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...     

Relevance of lipopolysaccharide levels in HIV-associated neurocognitive impairment: the Neuradapt study

Contributory factors to HIV-associated neurocognitive disorders (HAND) have been shown to include age, co-morbid infections, medication toxicity, virological, genetic and vascular mechanisms, as well as microbial translocation of lipopolysaccharide (LPS), which is suspected to trigger monocyte activation and increase trafficking of infected cells into the brain. In this study, our aim was to assess the degree of neurocognitive impairment in a group of randomly selected HIV-infected patients and investigate potential risk factors, including LPS plasma levels. Furthermore, we evaluated the relevance of LPS as a potential marker for screening patients with mild neurocognitive impairment. LPS plasma levels were compared among patients with HAND and those with no HAND. As LPS has also been shown to be elevated in hepatitis C co-infection, the analysis was stratified according to the presence or not of hepatitis C virus (HCV) co-infection. Differences between groups were evaluated using chi-square tests and Kruskal–Wallis non-parametric tests. Stepwise logistic regression was performed to identify independent risk factors for HAND in the subgroups of HCV-positive and negative patients. A p value <0.05 was considered significant. Analyses were conducted using SPSS® software. From December 2007 to July 2009, 179 patients were tested (mean age 44, 73 % male, 87 % on treatment, 30 % HCV co-infected, median CD4 504/ml and 67 % with viral load below 40 copies/ml). HAND was identified in 40/179 patients (22 %), the majority displaying asymptomatic neurocognitive impairment or mild neurocognitive disorder. Univariate analysis showed that age, illicit drug use, hepatitis C co-infection, prior AIDS-defining events, CD4/CD8 ratio and LPS plasma levels were significantly associated with HAND. The median LPS level was 98.2 pg/ml in the non-HAND group versus 116.1 pg/ml in the HAND group (p?<?0.014). No differences were found in LPS values between subgroups of impairment. There was a clear association between LPS levels and HAND in the HCV-positive group (p?=?0.036), while there was none in the HCV-negative group (p?=?0.502). No difference in degree of hepatic fibrosis was found between the HAND and non-HAND groups. In conclusion, LPS levels were associated with HAND in the HCV-positive group, while, in the HCV-negative group, age and pro-viral DNA were the only variables independently associated with HAND. There was no difference in degree of liver disease as predicted by score of fibrosis between HAND and non-HAND groups. The role of HCV co-infection and higher LPS levels in the pathogenesis of HAND in patients with viral suppression on treatment requires further investigation.     

CSF proteomic fingerprints for HIV-associated cognitive impairment

Cognitive impairment remains a major complication of advanced human immunodeficiency virus (HIV) infection despite the widespread use of anti-retroviral therapy. Diagnosis is made by exclusion making biomarkers of great potential use. Thus, we used an integrated proteomics platform to assess cerebrospinal fluid protein profiles from 50 HIV-1 seropositive Hispanic women. Nine of 38 proteins identified were unique in those patients with cognitive impairment (CI). These proteins were linked to cell signaling, structural function, and antioxidant activities. This work highlights, in a preliminary manner, the utility of proteomic profiling for biomarker discovery for HIV-1 associated cognitive dysfunction.     

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.     

Initial validation of a screening battery for the detection of HIV-associated cognitive impairment

This study sought to develop and validate a screening battery for detecting HIV-related neuropsychological (NP) impairment. Six NP measures representing the ability areas most likely affected by HIV infection were paired in 14 combinations and their diagnostic accuracy rates compared. The measures were selected from a larger NP battery administered to 190 HIV-seropositive (HIV+) participants. Screening battery performance was classified as NP impaired if demographically corrected T-scores fell below 40 on both tests, or below 35 on one test. Using blind clinical ratings of NP test results from the larger battery as the "gold standard" for global NP status (impaired or unimpaired), we found that several test combinations demonstrated adequate diagnostic accuracy in detecting NP impairment. The most sensitive test combinations were the Hopkins Verbal Learning Test-Revised (HVLT-R; Total Recall) and the Grooved Pegboard Test nondominant hand (PND) pair and the HVLT-R and WAIS-III Digit Symbol (DS) subtest pair (sensitivity = 78% and 75%, respectively). Both test combinations (HVLT-R/PND, HVLT-R/DS) were more accurate than the HIV Dementia Scale (HDS) in classifying HIV+ participants as NP impaired or unimpaired. Results suggest that demographically corrected T-scores from pairs of common NP measures may serve as valid screening instruments to identify subjects with HIV-related neurocognitive impairment who could benefit from more extensive NP examination.     

Transdermal selegiline in HIV-associated cognitive impairment: pilot, placebo-controlled study

The authors conducted a pilot randomized, double-blind, placebo-controlled clinical trial of the transdermal administration of selegiline in HIV+ patients to obtain preliminary data to assess its safety, tolerability, and impact on HIV-associated cognitive impairment. Both selegiline and placebo were well tolerated with few adverse events. Improvements favoring the selegiline group were suggested on single tests of verbal memory and motor/psychomotor performance, warranting a larger study.     

Utility of a brief computerized battery to assess HIV-associated neurocognitive impairment in a resource-limited setting

Despite the persistently high prevalence of neurocognitive impairment in HIV-positive patients, routine HIV care in many resource-limited settings does not include neuropsychological assessment. The objective of this study was to examine the utility of a brief computerized battery for identifying neurocognitive impairment in a busy HIV clinic in Uganda. Specifically, we compared performance on a gold standard neuropsychological exam to that on the CogState Brief Battery. In this cross-sectional study, 181 HIV-positive patients completed both assessment batteries in a randomized order. The primary outcome measures were neurocognitive impairment on the standard exam defined by the global deficit score and cumulative performance on the CogState Brief Battery. Sixty-nine participants (38 %) were classified as impaired on the standard neuropsychological exam, and participants who were classified as impaired performed significantly worse on CogState compared to those who were unimpaired (p?<?0.001). CogState had adequate specificity but low sensitivity, suggesting that it may not be a clinically useful screening tool to identify patients who likely have neurocognitive impairment in Uganda. This study supports the feasibility of using a computerized battery for assessing neurocognitive impairment in HIV-positive patients in resource-limited settings, but additional research is needed to identify screening tools with higher sensitivity for use in HIV clinics.     

Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report

In vitro and animal model data demonstrate that valproic acid (VPA) can ameliorate HIV-associated neurotoxicity. The authors conducted a pilot 10-week placebo-controlled study of VPA 250 mg twice daily in 22 HIV-infected individuals with (n = 16) and without (n = 6) cognitive impairment. VPA was safe and well tolerated, with trends toward improved neuropsychological performance and brain metabolism in the impaired subjects.     

Paroxetine and fluconazole therapy for HIV-associated neurocognitive impairment: results from a double-blind,placebo-controlled trial

Paroxetine and fluconazole have neuroprotective effects in an in vitro model of HIV protein-mediated neuronal injury. This study evaluated the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). A 24-week randomized double-blind, placebo-controlled 2 × 2 factorial design study was used. HIV+ individuals with cognitive impairment were enrolled in the 24-week trial. Participants were randomly assigned to one of four groups: (1) paroxetine 20 mg/day, (2) fluconazole 100 mg every 12 h, (3) paroxetine and fluconazole, or (4) placebo. Safety, tolerability, and efficacy were evaluated. Forty-five HIV+ individuals were enrolled. Medications were well tolerated. Compared to no paroxetine arms, HIV+ individuals receiving paroxetine showed improved NPZ8 summary scores, (mean change = 0.25 vs ??0.19, p = 0.049), CalCAP sequential test reaction time (mean change = 0.34 vs ?0.23, p = 0.014), Trail Making Part B test performance (mean change = 0.49 vs ??0.33, p = 0.041), and FAS verbal fluency (mean change = 0.25 vs 0.02, p = 0.020) but a decline in the Letter number sequencing test (mean change = ??0.40 vs 0.26, p = 0.023). Biomarkers of cellular stress, inflammation, and neuronal damage were not affected by paroxetine. HIV+ individuals receiving fluconazole did not show a benefit in cognition and showed an increase in multiple markers of cellular stress compared to the no fluconazole arms. In conclusion, paroxetine was associated with improvement in a summary neuropsychological test measure and in several neuropsychological tests but worse performance in one neuropsychological test. Further studies of paroxetine for the treatment of HAND and to define its precise neuroprotective properties are warranted.     

Stability of neurocognitive impairment in different subtypes of mild cognitive impairment

There has been increasing interest in delineating different cognitive subtypes of mild cognitive impairment (MCI). It remains unclear, however, the extent to which neuropsychological impairment associated with amnestic, nonamnestic, and amnestic+ subtypes of MCI remains stable over time. In this study, 70 persons meeting the criteria for MCI and 38 cognitively normal elderly subjects received a baseline neuropsychological evaluation and were reevaluated 1 year later. Our results indicated that 84.6% of the persons initially classified as amnestic, 75% of those classified as nonamnestic, and 80% of the persons classified as MCI+ evidenced stable or more pronounced neuropsychological impairment across the follow-up period. Less than 7% of the amnestic and amnestic+ cases had nonimpaired neuropsychological profiles at their reevaluation at 12 months, and 16.7% of the nonamnestic cases had nonimpaired neuropsychological test profiles at follow-up. Approximately 87% of the cognitively normal subjects at baseline continued to have unimpaired neuropsychological performance at follow-up. These results indicate that the presence of neuropsychological impairment is relatively stable over a 12-month follow-up period among different cognitive subtypes of MCI, although 15-25% of the cases did not exhibit the specific cognitive deficits that characterized their performance at baseline.     

Prevalence of non-confounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression

HIV-associated neurocognitive disorder is known to occur in the context of successful combination antiretroviral therapy (cART; plasma HIV RNA <50 copies/ml). Here, we newly provide an analysis of its prevalence and nature in the absence of medical or psychiatric confounds that may otherwise inflate the prevalence rate. We enrolled a cohort of 116 advanced HIV + individuals on cART (51% virally suppressed (VS)). They were screened for active Hepatitis C, current substance use disorder and were assessed with standard neuropsychological (NP) testing. Our results showed that out of the entire sample, NP impairment occurred in 18.1% (21/116) in VS individuals which was not statistically different from the 24.1% (28/116) that were found to be NP-impaired and not VS. In comparison with NP-normal-VS persons, NP impairment in VS individuals was associated with shorter duration of current cART and lower pre-morbid ability. Higher cART CNS penetration effectiveness tended to be associated with lesser cognitive severity in NP-impaired VS individuals. Current CD4 cell count, depression symptoms and past CNS HIV-related diseases did not specifically account for persistent NP impairment in VS individuals. In conclusion, despite suppression of systemic viral load, non-confounded HIV-related NP-impairment prevalence reached 18.1%. Of the potential explanations for this persistent deficit, a “burnt-out” form of the disease and immune reconstitution inflammatory syndrome were the less likely explanations, while a shorter current cART duration and lower pre-morbid intellectual capacity were significant. Nonetheless, predictive modelling with these last two factors misclassified 27% and had low sensitivity (43%) emphasising that other yet-to-be-defined factors were operative.     

HIV-associated cognitive impairment before and after the advent of combination therapy

The objective of this study was to describe the occurrence of HIV dementia and neuropsychological testing abnormalities in a new cohort of HIV-seropositive individuals at high risk for HIV dementia and to compare these results to a cohort before the advent of highly active antiretroviral therapy (HAART). HAART has been associated with improvements in cognitive performance in some HIV-infected patients. However, it is uncertain whether HAART has changed the frequency of specific neurocognitive abnormalities. Baseline data from 272 HIV-seropositive subjects in the Dana cohort recruited from January, 1994, to December, 1995, and 251 HIV-seropositive subjects in the Northeastern AIDS Dementia Consortium (NEAD) cohort recruited from April, 1998, to August, 1999, were compared. Participants in both cohorts received nearly identical assessments. After adjusting for differences in age, education, gender, race, and CD4 count between the two cohorts, there were no differences in the occurrence of HIV dementia or abnormalities either 1 SD or 2 SDs below established norms for any of the neuropsychological tests. Even though HAART has reduced the incidence of HIV dementia, HIV-associated cognitive impairment continues to be a major clinical problem among individuals with advanced infection.     

HIV-associated cognitive impairment in sub-Saharan Africa--the potential effect of clade diversity

In the US, HIV dementia occurs in 10-15% of HIV-positive individuals with advanced infection. The prevalence of HIV dementia in sub-Saharan countries, where the vast majority of individuals with HIV reside, is largely unknown. This Review will summarize our current understanding of HIV-associated cognitive impairment in resource-limited settings, focusing specifically on the countries of sub-Saharan Africa. We will describe the frequency of HIV dementia and HIV-associated cognitive impairment from several case series in the sub-Saharan region. We will then summarize recent studies from Uganda and Ethiopia that included detailed neuropsychological assessments. The potential influence of clade diversity on HIV-associated cognitive impairment will be discussed. Differences between the results of the studies in Uganda and in Ethiopia raise the possibility that HIV subtypes might have different biological properties with respect to their capacity to cause HIV-associated cognitive impairment. Further studies are needed to determine the true prevalence of HIV dementia in sub-Saharan Africa and to establish whether specific clade subtypes might influence the presentation of neurological complications.     

Montreal cognitive assessment in detecting cognitive impairment in Chinese elderly individuals: a population-based study

The Montreal Cognitive Assessment (MoCA) has been proved brief and sensitive to screen for mild cognitive impairment (MCI) and early dementia in some developed countries or areas. However, little MoCA data are available from mainland China. In this study, the MoCA was applied to 8411 Chinese community dwellers aged 65 or older (6283 = cognitively normal [CN], 1687 = MCI, and 441 = dementia). The MoCA norms were established considering significant influential factors. The optimal cutoff points were 13/14 for illiterate individuals, 19/20 for individuals with 1 to 6 years of education, and 24/25 for individuals with 7 or more years of education. With the optimal cutoffs, the sensitivity of the MoCA was 83.8% for all cognitive impairments, 80.5% for MCI and 96.9% for dementia, and the specificity for identifying CN was 82.5%. These indicate that with optimal cutoffs, the MoCA is valid to screen for cognitive impairment in elderly Chinese living in communities.     

Diagnosing symptomatic HIV-associated neurocognitive disorders: self-report versus performance-based assessment of everyday functioning

Three types of HIV-associated neurocognitive disorders (HAND) exist that are distinguished by presence and severity of impairment in cognitive and everyday functioning. Although well-validated neurocognitive measures exist, determining impairment in everyday functioning remains a challenge. We aim to determine whether Self-Report measures of everyday functioning are as effective in characterizing HAND as Performance-Based measures. We assessed 674 HIV-infected participants with a comprehensive neurocognitive battery; 233 met criteria for a HAND diagnosis by having at least mild neurocognitive impairment. Functional decline was measured via Self-Report and Performance-Based measures. HAND diagnoses were determined according to published criteria using three approaches to assess functional decline: (1) Self-Report measures only, (2) Performance-Based measures only, and (3) Dual-method combining Self-Report and Performance-Based measures. The Dual-method classified the most symptomatic HAND, compared to either singular method. Singular method classifications were 76% concordant with each other. Participants classified as Performance-Based functionally impaired were more likely to be unemployed and more immunosuppressed, whereas those classified as Self-Report functionally impaired had more depressive symptoms. Multimodal methods of assessing everyday functioning facilitate detection of symptomatic HAND. Singular Performance-Based classifications were associated with objective functional and disease-related factors; reliance on Self-Report classifications may be biased by depressive symptoms.