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Background Hypertension and HIV are salient risk factors for cerebral small vessel disease and neurocognitive impairment, yet the effects of hypertension on neurocognitive performance in persons living with HIV remain poorly understood. This is the first study to examine the longitudinal associations between blood pressure, hypertension, and pulse pressure with neurocognitive performance in persons living with HIV. Setting New York City. Methods Analysis of medical, neurocognitive, and virologic data from 485 HIV+ participants collected by the Manhattan HIV Brain Bank, a prospective, observational, longitudinal study of neuroHIV. A series of multilevel linear growth curve models with random intercepts and slopes were estimated for blood pressure, hypertension status, and pulse pressure to predict change in neurocognitive performance. Results The baseline prevalence of hypertension was 23%. Longitudinal change in diastolic and systolic pressure were associated with 10.5-second and 4-second increase in Grooved Pegboard Test non-dominant hand performance, respectively. Longitudinal change in diastolic blood pressure was also associated a .3-point decline in correct categories and 3-point increase in perseverative responses and total errors on the Wisconsin Card Sorting Test. Increasing odds of prevalent and/or incident hypertension was associated with a .1-point decrease in correct categories and a .8-point increase in total errors on the Wisconsin Card Sorting Test. There was no association between pulse pressure and neurocognitive performance. Conclusions Results indicate linear longitudinal relations for blood pressure and hypertension with poorer neurocognitive test performance, particularly in psychomotor and executive functions in persons with HIV.

Objective: Atherosclerotic cardiovascular disease (ASCVD) is an increasing cause of morbidity and mortality in people with HIV since the introduction of combination antiretroviral therapy. Despite recent advances in our understanding of HIV ASCVD, controversy still exists on whether this increased risk of ASCVD is due to chronic HIV infection or other risk factors. Mounting biomarker studies indicate a role of monocyte/macrophage activation in HIV ASCVD; however, little is known about the mechanisms through which HIV infection mediates monocyte/macrophage activation in such a way as to engender accelerated atherogenesis. Here, we experimentally investigated whether HIV expression is sufficient to accelerate atherosclerosis and evaluated the role of caspase-1 activation in monocytes/macrophages in HIV ASCVD. Approach and Results: We crossed a well-characterized HIV mouse model, Tg26 mice, which transgenically expresses HIV-1, with ApoE −/− mice to promote atherogenic conditions ( Tg26 +/− / ApoE −/− ). Tg26 +/− /ApoE −/− have accelerated atherosclerosis with increased caspase-1 pathway activation in inflammatory monocytes and atherosclerotic vasculature compared with ApoE −/− . Using a well-characterized cohort of people with HIV and tissue-banked aortic plaques, we documented that serum IL (interleukin)-18 was higher in people with HIV compared with non–HIV-infected controls, and in patients with plaques, IL-18 levels correlated with monocyte/macrophage activation markers and noncalcified inflammatory plaques. In autopsy-derived aortic plaques, caspase-1+ cells and CD (clusters of differentiation) 163+ macrophages correlated. Conclusions: These data demonstrate that expression of HIV is sufficient to accelerate atherogenesis. Further, it highlights the importance of caspase-1 and monocyte/macrophage activation in HIV atherogenesis and the potential of Tg26 +/− /ApoE −/− as a tool for mechanistic studies of HIV ASCVD.

Author(s): Saloner, Rowan; Heaton, Robert K; Campbell, Laura M; Chen, Anna; Franklin, Donald; Ellis, Ronald J; Collier, Ann C; Marra, Christina; Clifford, David B; Gelman, Benjamin; Sacktor, Ned; Morgello, Susan; McCutchan, J Allen; Letendre, Scott; Grant, Igor; Fennema-Notestine, Christine; CHARTER Study Group | Abstract: ObjectiveThe influence of confounding neurocognitive comorbidities in people living with HIV (PLWH) on neuroimaging has not been systematically evaluated. We determined associations between comorbidity burden and brain integrity and examined the moderating effect of age on these relationships.DesignObservational, cross-sectional substudy of the CNS HIV Antiretroviral Therapy Effects Research cohort.MethodsA total of 288 PLWH (mean age = 44.2) underwent structural MRI and magnetic resonance spectroscopy as well as neurocognitive and neuromedical assessments. Consistent with Frascati criteria for HIV-associated neurocognitive disorders (HAND), neuromedical and neuropsychiatric comorbidity burden was classified as incidental (mild), contributing (moderate), or confounding (severe-exclusionary) to a diagnosis of HAND. Multiple regression modeling predicted neuroimaging outcomes as a function of comorbidity classification, age, and their interaction.ResultsComorbidity classifications were 176 incidental, 77 contributing, and 35 confounded; groups did not differ in HIV disease characteristics. Relative to incidental and contributing participants, confounded participants had less cortical gray matter and more abnormal white matter and ventricular cerebrospinal fluid, alongside more neuroinflammation (choline, myo-inositol) and less neuronal integrity (N-acetylaspartate). Older age exacerbated the impact of comorbidity burden: to a greater extent in the confounded group, older age was associated with more abnormal white matter (P = 0.017), less total white matter (P = 0.015), and less subcortical gray matter (P = 0.014).ConclusionNeuroimaging in PLWH reveals signatures associated with confounding neurocognitive conditions, emphasizing the importance of evaluating these among individuals with suspected HAND. Older age amplifies subcortical and white matter tissue injury, especially in PLWH with severe comorbidity burden, warranting increased attention to this population as it ages.

Background Mental health consequences of the COVID-19 pandemic have been observed. Psychiatric symptoms in people living with HIV, and their relationship to physical symptomatology and prior psychopathology, are not yet reported. Setting An HIV cohort sheltering-in-place in New York City. Methods Forty-nine participants in a longitudinal study were contacted by telephone in April 2020. A structured interview queried COVID-19-associated physical symptoms, and mental health screens were performed with the generalized anxiety disorder-2 (GAD-2) and patient health questionnaire-2 (PHQ-2). Prior medical and neuropsychiatric data were obtained from preceding study visits. Post-hoc analyses were performed. Results The mean age of respondents was 62.1 years, 39% were women, and 35% African American, 37% Latinx, and 28% Caucasian. COVID-19-indicator symptoms were present in 69%; 41% had respiratory and 61% extra-pulmonary symptoms. Mental health symptoms were endorsed in 45% with PHQ-2 and 43% with GAD-2, although threshold for major depression was met in only 4% and for GAD in 14%. Higher PHQ scores were associated with respiratory symptoms, but not prior mood or anxiety disorders. GAD-2 scores were higher with past mood disorders, but not with prior anxiety disorders or respiratory symptoms. Conclusions Physical symptoms were frequent and mild psychiatric symptoms were common, but serious anxiety and depression were not often endorsed by this group of people living with HIV at the acute height of the New York City COVID-19 pandemic. Reasons for this are unclear, as this preliminary report is descriptive in nature. Short- and long-term consequences of acute mental health symptoms require further study.

Objective To test whether HIV is associated with brain large artery vulnerable intima. Design Cross-sectional study of autopsied HIV-positive (HIV+) cases sex and age-matched to HIV-negative (HIV-) controls. Methods Brain large arteries from 302 autopsied cases (50% HIV+) were evaluated morphometrically for the presence of atherosclerosis, size of necrotic core, and fibrous cap thickness. Intima vulnerability was measured as intima elastolytic score [0-5, based on intimal metalloproteinases (MMP)-2, MMP-3, and MMP-9, and tissue inhibitor for MMP-1 and MMP-2 staining], intima inflammatory score (0-3, based on intimal presence of CD3 and CD68 cells and TNF-α staining), neoangiogenesis (factor VIII staining), and apoptosis (caspase 3 staining). Hierarchical generalized linear models were used to obtain the beta estimates and their 95% confidence intervals, adjusting for demographics and vascular risk factors. Results The prevalence of atherosclerosis did not differ by HIV status. Necrotic cores filled larger proportions of the intima in HIV+ individuals with CD4 cell count above 200 cells/μl at death compared to HIV- controls (adjusted B = 11.6%, P = 0.04). HIV+ individuals had greater elastolytic scores (adjusted B = 0.34, P = 0.02), especially those with less than 200 CD4 cells/μl at death (adjusted B = 0.41, P = 0.01). Intima inflammation, neoangiogenesis, and apoptosis were not different among HIV+ cases versus HIV- controls. Conclusion Individuals with HIV and CD4 cell count at least 200 cells/μl at death had relatively larger necrotic cores, whereas those with HIV and CD4 cell count below 200 cells/μl at death had evidence of increased connective tissue remodeling in the intima. These findings suggest an increased potential for endothelial erosion, thrombosis, and plaque rupture that may relate to higher risk for vascular events.

Background and Purpose— We tested the hypothesis that posterior brain arteries differ pathologically from anterior brain arteries and that this difference varies with age. Methods— Brain large arteries from 194 autopsied individuals (mean age 56±17 years, 63% men, 25% nonwhite, 17% with brain infarcts) were analyzed to obtain the areas of arterial layers and lumen as well as the relative content of elastin, collagen, and amyloid. Visual rating was used to determine the prevalence of atheroma, calcification, vasa vasorum , pattern of intima thickening, and internal elastic lamina gaps. We used multilevel models adjusting for age, sex, ethnicity, vascular risk factors, artery type and location, and multiple comparisons. Results— Of 1362 large artery segments, 5% had vasa vasorum, 5% had calcifications, 15% had concentric intimal thickening, and 11% had atheromas. Posterior brain arteries had thinner walls, less elastin, and more concentric intima thickening than anterior brain arteries. Compared to anterior brain arteries, the basilar artery had higher arterial area encircled by the internal elastic lamina, whereas the vertebral arteries had higher prevalence of elastin loss, concentric intima thickening, and nonatherosclerotic stenosis. In younger individuals, vertebral artery calcifications were more likely than calcification in anterior brain arteries, but this difference attenuated with age. Conclusions— Posterior brain arteries differ pathologically from anterior brain arteries in the degree of wall thickening, elastin loss, and concentric intimal thickening.

Introduction: Brain arteries, large and small, are exposed to aging and acquired risk factors simultaneously. Therefore, we hypothesize that pathological changes noted with brain large artery aging, such as intima thickening, luminal dilatation and/or atherosclerosis, will be observed in their penetrating arterial branches. Methods: We extracted 1,695 brain large arteries and 1,233 corresponding penetrating arteries from 211 autopsied brains (mean age 67 ± 18 years, 60% men, 73% non-Hispanic white, 17% with brain infarcts). From each arterial segment we obtained measures of lumen, wall, intima and interadventitial diameters, and percentage stenosis using a semi-automated method based on color-thresholding. We visually rated the presence of concentric intima thickening and/or atheromas. We used hierarchical models to relate large artery characteristics to their penetrating arteries. Results: Of the 1695 large arteries, 182 (11%) were sectioned in continuity with the ostia of penetrating arteries and 1,233 (42%) exhibited cross-sections of their penetrating arteries at their peripheries (Figure 1). Of the 182 penetrating artery ostia, 123 (67%) exhibited intima thickening and in 46 (37%), the ostia was the only location in the cross-section of the large artery that had intima thickening. The mean luminal diameter of penetrating branches was 280 ± 231 μ and 19% had intima thickening (Figure 1). Large artery characteristics were associated with measures of penetrating artery disease (table 1). Conclusion: We found evidence that pathological changes in brain large arteries are observed in their penetrating arterial branches, supporting the notion that brain arterial aging occurs as a continuum. The unique geometric configuration of the penetrating artery ostia may predispose them to intimal thickening early on. Segregating brain arterial disease into small or large artery underestimates the extent of cerebrovascular disease attributed to each category.

Background: Though Varicella Zoster Virus (VZV) causes cerebral vasculitis and is found in vessels of those at risk for reactivation, its effect on vessel structure is unclear. We hypothesized that VZV would be associated with inward cerebral arterial remodeling and inflammation, especially in HIV. Methods: Large and penetrating autopsied brain arteries from cases with and without HIV (age- and sex-matched) were stained with an anti-VZV latency-associated open reading frame 63 gene product antibody to identify likely-latent VZV presence and localization in arterial layers. For each artery, we found lumen, wall, intima and interadventitial diameters and percent stenosis, using a semi-automated method with color thresholding with excellent reliability. We visually rated the presence of concentric intima thickening and/or atheromas with good to excellent reliability. We stained for CD68 to assess macrophage presence in arterial walls. We used hierarchical models, adjusting for demographics and risk factors. Results: 66% of the 162 autopsied brains (mean age 49 + 9 years, 70% male, 56% non-white, 52% HIV+) had VZV in at least one vessel. In large arteries, VZV was associated with intima thinning similarly with and without HIV. Among those with HIV and CD4 < 200 cells/μl at death, VZV was inversely associated with intima thickness (ß= -24.22, p=0.01), interadventitial (ß= -222.80, p=0.02) and luminal diameters (ß= -186.80, p=0.03), and lumen-to-wall ratio (ß= -0.31, p=0.02). Intima VZV was associated with arterial wall CD68+ cells, and especially with intima CD68 (ß= 0.19, p=0.03). In a model stratified by HIV, VZV was associated with CD68 among those with HIV (ß=0.13, p=0.01), but not those without (ß=0.07, p=0.18). Conclusion: Likely-latent VZV is associated with small arteries and low lumen-to-wall ratios, especially in HIV with persistent immunosuppression. Monocytic inflammation with latent VZV may play a role in VZV- and HIV-induced brain arterial remodeling.

To test the hypothesis that brain arterial aging is associated with the pathologic diagnosis of Alzheimer disease (AD).Brain large arteries were assessed for diameter, gaps in the internal elastic lamina (IEL), luminal stenosis, atherosclerosis, and lumen-to-wall ratio. Elastin, collagen, and amyloid were assessed with Van Gieson, trichrome, and Congo red staining intensities, and quantified automatically. Brain infarcts and AD (defined pathologically) were assessed at autopsy. We created a brain arterial aging (BAA) score with arterial characteristics associated with aging after adjusting for demographic and clinical variables using cross-sectional generalized linear models.We studied 194 autopsied brains, 25 (13%) of which had autopsy evidence of AD. Brain arterial aging consisted of higher interadventitial and lumen diameters, thickening of the wall, increased prevalence of IEL gaps, concentric intima thickening, elastin loss, increased amyloid deposition, and a higher IEL proportion without changes in lumen-to-wall ratio. In multivariable analysis, a high IEL proportion (B = 1.96, p = 0.030), thick media (B = 3.50, p = 0.001), elastin loss (B = 6.16, p0.001), IEL gaps (B = 3.14, p = 0.023), and concentric intima thickening (B = 7.19, p0.001) were used to create the BAA score. Adjusting for demographics, vascular risk factors, atherosclerosis, and brain infarcts, the BAA score was associated with AD (B = 0.022, p = 0.002).Aging of brain large arteries is characterized by arterial dilation with a commensurate wall thickening, elastin loss, and IEL gaps. Greater intensity of arterial aging was associated with AD independently of atherosclerosis and brain infarcts. Understanding the drivers of arterial aging may advance the knowledge of the pathophysiology of AD.

Objectives We report a case of primary neurolymphomatosis (NL) with unusual presentation and excellent treatment response. Methods Chart review. Results A 64-year-old woman presented with 2 months of progressive pain, weakness, and numbness in her right leg. Nerve conduction study/electromyogram suggested a right lumbosacral radiculoplexus neuropathy with associated acute right peroneal neuropathy at the fibular head. L/S spine and right leg magnetic resonance imaging showed thickening and contrast enhancement of the right S1 nerve root and the right distal sciatic, tibial, and common peroneal nerves, as well as a lobular enhancing lesion of the right superficial peroneal nerve. Whole-body fludeoxyglucose-positron emission tomography scan showed no other lesions. A right superficial peroneal nerve lesion biopsy revealed infiltration of the nerve by diffuse large B-cell lymphoma. The lymphoma cells expressed BCL2 but not CD10, suggesting an origin in peripheral blood not lymph nodes. Despite the expression of BCL2, which is considered as a poor prognosis marker, our patient responded very well to the combined radiotherapy and chemotherapy with the R-MPV (rituximab, MTX, procarbazine, and vincristine) regimen. The patient showed marked clinical improvement and complete resolution of lymphoma lesions on the PET scan. Conclusions Our case broadens the clinical spectrum and illustrates the importance of early diagnosis and aggressive treatment of primary NL.

OBJECTIVE We tested our hypothesis that abdominal obesity when associated with increased levels of systemic and central nervous system immunoinflammatory mediators contributes to neurocognitive impairment (NCI). DESIGN Cross-sectional. SETTING Six Academic Centers. PARTICIPANTS One hundred fifty-two patients with plasma HIV RNA

Background: HIV-infected individuals may display chronic brain inflammation. It is unclear whether this inflammation may play a role in brain arterial pathologies that predispose patients with HIV to stroke. We tested the hypothesis that T cell infiltrates would be associated with brain arterial pathology. Methods: Large brain arteries from 162 patients (84 with HIV) were used in immunohistochemical analysis to detect CD3, a pan T cell marker. A semi-quantitative score of 0 to 3 (absent, mild, moderate, severe) was created by visually rating CD3+ cells within each arterial layer (intima, media, and adventitia). Arterial stenosis, lumen-to-wall ratio and presence of atherosclerosis were measured in each arterial segment of the circle of Willis using previously reported methods of good to excellent reliability. All models were adjusted for co-dependence between arteries of the same subject as well as for age, sex, ethnicity, vascular risks factors, cocaine use and artery type and location. Results: Brain arteries from HIV+ individuals had lower adventitial CD3 scores than HIV- (B = -1.65, p = 0.004). Further stratification demonstrated that the decreased arterial CD3 score was significant only among HIV+ subjects with premortem CD4 counts < 200 cells/μl (B = -2.28, p premortem CD4 counts ≥ 200 cells/μl, CD3 arterial scores were associated with brain atherosclerosis (B = 0.74, p=0.04). Independent of HIV status, CD3 score was associated with decreased lumen-to-wall ratio (B = -0.37, p = 0.02) and percentage luminal stenosis (B = 1.99, p = 0.004). Among HIV+ cases, higher CD3 score was noted with higher CD4 count at death (per 50, B=0.43, P=0.001), hypertension (B=7.14, P Conclusions: Among HIV+ individuals with premortem CD4 counts ≥ 200, there exists an association between brain arterial lymphocytic activity with atherosclerosis. These findings may suggest a role for lymphocytic inflammation in HIV-related atherosclerosis in the setting of immune reconstitution.

Introduction: By virtue of their infection, HIV+ patients are subject to chronic inflammation, and show an increased risk for stroke when compared to uninfected controls. We hypothesized that HIV infection would be associated with increased atherosclerotic plaque vulnerability. Methods: Large brain arteries from 162 autopsied individuals (84 with HIV) were stained for metalloproteinase (MMP)-2, MMP-3, MMP-9, Caspase-3, and tumor necrosis factor (TNF)-α, factors reported to increase plaque vulnerability. We measured intensity of staining for each protein in the fibrous cap and scored each as 0 (most intense staining not in cap) or 1 (most intense staining in cap). We then added the ratings from the five stains and created a vulnerability score ranging from 0-5. CD3+ cells (lymphocytes) and CD68+ cells (macrophages) were also rated using semi-quantitative scores. Rating was blind to HIV status. We constructed multilevel models to obtain the β estimates and their 95% confidence intervals (β, 95%CI), adjusting for demographic characteristics, vascular risk factors, and HIV-related immune variables. Results: For the entire sample, the plaque vulnerability score was associated with higher degree of luminal stenosis (0.04, 0.02-0.06) and larger arterial size (0.5 per mm, 0.2-0.8), but not with HIV (-0.65, -2.24-0.95). However, in a subset of individuals with atherosclerosis (n=21), there was a statistical interaction (P 200 cells/ul at death was associated with higher vulnerability score (1.42, 0.08-2.76) compared with subjects who remained immunosuppressed. Predictors of vulnerability score among HIV+ subjects included higher CD3 score (1.12, 0.15-2.09), older age (0.18 per year, 0.12-0.25), diabetes (3.00, 1.69-4.24), lower CD4 nadir (-0.01, -0.02to -0.007), antiretroviral use at death (-2.08, -3.84 to -0.32). Conclusions: Plaque vulnerability is positively associated with a higher blood CD4 count, lower CD4 nadir and higher lymphocytic inflammation in brain arteries among HIV+ cases. Investigating the role of HIV-related chronic inflammation and plaque vulnerability may help us better understand the higher risk of stroke among those with HIV.

Objective(s): HIV-associated neurocognitive disorders (HAND) remain prevalent in HIV-infected patients on antiretroviral therapy (ART), but the underlying mechanisms are unclear. Some features of HAND resemble those of age-associated cognitive decline in the absence of HIV, suggesting that overlapping mechanisms may contribute to neurocognitive impairment. Design: Cross-sectional analysis of cerebrospinal fluid (CSF) from 100 individuals (46 HIV-positive patients and 54 HIV-negative controls). Methods: Untargeted CSF metabolite profiling was performed using liquid/gas chromatography followed by mass spectrometry. Cytokine profiling was performed by Bioplex. Bioinformatic analyses were performed in Metaboanalyst and R. Results: Alterations in the CSF metabolome of HIV patients on ART mapped to pathways associated with neurotransmitter production, mitochondrial function, oxidative stress, and metabolic waste. Many CSF metabolites altered in HIV overlapped with those altered with advanced age in HIV-negative controls, suggesting a pattern indicative of accelerated aging. Machine learning models identified neurotransmitters (glutamate, N-acetylaspartate), markers of glial activation (myo-inositol), and ketone bodies (beta-hydroxybutyric acid, 1,2-propanediol) as top-ranked classifiers of HAND. These CSF metabolites correlated with worse neurocognitive test scores, plasma inflammatory biomarkers [interferon (IFN)-α, IFN-γ, interleukin (IL)-8, IL-1β, IL-6, IL-2Ra], and intrathecal IFN responses (IFN-γ and kynurenine : tryptophan ratio), suggesting inter-relationships between systemic and intrathecal inflammation and metabolic alterations in CSF. Conclusions: Alterations in the CSF metabolome of HIV patients on ART suggest that persistent inflammation, glial responses, glutamate neurotoxicity, and altered brain waste disposal systems contribute to mechanisms involved in HAND that may be augmented with aging.

BACKGROUND Activated monocytes/macrophages play a role in severe forms of HIV-associated neurocognitive disorders (HAND), but little is known about the mechanisms driving milder forms that are prevalent despite combination antiretroviral therapy (cART). To examine relationships of monocyte activation markers to HAND of varying severity, we compared plasma and cerebrospinal fluid (CSF) biomarker levels with neurocognitive test scores in HIV+ subjects. METHODS Plasma and CSF soluble CD14 (sCD14), CCL2, and interleukin (IL) 6 were measured by enzyme-linked immunosorbent assay in 67 HIV+ subjects with nadir CD4

To measure maraviroc total cerebrospinal fluid (CSF) concentrations and compare them with total and unbound plasma concentrations. Total maraviroc was measured by reverse-phase high-performance liquid chromatography with tandem mass spectrometry, whereas ultrafiltration was used for unbound maraviroc. Maraviroc was detected in all nine CSF/plasma pairs with a median CSF total concentration of 2.4 ng/ml. CSF concentrations exceeded the 50% inhibitory concentration of wild-type CC chemokine receptor 5-tropic HIV-1 in all specimens. CSF concentrations are lower than expected based on plasma concentrations and physicochemical characteristics. Unbound maraviroc plasma concentrations may be informative in estimating concentrations in CSF.

To determine how serious a confound substance use (SU) might be in studies on HIV-associated neurocognitive disorder (HAND), we examined the relationship of SU history to neurocognitive impairment (NCI) in participants enrolled in the Central Nervous System HIV Antiretroviral Therapy Effects Research study.: After excluding cases with behavioral evidence of acute intoxication and histories of factors that independently could account for NCI (eg, stroke), baseline demographic, medical, SU, and neurocognitive data were analyzed from 399 participants. Potential SU risk for NCI was determined by the following criteria: lifetime SU Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis, self-report of marked lifetime SU, or positive urine toxicology. Participants were divided into 3 groups as follows: no SU (n = 134), nonsyndromic SU (n = 131), syndromic SU (n = 134) and matched on literacy level, nadir CD4, and depressive symptoms.: Although approximately 50% of the participants were diagnosed with HAND, a multivariate analysis of covariance of neurocogntive summary scores, covarying for urine toxicology, revealed no significant effect of SU status. Correlational analyses indicated weak associations between lifetime heroin dosage and poor recall and working memory and between cannabis and cocaine use and better verbal fluency.: These data indicate that HIV neurocognitive effects are seen at about the same frequency in those with and without historic substance abuse in cases that are equated on other factors that might contribute to NCI. Therefore, studies on neuroAIDS and its treatment need not exclude such cases. However, the effects of acute SU and current SU disorders on HAND require further study.

Author(s): Lyons, Jennifer L; Uno, Hajime; Ancuta, Petronela; Kamat, Anupa; Moore, David J; Singer, Elyse J; Morgello, Susan; Gabuzda, Dana | Abstract: ObjectiveMild forms of HIV-associated neurocognitive disorders (HAND) remain prevalent in the era of combination antiretroviral therapy (cART). Although elevated lipopolysaccharide (LPS) and immune activation are implicated in HAND pathogenesis, relationships of LPS and inflammatory markers to mild forms of HAND or impairment in specific cognitive domains are unknown. To examine these relationships, we compared plasma soluble CD14 (sCD14), CCL2, and LPS levels with neurocognitive test scores in a cART era cohort.MethodsWe analyzed plasma from HIV+ subjects (n = 97) with nadir CD4 counts l300 and high frequency of hepatitis C virus coinfection and illicit drug use for relationships between sCD14, CCL2, and LPS levels and neurocognitive test scores.ResultsPlasma sCD14 levels were higher in subjects with test scores indicating global impairment (P = 0.007), particularly in attention and learning domains (P = 0.015 and P = 0.03, respectively), regardless of HAND diagnosis. Plasma sCD14 levels correlated inversely with global, attention, and learning T scores (P = 0.036, 0.047, and 0.007, respectively) and yielded higher area under receiver operating characteristic values for predicting impaired scores than single-marker models based on plasma or cerebrospinal fluid viral load or CD4 count (area under receiver operating characteristic values = 0.71, 0.81, and 0.71, respectively) and in 4-marker models based on plasma sCD14 and 3 conventional markers compared with the 3-marker models.ConclusionsPlasma sCD14 is a biomarker associated with impaired neurocognitive testing in attention and learning domains in HIV-infected individuals with advanced disease, suggesting involvement of cortical and limbic pathways by inflammatory processes in the cART era. Plasma sCD14 is a potential biomarker to monitor HAND progression and therapeutic responses.

Dynorphins, the endogenous ligands for the κ opioid receptor, are implicated in neuropsychiatric disorders through modulation of basal and stimuli-induced dopaminergic, glutamatergic, and serotonergic tones. Expression of the prodynorphin gene (PDYN) is critical for rewarding properties of drugs of abuse and stress-induced responses. Epigenetic factors, such as DNA methylation, play an important role in modulation of gene expression.We analyzed DNA methylation patterns of three CpG-rich regions of PDYN, a CpG island, and cluster A in the proximal promoter, and cluster B in coding exon 4, by bisulfite sequencing of DNA from the caudate and anterior cingulate cortex from post-mortem brain of 35 individuals (22 HIV seropositive), and in peripheral blood mononuclear cells from 21 of these individuals.We found remarkably similar patterns of methylation across CpG sites in these tissues. However, there were tissue-specific differences in methylation levels (P=0.000001) of the CpG island: higher levels in peripheral blood mononuclear cells (82%) than in the brain tissues, the caudate (62%), and the anterior cingulate cortex (44%). But there was higher PDYN expression in the caudate than in the anterior cingulate cortex. In contrast, cluster A near the transcription start site is hypomethylated.This DNA methylation profile of the PDYN gene is typical for primary responsive genes with regulatory elements for both basal and tissue-specific transcription. Our findings provide a rationale for further studies of the role of other epigenetic factors in the regulation of PDYN expression in individuals with psychiatric and neurological disorders.

Sensory neuropathy (HIV-SN) is a common cause of pain in HIV-infected people. Establishing a diagnosis of HIV-SN is important, especially when contemplating opioid use in high-risk populations. However physical findings of HIV-SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self-report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV-SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV-SN were measured by a modified Total Neuropathy Score (TNS), composed of six objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self-report of DNPP was associated with all six TNS items in univariate analysis and with four TNS items in multivariate analysis. The sensitivity and specificity of self-report of DNPP in detecting the presence of a sensory abnormality were 52% and 92%, respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV-infected patients reporting symptoms consistent with HIV-SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV-SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history.

Background: In the pre-highly active antiretroviral therapy (HAART) era, distal sensory polyneuropathy (DSP) was associated with markers of advanced HIV infection and the use of neurotoxic antiretrovirals (ARVs). As HAART became widespread, and the AIDS epidemic shifted into minority populations, the risk factors for DSP became less clear. We explore the roles of ethnicity and ARV in the development of DSP in an HAART era cohort. Methods: Data from 336 HIV-positive adults were obtained from the Manhattan HIV Brain Bank. One hundred four participants had no DSP at entry visit; at least 1 follow-up visit; and a self-identified ethnicity of non-Hispanic white, Hispanic, or African American. Results: Fifty percent of participants developed DSP; of those, 67% were symptomatic. Participants who developed DSP were older (P = 0.02) and had higher CD4 counts (P = 0.001). ARV-DSP was more common in Hispanics (P = 0.02) and intravenous drug users (P = 0.02). There was a trend for higher pain scores in Hispanics with symptomatic DSP (P = 0.08). Conclusions: This study suggests that there are ethnic disparities in the clinical manifestations of HIV-related neuropathies including pain and the susceptibility to ARV-DSP Further studies of larger cohorts are indicated to explore the etiology of these differences.

Background: The incidence of cerebrovascular events is rising in the HIV population but little is known about the mechanisms of vascular injury among patients with HIV population. Methods: Large cerebral arteries were obtained from autopsies in 80 HIV+ cases and 80 HIV- controls, matched for sex and age ± 3 years, range 30-84. Arterial size, atherosclerosis phenotype, luminal stenosis, and media thickness were obtained in each artery. The average pixel intensities (AI) of metalloproteinase (MMP)-2, MMP-3, MMP-9, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 was assessed with immunohistochemistry defining high intensity as an AI in the upper tertile. Inflammation was assessed with CD68 staining. All estimates were adjusted for age, sex, ethnicity, vascular risk factors and cocaine use. Results: Arterial inflammation was associated with greater staining intensity of MMP3 (Beta=0.36, P=0.003) and TIMP2 (Beta=0.29, P=0.002) in HIV+ cases, but not in HIV- controls. The association of HIV with MMP3 was independent of whether the inflammation was located in the media, intima, or adventitia, while for TIMP-2 the association was only significant with intima inflammation (Beta=-0.36, P=0.03). Cerebral arteries in HIV + cases with high intensity of MMP3 staining had thinner media (Beta=-2.3, P= 50 viral copies/mL (B=0.62, P=0.04), Nucleoside Reverse Transcriptase Inhibitor (B=1.08, P=0.009) or protease inhibitor use at the time of death (B=-0.64, P=0.05), vascular risk factors (B=0.51, P= Conclusions: Arterial inflammation in HIV+ cases is associated with greater expression of MMP3, and arteries with higher expression of MMP3 have a thinner media, despite thicker walls, and greater degrees of luminal narrowing. Through thinning of the media, MMP3 may play a role in HIV-associated dolichoectasia; through secondary effects, it may contribute to paradoxical luminal stenosis.

Background: There is paucity of data about arterial wall characteristics of the smallest and largest caliber cerebral vessels. Determining the relationship between the lumen and the wall might shed new insights into cerebral artery remodeling. Objective: To test the hypotheses that arteries with larger luminal diameters have a thinner wall and that arteries with the smallest lumina have thicker walls. Methods: Cross-sectional segments from large arteries (N=1392) were obtained from the circle of Willis in 196 autopsied brains (mean age 55 ± 17 yrs, 39% with hypertension, 15% with diabetes and 20% with dyslipidemia). Lumen diameter, stenosis percentage, and thicknesses of intima, media, and adventitia were calculated in digital microphotography after staining. Atheromas and internal elastic lamina (IEL) disruption were rated visually. Arteries were categorized into the top 5% (“dilated”) and bottom 5% (“narrowed”) of the luminal diameters, as well as an intermediate category (90% of sample as reference). We used logistic regression to obtain the odds of association (OR, 95% CI) after adjusting for demographic and vascular variables. Results: Narrowed arteries were more frequently found in men (OR 2.7, 95%CI 1.3-5.9) and with dyslipidemia (4.2, 1.6-11.1) while dilated arteries were more frequently found in women (5.6, 2.2-14.0), in smokers (2.6, 1.0-6.5) and those with prior MI (7.7, 1.2-48.7). Narrowed arteries were more likely to have atheromas (20.8, 4.8-90.3), greater luminal stenosis (per %, 1.1, 1.1-1.2), thicker vessel walls (1.3, 1.2-1.4), but thinner medias (0.9, 0.8-1.0). Conversely, larger arteries exhibited less IEL disruption (0.3, 0.1-0.9), atheromas (0.34, 0.1-0.9) and stenosis (0.8, 0.8-0.9), their walls were thinner (0.8, 0.8-0.9) but the media was thicker (1.1, 1.1-1.2). Conclusions: Narrowed cerebral arteries were more likely to have atheromas while dilated arteries had thinner walls and were more frequent in subjects with prior MI. These findings suggest that both extremes of the arterial spectrum might be differentially related with vascular disease, underscoring the need to revisit whether standard preventive measures for vascular disease are equally effective in patients harboring such disparate arterial phenotypes.

Objectives: To examine the effects of liver function and hepatitis C virus (HCV) serostatus on neurological, neuropsychological, and psychiatric abnormalities in an advanced-stage HIV-infected cohort. Design: A correlational analysis of baseline data accumulated on 137 participants in the Manhattan HIV Brain Bank, a longitudinal study of HIV-infected individuals. Methods: Patients underwent a battery of neuropsychological tests, a semi-structured psychiatric interview, and a neurological examination. The resulting diagnostic data were correlated with biochemical indices of hepatic function and HCV serostatus. Results: Biochemical indices of liver function correlated with motor dysfunction determined by neurological evaluation, but nor with neuropsychological or psychiatric disorders. Discrete neurological diagnostic entities showed no relationship with biochemical indices, with one exception: patients with cryptococcal leptomeningitis had worse liver function than those without. HCV had no relationship with any neurological disorder or symptom complex. In contrast, HCV serostatus was related to neuropsychological and psychiatric abnormalities, and indices of liver function were not. HCV-seropositive patients were more likely to have histories of opiate, cocaine or stimulant dependency, to have greater impairment in executive functioning, and to meet diagnostic criteria for AIDS dementia, compared with HCV-negative individuals of similar immunological and virological status. Conclusions: HCV and biochemical indices of liver function associate differentially with nervous system abnormalities in this HiV-infected population. Neurological abnormalities correlate with biochemical indices of liver function, whereas neuropsychological and psychiatric dysfunction an I inked to HCV infection. We postulate that multifactorial impacts of HCV and liver disease on HIV-related nervous system disorders may originate in different anatomical and cellular compartments.

Co-infection with HIV and hepatitis C has become increasingly prevalent. It is a major source of morbidity in HIV-infected populations. Distal symmetric polyneuropathy is the most common form of peripheral neuropathy in HIV as well as hepatitis C mono-infection. There is considerable overlap in the symptoms and signs of HIV and hepatitis C neuropathy. It is not known whether there are additive or synergistic effects on the peripheral nerve by these two viruses. There is a need for studies to further elucidate the mechanisms involved.

Objective:To determine whether hepatitis C (HCV) contributes to CNS dysfunction among HIV-infected individuals.Methods:Using a cross-sectional design, the neuropsychiatric profile of individuals with advanced HIV coinfected with hepatitis C (HIV+/HCV+) was compared to similarly advanced HIV patients without HCV coinfection (HIV+/HCV−). Participants were derived from the Manhattan HIV Brain Bank and underwent neurocognitive testing and semistructured psychiatric interviews. Evidence of HCV infection was determined by serology performed prior to study entry. Hepatic function was determined by serum chemistries (bilirubin, creatinine, and international normalized ratio) at the time of the cognitive assessments.Results:Coinfected (HIV+/HCV+) individuals were significantly more likely to have had past opiate or cocaine or stimulant dependence. HIV+/HCV+ participants also had significantly greater rates of past substance-induced major depression. There were no significant differences in rates of primary mental disorders. Forty-two percent of both the HIV+/HCV+ and HIV+/HCV− participants met criteria for current major depression. There was a trend for HIV+/HCV+ patients to perform worse neurocognitively. On tests of executive functioning, HIV+/HCV+ individuals exhibited a greater rate of impairment and had significantly more perseveration. Differences in cognitive functioning were associated with serology but did not correlate with indices of liver disease severity. The HCV+ patients were also more likely to be diagnosed with HIV-associated dementia.Conclusions:There appears to be a neuropsychiatric impact of HCV that is detectable even among an advanced HIV cohort.

White matter vacuolization of the spinal cord is common in patients with AIDS and may lead to clinical manifestations of myelopathy. The pathogenesis of AIDS-associated myelopathy (AM) is unknown and may be related to metabolic abnormalities rather than to direct HIV infection. The striking pathologic similarity between AM and the vacuolar myelopathy associated with vitamin B(12) deficiency suggests that abnormal metabolism of the B(12)-dependent transmethylation pathway may be important in the pathogenesis of AM.The authors compared S-adenosyl-methionine (SAM), methionine, homocysteine, and glutathione in serum and CSF of 15 patients with AM vs. 13 HIV-infected controls without myelopathy (HWM). They also compared the results with a non-HIV--infected reference population (NC). All patients had normal B(12), folate, and methylmalonic acid levels.There was a decrease in CSF SAM in the AM group compared with the HWM group (p0.0001) and the NC group (p0.0001). CSF SAM in the HWM group was also lower than that in the NC group (p = 0.015). Serum methionine was also reduced in serum of the myelopathic group compared with the NC group (p = 0.006).AM is associated with an abnormality of the vitamin B(12)-dependent transmethylation pathway.

INTRODUCTION: Individuals with HIV live longer since the advent of antiretroviral (ARV) drugs. However, aging with HIV is now associated with vascular disease. Mechanisms underlying this association have not been fully elucidated. We explored arterial correlates that might lead the association between HIV and cerebral infarction. Methods: The Brain Arterial Remodeling Study (BARS) is a collection of 336 brains from donors in the US (69%) and Macedonia (31%) from which large brain arteries have been collected, cut, embedded and stained with H&E and van Gieson. Atherosclerosis and stenosis were graded using Glagov’s method. Cerebral infarction was identified in autopsy. For this analysis, HIV cases (n=138) were age- and sex-matched to controls without HIV. Multivariate logistic and linear regressions were used to determine odds ratios and 95% confidence intervals (OR, 95% CI) assessed associations at P< 0.05. Results: Those with HIV (mean age 48.8 ± 9.1 years, 75% men) were more likely to be black (OR 5.0, 2.4-10.4) or Hispanic (OR 2.2, 1.2-3.9), hypertensive (OR 2.2, 1.3-3.5), dyslipidemic (OR 3.5, 1.1-11.0), cocaine users (OR 10.1, 4.6-22.4) and have cardiac disease (OR 2.0, 1.2-3.5). Cerebral infarction was more common with HIV (adjusted OR 2.8, 1.1-6.8). HIV brains were less likely to have atherosclerosis (OR 0.4, 0.3-0.7) or any stenosis > 25% (OR 0.4, 0.1-1.0). Among those with HIV, after adjusting for demographic and vascular risks, cerebral infarction was more prevalent with prior opportunistic infections (5.3, 1.2-22.9), higher CD4 count (OR 1.2, 1.0-1.4 per every 50 CD4 cell increment), and in those with intimal thickening in more than 75% of the lumen circumference (OR 4.0, 1.1-14.5). Predictors of circumferential intimal thickening in the HIV group included ARV at death (Beta 0.17, P=0.007), internal elastic lamina (IEL) gaps, Beta 0.22, P=0.02), and IEL duplication (Beta 0.28, P=0.001). CONCLUSIONS: Individuals with HIV in this study have a greater prevalence of vascular risks and cerebral infarction, yet the increased infarction prevalence is not associated with atherosclerosis. Patients with HIV have a non-atherosclerotic arterial phenotype consisting of circumferential intimal thickening with disruption of the internal elastic lamina.

Pituicytoma is a rare, poorly characterized tumor of the sella and suprasellar region that is distinct morphologically from other local tumors and is thought to be derived from neurohypophyseal pituicytes. Clinical data, neuroimaging studies, and microsections were reviewed from nine such low-grade gliomas. Immunostains for glial, neuronal, and proliferation markers were performed on all nine tumors and six control neurohypophyses. Three tumors were studied ultrastructurally. Six men and three women, age 30 to 83 years (mean, 48 years), presented with visual symptoms, headache, or hypopituitarism. Magnetic resonance images showed solid, discrete, contrast-enhancing masses, four within the sella and five in the suprasellar space. The tumors consisted of sheets and/or fascicles of plump spindle cells with slightly fibrillar cytoplasm and slightly pleomorphic, oval-to-elongate nuclei with pinpoint nucleoli. Extracellular mucin was prominent in one tumor. Rosenthal fibers, granular bodies, and Herring bodies (granular axonal dilatations characteristic of the normal neurohypophysis) were lacking. Mitoses were rare or absent. MIB-1 labeling indices were low (0.5-2%). Tumor cells were strongly reactive for vimentin and S-100 protein, variably positive for glial fibrillary acidic protein, and nonreactive for synaptophysin and neurofilament protein. Cytoplasm varied in electron density and contained intermediate filaments. Neither meningothelial nor ependymal features were noted. Two tumors recurred at 20 and 26 months after subtotal resection, but none of the six completely resected tumors have done so. Pituicytomas are discrete, largely noninfiltrative low-grade gliomas of the sellar region that occur in adults. Their histologic appearance is distinct from pilocytic and ordinary, infiltrative astrocytomas. The distinction between pituicytoma and normal neurohypophysis is aided by the latter's content of axons, Herring bodies, and perivascular anucleate zones rich in axonal terminations. Although curable by total excision, subtotal resection can be associated with recurrence.

Introduction: The pathophysiology of stroke in HIV involves alterations in vessel wall structure, both inward (stenosis) and outward remodeling (dilatation). Metalloproteinase-2 (MMP-2) has been implicated in the remodeling of large arteries, but it has not been studied in the cerebral arteries. Objectives: To assess the potential role of MMP-2 in brain arterial remodeling in HIV infection. Methods: Circle of Willis arteries were obtained from 38 brain donors with and without HIV infection, autopsied by the Manhattan HIV Brain Bank. The lumen-to-wall-ratio (LWR) was obtained from transversal Van Gieson stains and used to assess remodeling with larger ratios indicating outward remodeling. Immunohistochemistry was used to assess MMP-2 expression in the arterial wall, scored as average pixel intensity and expressed as arbitrary units (AU). Demographic and clinical variables were used as covariates of remodeling in linear regression models. Results: The sample included 38 middle cerebral arteries from 28 individuals with HIV and 10 without. Compared to non-HIV controls, the HIV group was younger (57 vs. 45 years, P=0.001), more frequently male (40 vs. 70 %, P=0.08) and African American (43 vs. 20%, P=0.18), but reported less hypertension (50 vs. 25%, P=0.14) and diabetes (66 vs. 33%, P=0.03). The expression of MMP-2 was higher in the HIV group (171 vs. 186 AU, P=0.14). After adjusting for age, sex, ethnicity, hypertension and diabetes, subjects with HIV had higher LWR (β=4.7, P=0.03, R 2 =0.22), although adjusting for MMP-2 reduced the strength of the association (β= 3.7, P=0.20, R 2 =0.52). Stratifying by HIV status, MMP-2 was the only significant predictor of outward remodeling in the HIV group (P=0.02). In this group, age >45 years (P=0.005), CD4 count Conclusion: MMP-2 may be associated with outward remodeling of cerebral arteries in HIV-infected individuals, particularly in the context of hypertension and immunosuppression. More studies are needed to better understand this arterial physiopathology given the increased cerebrovascular disease seen in the HIV-infected population.

Because no data are available concerning the histopathological effects of the potassium titanyl phosphate (KTP) laser on central nervous tissue, a study was performed using a canine model to compare the histopathological effects of a commonly used laser (CO2) and the KTP laser on brain and spinal cord tissue. Exposed brain and spinal cord tissue were irradiated with 0.1-s pulses (x10), with spot sizes of 1 mm (in focus) over a range of 1 to 10 W. Wedge-shaped lesions were produced with the CO2 laser, while more blunt, semilunar-shaped lesions were produced by the KTP laser. The depth and width of the lesions were proportional to the energy applied. The lesions ranged in surface diameter from 0.6 to 1.3 mm for CO2 and 0.8 to 1.6 mm for KTP lasers, respectively. The depth of the lesions varied from 0.4 to 2.0 mm for CO2 and 0.3 to 1.1 mm for KTP lesions. Histopathologically, a central zone of tissue destruction and vaporization was surrounded by a zone of coagulative necrosis, in turn surrounded peripherally by a zone of pallor. CO2-induced lesions were histologically more hemorrhagic than KTP-induced lesions. In view of the histopathological findings, the KTP laser appears as safe as the CO2 laser in terms of tissue lateral thermal change (penetration) and tissue absorption. The additional hemostatic advantage observed clinically for the KTP laser is demonstrated histologically as well. Although the wavelength of the KTP and argon laser light are similar, the histopathological effects seem to be less pigment dependent. The KTP laser seems well suited for neurosurgery and has the versatility provided by a fiberoptic delivery system.

Objective: To evaluate C-C chemokine receptor type 2 (CCR2) on monocyte subsets as a prognostic peripheral blood biomarker of HIV-associated neurocognitive disorders (HAND). Methods: We characterized monocyte populations in HIV-infected individuals with and without HAND from 2 cohorts and assessed their transmigration across an in vitro model of the human blood-brain barrier (BBB). We examined CCR2 expression among the monocyte populations as a prognostic/predictive biomarker of HAND and its functional consequences in facilitating monocyte diapedesis. Results: We determined that CCR2 was significantly increased on CD14 + CD16 + monocytes in individuals with HAND compared to infected people with normal cognition. CCR2 remained elevated irrespective of the severity of cognitive impairment, combined antiretroviral therapy status, viral load, and current or nadir CD4 T-cell count. There was no association between CCR2 on other monocyte populations and HAND. There was a functional consequence to the increase in CCR2, as CD14 + CD16 + monocytes from individuals with HAND transmigrated across our model of the human BBB in significantly higher numbers in response to its ligand chemokine (C-C) motif ligand 2 (CCL2) compared to the cell migration that occurred in people with no cognitive deficits. It should be noted that our study had the limitation of a smaller sample size of unimpaired individuals. In contrast, there was no difference in the transmigration of other monocyte subsets across the BBB in response to CCL2 in seropositive individuals with or without HAND. Conclusions: Our findings indicate CCR2 on CD14 + CD16 + monocytes is a novel peripheral blood biomarker of HAND.

Objectives: With the aging of HIV populations, vascular contributions to neuropathogenesis are increasingly important. Indirect analyses of cerebral small vessel disease have been performed, but there have been no direct studies of human brain to elucidate risk factors for arteriolar sclerosis. Methods: Mean arteriolar wall thickness (sclerotic index, SI) was measured in the deep cerebral white matter of 126 brains (96 HIV+, 30 HIV−). Correlations with SI were performed for age, sex, race, hypertension, hyperlipidemia, diabetes, obesity, cirrhosis, hepatitis C virus (HCV) infection, herpes infection, HIV infection, HIV risk, cocaine use, CD4 count, plasma HIV load, and combination antiretroviral therapy (cART) at the time of death. Results: Age, hypertension, race, HCV, and cirrhosis were associated with SI; of the HIV variables, only cART at death was associated with SI. To address colinearity, partial correlations were run with HCV and cirrhosis, hypertension and race, and hypertension and age. With HCV controlled, cirrhosis lost significance; with hypertension controlled, age lost significance. For the entire sample, HCV, African American race, and hypertension accounted for 15% of SI variance in multivariate analysis. Each was independently associated with SI, and HCV had the largest effect. For the HIV sample, inclusion of cART in the model increased R 2 to 0.205, with only HCV, hypertension, and cART remaining significant or trend level. Conclusions: This tissue-based analysis of cerebral arteriolar disease demonstrates that HCV constitutes an independent risk, in addition to African American race, hypertension, and cART. Further study is needed to understand what aspects of HCV and cART contribute to cerebrovascular neuropathogenesis.

T-cell lymphoma may involve the CNS as either a primary or secondary neoplasm. This report describes 8 patients with either primary or secondary T-cell malignancies in the CNS. Five patients presented with symptoms and signs of CNS disease that included seizures, visual impairment, cranial nerve palsies, sensory and motor deficits, gait ataxia, and paraparesis. Three of them had primary parenchymal CNS lymphoma, and 2 had epidural lymphoma that originated in adjacent bone marrow. Three patients were neurologically asymptomatic, but had leptomeningeal tumor and focal parenchymal infiltration at postmortem examination. Histologically, 4 lymphomas were large cell, 3 were mixed large and small cell, and 1 could not be classified by the working formulation for non-Hodgkin's lymphomas. The clinical and pathologic manifestations of T-cell lymphoma in the CNS may be diverse. This report demonstrates that neurologic abnormalities may be the presenting signs of either primary CNS or systemic T-cell lymphoma.