Christina M Marra

University of Washington Seattle, Seattle, Washington, United States

Are you Christina M Marra?

Claim your profile

Publications (148)937.93 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Infrastructure for conducting neurological research in resource-limited settings (RLS) is limited. The lack of neurological and neuropsychological (NP) assessment and normative data needed for clinical interpretation impedes research and clinical care. Here, we report on ACTG 5271, which provided neurological training of clinical site personnel and collected neurocognitive normative comparison data in diverse settings. At ten sites in seven RLS countries, we provided training for NP assessments. We collected normative comparison data on HIV- participants from Brazil (n = 240), India (n = 480), Malawi (n = 481), Peru (n = 239), South Africa (480), Thailand (n = 240), and Zimbabwe (n = 240). Participants had a negative HIV test within 30 days before standardized NP exams were administered at baseline and 770 at 6 months. Participants were enrolled in eight strata, gender (female and male), education (<10 and ≥10 years), and age (<35 and ≥35 years). Of 2400 enrolled, 770 completed the 6-month follow-up. As expected, significant between-country differences were evident in all the neurocognitive test scores (p < 0.0001). There was variation between the age, gender, and education strata on the neurocognitive tests. Age and education were important variables for all tests; older participants had poorer performance, and those with higher education had better performance. Women had better performance on verbal learning/memory and speed of processing tests, while men performed better on motor tests. This study provides the necessary neurocognitive normative data needed to build infrastructure for future neurological and neurocognitive studies in diverse RLS. These normative data are a much-needed resource for both clinicians and researchers.
    No preview · Article · Jan 2016 · Journal of NeuroVirology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Major depressive disorder is the most common neuropsychiatric complication in human immunodeficiency virus (HIV) infections and is associated with worse clinical outcomes. We determined if detectable cerebrospinal fluid (CSF) HIV ribonucleic acid (RNA) at threshold ≥50 copies/ml is associated with increased risk of depression. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort is a six-center US-based prospective cohort with bi-annual follow-up of 674 participants. We fit linear mixed models (N = 233) and discrete-time survival models (N = 154; 832 observations) to evaluate trajectories of Beck Depression Inventory (BDI) II scores and the incidence of new-onset moderate-to-severe depressive symptoms (BDI ≥ 17) among participants on combination antiretroviral therapy (cART), who were free of depression at study entry and received a minimum of three CSF examinations over 2496 person-months follow-up. Detectable CSF HIV RNA (threshold ≥50 copies/ml) at any visit was associated with a 4.7-fold increase in new-onset depression at subsequent visits adjusted for plasma HIV RNA and treatment adherence; hazard ratio (HR) = 4.76, (95 % CI 1.58-14.3); P = 0.006. Depression (BDI) scores were 2.53 points higher (95 % CI 0.47-4.60; P = 0.02) over 6 months if CSF HIV RNA was detectable at a prior study visit in fully adjusted models including age, sex, race, education, plasma HIV RNA, duration and adherence of CART, and lifetime depression diagnosis by Diagnostic Statistical Manual (DSM-IV) criteria. Persistent CSF but not plasma HIV RNA is associated with an increased risk for new-onset depression. Further research evaluating the role of immune activation and inflammatory markers may improve our understanding of this association.
    No preview · Article · Jan 2016 · Journal of NeuroVirology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Anemia has been linked to adverse HIV outcomes, including dementia, in the pre-highly active antiretroviral therapy (HAART) era. Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown. Methods: We evaluated time-dependent associations of anemia and cross-sectional associations of red cell indices with neurocognitive impairment in a multi-center, HAART-era HIV cohort study (N=1261), adjusting for potential confounders, including age, nadir CD4(+) T-cell count, zidovudine use and comorbidities. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments. Results: HAND, defined by standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were positively associated with the Global Deficit Score, a continuous measure of neurocognitive impairment (both p<0.01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all p<0.05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted HR 1.55 p<0.01). Conclusions: Anemia and red cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons.
    No preview · Article · Dec 2015 · The Journal of Infectious Diseases
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: HIV-infected individuals may have poorer serological responses to syphilis treatment and may be more likely to experience neurosyphilis. Treponema pallidum is cleared from sites of infection by opsonization, ingestion and killing by macrophages. Methods: Sera from 235 individuals with syphilis were tested for T. pallidum-specific opsonic activity. Blood T. pallidum concentration was determined by real time polymerase chain reaction (PCR) amplification of the tp0574 gene, and T. pallidum was detected in CSF by reverse transcriptase PCR of 16S rRNA. Results: Opsonic activity was higher with higher serum RPR titers (P<0.001), and in those treated for uncomplicated syphilis before serum collection (P<0.001). Opsonic activity was lower in HIV-infected compared to HIV-uninfected even after taking into account the above factors (P=0.006). In participants in whom blood T. pallidum was detectable, those with the highest opsonic activity had lower blood T. pallidum concentrations. In multivariable analyses, there was not a significant relationship between opsonic activity and detection of T. pallidum in cerebrospinal fluid (CSF) or CSF-Venereal Disease Research Laboratory reactivity. Conclusions: Serum T. pallidum-specific opsonic activity is significantly lower in HIV-infected individuals. Impaired T. pallidum-specific immune responses in HIV-infected individuals could contribute to differences in the course of disease or treatment response.
    No preview · Article · Dec 2015 · The Journal of Infectious Diseases
  • Christina M Marra
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose of review: This article reviews the etiology, clinical manifestations, diagnosis, and treatment of neurosyphilis, with a focus on issues of particular relevance to neurologists. Recent findings: The number of cases of infectious syphilis in the United States has steadily increased since 2000. The highest rates are among men who have sex with men, and approximately half of these individuals are infected with human immunodeficiency virus (HIV). Neurosyphilis is a serious complication of syphilis that can develop at any time in the course of syphilis. Two neuroimaging patterns should alert the neurologist to a diagnosis of neurosyphilis: cerebral gummas, which are dural-based lesions that can mimic meningiomas, and medial temporal lobe abnormalities that can mimic herpes encephalitis. Penicillin G is the recommended treatment for neurosyphilis, but ceftriaxone may be an acceptable alternative. Summary: The diagnosis of neurosyphilis can be challenging. A sound understanding of the clinical manifestations and the strengths and limitations of diagnostic tests are essential tools for the neurologist.
    No preview · Article · Dec 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: We reviewed 68 cases of possible neurosyphilis among 573 syphilis cases in King County, WA, from 3rd January 2012 to 30th September 2013; 7.9% (95% confidence interval, 5.8%-10.5%) had vision or hearing changes, and 3.5% (95% confidence interval, 2.2%-5.4%) had both symptoms and objective confirmation of complicated syphilis with either abnormal cerebrospinal fluid or an abnormal ophthalmologic examination.
    No preview · Article · Nov 2015 · Sexually transmitted diseases

  • No preview · Article · Oct 2015 · MMWR. Morbidity and mortality weekly report
  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.
    No preview · Article · Sep 2015 · Journal of NeuroVirology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Neurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated with outcomes of HIV infection and combination antiretroviral therapy (CART), and with neurodegenerative diseases. We hypothesize that mtDNA haplogroups are associated with NCI in HIV-infected adults and performed a genetic association study in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. Methods: CHARTER is an observational study of ambulatory HIV-infected adults. Haplogroups were assigned using mtDNA sequence, and principal components were derived from ancestry-informative nuclear DNA variants. Outcomes were cross-sectional global deficit score (GDS) as a continuous measure, GDS impairment (GDS ≥ 0.50), and HIV-associated neurocognitive disorder (HAND) using international criteria. Multivariable models were adjusted for comorbidity status (incidental vs contributing), current CART, plasma HIV RNA, reading ability, and CD4 cell nadir. Results: Haplogroups were available from 1027 persons; median age 43 years, median CD4 nadir 178 cells/mm(3), 72% on CART, and 46% with HAND. The 102 (9.9%) persons of genetically determined admixed Hispanic ancestry had more impairment by GDS or HAND than persons of European or African ancestry (P < .001 for all). In multivariate models including persons of admixed Hispanic ancestry, those with haplogroup B had lower GDS (β = -0.34; P = .008) and less GDS impairment (odds ratio = 0.16; 95% confidence interval, .04, .63; P = .009) than other haplogroups. There were no significant haplogroup associations among persons of European or African ancestry. Conclusions: In these mostly CART-treated persons, mtDNA haplogroup B was associated with less NCI among persons of genetically determined Hispanic ancestry. mtDNA variation may represent an ancestry-specific factor influencing NCI in HIV-infected persons.
    No preview · Article · Jun 2015 · Clinical Infectious Diseases
  • [Show abstract] [Hide abstract]
    ABSTRACT: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R 2 0.179, p
    No preview · Article · Jun 2015 · Journal of NeuroVirology
  • Christina M Marra
    [Show abstract] [Hide abstract]
    ABSTRACT: The current prevalence of cognitive impairment in HIV-infected individuals is surprisingly high, even in those with undetectable plasma HIV RNA. The etiology is unknown, but one possibility is inadequate control of persistent central nervous system (CNS) HIV infection. The CNS Penetration Effectiveness (CPE) rank has been proposed to predict how well an ARV regimen treats CNS infection. Fabbiani and colleagues report that "correcting" the CPE rank of each drug in an individual's regimen for the results of genotypic susceptibility (the CPE-GSS score) results in better ability to predict whether the regimen will improve cognition. The CPE-GSS score may help us better understand the etiology of HIV-associated cognitive impairment. Whether it will be useful in the management of individual patients requires further study.
    No preview · Article · Mar 2015 · Antiviral therapy
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite modern combination antiretroviral therapy (CART), distal neuropathic pain (DNP) continues to affect many individuals with HIV infection. We evaluated risk factors for new onset DNP in the CNS Antiretroviral Therapy Effects Research (CHARTER) study, an observational cohort. Standardized, semi-annual clinical evaluations were administered at six U.S. sites. DNP was defined by using a clinician-administered instrument standardized across sites. All participants analyzed were free of DNP at study entry. New onset DNP was recorded at the first follow-up visit at which it was reported. Mixed effects logistic regression was used to evaluate potential predictors including HIV disease and treatment factors, demographics, medical comorbidities and neuropsychiatric factors. Among 493 participants, 131 (27%) reported new DNP over 2,306 visits during a median follow-up of 24 months [interquartile range (IQR) 12-42]. In multivariable regression, after adjusting for other covariates, significant entry predictors of new DNP were older age, female sex, current and past antiretroviral treatment, lack of virologic suppression, and lifetime history of opioid use disorder. During follow-up, more severe depression symptoms conferred a significantly elevated risk. The associations with opioid use disorders and depression reinforce the view that the clinical expression of neuropathic pain with peripheral nerve disease is strongly influenced by neuropsychiatric factors. Delineating such risk factors might help target emerging preventive strategies, for example, to individuals with a prior history of opioid use disorder, or might lead to new treatment approaches such as the use of tools to ameliorate depressed mood.
    No preview · Article · Feb 2015 · Pain

  • No preview · Article · Feb 2015 · Clinical Infectious Diseases
  • Emily L Ho · Lauren C Tantalo · Trudy Jones · Sharon K Sahi · Christina M Marra
    [Show abstract] [Hide abstract]
    ABSTRACT: The laboratory diagnosis of neurosyphilis rests upon identifying cerebrospinal fluid (CSF) abnormalities, including CSF-Venereal Disease Research Laboratory (VDRL) reactivity. The CSF-VDRL may not be available in the parts of the world where neurosyphilis is most common. Treponemal immunochromatographic strip tests (ICSTs) have been developed as point-of-care tests on blood for syphilis diagnosis in resource-limited settings. We optimized 3 commercial ICSTs for performance on CSF and tested CSF samples from 217 patients with syphilis. The Syphicheck-WB test (Qualpro Diagnostics, Goa, India; "Syphicheck") was chosen for further study based on agreement with CSF-VDRL test results. We determined CSF-Syphicheck titers for 152 samples. We modified the CSF-Syphicheck for point-of-care testing in a US sexually transmitted diseases clinic and compared results on 102 paired centrifuged and uncentrifuged CSF samples obtained in the laboratory to the results obtained at point of care; results of samples diluted 1:4 were compared in a subset. The diagnostic sensitivity of a reactive CSF-Syphicheck (62%-64%) and the diagnostic specificity of a CSF-Syphicheck titer at or above 1:4 (79%-81%) were equivalent to the CSF-VDRL (54%-69% sensitivity, 73%-75% specificity) for laboratory and clinical neurosyphilis diagnoses. The CSF-Syphicheck normalized after neurosyphilis therapy similarly to the CSF-VDRL. The modified CSF-Syphicheck performed well at the point of care, albeit with better performance on cell-free compared with uncentrifuged CSF. Cerebrospinal fluid treponemal ICSTs hold promise for point-of-care neurosyphilis diagnosis in regions where the CSF-VDRL is not available. Further study should address the performance of CSF ICSTs in resource-limited settings.
    No preview · Article · Jan 2015 · Sex Transm Dis
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the effect of hepatitis C virus (HCV) on neurocognitive performance in chronically HIV-infected patients enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study. A total of 1,582 participants in CHARTER who were tested for HCV antibody underwent neurocognitive testing; serum HCV RNA was available for 346 seropositive patients. Neurocognitive performance was compared in 408 HCV-seropositive and 1,174 HCV-seronegative participants and in a subset of 160 seropositive and 707 seronegative participants without serious comorbid neurologic conditions that might impair neurocognitive performance, using linear regression and taking into account HIV-associated and demographic factors (including IV drug use) and liver function. Neurocognitive performance characterized by global deficit scores and the proportion of individuals who were impaired were the same in the HCV-seropositive and HCV-seronegative groups. In univariable analyses in the entire sample, only verbal domain scores showed small statistically different superior performance in the HCV+ group that was not evident in multivariable analysis. In the subgroup without significant comorbidities, scores in all 7 domains of neurocognitive functioning did not differ by HCV serostatus. Among the HCV-seropositive participants, there was no association between neurocognitive performance and serum HCV RNA concentration. In HIV-infected patients, HCV coinfection does not contribute to neurocognitive impairment, at least in the absence of substantial HCV-associated liver damage, which was not evident in our cohort. © 2014 American Academy of Neurology.
    No preview · Article · Dec 2014 · Neurology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We tested our hypothesis that abdominal obesity when associated with increased levels of systemic and CNS immuno-inflammatory mediators contributes to neurocognitive impairment (NCI). Cross-sectional SETTING:: Six Academic Centers PARTICIPANTS:: 152 patients with plasma HIV RNA <1,000copies/ml had clinical evaluations and cognitive function quantified by global deficit scores (GDS). GDS, waist circumference (WC) and plasma IL-6, sCD163, and sCD14 and CSF sCD40L, sTNFrII, MCP-1, sICAM, and MMP-9. WC and plasma IL-6 levels positively correlated with GDS; the WC correlation was strongest in the high tertile of IL-6 (rho=0.39, p=0.005). IL-6 correlated with GDS only if WC was ≥99cm. In the high tertile of CSF sCD40L, a biomarker of macrophage and microglial activation, the correlation of IL-6 to GDS was strongest (rho=0.60, p<0.0001). Across 3-5 visits within ±1year of the index visit, GDS remained worse in patients with IL-6 levels in the high-versus-low tertile (p=0.02). Path analysis to explore potential mediators of NCI produced a strong, integrated model for patients in the high CSF sCD40L tertile. In this model, WC affected GDS both directly and via a second path that was mediated by IL-6. Inclusion of plasma sCD14 levels strengthened the model. NCI was more common in men and for individuals with components of the metabolic syndrome. NC function was significantly linked to abdominal obesity, systemic inflammation (high IL-6), and immune activation in plasma (high sCD14) and CSF (high sCD40L). Abdominal obesity, inflammation, and CNS immune activation are potential therapeutic targets for NCI in HIV+ patients.
    Full-text · Article · Dec 2014 · JAIDS Journal of Acquired Immune Deficiency Syndromes
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rates of depression are high among individuals living with HIV. Accurate assessment of depressive symptoms among this population is important for ensuring proper diagnosis and treatment. The Beck Depression Inventory-II (BDI-II) is a widely used measure for assessing depression, however its psychometric properties have not yet been investigated for use with HIV-positive populations in the United States. The current study was the first to assess the psychometric properties of the BDI-II among a large cohort of HIV-positive participants sampled at multiple sites across the United States as part of the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study. The BDI-II test scores showed good internal consistency (α = .93) and adequate test-retest reliability (internal consistency coefficient = 0.83) over a 6-mo period. Using a "gold standard" of major depressive disorder determined by the Composite International Diagnostic Interview, sensitivity and specificity were maximized at a total cut-off score of 17 and a receiver operating characteristic analysis confirmed that the BDI-II is an adequate diagnostic measure for the sample (area under the curve = 0.83). The sensitivity and specificity of each score are provided graphically. Confirmatory factor analyses confirmed the best fit for a three-factor model over one-factor and two-factor models and models with a higher-order factor included. The results suggest that the BDI-II is an adequate measure for assessing depressive symptoms among U.S. HIV-positive patients. Cut-off scores should be adjusted to enhance sensitivity or specificity as needed and the measure can be differentiated into cognitive, affective, and somatic depressive symptoms. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    No preview · Article · Nov 2014 · Psychological Assessment
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery. Methods: We investigated the incidence and predictors of NC change over 16-72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change. Results: Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001). Conclusions: NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.
    Full-text · Article · Oct 2014 · Clinical Infectious Diseases
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity and other metabolic variables are associated with abnormal brain structural volumes and cognitive dysfunction in HIV-uninfected populations. Since individuals with HIV infection on combined antiretroviral therapy (CART) often have systemic metabolic abnormalities and changes in brain morphology and function, we examined associations among brain volumes and metabolic factors in the multisite CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort, cross-sectional study of 222 HIV-infected individuals. Metabolic variables included body mass index (BMI), total blood cholesterol (C), low- and high-density lipoprotein C (LDL-C and HDL-C), blood pressure, random blood glucose, and diabetes. MRI measured volumes of cerebral white matter, abnormal white matter, cortical and subcortical gray matter, and ventricular and sulcal CSF. Multiple linear regression models allowed us to examine metabolic variables separately and in combination to predict each regional volume. Greater BMI was associated with smaller cortical gray and larger white matter volumes. Higher total cholesterol (C) levels were associated with smaller cortex volumes; higher LDL-C was associated with larger cerebral white matter volumes, while higher HDL-C levels were associated with larger sulci. Higher blood glucose levels and diabetes were associated with more abnormal white matter. Multiple atherogenic metabolic factors contribute to regional brain volumes in HIV-infected, CART-treated patients, reflecting associations similar to those found in HIV-uninfected individuals. These risk factors may accelerate cerebral atherosclerosis and consequent brain alterations and cognitive dysfunction.
    No preview · Article · Sep 2014 · Journal of NeuroVirology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p<0.05) and 5 variants in 4 genes (p<0.01) were nominally associated with DNP: polymorphisms in TF, TFRC, BMP6, ACO1, SLC11A2, and FXN conferred reduced risk (adjusted odds ratios [ORs] ranging from 0.2 to 0.7, all p<0.05); other variants in TF, CP, ACO1, BMP6, and B2M conferred increased risk (ORs ranging from 1.3 to 3.1, all p<0.05). Risks associated with some variants were statistically significant either in black or white subgroups but were consistent in direction. ACO1 rs2026739 remained significantly associated with DNP in whites (permutation p<0.0001) after correction for multiple tests. Several of the same iron-regulatory-gene polymorphisms, including ACO1 rs2026739, were also associated with severity of DNP (all p<0.05). Common polymorphisms in iron-management genes are associated with DNP and with DNP severity in HIV-infected persons receiving cART. Consistent risk estimates across population subgroups and persistence of the ACO1 rs2026739 association after adjustment for multiple testing suggest that genetic variation in iron-regulation and transport modulates susceptibility to DNP.
    Full-text · Article · Aug 2014 · PLoS ONE

Publication Stats

7k Citations
937.93 Total Impact Points

Institutions

  • 1991-2016
    • University of Washington Seattle
      • • Department of Neurology
      • • Department of Medicine
      Seattle, Washington, United States
  • 2014
    • Swedish Medical Center Seattle
      Seattle, Washington, United States
  • 1992-2014
    • Johns Hopkins University
      • Department of Neurology
      Baltimore, Maryland, United States
  • 2011
    • Mount Sinai School of Medicine
      • Department of Neurology
      Manhattan, New York, United States
  • 2002-2009
    • Harvard University
      Cambridge, Massachusetts, United States
    • Columbia University
      New York, New York, United States
  • 2008
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 1999
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States