Vitamin D is not associated with HIV-associated neurocognitive disorder in Rakai,Uganda

Journal of NeuroVirology - We investigated whether vitamin D is associated with HIV-associated neurocognitive disorder (HAND). HIV-infected (HIV+) antiretroviral therapy (ART)-naïve adults in...     

Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder

We assessed ferumoxytol-enhanced brain MRI to identify monocyte/macrophage accumulation in HIV-associated neurocognitive disorder (HAND). Four HIV-infected subjects with undetectable HIV RNA levels on antiretroviral therapy, HIV DNA level in CD14+ cells ≥10 copies/10⁶ cells, and cognitive impairment underwent ferumoxytol-enhanced brain MRI. On post-ferumoxytol susceptibility-weighted images, all HIV-infected subjects demonstrated a diffuse “tram track” appearance in the perivascular regions of cortical and deep white matter vessels suggesting ferumoxytol uptake in monocytes/macrophages. This finding was not present in an HIV-seronegative control. While ferumoxytol may have potential as an imaging biomarker for monocyte/macrophage accumulation in patients with HAND, future study is needed.     

Vascular cognitive impairment and HIV-associated neurocognitive disorder: a new paradigm

Journal of NeuroVirology - In this review, we propose that vascular cognitive impairment (VCI), with relevance for the global HIV population, is fundamentally and clinically linked to the...     

Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China

In the current era of highly active antiretroviral therapy (HAART), the incidence of HIV dementia has declined, but the prevalence of HIV-associated neurocognitive disorder (HAND) remains high. HIV-induced systemic and localized inflammation is considered to be one of the mechanisms of HAND. Changes in cytokine levels in the cerebrospinal fluid (CSF) during HIV infection might help to identify HAND. To investigate whether the cytokine profile of the CSF during HIV infection could be used as a biomarker of HAND, we compared cytokine levels in the CSF of HIV-infected cases with and without neurocognitive impairment. Cytokine concentrations in the CSF were measured by quantification bioassays (Luminex xMAP). HIV-infected cases with neurocognitive impairment demonstrated higher levels of interleukin (IL)-8, monocyte chemotactic protein (MCP)-1, induced protein (IP)-10, and granulocyte colony-stimulating factor (G-CSF) in the CSF than those without neurocognitive impairment (G-CSF (p?=?0.0003), IL-8 (p?=?0.0046), IP-10 (p?<?0.0001), and MCP-1 (p?<?0.0001)). There was no significant impact of HAART on cytokine levels in the CSF, except for IP-10, which was higher in HAART-treated patients with impaired cognition (p?=?0.0182). Findings from this preliminary study suggest that elevated levels of the cytokines IL-8, MCP-1, G-CSF, and IP-10 in the CSF are associated with neurocognitive impairment in HIV infection, and these cytokines likely represent a biomarker profile for HAND.     

TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use

Journal of NeuroVirology - In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the...     

Determining optimal impairment rating methodology for a new HIV-associated neurocognitive disorder screening procedure

Introduction: The current study sought to determine the optimal impairment rating definition for a new HIV-associated neurocognitive disorder (HAND) screening procedure as compared to standard neuropsychological testing.

Method: A total of 55 HIV-infected (HIV+; 19% AIDS; 87% on combination antiretroviral therapy, cART; 80% plasma undetectable) and 22 demographically comparable HIV-uninfected (HIV–) control adults (all male) enrolled in an urban Australian primary care cohort study completed the CogState computerized cognitive screen, a standard independence in activities of daily living (ADL) questionnaire, and a standard neuropsychological test battery. Local or American demographically adjusted norms were applied to the neuropsychological data, taking into account premorbid reading level. CogState norms that corrected for age and sex were applied to raw CogState data. The HAND Frascati classification criteria were implemented to determine “impairment” on both the standard neuropsychological test and the CogState-based screen using two established methods: a battery-wide summary score (global deficit score; GDS), and cognitive domain rating, both combined with ADL independence data. Criterion validity was operationalized by comparing rate of impairment derived from the CogState-based screen to that obtained from the standard neuropsychological test battery first in the combined HIV– and HIV+ sample, and then in the HIV+ sample only.

Results: In the combined sample, CogState-based screen criterion validity was higher using the GDS (79% correct classification, 73% sensitivity, 82% specificity) over the cognitive domain rating (correct classification, sensitivity, specificity all 69%) method. A similar pattern was found for the HIV+ group separately [GDS (74% correct classification, 76% sensitivity, 71% specificity) versus cognitive domain rating (64% correct classification, 72% sensitivity, 57% specificity)]. The cases that resulted in disagreement across the two methods were those with borderline impaired/unimpaired cognitive performance.

Conclusions: The GDS is a relatively easy statistical method for computing impairment rate when using the CogState-based screen that yields adequate criterion validity compared to standard neuropsychological testing. Feasibility of standardized test administration and appropriate interpretation of results for this CogState-based screen in primary care was enhanced by the training and consultation provided by study neuropsychologists.     

Glutamate metabolism and HIV-associated neurocognitive disorders

HIV-1 infection can lead to neurocognitive impairment collectively known as HIV-associated neurocognitive disorders (HAND). Although combined antiretroviral treatment (cART) has significantly ameliorated HIV’s morbidity and mortality, persistent neuroinflammation and neurocognitive dysfunction continue. This review focuses on the current clinical and molecular evidence of the viral and host factors that influence glutamate-mediated neurotoxicity and neuropathogenesis as an important underlying mechanism during the course of HAND development. In addition, discusses potential pharmacological strategies targeting the glutamatergic system that may help prevent and improve neurological outcomes in HIV-1-infected subjects.     

Frequency and risk factors for HIV-associated neurocognitive disorder and depression in older individuals with HIV in northeastern Brazil

ABSTRACT Background: The study was undertaken to describe the frequency of HIV-associated neurocognitive disorders (HAND) and depressive symptoms in an older population with human immunodeficiency virus (HIV). Methods: A cross-sectional analysis of patients aged 50 years or older infected with HIV was carried out in an outpatient setting in Brazil from March to November 2008. Patients selected were submitted to cognitive evaluation using the Mini-Mental State Examination and International HIV Dementia Scale, and also to functional and depression evaluations. Results: Among the 52 patients evaluated, the frequency of neurocognitive disorder was 36.5%, while for dementia the frequency was 13.5%. No risk factors were identified. Among the patients with cognitive impairment, 73.7% had cortical impairment. The frequency of depressive symptoms was of 34.6%. The female gender was identified as a risk factor (p = 0.018) and patients with depressive symptoms had greater functional impairment (p < 0.001). Conclusion: HAND and depressive symptoms are common in an older population. Patients with cognitive impairment achieved lower scores on the cortical assessment scales. Depressive symptoms are a stronger factor for functional impairment.     

Novel method to quantify phenotypic markers of HIV-associated neurocognitive disorder in a murine SCID model

Journal of NeuroVirology - Despite combined antiretroviral therapy (cART), HIV infection in the CNS persists with reported increases in activation of macrophages (MΦ), microglia, and...     

Genetic shift of env V3 loop viral sequences in patients with HIV-associated neurocognitive disorder during antiretroviral therapy

The development of human immunodeficiency virus type 1 (HIV)-associated neurocognitive disorder (HAND) involves the adaptation of viral sequences coding for the V3 loop of the env protein. The plasma and cerebrospinal fluid (CSF) may contain viral populations from various cellular sources and with differing pathogenicity. Combination antiretroviral therapy (cART) may alter the relative abundance of these viral populations, leading to a genetic shift. We characterized plasma and CNS viral populations prior to and during cART and relate the findings to viral elimination kinetics and the clinical phenotype. Longitudinal plasma and CSF samples of five chronically infected HIV patients, four of whom had HAND, and one seroconverter were analyzed for V3 sequences by RT-PCR and sequence analysis. In the chronically infected patients, pre-cART plasma and CSF viral sequences were different irrespective of viral elimination kinetics and clinical phenotype. cART induced replacement of plasma viral populations in all subjects. CSF viral populations underwent a clear genetic shift in some patients but remained stable in others. This was not dependent on the presence of HAND. The genetic shift of CSF V3 sequences was absent in the two subjects whose CSF viral load initially increased during cART. In one patient, pre- and post-treatment CSF sequences were closely related to the post-treatment plasma sequences, suggesting a common cellular source. We found heterogeneous patterns of genetic compartmentalization and genetic shift over time. Although these did not closely match viral elimination kinetics and clinical phenotype, the results imply different patterns of the dynamics and relative contribution of compartment-specific virus populations in chronic HIV infection.     

Diagnosis and treatment of HIV-associated neurocognitive disorders

Although significant strides have been made in recent years in treating HIV disease with new antiretroviral medications, the management of neurocognitive disorders continues to remain a challenge. This chapter provides an overview of the current epidemiology, neuropathogenesis, clinical features, diagnosis, and treatment of the central nervous system complications of HIV infection.     

Updated research nosology for HIV-associated neurocognitive disorders

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.     

Changing clinical phenotypes of HIV-associated neurocognitive disorders

HIV-associated neurocognitive disorder (HAND) remains a common cause of cognitive impairment and persists in 15–55% of HIV+ individuals in the combination antiretroviral therapy (CART) era. CART is now the primary treatment for HAND, but it is effective in only a subset of patients. In the pre-CART era, HIV-associated dementia was the most common form of HAND. However, in CART-treated patients, the prevalence of HIV-associated dementia has declined substantially, and milder stages of HAND, i.e., ANI and MND predominate. HIV+ patients with mild neurocognitive disorder (MND) can still have significant functional impairment in some activities of daily living. There have been several other significant changes in the clinical features of HAND in the CART era. The mean survival for an individual diagnosed with HIV dementia has increased dramatically. In HIV+ individuals on CART with a suppressed systemic viral load, the majority of individuals with HAND remain stable, with a small proportion showing deterioration. Extrapyramidal signs are now less common in patients with HAND on CART. In the CART era, HAND may have a mixed pattern of both cortical and subcortical features with greater deficits in executive functioning and working memory. Despite the milder clinical phenotype, in the CART era, patients with HAND still have persistent laboratory and neuroimaging abnormalities in the central nervous system even with systemic viral suppression. As the HIV+ patient population ages, cerebrovascular disease risk factors such as hypertension, diabetes, and hypercholesterolemia are increasingly recognized as risk factors for cognitive impairment in HIV+ patients on CART. HAND remains a common neurological condition globally in the CART era, necessitating the need for new animal models to examine pathogenesis and potential treatments for HAND.     

S100B and its association with HIV-associated neurocognitive disorders

Journal of NeuroVirology -     

An initial screening for HIV-associated neurocognitive disorders of HIV-1 infected patients in China

HIV-associated neurocognitive disorders (HAND), characterized by cognitive, motor, and behavioral abnormalities, are common among people living with HIV and AIDS. In combined antiretroviral therapy era in Western countries, nearly 40% of HIV-infected patients continue to suffer from HAND, mainly with mild or asymptomatic cognitive impairment. However, the prevalence and the clinical features of HAND in China are still not well known. In this study, a multi-center cross-sectional study was performed to determine the prevalence and clinical features of HAND in 134 HIV-1 infected patients in China. The International HIV Dementia Scale and a neuropsychological test battery were administered for screening and diagnosis HAND. Subjective complaints, CD4 count and viral loads in both blood plasma and cerebrospinal fluid were correlated with diagnosis of HAND. The results showed that the prevalence of HAND was approximately 37% in these patients. CD4 counts at time of sampling were significant lower in the HAND group than in the non-HAND group. But the distribution of the HAND severity did not differ by CD4 count or viral load. The presence of HAND was associated with cognitive and behavior disorder complaints (4.9- and 4.1-fold higher than those without HAND, respectively). The present data suggest that CD4 count and viral load cannot predict the severity of HAND, although the prevalence of HAND is similar to previous report in these patients. Cognitive and behavioral disorder is major complaint rather than cognitive and motor impairment. A larger prospective study is needed to obtain better estimates of HAND in China.