Publications by authors named "Dima A Hammoud"

72 Publications

Global and regional brain hypometabolism on FDG-PET in treated HIV-infected individuals.

Neurology 2018 10 26;91(17):e1591-e1601. Epub 2018 Sep 26.

From the Center for Infectious Disease Imaging, Radiology and Imaging Sciences (D.A.H., S. Sinharay), Clinical Center, National Institute of Neurological Diseases and Stroke (S. Steinbach, K.G., B.R.S., A.N.), Biostatistics and Clinical Epidemiology Service (P.G.W.), Clinical Center, National Institute of Mental Health (K.T., J.S.), National Heart, Lung, and Blood Institute (A.K.D., N.N.M.), National Institute for Allergy and Infectious Diseases (E.T.), and National Institute on Alcohol Abuse and Alcoholism (S.I.R.), NIH, Bethesda, MD.

Objective: To quantitatively measure brain glucose metabolism in treated HIV-positive individuals with [F]-labeled fluorodeoxyglucose (FDG) PET/CT.

Methods: We performed a cross-sectional comparison of FDG uptake in 47 treated HIV+ individuals, 10 age-matched controls (HIV-) sharing many of the comorbid conditions seen in the HIV+ group, and 19 age-matched healthy controls (HCs). We compared whole-brain (WB) and regional FDG standardized uptake values (SUVs) of select subcortical/central structures among the groups and correlated the values to clinical and neuropsychological assessments. A variable selection model was used to predict SUVs in HIV+ (n = 47) and in combined HIV+ and HIV- participants (n = 57).

Results: We found lower WB SUVmax in HIV+ participants compared to HCs but not to HIV- participants. Among the relative SUVmean measurements (regional SUVmean/WB SUVmean), only relative thalamic uptake values were lower in HIV+ compared to HIV- participants. When HIV+ and HIV- participants were grouped, cardiovascular disease risk scores best predicted WB SUVmean and SUVmax, while HIV status best predicted thalamic relative SUVmean.

Conclusions: We identified an important role for cardiovascular disease in neuronal loss/dysfunction, as measured by FDG-PET, in treated HIV+ patients. This underscores the need for shifting the focus of clinical intervention in this vulnerable population from HIV effects alone to a wider set of comorbid conditions, mainly cardiovascular disease. Only the thalamus showed significantly lower relative uptake in the HIV+ compared to the HC and HIV- groups. This needs to be further evaluated for underlying pathophysiology and potential association with memory, executive functioning, and attention deficits seen in the HIV+ population.
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http://dx.doi.org/10.1212/WNL.0000000000006398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205691PMC
October 2018

Increased Metabolic Activity on 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography in Human Immunodeficiency Virus-Associated Immune Reconstitution Inflammatory Syndrome.

Clin Infect Dis 2019 01;68(2):229-238

Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda.

Background: Immune reconstitution inflammatory syndrome (IRIS) represents an unexpected inflammatory response shortly after initiation of antiretroviral therapy (ART) in some human immunodeficiency virus (HIV)-infected patients with underlying neoplasia or opportunistic infections, including tuberculosis. We hypothesized that IRIS is associated with increased glycolysis and that 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) could help identify high-risk subjects.

Methods: In this prospective cohort study, 30 HIV-infected patients (CD4+ count <100 cells/µL) underwent FDG-PET/CT scans at baseline and 4-8 weeks after ART initiation. Ten patients developed IRIS (6 mycobacterial).

Results: At baseline, total glycolytic activity, total lesion volume, and maximum standardized uptake values (SUVs) of pathologic FDG uptake (reflective of opportunistic disease burden) were significantly higher in IRIS vs non-IRIS (P = .010, .017, and .029, respectively) and significantly correlated with soluble inflammatory biomarkers (interferon-γ, myeloperoxidase, tumor necrosis factor, interleukin 6, soluble CD14). Baseline bone marrow (BM) and spleen FDG uptake was higher in mycobacterial IRIS specifically. After ART initiation, BM and spleen mean SUV decreased in non-IRIS (P = .004, .013) but not IRIS subjects. Our results were supported by significantly higher glucose transporter 1 (Glut-1) expression of CD4+ cells and monocytes after ART initiation in IRIS/mycobacterial IRIS compared with non-IRIS patients.

Conclusions: We conclude that increased pathologic metabolic activity on FDG-PET/CT prior to ART initiation is associated with IRIS development and correlates with inflammatory biomarkers. Abnormally elevated BM and spleen metabolism is associated with mycobacterial IRIS, HIV viremia, and Glut-1 expression on CD4+ cells and monocytes.

Clinical Trials Registration: NCT02147405.
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http://dx.doi.org/10.1093/cid/ciy454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321853PMC
January 2019

Carotid magnetic resonance imaging in persons living with HIV and 10-year atherosclerotic cardiovascular disease risk score.

Antivir Ther 2018 ;23(8):695-698

Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD, USA.

Background: Both traditional and HIV-specific risk factors contribute to greater incidence of cardiovascular disease in persons living with HIV (PLWH). Using state-of-the-art, high-resolution magnetic resonance (MR) imaging of the common carotid arteries, this study aimed to evaluate the relationship between carotid vessel wall thickness (c-VWT) and atherosclerotic cardiovascular disease (ASCVD) risk score in PLWH.

Methods: Cross-sectional determinations of c-VWT using MR imaging in virally suppressed PLWH without known cardiovascular disease (n=32) and matched controls (n=13) were completed. Clinical data, including ASCVD risk and c-VWT, were compared between groups and regression analyses performed to identify predictors of c-VWT.

Results: PLWH had significantly higher c-VWT (1.15 ±0.11 mm versus 1.08 ±0.08 mm; P=0.02) as well as higher diastolic blood pressure compared to controls, but exhibited no differences in 10-year ASCVD risk score, systolic blood pressure or smoking. Ten-year ASCVD risk score (r=0.53, P-value =0.0002), age (r=0.30, P-value <0.05), triglycerides (r=0.33, P-value =0.03) and waist circumference (r=0.36, P-value =0.02) were significantly associated with increased c-VWT. Among PLWH, c-VWT did not differ by protease inhibitor use. In a multivariate regression analysis, ASCVD risk score was the only variable significantly associated with c-VWT (P-value =0.02), whereas, HIV status was not.

Conclusions: In this cross-sectional study MR imaging demonstrated that c-VWT, a known marker for CVD risk, was increased in PLWH relative to controls, and that 10-year ASCVD risk was closely related to c-VWT, independent of HIV infection. Our data suggest that traditional cardiovascular disease risk factors in PLWH are adequately captured in the ASCVD risk score which was closely associated with subclinical carotid disease.
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http://dx.doi.org/10.3851/IMP3258DOI Listing
September 2019

Brain F-FDG PET of SIV-infected macaques after treatment interruption or initiation.

J Neuroinflammation 2018 Jul 14;15(1):207. Epub 2018 Jul 14.

Center for Infectious Diseases Imaging (CIDI), Clinical Center, National Institutes of Health (NIH), 10 Center Drive, Building 10, Room 1C-368, Bethesda, MD, 20892, USA.

Background: Although rates of severe HIV-associated neurocognitive disorders have declined in the post-antiretroviral treatment (ART) era, subtle deficits persist, possibly exacerbated by treatment non-adherence. The actual effects of ART interruption/initiation on brain glucose metabolism as a reflection of viral replication and neuroinflammation remain unclear. Our study investigates how treatment initiation and interruption alter brain glucose metabolism in SIV-infected macaques, using F-FDG PET in correlation with plasma and CSF viral loads (VL) and cytokine levels.

Methods: SIV-infected macaques (n = 7) underwent ART initiation only, ART interruption only, or both. Five uninfected animals served as controls. F-FDG PET imaging was performed at baseline and 1, 3, and 6 months after treatment modification. Mean and maximum standardized uptake values (SUV) for the whole-brain and subregions were calculated. Plasma and CSF VL and cytokine levels were measured. Paired t tests evaluated acute changes in whole-brain SUV from baseline to 1 month, while mixed-effect linear regression models evaluated changes over multiple timepoints and correlated SUV values with disease markers.

Results: ART interruption was associated with increased SUVmean and SUVmax acutely, after 1 month (SUVmean 95% CI [0.044-0.786 g/ml], p = 0.037; SUVmax 95% CI [0.122-3.167 g/ml], p = 0.041). The correlation between SUV and time, however, was not significant when evaluated across all timepoints. Increased SUVmean and SUVmax correlated with decreased CD4+ and CD8+ T-cell counts and increased plasma VL. SUVmax was positively associated with increases in CSF VL, and there were borderline positive associations between SUVmax and IL-2, and between SUVmean and IL-15. The treatment initiation group showed no associations between imaging and disease biomarkers despite viral suppression, reduced cytokine levels, and increased CD4+ and CD8+ T-cell counts.

Conclusions: ART interruption is associated with increased brain glucose metabolism within 1 month of treatment cessation, which, in concert with increased levels of pro-inflammatory cytokines in the CSF, may reflect neuroinflammation in the setting of viral rebound. Although we cannot assert neurologic damage in association with cerebral hypermetabolism, it is a concerning outcome of ART non-adherence. Treatment initiation, meanwhile, did not result in significant changes in brain metabolism. HIV-induced neuroinflammation may require a longer period to abate than our follow-up period allowed.
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http://dx.doi.org/10.1186/s12974-018-1244-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046092PMC
July 2018

On the detection of cerebral metabolic depression in experimental traumatic brain injury using Chemical Exchange Saturation Transfer (CEST)-weighted MRI.

Sci Rep 2018 01 12;8(1):669. Epub 2018 Jan 12.

Frank Laboratory, Radiology & Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States.

Metabolic abnormalities are commonly observed in traumatic brain injury (TBI) patients exhibiting long-term neurological deficits. This study investigated the feasibility and reproducibility of using chemical exchange saturation transfer (CEST) MRI to detect cerebral metabolic depression in experimental TBI. Phantom and in vivo CEST experiments were conducted at 9.4 Tesla to optimize the selective saturation for enhancing the endogenous contrast-weighting of the proton exchanges over the range of glucose proton chemical shifts (glucoCEST) in the resting rat brain. The optimized glucoCEST-weighted imaging was performed on a closed-head model of diffuse TBI in rats with 2-deoxy-D-[C]-glucose (2DG) autoradiography validation. The results demonstrated that saturation duration of 1‒2 seconds at pulse powers 1.5‒2µT resulted in an improved contrast-to-noise ratio between the gray and white matter comparable to 2DG autoradiographs. The intrasubject (n = 4) and intersubject (n = 3) coefficient of variations for repeated glucoCEST acquisitions (n = 4) ranged between 8‒16%. Optimization for the TBI study revealed that glucoCEST-weighted images with 1.5μT power and 1 s saturation duration revealed the greatest changes in contrast before and after TBI, and positively correlated with 2DG autoradiograph (r = 0.78, p < 0.01, n = 6) observations. These results demonstrate that glucoCEST-weighted imaging may be useful in detecting metabolic abnormalities following TBI.
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http://dx.doi.org/10.1038/s41598-017-19094-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766554PMC
January 2018

MR brain volumetric measurements are predictive of neurobehavioral impairment in the HIV-1 transgenic rat.

Neuroimage Clin 2018 21;17:659-666. Epub 2017 Nov 21.

Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, United States. Electronic address:

Introduction: HIV infection is known to be associated with brain volume loss, even in optimally treated patients. In this study, we assessed whether dynamic brain volume changes over time are predictive of neurobehavorial performance in the HIV-1 transgenic (Tg) rat, a model of treated HIV-positive patients.

Materials And Methods: Cross-sectional brain MRI imaging was first performed comparing Tg and wild type (WT) rats at 3 and 19 months of age. Longitudinal MRI and neurobehavioral testing of another group of Tg and WT rats was then performed from 5 to 23 weeks of age. Whole brain and subregional image segmentation was used to assess the rate of brain growth over time. We used repeated-measures mixed models to assess differences in brain volumes and to establish how predictive the volume differences are of specific neurobehavioral deficits.

Results: Cross-sectional imaging showed smaller whole brain volumes in Tg compared to WT rats at 3 and at 19 months of age. Longitudinally, Tg brain volumes were smaller than age-matched WT rats at all time points, starting as early as 5 weeks of age. The Tg striatal growth rate delay between 5 and 9 weeks of age was greater than that of the whole brain. Striatal volume in combination with genotype was the most predictive of rota-rod scores and in combination with genotype and age was the most predictive of total exploratory activity scores in the Tg rats.

Conclusion: The disproportionately delayed striatal growth compared to whole brain between 5 and 9 weeks of age and the role of striatal volume in predicting neurobehavioral deficits suggest an important role of the dopaminergic system in HIV associated neuropathology. This might explain problems with motor coordination and executive decisions in this animal model. Smaller brain and subregional volumes and neurobehavioral deficits were seen as early as 5 weeks of age, suggesting an early brain insult in the Tg rat. Neuroprotective therapy testing in this model should thus target this early stage of development, before brain damage becomes irreversible.
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http://dx.doi.org/10.1016/j.nicl.2017.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705794PMC
July 2018

Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV.

Nucl Med Biol 2017 Dec 31;55:27-33. Epub 2017 Aug 31.

Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, Clinical Center, National Institutes of Health (NIH), Bethesda, MD, USA. Electronic address:

Introduction: In vivo imaging biomarkers of various HIV neuropathologies, including dopaminergic dysfunction, are still lacking. Towards developing dopaminergic biomarkers of brain involvement in HIV, we assessed the pre and postsynaptic components of the dopaminergic system in the HIV-1 transgenic rat (Tg), a well-characterized model of treated HIV+ patients, using small-animal PET imaging.

Methods: Fifteen to 18 month-old Tg and wild type (WT) rats were imaged with both [18F]-FP-CMT, a dopamine transporter (DAT) ligand (n=16), and [18F]-Fallypride, a D2/D3 dopamine receptor (D2/D3DR) ligand (n=16). Five to 8 month-old Tg and WT rats (n=18) were also imaged with [18F]-FP-CMT. A subset of animals was imaged longitudinally at 7 and 17 months of age. Multiplex immunohistochemistry staining for DAT, tyrosine hydroxylase, D2DR, D3DR GFAP, Iba1 and NeuN was performed on a subgroup of the scanned animals.

Results: [18F]-FP-CMT and [18F]-Fallypride binding potential (BP) values were significantly lower in 15-18 month-old Tg compared to age-matched WT rats (p<0.0001 and 0.001, respectively). [18F]-FP-CMT BP values in 5-8 month-old rats, however, were not significantly different. Longitudinal age-related decrease in [18F]-FP-CMT BP was exacerbated in the Tg rat. Immunohistochemistry showed decreased staining of dopaminergic markers in Tg rats. Rats with higher serum gp120 had lower mean BP values for both ligands.

Conclusions: We found presynaptic and postsynaptic dopaminergic dysfunction/loss in older Tg compared to WT rats. We believe this to be related to neurotoxicity of viral proteins present in the Tg rats' serum and brain.

Advances In Knowledge: Our findings confirm prior reports of neurobehavioral abnormalities suggestive of dopaminergic dysfunction in this model. They also suggest similarities between the Tg rat and HIV+ patients as far as dopaminergic dysfunction.

Implications For Patient Care: The Tg rat, along with the above-described quantitative PET imaging biomarkers, can have a role in the evaluation of HIV neuroprotective therapies prior to human translation.
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http://dx.doi.org/10.1016/j.nucmedbio.2017.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709197PMC
December 2017

Choroid Plexitis and Ependymitis by Magnetic Resonance Imaging are Biomarkers of Neuronal Damage and Inflammation in HIV-negative Cryptococcal Meningoencephalitis.

Sci Rep 2017 08 23;7(1):9184. Epub 2017 Aug 23.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

CNS cryptococcal meningoencephalitis in both HIV positive (HIV+) and HIV negative (HIV-) subjects is associated with high morbidity and mortality despite optimal antifungal therapy. We thus conducted a detailed analysis of the MR imaging findings in 45 HIV- and 11 HIV+ patients to identify imaging findings associated with refractory disease. Ventricular abnormalities, namely ependymitis and choroid plexitis were seen in HIV- but not in HIV+ subjects. We then correlated the imaging findings in a subset of HIV- subjects (n = 17) to CSF levels of neurofilament light chain (NFL), reflective of axonal damage and sCD27, known to best predict the presence of intrathecal T-cell mediated inflammation. We found that ependymitis on brain MRI was the best predictor of higher log(sCD27) levels and choroid plexitis was the best predictor of higher log(NFL) levels. The availability of predictive imaging biomarkers of inflammation and neurological damage in HIV- subjects with CNS cryptococcosis may help gauge disease severity and guide the therapeutic approach in those patients.
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http://dx.doi.org/10.1038/s41598-017-09694-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569007PMC
August 2017

Spinal Arachnoiditis as a Complication of Cryptococcal Meningoencephalitis in Non-HIV Previously Healthy Adults.

Clin Infect Dis 2017 Feb 10;64(3):275-283. Epub 2016 Nov 10.

Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda,Maryland.

Background: Cryptococcus can cause meningoencephalitis (CM) among previously healthy non-HIV adults. Spinal arachnoiditis is under-recognized, since diagnosis is difficult with concomitant central nervous system (CNS) pathology.

Methods: We describe 6 cases of spinal arachnoiditis among 26 consecutively recruited CM patients with normal CD4 counts who achieved microbiologic control. We performed detailed neurological exams, cerebrospinal fluid (CSF) immunophenotyping and biomarker analysis before and after adjunctive immunomodulatory intervention with high dose pulse corticosteroids, affording causal inference into pathophysiology.

Results: All 6 exhibited severe lower motor neuron involvement in addition to cognitive changes and gait disturbances from meningoencephalitis. Spinal involvement was associated with asymmetric weakness and urinary retention. Diagnostic specificity was improved by MRI imaging which demonstrated lumbar spinal nerve root enhancement and clumping or lesions. Despite negative fungal cultures, CSF inflammatory biomarkers, sCD27 and sCD21, as well as the neuronal damage biomarker, neurofilament light chain (NFL), were elevated compared to healthy donor (HD) controls. Elevations in these biomarkers were associated with clinical symptoms and showed improvement with adjunctive high dose pulse corticosteroids.

Conclusions: These data suggest that a post-infectious spinal arachnoiditis is an important complication of CM in previously healthy individuals, requiring heightened clinician awareness. Despite microbiological control, this syndrome causes significant pathology likely due to increased inflammation and may be amenable to suppressive therapeutics.
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http://dx.doi.org/10.1093/cid/ciw739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241780PMC
February 2017

Trauma-Specific Brain Abnormalities in Suspected Mild Traumatic Brain Injury Patients Identified in the First 48 Hours after Injury: A Blinded Magnetic Resonance Imaging Comparative Study Including Suspected Acute Minor Stroke Patients.

J Neurotrauma 2017 01 10;34(1):23-30. Epub 2016 Jun 10.

1 Stroke Diagnostics and Therapeutics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland.

We assessed the utility of a brief MRI protocol, appropriate for the acute setting, to detect acute traumatic brain injury (TBI) in patients with suspected mild TBI (mTBI) and distinguish traumatic from nontraumatic brain injury by comparing trauma with nontrauma patients. Twenty-two patients with suspected mTBI were included in this exploratory study over a period of 9 months. Median time from injury to MR scanning was 5.4 h (interquartile range 3.6-15.3). To determine the specificity of certain findings for TBI, 61 patients presenting with suspected minor acute stroke were included as a comparative group using the same MRI methods. A selected series of MRI sequences (diffusion-weighted imaging, fluid attenuated inversion recovery [FLAIR], and T2* weighted) were independently evaluated by two neuroradiologists blinded to clinical diagnosis, for presence of specific findings. In a separate session, all cases in which at least one MRI sequence above was positive were classified as TBI, stroke, or indeterminate. Intracranial MRI abnormalities were observed in 47 (57%) of the 83 studied patients. Based on findings on MRI, 12 (55%) of 22 suspected mTBI patients were classified as having traumatic injury. Nine (47%) of the 19 suspected mTBI patients with a negative CT had findings on MRI. Abnormalities on MRI consistent with trauma were observed most frequently on postcontrast FLAIR (83%) and T2*-weighted (58%) sequences. We demonstrated the ability of a fast MRI protocol to identify trauma-related abnormalities not seen on CT, and differentiate acute trauma from nonspecific chronic disease in a blinded cohort of mTBI patients.
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http://dx.doi.org/10.1089/neu.2015.4338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198056PMC
January 2017

Molecular Imaging of Inflammation: Current Status.

Authors:
Dima A Hammoud

J Nucl Med 2016 Aug 12;57(8):1161-5. Epub 2016 May 12.

Center for Infectious Disease Imaging, Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland

The ability to image inflammation in vivo can improve our understanding of the pathophysiology underlying various disease etiologies, including cancer, atherosclerosis, and neurodegeneration. A great wealth of preclinical and translational research has been and is currently being developed to decipher the involvement of the immune system in disease pathophysiology, quantify the course of a disease, and visualize the potential detrimental effects of excessive inflammation. Down the road, the ultimate goal is to have clinical noninvasive in vivo imaging biomarkers of inflammation that will help diagnose disease, establish prognosis, and gauge response to preventative and therapeutic strategies.
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http://dx.doi.org/10.2967/jnumed.115.161182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572792PMC
August 2016

Exposure of rhesus monkeys to cowpox virus Brighton Red by large-particle aerosol droplets results in an upper respiratory tract disease.

J Gen Virol 2016 08 9;97(8):1942-1954. Epub 2016 May 9.

Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA.

We previously demonstrated that small-particle (0.5-3.0 µm) aerosol infection of rhesus monkeys (Macaca mulatta) with cowpox virus (CPXV)-Brighton Red (BR) results in fulminant respiratory tract disease characterized by severe lung parenchymal pathology but only limited systemic virus dissemination and limited classic epidermal pox-like lesion development (Johnson et al., 2015). Based on these results, and to further develop CPXV as an improved model of human smallpox, we evaluated a novel large-particle aerosol (7.0-9.0 µm) exposure of rhesus monkeys to CPXV-BR and monitored for respiratory tract disease by serial computed tomography (CT). As expected, the upper respiratory tract and large airways were the major sites of virus-induced pathology following large-particle aerosol exposure. Large-particle aerosol CPXV exposure of rhesus macaques resulted in severe upper airway and large airway pathology with limited systemic dissemination.
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http://dx.doi.org/10.1099/jgv.0.000501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764124PMC
August 2016

Neurobehavioral Abnormalities in the HIV-1 Transgenic Rat Do Not Correspond to Neuronal Hypometabolism on 18F-FDG-PET.

PLoS One 2016 24;11(3):e0152265. Epub 2016 Mar 24.

Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland, United States of America.

Motor and behavioral abnormalities are common presentations among individuals with HIV-1 associated neurocognitive disorders (HAND). We investigated whether longitudinal motor and behavioral performance in the HIV-1 transgenic rat (Tg), a commonly used neuro-HIV model, corresponded to in vivo neuronal death/dysfunction, by using rotarod and open field testing in parallel to [18F] 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET). We demonstrated that age-matched non-Tg wild type (WT) rats outperformed the HIV-1 Tg rats at most time points on rotarod testing. Habituation to rotarod occurred at 8 weeks of age (fifth weekly testing session) in the WT rats but it never occurred in the Tg rats, suggesting deficits in motor learning. Similarly, in open field testing, WT rats outperformed the Tg rats at most time points, suggesting defective exploratory/motor behavior and increased emotionality in the Tg rat. Despite the neurobehavioral abnormalities, there were no concomitant deficits in 18F-FDG uptake in Tg rats on PET compared to age-matched WT rats and no significant longitudinal loss of FDG uptake in either group. The negative PET findings were confirmed using 14C- Deoxy-D-glucose autoradiography in 32 week-old Tg and WT rats. We believe that the neuropathology in the HIV-1 Tg rat is more likely a consequence of neuronal dysfunction rather than overt neurodegeneration/neuronal cell death, similar to what is seen in HIV-positive patients in the post-ART era.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152265PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807106PMC
August 2016

Characterization of neuropathology in the HIV-1 transgenic rat at different ages.

J Neuroimmunol 2016 Mar 3;292:116-25. Epub 2016 Feb 3.

Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA. Electronic address:

The transgenic HIV-1 rat (Tg) is a commonly used neuroHIV model with documented neurologic/behavioral deficits. Using immunofluorescent staining of the Tg brain, we found astrocytic dysfunction/damage, as well as dopaminergic neuronal loss/dysfunction, both of which worsening significantly in the striatum with age. We saw mild microglial activation in young Tg brains, but this decreased with age. There were no differences in neurogenesis potential suggesting a neurodegenerative rather than a neurodevelopmental process. Gp120 CSF levels exceeded serum gp120 levels in some animals, suggesting local viral protein production in the brain. Further probing of the pathophysiology underlying astrocytic injury in this model is warranted.
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http://dx.doi.org/10.1016/j.jneuroim.2016.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779503PMC
March 2016

Lack of neuroinflammation in the HIV-1 transgenic rat: an [(18)F]-DPA714 PET imaging study.

J Neuroinflammation 2015 Sep 17;12:171. Epub 2015 Sep 17.

Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, National Institutes of Health/Clinical Center, 10 Center Drive, Room 1C368, Bethesda, MD, 20814-9692, USA.

Background: HIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND). In this study, we used micropositron emission tomography (PET) imaging to quantify neuroinflammation in HIV-1 transgenic rat (Tg), a small animal model of HIV, known to develop neurological and behavioral problems.

Methods: Dynamic [(18)F]DPA-714 PET imaging was performed in Tg and age-matched wild-type (WT) rats in three age groups: 3-, 9-, and 16-month-old animals. As a positive control for neuroinflammation, we performed unilateral intrastriatal injection of quinolinic acid (QA) in a separate group of WT rats. To confirm our findings, we performed multiplex immunofluorescent staining for Iba1 and we measured cytokine/chemokine levels in brain lysates of Tg and WT rats at different ages.

Results: [(18)F]DPA-714 uptake in HIV-1 Tg rat brains was generally higher than in age-matched WT rats but this was not statistically significant in any age group. [(18)F]DPA-714 uptake in the QA-lesioned rats was significantly higher ipsilateral to the lesion compared to contralateral side indicating neuroinflammatory changes. Iba1 immunofluorescence showed no significant differences in microglial activation between the Tg and WT rats, while the QA-lesioned rats showed significant activation. Finally, cytokine/chemokine levels in brain lysates of the Tg rats and WT rats were not significantly different.

Conclusion: Microglial activation might not be the primary mechanism for neuropathology in the HIV-1 Tg rats. Although [(18)F]DPA-714 is a good biomarker of neuroinflammation, it cannot be reliably used as an in vivo biomarker of neurodegeneration in the HIV-1 Tg rat.
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http://dx.doi.org/10.1186/s12974-015-0390-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574011PMC
September 2015

Small particle aerosol inoculation of cowpox Brighton Red in rhesus monkeys results in a severe respiratory disease.

Virology 2015 Jul 14;481:124-35. Epub 2015 Mar 14.

Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA; Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, MD 21702, USA.

Cowpox virus (CPXV) inoculation of nonhuman primates (NHPs) has been suggested as an alternate model for smallpox (Kramski et al., 2010, PLoS One, 5, e10412). Previously, we have demonstrated that intrabronchial inoculation of CPXV-Brighton Red (CPXV-BR) into cynomolgus monkeys resulted in a disease that shared many similarities to smallpox; however, severe respiratory tract disease was observed (Smith et al., 2011, J. Gen. Virol.). Here we describe the course of disease after small particle aerosol exposure of rhesus monkeys using computed tomography (CT) to monitor respiratory disease progression. Subjects developed a severe respiratory disease that was uniformly lethal at 5.7 log10 PFU of CPXV-BR. CT indicated changes in lung architecture that correlated with changes in peripheral blood monocytes and peripheral oxygen saturation. While the small particle aerosol inoculation route does not accurately mimic human smallpox, the data suggest that CT can be used as a tool to monitor real-time disease progression for evaluation of animal models for human diseases.
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http://dx.doi.org/10.1016/j.virol.2015.02.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535421PMC
July 2015

PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis.

Sci Transl Med 2014 Dec;6(265):265ra166

Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Institute of Infectious Disease and Molecular Medicine, and the Department of Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Rondebosch 7701, South Africa.

Definitive clinical trials of new chemotherapies for treating tuberculosis (TB) require following subjects until at least 6 months after treatment discontinuation to assess for durable cure, making these trials expensive and lengthy. Surrogate endpoints relating to treatment failure and relapse are currently limited to sputum microbiology, which has limited sensitivity and specificity. We prospectively assessed radiographic changes using 2-deoxy-2-[(18)F]-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) at 2 and 6 months (CT only) in a cohort of subjects with multidrug-resistant TB, who were treated with second-line TB therapy for 2 years and then followed for an additional 6 months. CT scans were read semiquantitatively by radiologists and were computationally evaluated using custom software to provide volumetric assessment of TB-associated abnormalities. CT scans at 6 months (but not 2 months) assessed by radiologist readers were predictive of outcomes, and changes in computed abnormal volumes were predictive of drug response at both time points. Quantitative changes in FDG uptake 2 months after starting treatment were associated with long-term outcomes. In this cohort, some radiologic markers were more sensitive than conventional sputum microbiology in distinguishing successful from unsuccessful treatment. These results support the potential of imaging scans as possible surrogate endpoints in clinical trials of new TB drug regimens. Larger cohorts confirming these results are needed.
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http://dx.doi.org/10.1126/scitranslmed.3009501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567784PMC
December 2014

Neuroimaging of HIV-associated neurocognitive disorders (HAND).

Curr Opin HIV AIDS 2014 Nov;9(6):545-51

aDepartment of Neurology, School of Medicine bDepartment of Radiology cDepartment of Biomedical Engineering, Washington University in St Louis, Saint Louis, Missouri dCenter for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.

Purpose Of Review: HIV enters the brain after initial infection, and with time can lead to HIV-associated neurocognitive disorders (HAND). Although the introduction of combination antiretroviral therapy has reduced the more severe forms of HAND, milder forms are still highly prevalent. The 'gold standard' for HAND diagnosis remains detailed neuropsychological performance testing but additional biomarkers (including neuroimaging) may assist in early detection of HAND.

Recent Findings: We review the application of recently developed noninvasive MRI and PET techniques in HIV+ individuals. In particular, magnetic resonance spectroscopy may be more sensitive than conventional MRI alone in detecting HIV associated changes. Diffusion tensor imaging has become increasingly popular for assessing changes in white matter structural integrity due to HIV. Both functional MRI and PET have been limitedly performed but could provide keys for characterizing neuropathophysiologic changes due to HIV.

Summary: It is hoped that continued progress will allow novel neuroimaging methods to be included in future HAND management guidelines.
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http://dx.doi.org/10.1097/COH.0000000000000112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217490PMC
November 2014

Imaging dopaminergic dysfunction as a surrogate marker of neuropathology in a small-animal model of HIV.

Mol Imaging 2014 ;13

The dopaminergic system is especially vulnerable to the effects of human immunodeficiency virus (HIV) infection, rendering dopaminergic deficits early surrogate markers of HIV-associated neuropathology. We quantified dopamine D2/3 receptors in young HIV-1 transgenic (Tg) (n  =  6) and age-matched control rats (n  =  7) and adult Tg (n  =  5) and age-matched control rats (n  =  5) using [18F]fallypride positron emission tomography (PET). Regional uptake was quantified as binding potential (BPND) using the two-tissue reference model with the cerebellum as the reference. Time-activity curves were generated for the ventral striatum, dorsal striatum, thalamus, and cerebellum. Whereas BPND values were significantly lower in the ventral striatum (p < .001) and dorsal striatum (p  =  .001) in the adult Tg rats compared to controls rats, they were significantly lower only in the dorsal striatum (p < .05) in the young rats. Tg rats had smaller striatal volumes on magnetic resonance imaging. We also found lower expression levels of tyrosine hydroxylase on immunohistochemistry in the Tg animals. Our findings suggest that progressive striatal D2/3 receptor deficits occur in Tg rats as they age and can be detected using small-animal PET imaging. The effectiveness of various approaches in preventing or halting this dopaminergic loss in the Tg rat can thus be measured preclinically using [18F]fallypride PET as a molecular imaging biomarker of HIV-associated neuropathology.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545977PMC
http://dx.doi.org/10.2310/7290.2014.00031DOI Listing
March 2015

Diffusion tensor and volumetric magnetic resonance measures as biomarkers of brain damage in a small animal model of HIV.

PLoS One 2014 21;9(8):e105752. Epub 2014 Aug 21.

Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, Clinical Center, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.

Background: There are currently no widely accepted neuro-HIV small animal models. We wanted to validate the HIV-1 Transgenic rat (Tg) as an appropriate neuro-HIV model and then establish in vivo imaging biomarkers of neuropathology, within this model, using MR structural and diffusion tensor imaging (DTI).

Methods: Young and middle-aged Tg and control rats were imaged using MRI. A subset of middle-aged animals underwent longitudinal repeat imaging six months later. Total brain volume (TBV), ventricular volume (VV) and parenchymal volume (PV = TBV-VV) were measured. Fractional anisotropy (FA) and mean diffusivity (MD) values of the corpus callosum (CC) were calculated from DTI data.

Results: TBV and PV were smaller in Tg compared to control rats in young and middle-aged cohorts (p<0.0001). VV increased significantly (p = 0.005) over time in the longitudinal Tg cohort. There were lower FA (p<0.002) and higher MD (p<0.003) values in the CC of middle-aged Tg rats compared to age-matched controls. Longitudinally, MD significantly decreased over time in Tg rats (p<0.03) while it did not change significantly in the control cohort over the same period of time (p>0.05).

Conclusions: We detected brain volume loss in the Tg rat, probably due to astrocytic dysfunction/loss, loss of structural/axonal matrix and striatal neuronal loss as suggested by immunofluorescence. Increased MD and decreased FA in the CC probably reflect microstructural differences between the Tg and Control rats which could include increased extracellular space between white matter tracts, demyelination and axonal degeneration, among other pathologies. We believe that the Tg rat is an adequate model of neuropathology in HIV and that volumetric MR and DTI measures can be potentially used as biomarkers of disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140825PMC
November 2015

Addition of MR imaging features and genetic biomarkers strengthens glioblastoma survival prediction in TCGA patients.

J Neuroradiol 2015 Jul 2;42(4):212-21. Epub 2014 Jul 2.

Division of Neuroradiology, University of Virginia Health System, Charlottesville, VA, United States; CHU de Vaudois, Department of Radiology, Lausanne, Switzerland. Electronic address:

Purpose: The purpose of our study was to assess whether a model combining clinical factors, MR imaging features, and genomics would better predict overall survival of patients with glioblastoma (GBM) than either individual data type.

Methods: The study was conducted leveraging The Cancer Genome Atlas (TCGA) effort supported by the National Institutes of Health. Six neuroradiologists reviewed MRI images from The Cancer Imaging Archive (http://cancerimagingarchive.net) of 102 GBM patients using the VASARI scoring system. The patients' clinical and genetic data were obtained from the TCGA website (http://www.cancergenome.nih.gov/). Patient outcome was measured in terms of overall survival time. The association between different categories of biomarkers and survival was evaluated using Cox analysis.

Results: The features that were significantly associated with survival were: (1) clinical factors: chemotherapy; (2) imaging: proportion of tumor contrast enhancement on MRI; and (3) genomics: HRAS copy number variation. The combination of these three biomarkers resulted in an incremental increase in the strength of prediction of survival, with the model that included clinical, imaging, and genetic variables having the highest predictive accuracy (area under the curve 0.679±0.068, Akaike's information criterion 566.7, P<0.001).

Conclusion: A combination of clinical factors, imaging features, and HRAS copy number variation best predicts survival of patients with GBM.
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http://dx.doi.org/10.1016/j.neurad.2014.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511631PMC
July 2015

Neurobehavioral profiles in individuals with hyperimmunoglobulin E Syndrome (HIES) and brain white matter hyperintensities.

J Clin Immunol 2013 Oct 21;33(7):1175-84. Epub 2013 Aug 21.

Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, 20892, USA,

Purpose: Individuals with hyperimmunoglobulin E Syndrome (HIES) have central nervous system abnormalities, including focal white matter hyperintensities (WMH), or unidentified bright objects. This cross-sectional study aimed to describe the cognitive and emotional functioning and quality of life of people with HIES. We also sought to explore the relationship between cognitive functioning and WMHs in this population.

Methods: Twenty-nine individuals (13 males) with autosomal-dominant HIES (mean age = 35.1 years, range 16-55) were administered a comprehensive psychological assessment as part of a natural history protocol. The assessment included measures of global cognitive functioning (Wechsler Adult Intelligence Scale-III), memory (California Verbal Learning Test-II, Wechsler Memory Scale-III), executive skills (Delis Kaplan Executive Function System), and attention (Test of Everyday Attention). Emotional symptoms and quality of life also were assessed.

Results: All mean cognitive scores were within normal limits. Mean scores on memory and executive functioning measures were significantly lower than Full Scale IQ scores (ps < .05). Substantial percentages of patients self-reported executive skills to be in the clinical range. Patients with fewer (1-20) versus more (21+) WMHs scored significantly better on measures of global cognitive skills, visual-perceptual skills, and working memory. Mean scores on emotional symptom and quality of life measures were in the average range and unrelated to WMHs.

Conclusions: Global cognitive functioning was average to high average in our sample of individuals with HIES. However, focal brain lesions were associated with lower scores in specific domains. Emotional functioning and quality of life are within normal limits in this sample.
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http://dx.doi.org/10.1007/s10875-013-9932-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467306PMC
October 2013

Cerebrospinal fluid HIV-1 compartmentalization in a patient with AIDS and acute varicella-zoster virus meningomyeloradiculitis.

Clin Infect Dis 2013 Sep 31;57(5):e135-42. Epub 2013 May 31.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1684, USA.

We report a case of AIDS presenting as varicella-zoster virus (VZV) meningomyeloradiculitis associated with human immunodeficiency virus (HIV) quasispecies compartmentalization within the cerebrospinal fluid (CSF), and a CSF viral load that was 1 log higher than in peripheral blood. Prolonged antiviral therapy for both VZV and HIV type 1 was associated with partial resolution.
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http://dx.doi.org/10.1093/cid/cit356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739464PMC
September 2013

The use of 14C-FIAU to predict bacterial thymidine kinase presence: implications for radiolabeled FIAU bacterial imaging.

Nucl Med Biol 2013 Jul 27;40(5):638-42. Epub 2013 Mar 27.

Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20814-9692, USA.

Unlabelled: Currently available infectious disease imaging techniques cannot differentiate between infection and sterile inflammation or between different types of infections. Recently, radiolabeled FIAU was found to be a substrate for the thymidine kinase (TK) enzyme of multiple pathogenic bacteria, leading to its translational use in the imaging of bacterial infections. Patients with immunodeficiencies, however, are susceptible to a different group of pathogenic bacteria when compared to immunocompetent subjects. In this study, we wanted to predict the usefulness of radiolabeled FIAU in the detection of bacterial infections commonly occurring in patients with immunodeficiencies, in vitro, prior to attempting in vivo imaging with (124)I-FIAU-PET.

Methods: We obtained representative strains of bacterial pathogens isolated from actual patients with genetic immunodeficiencies. We evaluated the bacterial susceptibility of different strains to the effect of incubation with FIAU, which would implicate the presence of the thymidine kinase (TK) enzyme. We also incubated the bacteria with (14)C-FIAU and consequently measured its rate of incorporation in the bacterial DNA using a liquid scintillation counter.

Results: Unlike the other bacterial strains, the growth of Pseudomonas aeruginosa was not halted by FIAU at any concentration. All the tested clinical isolates demonstrated different levels of (14)C-FIAU uptake, except for P. aeruginosa.

Conclusion: Radiolabeled FIAU has been successful in delineating bacterial infections, both in preclinical and pilot translational studies. In patients with immunodeficiencies, Pseudomonas infections are commonly encountered and are usually difficult to differentiate from fungal infections. The use of radiolabeled FIAU for in vivo imaging of those patients, however, would not be useful, considering the apparent lack of TK enzyme in Pseudomonas. One has to keep in mind that not all pathogenic bacteria possess the TK enzyme and as such will not all retain FIAU. Our technique is simple, and can be easily used to assess whether a certain bacterial strain of interest can or cannot be visualized using radiolabeled FIAU.
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http://dx.doi.org/10.1016/j.nucmedbio.2013.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665620PMC
July 2013

Role of CTR4 in the Virulence of Cryptococcus neoformans.

mBio 2012 2;3(5). Epub 2012 Oct 2.

Section of Infectious Diseases, Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois, USA.

Unlabelled: While research has identified an important contribution for metals, such as iron, in microbial pathogenesis, the roles of other transition metals, such as copper, remain mostly unknown. Recent evidence points to a requirement for copper homeostasis in the virulence of Cryptococcus neoformans based on a role for a CUF1 copper regulatory factor in mouse models and in a human patient cohort. C. neoformans is an important fungal pathogen that results in an estimated 600,000 AIDS-related deaths yearly. In the present studies, we found that a C. neoformans mutant lacking the CUF1-dependent copper transporter, CTR4, grows normally in rich medium at 37°C but has reduced survival in macrophages and attenuated virulence in a mouse model. This reduced survival and virulence were traced to a growth defect under nutrient-restricted conditions. Expression studies using a full-length CTR4-fluorescent fusion reporter construct demonstrated robust expression in macrophages, brain, and lung, the latter shown by ex vivo fluorescent imaging. Inductively coupled mass spectroscopy (ICP-MS) was used to probe the copper quota of fungal cells grown in defined medium and recovered from brain, which suggested a role for a copper-protective function of CTR4 in combination with cell metallothioneins under copper-replete conditions. In summary, these data suggest a role for CTR4 in copper-related homeostasis and subsequently in fungal virulence.

Importance: Crytococcus neoformans is a significant global fungal pathogen, and copper homeostasis is a relatively unexplored aspect of microbial pathogenesis that could lead to novel therapeutics. Previous studies correlated expression levels of a Ctr4 copper transporter to development of meningoencephalitis in a patient cohort of solid-organ transplants, but a direct role for Ctr4 in mammalian pathogenesis has not been demonstrated. The present studies utilize a Δctr4 mutant strain which revealed an important role for CTR4 in C. neoformans infections in mice and relate the gene product to homeostatic control of copper and growth under nutrient-restricted conditions. Robust expression levels of CTR4 during fungal infection were exploited to demonstrate expression and lung cryptococcal disease using ex vivo fluorescence imaging. In summary, these studies are the first to directly demonstrate a role for a copper transporter in fungal disease and provide an ex vivo imaging tool for further study of cryptococcal gene expression and pathogenesis.
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http://dx.doi.org/10.1128/mBio.00285-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518914PMC
January 2013

Role of early postradiation magnetic resonance imaging scans in children with diffuse intrinsic pontine glioma.

Int J Radiat Oncol Biol Phys 2012 Jul 25;83(4):1252-1256. Epub 2012 Jan 25.

Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: To determine optimal timing of assessing postradiation radiographic response on magnetic resonance imaging (MRI) scans in pediatric patients with diffuse intrinsic pontine glioma (DIPG).

Methods And Materials: Patients were treated on a prospective study at the National Cancer Institute (Protocol #06-C-0219) evaluating the effects of radiotherapy (RT). Standard RT was administered in standard fractionation over 6 weeks. Postradiation MRI scans were performed at 2 and 6-8 weeks.

Results: Eleven patients with DIPG were evaluated. Median age was 6 years (range, 4-13 years). Patients were treated with external-beam RT to 55.8 Gy (n = 10) or 54 Gy (n = 1), with a gross tumor volume to planning target volume expansion of 1.8-2.0 cm. All patients received prescribed dose and underwent posttreatment MRI scans at 2 and 6-8 weeks. Pretreatment imaging revealed compression of fourth ventricle (n = 11); basilar artery encasement (n = 9); tumor extension outside the pons (n = 11); and tumor hemorrhage (n = 2). At the 2-week scan, basilar artery encasement improved in 7 of 9 patients, and extent of tumor was reduced in 5 of 11 patients. Fourth ventricle compression improved in 6 of 11 patients but worsened in 3 of 11 patients. Presumed necrosis was observed in 5 of 11 patients at 2 weeks and in 1 additional patient at 6-8 weeks. There was no significant difference in mean anteroposterior and transverse diameters of tumor between the 2- and 6-8-week time points. Six of 11 patients had increasing ventricular size, with no evidence of obstruction.

Conclusions: There is no significant difference in tumor size of DIPG patients who have received standard RT when measured at 2 weeks vs. 6-8 weeks after RT. The majority of patients had the largest change in tumor size at the 2-week post-RT scan, with evolving changes documented on the 6-8-week scan. Six of 11 patients had progressive ventriculomegaly without obstruction, suggestive of communicating hydrocephalus. To the best of our knowledge, this is the first documentation of this phenomenon in this cohort of patients.
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http://dx.doi.org/10.1016/j.ijrobp.2011.09.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324534PMC
July 2012

Decreased microglial activation in MS patients treated with glatiramer acetate.

J Neurol 2012 Jun 9;259(6):1199-205. Epub 2011 Dec 9.

Department of Neurology, Johns Hopkins University School of Medicine, 600 North Wolfe St, Pathology 627, Baltimore, MD 21287-6985, USA.

Activated microglia are thought to be an important contributor to tissue damage in multiple sclerosis (MS). The level of microglial activation can be measured non-invasively using [(11)C]-R-PK11195, a radiopharmaceutical for positron emission tomography (PET). Prior studies have identified abnormalities in the level of [(11)C]-R-PK11195 uptake in patients with MS, but treatment effects have not been evaluated. Nine previously untreated relapsing-remitting MS patients underwent PET and magnetic resonance imaging of the brain at baseline and after 1 year of treatment with glatiramer acetate. Parametric maps of [(11)C]-R-PK11195 uptake were obtained for baseline and post-treatment PET scans, and the change in [(11)C]-R-PK11195 uptake pre- to post-treatment was evaluated across the whole brain. Region-of-interest analysis was also applied to selected subregions. Whole brain [(11)C]-R-PK11195 binding potential per unit volume decreased 3.17% (95% CI: -0.74, -5.53%) between baseline and 1 year (p = 0.018). A significant decrease was noted in cortical gray matter and cerebral white matter, and a trend towards decreased uptake was seen in the putamen and thalamus. The results are consistent with a reduction in inflammation due to treatment with glatiramer acetate, though a larger controlled study would be required to prove that association. Future research will focus on whether the level of baseline microglial activation predicts future tissue damage in MS and whether [(11)C]-R-PK11195 uptake in cortical gray matter correlates with cortical lesion load.
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http://dx.doi.org/10.1007/s00415-011-6337-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478150PMC
June 2012

Reference tissue modeling with parameter coupling: application to a study of SERT binding in HIV.

Phys Med Biol 2011 Apr 25;56(8):2499-513. Epub 2011 Mar 25.

Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.

When applicable, it is generally preferred to evaluate positron emission tomography (PET) studies using a reference tissue-based approach as that avoids the need for invasive arterial blood sampling. However, most reference tissue methods have been shown to have a bias that is dependent on the level of tracer binding, and the variability of parameter estimates may be substantially affected by noise level. In a study of serotonin transporter (SERT) binding in HIV dementia, it was determined that applying parameter coupling to the simplified reference tissue model (SRTM) reduced the variability of parameter estimates and yielded the strongest between-group significant differences in SERT binding. The use of parameter coupling makes the application of SRTM more consistent with conventional blood input models and reduces the total number of fitted parameters, thus should yield more robust parameter estimates. Here, we provide a detailed evaluation of the application of parameter constraint and parameter coupling to [(11)C]DASB PET studies. Five quantitative methods, including three methods that constrain the reference tissue clearance (k(r)(2)) to a common value across regions were applied to the clinical and simulated data to compare measurement of the tracer binding potential (BP(ND)). Compared with standard SRTM, either coupling of k(r)(2) across regions or constraining k(r)(2) to a first-pass estimate improved the sensitivity of SRTM to measuring a significant difference in BP(ND) between patients and controls. Parameter coupling was particularly effective in reducing the variance of parameter estimates, which was less than 50% of the variance obtained with standard SRTM. A linear approach was also improved when constraining k(r)(2) to a first-pass estimate, although the SRTM-based methods yielded stronger significant differences when applied to the clinical study. This work shows that parameter coupling reduces the variance of parameter estimates and may better discriminate between-group differences in specific binding.
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http://dx.doi.org/10.1088/0031-9155/56/8/011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094021PMC
April 2011

Magnetic resonance imaging features of pituicytomas: analysis of 10 cases.

J Comput Assist Tomogr 2010 Sep-Oct;34(5):757-61

Radiology and Imaging Sciences, National Institutes of Health/Clinical Center, Bethesda, MD 20892, USA.

Objective: To describe the magnetic resonance imaging features of pituicytomas and identify any specific features that could differentiate this tumor from other sellar/suprasellar masses.

Methods: Magnetic resonance images, clinical histories, and pathological findings of 10 patients with pituicytoma were retrospectively reviewed. Reports of clinical history, pathology, and magnetic resonance imaging findings were reviewed for 28 additional histologically proven pituicytoma cases, previously reported in the literature.

Results: Pituicytomas were mostly round or oval, sharply defined, and located in the sellar and/or suprasellar region. Tumors were generally isointense to gray matter on T1-weighted images and isointense to slightly hyperintense on T2-weighted images, and they enhanced intensely.

Conclusions: Magnetic resonance imaging features of pituicytomas overlap with those of other, more common lesions that occur in the region. With the exception of a purely suprasellar-enhancing mass or a clearly defined neurohypophyseal mass separate from the anterior pituitary, the similarity to common tumors such as macroadenomas and meningiomas probably precludes effective prospective diagnosis of pituicytomas.
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http://dx.doi.org/10.1097/RCT.0b013e3181e289c0DOI Listing
October 2010
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