel Institute for Neuroscience, University of California Los Angeles, Los Angeles, CA, USA.

In many patients, ostensible idiopathic attention deficit-hyperactivity disorder (ADHD) may actually stem from covert prenatal alcohol exposure (PAE), a treatment-relevant distinction. This study attempted a receiver-operator characteristic (ROC) classification of children with ADHD into those with PAE (ADHD+PAE) and those without (ADHD-PAE) using neurobehavioral instruments alongside magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of supraventricular brain white matter. Neurobehavioral, MRS, and DTI endpoints had been suggested by prior findings. Participants included children aged 8-13 years, 23 with ADHD+PAE, 19 with familial ADHD-PAE, and 28 typically developing (TD) controls. With area-under-the-curve (AUC) >0.90, the Conners 3 Parent Rating Scale Inattention (CIn) and Hyperactivity/Impulsivity (CHp) scores and the Behavioral Regulation Index (BRI) of the Behavior Rating Inventory of Executive Function (BRIEF2) excellently distinguished the clinical groups from TD, but not from each other (AUC < 0.70). Combinations of MRS glutamate (Glu) and N-acetyl-compounds (NAA) and DTI mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) yielded "good" (AUC > 0.80) discrimination. Neuroimaging combined with CIn and BRI achieved AUC 0.72 and AUC 0.84, respectively. But neuroimaging combined with CHp yielded 14 excellent combinations with AUC ≥ 0.90 (all p < 0.0005), the best being Glu·AD·RD·CHp/(NAA·FA) (AUC 0.92, sensitivity 1.00, specificity 0.82, p < 0.0005). Using Cho in lieu of Glu yielded AUC 0.83. White-matter microstructure and metabolism may assist efforts to discriminate ADHD etiologies and to detect PAE, beyond the ability of commonly used neurobehavioral measures alone.
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http://dx.doi.org/10.1007/s11682-021-00477-wDOI Listing
June 2021

Neuroimaging of Supraventricular Frontal White Matter in Children with Familial Attention-Deficit Hyperactivity Disorder and Attention-Deficit Hyperactivity Disorder Due to Prenatal Alcohol Exposure.

Neurotox Res 2021 Aug 22;39(4):1054-1075. Epub 2021 Mar 22.

Division of Child & Adolescent Psychiatry, Jane & Terry Semel Instutute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.

Attention-deficit hyperactivity disorder (ADHD) is common in patients with (ADHD+PAE) and without (ADHD-PAE) prenatal alcohol exposure (PAE). Many patients diagnosed with idiopathic ADHD actually have covert PAE, a treatment-relevant distinction. To improve differential diagnosis, we sought to identify brain differences between ADHD+PAE and ADHD-PAE using neurobehavioral, magnetic resonance spectroscopy, and diffusion tensor imaging metrics that had shown promise in past research. Children 8-13 were recruited in three groups: 23 ADHD+PAE, 19 familial ADHD-PAE, and 28 typically developing controls (TD). Neurobehavioral instruments included the Conners 3 Parent Behavior Rating Scale and the Delis-Kaplan Executive Function System (D-KEFS). Two dimensional magnetic resonance spectroscopic imaging was acquired from supraventricular white matter to measure N-acetylaspartate compounds, glutamate, creatine + phosphocreatine (creatine), and choline-compounds (choline). Whole brain diffusion tensor imaging was acquired and used to to calculate fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity from the same superventricular white matter regions that produced magnetic resonance spectroscopy data. The Conners 3 Parent Hyperactivity/Impulsivity Score, glutamate, mean diffusivity, axial diffusivity, and radial diffusivity were all higher in ADHD+PAE than ADHD-PAE. Glutamate was lower in ADHD-PAE than TD. Within ADHD+PAE, inferior performance on the D-KEFS Tower Test correlated with higher neurometabolite levels. These findings suggest white matter differences between the PAE and familial etiologies of ADHD. Abnormalities detected by magnetic resonance spectroscopy and diffusion tensor imaging co-localize in supraventricular white matter and are relevant to executive function symptoms of ADHD.
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http://dx.doi.org/10.1007/s12640-021-00342-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442735PMC
August 2021

The clinical utility of proton magnetic resonance spectroscopy in traumatic brain injury: recommendations from the ENIGMA MRS working group.

Brain Imaging Behav 2021 Apr;15(2):504-525

Center for Clinical Spectroscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Proton (H) magnetic resonance spectroscopy provides a non-invasive and quantitative measure of brain metabolites. Traumatic brain injury impacts cerebral metabolism and a number of research groups have successfully used this technique as a biomarker of injury and/or outcome in both pediatric and adult TBI populations. However, this technique is underutilized, with studies being performed primarily at centers with access to MR research support. In this paper we present a technical introduction to the acquisition and analysis of in vivo H magnetic resonance spectroscopy and review H magnetic resonance spectroscopy findings in different injury populations. In addition, we propose a basic H magnetic resonance spectroscopy data acquisition scheme (Supplemental Information) that can be added to any imaging protocol, regardless of clinical magnetic resonance platform. We outline a number of considerations for study design as a way of encouraging the use of H magnetic resonance spectroscopy in the study of traumatic brain injury, as well as recommendations to improve data harmonization across groups already using this technique.
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http://dx.doi.org/10.1007/s11682-020-00330-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882010PMC
April 2021

Low Dose CT Perfusion With K-Space Weighted Image Average (KWIA).

IEEE Trans Med Imaging 2020 12 30;39(12):3879-3890. Epub 2020 Nov 30.

CTP (Computed Tomography Perfusion) is widely used in clinical practice for the evaluation of cerebrovascular disorders. However, CTP involves high radiation dose (≥~200mGy) as the X-ray source remains continuously on during the passage of contrast media. The purpose of this study is to present a low dose CTP technique termed K-space Weighted Image Average (KWIA) using a novel projection view-shared averaging algorithm with reduced tube current. KWIA takes advantage of k-space signal property that the image contrast is primarily determined by the k-space center with low spatial frequencies and oversampled projections. KWIA divides each 2D Fourier transform (FT) or k-space CTP data into multiple rings. The outer rings are averaged with neighboring time frames to achieve adequate signal-to-noise ratio (SNR), while the center region of k-space remains unchanged to preserve high temporal resolution. Reduced dose sinogram data were simulated by adding Poisson distributed noise with zero mean on digital phantom and clinical CTP scans. A physical CTP phantom study was also performed with different X-ray tube currents. The sinogram data with simulated and real low doses were then reconstructed with KWIA, and compared with those reconstructed by standard filtered back projection (FBP) and simultaneous algebraic reconstruction with regularization of total variation (SART-TV). Evaluation of image quality and perfusion metrics using parameters including SNR, CNR (contrast-to-noise ratio), AUC (area-under-the-curve), and CBF (cerebral blood flow) demonstrated that KWIA is able to preserve the image quality, spatial and temporal resolution, as well as the accuracy of perfusion quantification of CTP scans with considerable (50-75%) dose-savings.
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http://dx.doi.org/10.1109/TMI.2020.3006461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704693PMC
December 2020

Dorsolateral prefrontal γ-aminobutyric acid in patients with treatment-resistant depression after transcranial magnetic stimulation measured with magnetic resonance spectroscopy

J Psychiatry Neurosci 2019 Nov;44(6):386-394

From the Neuromodulation Division, Semel Institute for Neuroscience and Human Behavior at UCLA, Los Angeles (Levitt, Diaz, Cook, Ginder, Krantz, Minzenberg, Vince-Cruz, Nguyen, Leuchter); the Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles (Levitt, Kalender, O’Neill, Cook, Krantz, Minzenberg, Leuchter); the Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles (Kalender); the Division of Child and Adolescent Psychiatry, Semel Institute for Neuroscience and Human Behavior at UCLA, Los Angeles (Levitt, O’Neill); the Department of Bioengineering, Henry Samueli School of Engineering at Applied Science at UCLA, Los Angeles (Cook); the Department of Neurology, UCLA David Geffen School of Medicine at UCLA, Los Angeles (Alger); the Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas (Alger); and the NeuroSpectroScopics, LCC, Sherman Oaks, California (Alger).

Background: The therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC).

Methods: In 26 adults with TRD, we used Mescher–Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents.

Results: Mean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment.

Limitations: This study had an open-label design in a population receiving naturalistic treatment.

Conclusion: Treatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.
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http://dx.doi.org/10.1503/jpn.180230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821508PMC
November 2019

Progressive brain atrophy in chronically infected and treated HIV+ individuals.

J Neurovirol 2019 06 14;25(3):342-353. Epub 2019 Feb 14.

Department of Public Health, Infection Unit, Tufts University School of Medicine, Boston, MA, USA.

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.
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http://dx.doi.org/10.1007/s13365-019-00723-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635004PMC
June 2019

N-Acetyl and Glutamatergic Neurometabolites in Perisylvian Brain Regions of Methamphetamine Users.

Int J Neuropsychopharmacol 2019 01;22(1):1-9

Laboratory of Molecular Neuroimaging, Semel Institute for Neuroscience and Human Behavior and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, California.

Background: Methamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms.

Methods: Magnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety.

Results: In right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47).

Conclusions: The inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users.
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http://dx.doi.org/10.1093/ijnp/pyy042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313110PMC
January 2019

Whole Brain Magnetic Resonance Spectroscopic Determinants of Functional Outcomes in Pediatric Moderate/Severe Traumatic Brain Injury.

J Neurotrauma 2018 07 18;35(14):1637-1645. Epub 2018 May 18.

11 Departments of Psychology and Psychiatry and Brain Research Institute , David Geffen School of Medicine, Los Angeles, California.

Diffuse axonal injury contributes to the long-term functional morbidity observed after pediatric moderate/severe traumatic brain injury (msTBI). Whole-brain proton magnetic resonance echo-planar spectroscopic imaging was used to measure the neurometabolite levels in the brain to delineate the course of disruption/repair during the first year post-msTBI. The association between metabolite biomarkers and functional measures (cognitive functioning and corpus callosum [CC] function assessed by interhemispheric transfer time [IHTT] using an event related potential paradigm) was also explored. Pediatric patients with msTBI underwent assessments at two times (post-acutely at a mean of three months post-injury, n = 31, and chronically at a mean of 16 months post-injury, n = 24). Healthy controls also underwent two evaluations, approximately 12 months apart. Post-acutely, in patients with msTBI, there were elevations in choline (Cho; marker for inflammation and/or altered membrane metabolism) in all four brain lobes and the CC and decreases in N-acetylaspartate (NAA; marker for neuronal and axonal integrity) in the CC compared with controls, all of which normalized by the chronic time point. Subgroups of TBI showed variable patterns chronically. Patients with slow IHTT had lower lobar Cho chronically than those with normal IHTT; they also did not show normalization in CC NAA whereas those with normal IHTT showed significantly higher levels of CC NAA relative to controls. In the normal IHTT group only, chronic CC Cho and NAA together explained 70% of the variance in long-term cognitive functioning. MR based whole brain metabolic evaluations show different patterns of neurochemistry after msTBI in two subgroups with different outcomes. There is a dynamic relationship between prolonged inflammatory responses to brain damage, reparative processes/remyelination, and subsequent neurobehavioral outcomes. Multimodal studies allow us to test hypotheses about degenerative and reparative processes in patient groups that have divergent functional outcome, with the ultimate goal of developing targeted therapeutic agents.
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http://dx.doi.org/10.1089/neu.2017.5366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016095PMC
July 2018

tcaSIM: A Simulation Program for Optimal Design of C Tracer Experiments for Analysis of Metabolic Flux by NMR and Mass Spectroscopy.

Curr Metabolomics 2018 ;6(3):176-187

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Increasingly sophisticated instrumentation for chemical separations and identification has facilitated rapid advancements in our understanding of the metabolome. Since many analyses are performed using either mass spectroscopy (MS) or nuclear magnetic resonance (NMR) spectroscopy, the spin ½ stable C isotope is now widely used as a metabolic tracer. There is strong interest in quantitative analysis of metabolic flux through pathways , particularly in human patients. Although instrumentation advances and scientific interests in metabolism are increasing in parallel, a practical and rational design of a C tracer study can be challenging. Prior to planning the details of a tracer experiment, is it important to consider whether the analytical results will be sensitive to flux through the pathways of interest. Here, we briefly summarize the various approaches that have been used to design carbon tracer experiments, outline the sources of complexity, and illustrate the use of a software tool, tcaSIM, to aid in the experimental design of both MS and NMR data in complex systems including patients.
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http://dx.doi.org/10.2174/2213235X07666181219115856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863451PMC
January 2018

Glutamate in Pediatric Obsessive-Compulsive Disorder and Response to Cognitive-Behavioral Therapy: Randomized Clinical Trial.

Neuropsychopharmacology 2017 Nov 4;42(12):2414-2422. Epub 2017 Apr 4.

Division of Child and Adolescent Psychiatry, UCLA Semel Institute for Neuroscience, Los Angeles, CA, USA.

Cognitive-behavioral therapy (CBT) is effective for pediatric obsessive-compulsive disorder (OCD), but non-response is common. Brain glutamate (Glu) signaling may contribute to OCD pathophysiology and moderate CBT outcomes. We assessed whether Glu measured with magnetic resonance spectroscopy (MRS) was associated with OCD and/or CBT response. Youths aged 7-17 years with DSM-IV OCD and typically developing controls underwent 3 T proton echo-planar spectroscopic imaging (PEPSI) MRS scans of pregenual anterior cingulate cortex (pACC) and ventral posterior cingulate cortex (vPCC)-regions possibly affected by OCD-at baseline. Controls returned for re-scan after 8 weeks. OCD youth-in a randomized rater-blinded trial-were re-scanned after 12-14 weeks of CBT or after 8 weeks of minimal-contact waitlist; waitlist participants underwent a third scan after crossover to 12-14 weeks of CBT. Forty-nine children with OCD (mean age 12.2±2.9 years) and 29 controls (13.2±2.2 years) provided at least one MRS scan. At baseline, Glu did not differ significantly between OCD and controls in pACC or vPCC. Within controls, Glu was stable from scan-to-scan. Within OCD subjects, a treatment-by-scan interaction (p=0.034) was observed, driven by pACC Glu dropping 19.5% from scan-to-scan for patients randomized to CBT, with minor increases (3.8%) for waitlist participants. The combined OCD participants (CBT-only plus waitlist-CBT) also showed a 16.2% (p=0.004) post-CBT decrease in pACC Glu. In the combined OCD group, within vPCC, lower pre-CBT Glu predicted greater post-CBT improvement in symptoms (CY-BOCS; r=0.81, p=0.00025). Glu may be involved in the pathophysiology of OCD and may moderate response to CBT.
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http://dx.doi.org/10.1038/npp.2017.77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645751PMC
November 2017

Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability.

Endocrinology 2017 04;158(4):936-949

Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center at the UCLA Children's Discovery and Innovation Institute, Los Angeles, California, U.S.A.

We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.
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http://dx.doi.org/10.1210/en.2016-1816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460805PMC
April 2017

Multisite, multimodal neuroimaging of chronic urological pelvic pain: Methodology of the MAPP Research Network.

Neuroimage Clin 2016 6;12:65-77. Epub 2016 Jan 6.

UCLA Brain Research Institute, David Geffen School of Medicine at UCLA, USA; UCLA Ahmanson-Lovelace Brain Mapping Center, David Geffen School of Medicine at UCLA, USA; Department of Internal Medicine, David Geffen School of Medicine at UCLA, USA; Oppenheimer Center for Neurobiology of Stress at UCLA, David Geffen School of Medicine at UCLA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, USA.

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.
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http://dx.doi.org/10.1016/j.nicl.2015.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925887PMC
November 2017

Cingulate and thalamic metabolites in obsessive-compulsive disorder.

Psychiatry Res Neuroimaging 2016 Aug 24;254:34-40. Epub 2016 May 24.

Division of Adult Psychiatry, UCLA Semel Institute for Neuroscience, Los Angeles, CA, United States.

Focal brain metabolic effects detected by proton magnetic resonance spectroscopy (MRS) in obsessive-compulsive disorder (OCD) represent prospective indices of clinical status and guides to treatment design. Sampling bilateral pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and thalamus in 40 adult patients and 16 healthy controls, we examined relationships of the neurometabolites glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), and choline-compounds (Cho) with OCD diagnosis and multiple symptom types. The latter included OC core symptoms (Yale-Brown Obsessive-Compulsive Scale - YBOCS), depressive symptoms (Montgomery-Åsberg Depression Rating Scale - MADRS), and general functioning (Global Assessment Scale - GAS). pACC Glx was 9.7% higher in patients than controls. Within patients, Cr and Cho correlated negatively with YBOCS and MADRS, while Cr correlated positively with the GAS. In aMCC, Cr and Cho correlated negatively with MADRS, while Cr in thalamus correlated positively with GAS. These findings present moderate support for glutamatergic and cingulocentric perspectives on OCD. Based on our prior metabolic model of OCD, we offer one possible interpretation of these group and correlational effects as consequences of a corticothalamic state of elevated glutamatergic receptor activity alongside below-normal glutamatergic transporter activity.
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http://dx.doi.org/10.1016/j.pscychresns.2016.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780184PMC
August 2016

Traumatic hemorrhagic brain injury: impact of location and resorption on cognitive outcome.

J Neurosurg 2017 Mar 27;126(3):796-804. Epub 2016 May 27.

Departments of 1 Neurosurgery.

OBJECTIVE Hemorrhagic contusions are often the most visible lesions following traumatic brain injury. However, the incidence, location, and natural history of traumatic parenchymal hemorrhage and its impact on neurological outcome have been understudied. The authors sought to examine the location and longitudinal evolution of traumatic parenchymal hemorrhage and its association with cognitive outcome. METHODS Sixteen patients with hemorrhagic contusions due to acceleration-deceleration injuries underwent MRI in the acute (mean 6.3 days postinjury) and chronic (mean 192.9 days postinjury) phases. ImageJ was used to generate GRE and FLAIR volumes. To account for the effect of head-size variability across individuals, the authors calculated each patient's total brain tissue volume using SIENAX. GRE and FLAIR volumes were normalized to the total brain tissue volume, and values for absolute and percent lesion volume and total brain volume change were generated. Spearman's rank correlations were computed to determine associations between neuroimaging and 6-month postinjury neuropsychological testing of attention (Symbol Digit Modalities Test [SDMT], oral [O] and written [W] versions), memory (Selective Reminding Test, total learning and delayed recall), and executive function (Trail Making Test Part B [TMT-B]). RESULTS The patients' mean age was 31.4 ± 14.0 years and their mean Glasgow Coma Scale score at admission was 7.9 ± 2.8. Lesions were predominantly localized to the frontal (11 lesions) and temporal (9 lesions) lobes. The average percent reductions in GRE and FLAIR volumes were 44.2% ± 46.1% and 80.5% ± 26.3%, respectively. While total brain and frontal lesion volumes did not correlate with brain atrophy, larger temporal lobe GRE and FLAIR volumes were associated with larger volumes of atrophy (GRE: acute, -0.87, p < 0.01, chronic, -0.78, p < 0.01; FLAIR: acute, -0.81, p < 0.01, chronic, -0.88, p < 0.01). Total percent volume change of GRE lesions correlated with TMT-B (0.53, p < 0.05) and SDMT-O (0.62, p < 0.05) scores. Frontal lobe lesion volume did not correlate with neuropsychological outcome. However, robust relationships were seen in the temporal lobe, with larger acute temporal lobe GRE volumes were associated with worse scores on both oral and written versions of the SDMT (SDMT-W, -0.85, p < 0.01; SDMT-O, -0.73, p < 0.05). Larger absolute change in temporal GRE volume was strongly associated with worse SDMT scores (SDMT-W, 0.88, p < 0.01; SDMT-O, 0.75, p < 0.05). The same relationships were also seen between temporal FLAIR lesion volumes and neuropsychological outcome. CONCLUSIONS Traumatic parenchymal hemorrhages are largely clustered in the frontal and temporal lobes, and significant residual blood products are present at 6 months postinjury, a potential source of ongoing secondary brain injury. Neuropsychological outcome is closely tied to lesion volume size, particularly in the temporal lobe, where larger GRE and FLAIR volumes are associated with more brain atrophy and worse SDMT scores. Interestingly, larger volumes of hemorrhage resorption were associated with worse SDMT and TMT-B scores, suggesting that the initial tissue damage had a lasting impact on attention and executive function.
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http://dx.doi.org/10.3171/2016.3.JNS151781DOI Listing
March 2017

Plasma and Cerebrospinal Fluid Biomarkers Predict Cerebral Injury in HIV-Infected Individuals on Stable Combination Antiretroviral Therapy.

J Acquir Immune Defic Syndr 2015 May;69(1):29-35

*Emory University, Atlanta, GA; †Indiana University, Indianapolis, IN; ‡University of California, San Diego, San Diego, CA; §University of California, Los Angeles, CA; ‖University of Rochester School of Medicine, Rochester, NY; ¶University of Colorado Medical Center, Denver, CO; #University of Pittsburgh, Pittsburgh, PA; **University of Hawaii, Honolulu, HI; ††University of Florida, Gainesville, FL; and ‡‡Tufts University School of Medicine, Boston, MA.

Objectives: HIV-associated brain injury persists despite combination antiretroviral therapy, but contributing factors remain poorly understood. We postulated that inflammation-associated biomarkers will be associated with cerebral injury on proton magnetic resonance spectroscopy in chronically HIV-infected subjects.

Methods: Five biomarkers were measured in 197 HIV-infected subjects: soluble CD14, MCP-1, IP-10, MIP-1β, and fractalkine. Levels of N-acetyl aspartate (NAA), Choline (Cho), Myoinositol (MI), Glutamate + Glutamine (Glx), and Creatine (Cr) were acquired in the midfrontal cortex (MFC), frontal white matter, and basal ganglia (BG). Predictive models were built through linear regression, and the best models were chosen using the Akaike Information Criterion.

Results: Increases in plasma or CSF MCP-1 were associated with lower NAA/Cr in the MFC and BG, whereas metabolite changes in the frontal white matter for NAA/Cr, GlxCr, and Cho/Cr were explained almost exclusively by a single factor, sCD14. Plasma and CSF levels of this factor were also significantly associated with Glx/Cr in MFC and BG. Higher CSF FKN was associated with higher NAA/Cr in BG. Best predictors for higher Cho/Cr in BG and MFC were CSF sCD14 and CSF MIP-1β. Plasma and CSF IP-10 were only associated with Cho/Cr in MFC. Of the 3 models that simultaneously accounted for both plasma and CSF, there were more associations between CSF biomarkers and magnetic resonance spectroscopy metabolites.

Conclusions: Markers of inflammation and immune activation, in particular MCP-1 and sCD14, predominantly reflecting CNS sources, contribute to the persistence of brain injury in a metabolite and region-dependent manner in chronically HIV-infected patients on stable combination antiretroviral therapy.
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http://dx.doi.org/10.1097/QAI.0000000000000532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424074PMC
May 2015

Relationship between hippocampal atrophy and neuropathology markers: a 7T MRI validation study of the EADC-ADNI Harmonized Hippocampal Segmentation Protocol.

Alzheimers Dement 2015 Feb 22;11(2):139-50. Epub 2015 Jan 22.

LENITEM (Laboratory of Epidemiology, Neuroimaging and Telemedicine), IRCCS S.Giovanni di Dio- Fatebenefratelli, Brescia, Italy; University Hospitals and University of Geneva, Geneva, Switzerland.

Objective: The pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).

Methods: Temporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aβ, and tau burden for each hippocampal subfield were obtained.

Results: We found significant correlations between hippocampal volume and Braak and Braak staging (ρ = -0.75, P = .001), tau (ρ = -0.53, P = .034), Aβ burden (ρ = -0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield-wise significant associations were found for Aβ in Cornu Ammonis (CA)1 (ρ = -0.58, P = .019) and subiculum (ρ = -0.75, P = .001), tau in CA2 (ρ = -0.59, P = .016), and CA3 (ρ = -0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001).

Conclusions: The observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.
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http://dx.doi.org/10.1016/j.jalz.2015.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348340PMC
February 2015

Postischemic hyperperfusion on arterial spin labeled perfusion MRI is linked to hemorrhagic transformation in stroke.

J Cereb Blood Flow Metab 2015 Mar 31;35(4):630-7. Epub 2015 Mar 31.

1] Department of Neurology, UCLA, Los Angeles, California, USA [2] Department of Radiology, UCLA, Los Angeles, California, USA.

The purpose of this study was to investigate the relationship between hyperperfusion and hemorrhagic transformation (HT) in acute ischemic stroke (AIS). Pseudo-continuous arterial spin labeling (ASL) with background suppressed 3D GRASE was performed during routine clinical magnetic resonance imaging (MRI) on AIS patients at various time points. Arterial spin labeling cerebral blood flow (CBF) maps were visually inspected for the presence of hyperperfusion. Hemorrhagic transformation was followed during hospitalization and was graded on gradient recalled echo (GRE) scans into hemorrhagic infarction (HI) and parenchymal hematoma (PH). A total of 361 ASL scans were collected from 221 consecutive patients with middle cerebral artery stroke from May 2010 to September 2013. Hyperperfusion was more frequently detected posttreatment (odds ratio (OR) = 4.8, 95% confidence interval (CI) 2.5 to 8.9, P < 0.001) and with high National Institutes of Health Stroke Scale (NIHSS) scores at admission (P<0.001). There was a significant association between having hyperperfusion at any time point and HT (OR = 3.5, 95% CI 2.0 to 6.3, P < 0.001). There was a positive relationship between the grade of HT and time-hyperperfusion with the Spearman's rank correlation of 0.44 (P = 0.003). Arterial spin labeling hyperperfusion may provide an imaging marker of HT, which may guide the management of AIS patients post tissue-type plasminogen activator (tPA) and/or endovascular treatments. Late hyperperfusion should be given more attention to prevent high-grade HT.
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http://dx.doi.org/10.1038/jcbfm.2014.238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420881PMC
March 2015

Multivendor implementation and comparison of volumetric whole-brain echo-planar MR spectroscopic imaging.

Magn Reson Med 2015 Nov 29;74(5):1209-20. Epub 2014 Oct 29.

Department of Radiology, University of Miami, Miami, Florida, USA.

Purpose: To assess volumetric proton MR spectroscopic imaging (MRSI) of the human brain on multivendor MRI instruments.

Methods: Echo-planar spectroscopic imaging was developed on instruments from three manufacturers, with matched specifications and acquisition protocols that accounted for differences in sampling performance, radiofrequency (RF) power, and data formats. Intersite reproducibility was evaluated for signal-normalized maps of N-acetylaspartate (NAA), creatine (Cre), and choline using phantom and human subject measurements. Comparative analyses included metrics for spectral quality, spatial coverage, and mean values in atlas-registered brain regions.

Results: Intersite differences for phantom measurements were less than 1.7% for individual metabolites and less than 0.2% for ratio measurements. Spatial uniformity ranged from 79% to 91%. The human studies found differences of mean values in the temporal lobe, but good agreement in other white matter regions, with maximum differences relative to their mean of under 3.2%. For NAA/Cre, the maximum difference was 1.8%. In gray matter, a significant difference was observed for frontal lobe NAA. Primary causes of intersite differences were attributed to shim quality, B0 drift, and accuracy of RF excitation. Correlation coefficients for measurements at each site were over 0.60, indicating good reliability.

Conclusion: A volumetric intensity-normalized MRSI acquisition can be implemented in a comparable manner across multivendor MR instruments.
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http://dx.doi.org/10.1002/mrm.25510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414683PMC
November 2015

Clinical proton MR spectroscopy in central nervous system disorders.

Radiology 2014 Mar;270(3):658-79

From the Center for Magnetic Resonance Research, University of Minnesota, 2021 6th St SE, Minneapolis, MN 55455 (G.O.).

A large body of published work shows that proton (hydrogen 1 [(1)H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of (1)H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of (1)H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which (1)H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units.
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http://dx.doi.org/10.1148/radiol.13130531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263653PMC
March 2014

Multi-delay arterial spin labeling perfusion MRI in moyamoya disease--comparison with CT perfusion imaging.

Eur Radiol 2014 May 21;24(5):1135-44. Epub 2014 Feb 21.

State Key Laboratory of Brain and Cognitive Science, Beijing MRI Center for Brain Research, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China.

Objectives: To present a multi-delay pseudo-continuous ASL (pCASL) protocol that offers simultaneous measurements of cerebral blood flow (CBF) and arterial transit time (ATT), and to study correlations between multi-delay pCASL and CT perfusion in moyamoya disease.

Methods: A 4 post-labeling delay (PLD) pCASL protocol was applied on 17 patients with moyamoya disease who also underwent CT perfusion imaging. ATT was estimated using the multi-delay protocol and included in the calculation of CBF. ASL and CT perfusion images were rated for lesion severity/conspicuity. Pearson correlation coefficients were calculated across voxels between the two modalities in grey and white matter of each subject respectively and between normalized mean values of ASL and CT perfusion measures in major vascular territories.

Results: Significant associations between ASL and CT perfusion were detected using subjective ratings, voxel-wise analysis in grey and white matter and region of interest (ROI)-based analysis of normalized mean perfusion. The correlation between ASL CBF and CT perfusion was improved using the multi-delay pCASL protocol compared to CBF acquired at a single PLD of 2 s (P < 0.05).

Conclusions: There is a correlation between perfusion data from ASL and CT perfusion imaging in patients with moyamoya disease. Multi-delay ASL can improve CBF quantification, which could be a prognostic imaging biomarker in patients with moyamoya disease.

Key Points: • Simultaneous measurements of CBF and ATT can be achieved using multi-delay pCASL. • Multi-delay ASL was compared with CT perfusion in patients with moyamoya disease. • Statistical analyses showed significant associations between multi-delay ASL and CT perfusion. • Multi-delay ASL can improve CBF quantification in moyamoya disease.
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http://dx.doi.org/10.1007/s00330-014-3098-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143230PMC
May 2014

Disrupted cerebral metabolite levels and lower nadir CD4 + counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatment.

Neuroimage Clin 2013 3;3:132-42. Epub 2013 Aug 3.

Imaging Genetics Center, Laboratory of Neuro Imaging, Dept. of Neurology, UCLA School of Medicine, Los Angeles, CA, USA.

Cognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV + patients scanned with whole-brain MRI at 1.5 T (mean age: 48.6 ± 8.4 years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4 + count, with a 1-2% white matter volume reduction for each 25-point reduction in nadir CD4 +. Even so, brain volume measured by TBM showed no detectable association with current CD4 + count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex - were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage.
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http://dx.doi.org/10.1016/j.nicl.2013.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791291PMC
November 2013

Multi-delay multi-parametric arterial spin-labeled perfusion MRI in acute ischemic stroke - Comparison with dynamic susceptibility contrast enhanced perfusion imaging.

Neuroimage Clin 2013 6;3:1-7. Epub 2013 Jul 6.

Department of Neurology, UCLA, Los Angeles, CA, USA ; Department of Radiology, UCLA, Los Angeles, CA, USA.

The purpose of the present study was to present a multi-delay multi-parametric pseudo-continuous arterial spin labeling (pCASL) protocol with background suppressed 3D GRASE (gradient and spin echo) readout for perfusion imaging in acute ischemic stroke. PCASL data at 4 post-labeling delay times (PLD = 1.5, 2, 2.5, 3 s) were acquired within 4.5 min in 24 patients (mean age 79.7 ± 11.4 years; 11 men) with acute middle cerebral artery (MCA) stroke who also underwent dynamic susceptibility contrast (DSC) enhanced perfusion imaging. Arterial transit times (ATT) were estimated through the calculation of weighted delays across the 4 PLDs, which were included in the calculation of cerebral blood flow (CBF) and arterial cerebral blood volume (CBV). Mean perfusion parameters derived using pCASL and DSC were measured within MCA territories and infarct regions identified on diffusion weighted MRI. The results showed highly significant correlations between pCASL and DSC CBF measurements (r > = 0.70, p < = 0.0001) and moderately significant correlations between pCASL and DSC CBV measurements (r > = 0.45, p < = 0.027) in both MCA territories and infarct regions. ASL ATT showed correlations with DSC time to the maximum of tissue residual function (Tmax)(r = 0.66, p = 0.0005) and mean transit time (MTT)(r = 0.59, p = 0.0023) in leptomeningeal MCA territories. The present study demonstrated the feasibility for noninvasive multi-parametric perfusion imaging using ASL for acute stroke imaging.
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http://dx.doi.org/10.1016/j.nicl.2013.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791289PMC
October 2013

Ensemble segmentation for GBM brain tumors on MR images using confidence-based averaging.

Med Phys 2013 Sep;40(9):093502

TeraRecon Inc., 4000 East 3rd Avenue, Suite 200, Foster City, California 94404, USA.

Purpose: Ensemble segmentation methods combine the segmentation results of individual methods into a final one, with the goal of achieving greater robustness and accuracy. The goal of this study was to develop an ensemble segmentation framework for glioblastoma multiforme tumors on single-channel T1w postcontrast magnetic resonance images.

Methods: Three base methods were evaluated in the framework: fuzzy connectedness, GrowCut, and voxel classification using support vector machine. A confidence map averaging (CMA) method was used as the ensemble rule.

Results: The performance is evaluated on a comprehensive dataset of 46 cases including different tumor appearances. The accuracy of the segmentation result was evaluated using the F1-measure between the semiautomated segmentation result and the ground truth.

Conclusions: The results showed that the CMA ensemble result statistically approximates the best segmentation result of all the base methods for each case.
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http://dx.doi.org/10.1118/1.4817475DOI Listing
September 2013

Clinical utility of magnetic resonance spectroscopy to enhance diagnosis of HIV-associated mild neurocognitive disorder.

Neuropsychiatry (London) 2012 Oct;2(5):379-383

Department of Mental Health, AIDS Healthcare Foundation (AHF), 6255 W Sunset Boulevard, 21st Floor, Los Angeles, CA 90028, USA.

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http://dx.doi.org/10.2217/npy.12.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652484PMC
October 2012

Early metabolic crisis-related brain atrophy and cognition in traumatic brain injury.

Brain Imaging Behav 2013 Sep;7(3):307-15

Los Angeles Biomedical Research Institute, Psychology Division, Department of Psychiatry, Harbor-University of California, Los Angeles Medical Center, 1124 W. Carson St., B-4 South (Box 490), Torrance, CA, 90502, USA,

Traumatic brain injury often results in acute metabolic crisis. We recently demonstrated that this is associated with chronic brain atrophy, which is most prominent in the frontal and temporal lobes. Interestingly, the neuropsychological profile of traumatic brain injury is often characterized as 'frontal-temporal' in nature, suggesting a possible link between acute metabolic crisis-related brain atrophy and neurocognitive impairment in this population. While focal lesions and diffuse axonal injury have a well-established role in the neuropsychological deficits observed following traumatic brain injury, no studies to date have examined the possible contribution of acute metabolic crisis-related atrophy in the neuropsychological sequelae of traumatic brain injury. In the current study we employed positron emission tomography, magnetic resonance imaging, and neuropsychological assessments to ascertain the relationship between acute metabolic crisis-related brain atrophy and neurocognitive outcome in a sample of 14 right-handed traumatic brain injury survivors. We found that acute metabolic crisis-related atrophy in the frontal and temporal lobes was associated with poorer attention, executive functioning, and psychomotor abilities at 12 months post-injury. Furthermore, participants with gross frontal and/or temporal lobe atrophy exhibited numerous clinically significant neuropsychological deficits in contrast to participants with other patterns of brain atrophy. Our findings suggest that interventions that reduce acute metabolic crisis may lead to improved functional outcomes for traumatic brain injury survivors.
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http://dx.doi.org/10.1007/s11682-013-9231-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172457PMC
September 2013

Multi-center prediction of hemorrhagic transformation in acute ischemic stroke using permeability imaging features.

Magn Reson Imaging 2013 Jul 13;31(6):961-9. Epub 2013 Apr 13.

Department of Neurology, University of California, LA, USA.

Permeability images derived from magnetic resonance (MR) perfusion images are sensitive to blood-brain barrier derangement of the brain tissue and have been shown to correlate with subsequent development of hemorrhagic transformation (HT) in acute ischemic stroke. This paper presents a multi-center retrospective study that evaluates the predictive power in terms of HT of six permeability MRI measures including contrast slope (CS), final contrast (FC), maximum peak bolus concentration (MPB), peak bolus area (PB), relative recirculation (rR), and percentage recovery (%R). Dynamic T2*-weighted perfusion MR images were collected from 263 acute ischemic stroke patients from four medical centers. An essential aspect of this study is to exploit a classifier-based framework to automatically identify predictive patterns in the overall intensity distribution of the permeability maps. The model is based on normalized intensity histograms that are used as input features to the predictive model. Linear and nonlinear predictive models are evaluated using a cross-validation to measure generalization power on new patients and a comparative analysis is provided for the different types of parameters. Results demonstrate that perfusion imaging in acute ischemic stroke can predict HT with an average accuracy of more than 85% using a predictive model based on a nonlinear regression model. Results also indicate that the permeability feature based on the percentage of recovery performs significantly better than the other features. This novel model may be used to refine treatment decisions in acute stroke.
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http://dx.doi.org/10.1016/j.mri.2013.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676704PMC
July 2013

A trial of imaging selection and endovascular treatment for ischemic stroke.

N Engl J Med 2013 Mar 8;368(10):914-23. Epub 2013 Feb 8.

Department of Neurology and the Stroke Center, Georgetown University, Washington, DC 20007, USA.

Background: Whether brain imaging can identify patients who are most likely to benefit from therapies for acute ischemic stroke and whether endovascular thrombectomy improves clinical outcomes in such patients remains unclear.

Methods: In this study, we randomly assigned patients within 8 hours after the onset of large-vessel, anterior-circulation strokes to undergo mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. All patients underwent pretreatment computed tomography or magnetic resonance imaging of the brain. Randomization was stratified according to whether the patient had a favorable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core or small or absent penumbra). We assessed outcomes using the 90-day modified Rankin scale, ranging from 0 (no symptoms) to 6 (dead).

Results: Among 118 eligible patients, the mean age was 65.5 years, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbral pattern. Revascularization in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups. Among all patients, mean scores on the modified Rankin scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P=0.99). Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P=0.32). In the primary analysis of scores on the 90-day modified Rankin scale, there was no interaction between the pretreatment imaging pattern and treatment assignment (P=0.14).

Conclusions: A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care. (Funded by the National Institute of Neurological Disorders and Stroke; MR RESCUE ClinicalTrials.gov number, NCT00389467.).
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http://dx.doi.org/10.1056/NEJMoa1212793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690785PMC
March 2013
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