-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: Brain changes occurring early in HIV infection are not well characterized. The Chicago Early HIV Infection Study aimed to evaluate the presence and extent of structural brain alterations using quantitative MRI. METHODS: Forty-three HIV and 21 control subjects were enrolled. Mean length of infection was estimated as less than 1 year based on assay results. High-resolution neuroanatomical images were acquired. Automated image analysis was used to derive measurements for total brain, ventricular volume, and for tissue classes (total and cortical gray matter, white matter, and CSF). A separate image analysis algorithm was used to calculate measurements for individual brain regions. Cognitive function was assessed by neuropsychological evaluation. RESULTS: Reductions were quantified in total (p = 0.0547) and cortical (p = 0.0109) gray matter in the HIV group. Analysis of individual brain regions with a separate image analysis algorithm revealed consistent findings of reductions in cerebral cortex (p = 0.042) and expansion of third ventricle (p = 0.046). The early HIV group also demonstrated weaker performance on several neuropsychological tests, with the most pronounced difference in psychomotor speed (p = 0.001). CONCLUSIONS: This cross-sectional brain volumetric study indicates structural alterations early in HIV infection. The findings challenge the prevailing assumption that the brain is spared in this period. Revisiting the question of the brain's vulnerability to processes unfolding in the initial virus-host interaction and the early natural history may yield new insights into neurologic injury in HIV infection and inform neuroprotection strategies.
Neurology 11/2012; · 8.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Diffusion tensor imaging (DTI), magnetization transfer imaging (MT) and automated brain volumetry were used to summarize brain involvement in human immunodeficiency virus (HIV) infection. A multiparametric neuroimaging protocol was implemented at 1.5T in 10 HIV+ and 24 controls. Various summary parameters were calculated based on DTI, MT, and automated brain volumetry. The magnitude of the difference, as well as the between-group discrimination, was determined for each measure. Bivariate correlations were computed and redundancy among imaging parameters was examined by principal factor analysis. Significant or nearly significant differences were found for most measures. Large Cohen's d effect sizes were indicated for mean diffusivity (MD), fractional anisotropy (FA), magnetization transfer ratio (MTR) and gray matter volume fraction (GM). Between-group discrimination was excellent for FA and MTR and acceptable for MD. Correlations among all imaging parameters could be explained by three factors, possibly reflecting general atrophy, neuronal loss, and alterations. This investigation supports the utility of summary measurements of brain involvement in HIV infection. The findings also support assumptions concerning the enhanced sensitivity of DTI and MT to atrophic as well as alterations in the brain. These findings are broadly generalizable to brain imaging studies of physiological and pathological processes.
Psychiatry research. 08/2012; 203(1):95-9.
-
[show abstract]
[hide abstract]
ABSTRACT: Circulating levels of matrix metalloproteinases (MMP-1 and 7) have been found to correlate with the severity of brain injury in HIV-infected subjects. This study used high-resolution neuroanatomic imaging and automated segmentation algorithms to clarify this relationship. Both metalloproteinases were significantly correlated with increased cerebrospinal fluid volume fraction. Comprehensive brain volumetric analysis revealed a more marked relationship with atrophy for MMP-7, which was significantly correlated with neural injury in multiple brain regions and nearly all ventricular measurements. MMP-7 was also correlated with measures of virologic and cognitive status.
Journal of NeuroVirology 02/2011; 17(2):153-8. · 2.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To evaluate circulating cytokines and chemokines as correlates of the degree of brain injury in individuals with advanced human immunodeficiency virus (HIV) infection.
Study participants included ten well-characterized subjects in advanced stage HIV infection. High-throughput multiplexed analysis was used to quantify markers of interest at baseline and 3 years later in the clinical course. Objective measurements of the brain were derived in vivo with quantitative magnetic resonance segmentation algorithms and with diffusion tensor imaging.
Of the markers examined, monocyte chemoattractant protein-1 (MCP-1 or CCL-2) was the most prominent correlate of brain injury. Elevated MCP-1 levels correlated with brain white matter alterations at the initial assessment. The relationship to injury was more extensive 3 years later; elevated MCP-1 was significantly correlated with measures of brain microstructural alterations and of abject atrophy.
The findings build on our prior observations that elevated MCP-1 levels may be a useful predictive marker for HIV-associated neurocognitive disorder. As a potent chemoattractant, MCP-1 may mediate injury through participation in self-reinforcing cycles of chronic immune activation and cytokine/chemokine-mediated neurotoxicity.
PROTEOMICS - CLINICAL APPLICATIONS 03/2010; 4(3):295-303. · 1.81 Impact Factor
-
Neurology 08/2009; 73(4):e14-5. · 8.31 Impact Factor
-
Leon G Epstein,
Ali Jalali,
Ajit N Chary,
Sophia Khan,
Joshua Ross,
Justine Coppinger,
Katrin Carlson,
Joel Charrow,
Barbara Burton,
Donald Zimmerman,
John Curran,
Francine Kim,
Pam Nguyen,
Delilah Burrowes,
Brad Angle,
Cynthia Stack,
Lisa Shaffer,
John A Kessler,
Alexander G Bassuk
[show abstract]
[hide abstract]
ABSTRACT: De novo constitutional chromosomal anomalies provide important insights into the genetic loci responsible for congenital neurological disorders. However, most phenotypic descriptions of patients with rare chromosomal abnormalities are published as individual case reports or small group studies, making genotype-phenotype correlations unclear. Moreover, many clinical genetic reports do not include neuroimaging.
We conducted a retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006. The case series was selected from a database containing all chromosomal testing results, clinical data, and neuroimaging. Clinical examination results were assigned by board certified geneticists and/or neurologists and neuroimages were reviewed by both a neurologist or neuroradiologist and a blinded neurologist.
Of the 28,108 children in the series, we identified 34 children with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions.
This study demonstrates the utility of large clinical databases in assessing genotype-phenotype correlations and mapping loci for congenital neurological disorders. We describe a case-series strategy to analyze existing databases to reveal new genotype-phenotype correlations.
Birth Defects Research Part A Clinical and Molecular Teratology 05/2008; 82(4):200-10. · 2.27 Impact Factor
-
Lynn M Wachtman,
Richard L Skolasky,
Patrick M Tarwater,
Deneen Esposito,
Giovanni Schifitto,
Karen Marder,
Michael P McDermott,
Bruce A Cohen,
Avindra Nath,
Ned Sacktor, Leon G Epstein,
Joseph L Mankowski,
Justin C McArthur
[show abstract]
[hide abstract]
ABSTRACT: The identification of biomarkers identifying onset of human immunodeficiency virus-associated dementia (HIV-D) is critical for diagnosis and the elucidation of pathophysiologic pathways.
To examine the association between platelet decline from baseline and HIV-D.
Prospective cohort study within the North-East AIDS Dementia cohort.
Four participating referral centers in the United States.
A total of 396 subjects with advanced human immunodeficiency virus (HIV) infection recruited between 1998 and 2003 and undergoing serial neurologic assessments. Eligibility criteria required CD4 cell counts less than 200/microL or less than 300/microL with evidence of cognitive impairment. A cohort subset without prevalent HIV-D at baseline and without incident HIV-D at the visit immediately after baseline was analyzed (n = 146). Main Outcome Measure Time to first diagnosis of HIV-D.
After a median follow-up of 31.1 months, 40 subjects developed HIV-D. Platelet decline from baseline was associated with the development of HIV-D when examined as a time-dependent variable lagged by 6 to 12 months before outcome (multivariate hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.14-5.02; P = .02). This association was stronger during the first 2 years of follow-up (multivariate HR, 6.76; 95% CI, 2.36-19.41; P < .001) than during later years (multivariate HR, 0.94; 95% CI, 0.33-2.67; P = .90).
These results suggest that individuals with declining platelet counts are at greater risk for HIV-D and that the dynamics of circulating platelets vary with respect to the temporal progression of HIV-D. This highlights an avenue to be explored in the understanding of HIV-D pathogenesis.
Archives of Neurology 09/2007; 64(9):1264-72. · 7.58 Impact Factor
-
Jeffrey J Sevigny,
Steven M Albert,
Michael P McDermott,
Giovanni Schifitto,
Justin C McArthur,
Ned Sacktor,
Katherine Conant,
Ola A Selnes,
Yaakov Stern,
Daniel R McClernon,
Donna Palumbo,
Karl Kieburtz,
Garrett Riggs,
Bruce Cohen,
Karen Marder, Leon G Epstein
[show abstract]
[hide abstract]
ABSTRACT: Several markers of immune activation have been identified as potential prognostic markers for human immunodeficiency virus (HIV)-associated morbidity and mortality, but the results from studies are conflicting.
To evaluate whether neurocognitive status and baseline levels of plasma and cerebrospinal fluid tumor necrosis factor alpha (TNF-alpha), macrophage chemoattractant protein 1 (MCP-1), matrix metalloproteinase 2 (MMP-2), or macrophage colony-stimulating factor (M-CSF) are associated with time to death in a cohort with advanced HIV infection.
Cohort study.
Enrollees in the Northeast AIDS Dementia Study.
Three hundred twenty-nine subjects who were positive for HIV-1 and had a CD4 cell count of less than 200/microL (or <300/microL but with cognitive impairment at baseline) were assessed for CD4 cell count, neurocognitive status, pertinent demographic and clinical variables, and plasma and cerebrospinal fluid HIV RNA, TNF-alpha, MCP-1, MMP-2, and M-CSF levels.
Cox proportional hazards regression models were used to examine the associations between the variables of interest (using time-dependent covariates, where applicable) and time to death, adjusting for possible confounders.
There were 50 deaths in the cohort after a median of 25.2 months of follow-up. The cumulative incidences of death were 7% at 1 year and 16% at 2 years. In Cox proportional hazards regression analyses adjusting for demographic, clinical, and immunological variables, HIV-associated dementia (hazard rate, 6.10; P = .001) was significantly associated with time to death; (log) plasma MCP-1 level (hazard rate, 3.38; P = .08) trended toward significance.
In patients with advanced HIV infection, HIV-associated dementia is an independent predictor of time to death.
Archives of Neurology 02/2007; 64(1):97-102. · 7.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Primary angiitis of the central nervous system (PACNS) is a rare, idiopathic vasculitis diagnosed most frequently in adults. We describe 2 children presenting with hemiplegia from PACNS treated with cyclophosphamide. Diagnosis in one child was based on abnormal angiography. Oral, but not intravenous (IV), cyclophosphamide was effective in preventing progressive weakness. The second child had unremarkable angiography, but brain biopsy revealed vasculitis; IV cyclophosphamide prevented further weakness. Both cases highlight the importance of early diagnosis and treatment.
The Journal of Rheumatology 11/2006; 33(10):2078-80. · 3.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Diffusion tensor imaging (DTI) was used to derive in vivo tissue status measurements of subcortical brain regions that are vulnerable to injury in human immunodeficiency virus (HIV)-infected patients. Quantitative measurements, including the mean diffusivity (MD) and fractional anisotropy (FA), were determined in lateralized basal ganglia (caudate and putamen) and centrum semiovale in 11 well-characterized HIV patients and in 11 control subjects. DTI measurements were examined for patterns of relationship with markers of clinical and cognitive progression. DTI measures acquired in subcortical regions were significantly correlated with loss of function in specific cognitive domains. Significant relationships were identified between measures for putamen and verbal memory (MD), visual memory (FA), working memory (FA), and overall cognitive impairment (MD). Measures for caudate (FA) were significantly correlated with visual memory. Measures for centrum semiovale were significantly correlated with visual memory deficits (MD) and visuoconstruction (FA). Relationships between anisotropy measures and anemia (basal ganglia) and CD4 counts (centrum semiovale) were also observed. Findings from this investigation indicate that DTI is a sensitive tool for correlating neuroanatomic pathologic features with specific cognitive deficits in patients with HIV infection.
Journal of NeuroVirology 08/2005; 11(3):292-8. · 2.31 Impact Factor
-
Alexander G Bassuk,
David Craig,
Ali Jalali,
Abhishek Mukhopadhyay,
Francine Kim,
Joel Charrow,
Uzel Gulbu, Leon G Epstein,
Robin Bowman,
David McLone,
Hisato Yagi,
Rumiko Matsuoka,
Dietrich A Stephan,
John A Kessler
American Journal of Medical Genetics Part A 03/2005; 132(4):450-3. · 2.39 Impact Factor
-
Justin C McArthur,
Michael P McDermott,
Daniel McClernon,
Coryse St Hillaire,
Kathy Conant,
Karen Marder,
Giovanni Schifitto,
Ola A Selnes,
Ned Sacktor,
Yaakov Stern,
Steve M Albert,
Karl Kieburtz,
Joy A deMarcaida,
Bruce Cohen, Leon G Epstein
[show abstract]
[hide abstract]
ABSTRACT: Before the introduction of combination antiretroviral therapy (CART), neurological disease correlated with cerebrospinal fluid (CSF) levels of human immunodeficiency virus (HIV) RNA.
To investigate the relationships among HIV RNA levels, immune activation markers, and neurological status in patients receiving CART.
Multicenter cohort study.
Academic neurology departments.
A total of 371 patients unselected for neurological complaints and with CD4 cell counts less than 200/microL or with cognitive symptoms and CD4 cell counts less than 300/microL were enrolled into the Northeastern AIDS Dementia cohort in 1998-2002. Diagnoses of HIV-associated dementia (HIV-D) and minor cognitive-motor disorder (MCMD) were obtained with a computerized algorithm. Plasma and CSF levels of HIV RNA, monocyte chemotactic protein 1, macrophage colony-stimulating factor, and tumor necrosis factor alpha were quantified.
The mean +/- SD age was 41.5 +/- 7.2 years, and the mean +/- SD educational level was 12.3 +/- 2.2 years. Seventy percent of the cohort was black, and 30% were women. The mean +/- SD CD4 cell count was 136.8 +/- 87.9/microL, and CART was used in 71%. Twenty-nine percent of the patients were unimpaired (n = 106), 36% had MCMD (n = 133), and 35% had HIV-D (n = 128). Mean log(10) CSF HIV RNA copies per milliliter was 2.6 +/- 0.8, with no differences among the neurological groups, even after adjustments for baseline CD4 cell counts and antiretroviral therapy. Cerebrospinal fluid HIV RNA was undetectable in 47% of unimpaired, 46% of MCMD, and 43% of HIV-D patients (P = .91). Plasma levels of monocyte chemotactic protein type 1 and tumor necrosis factor alpha correlated weakly with HIV RNA levels but did not distinguish those with neurological deficits.
In contrast to observations in individuals not treated with CART, we found no relationship between CSF markers and neurological status in this CART-using cohort with advanced HIV/AIDS. This was not explicable by demographic differences or plasma virological control. CART may substantially attenuate the degree of central nervous system HIV infection and immune activation, and in CART users, CSF HIV RNA and immune activation markers may fail to discriminate milder degrees of HIV-D and MCMD.
Archives of Neurology 12/2004; 61(11):1687-96. · 7.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Quantitative MR imaging strategies may have considerable potential for in vivo assessment of neuropathologic changes associated with HIV. This investigation evaluated the prognostic significance of whole brain histogram-derived diffusion tensor imaging indices with respect to severity of cognitive impairment and measures of clinical status in cases of HIV.
Quantitative indices derived with diffusion tensor imaging, including whole brain fractional anisotropy and the apparent diffusion coefficient, were compared for six patients with HIV and eight control volunteers. Relationships between whole brain indices and specific measures of dementia severity and clinical status were examined.
Whole brain fractional anisotropy was reduced in patients with HIV and was significantly associated with severity of dementia, as indicated by several widely used clinical and functional status measures. Summary fractional anisotropy measures were more prognostic of dementia status than were apparent diffusion coefficient measures.
Findings from this investigation support the use of diffusion tensor imaging for noninvasive MR imaging measurement of neuropathologic changes in studies of HIV-associated cognitive impairment.
American Journal of Neuroradiology 03/2004; 25(2):195-200. · 2.93 Impact Factor
