Asymptomatic Neurocognitive Impairment Research Articles

Inflammatory Mechanisms and Cascades Contributing to Neurocognitive Impairment in HIV/AIDS.

Neurocognitive impairment caused by chronic human immunodeficiency virus (HIV) infection is a growing concern. In this chapter we discuss the inflammatory mechanisms underlying the pathology of asymptomatic and mild neurocognitive impairment in the context of antiretroviral therapy. We discuss the role of HIV, viral proteins, and virally infected cells on the development of neuroinflammation and the effect of viral proteins on the cells of the central nervous system.We examine how these collective factors result in an inflammatory context that triggers the development of neurocognitive impairment in HIV. We assess the contribution of antiretrovirals and drugs of abuse, including methamphetamine, cannabis, and opioids, to the neurotoxic and neuroinflammatory milieu that leads to the development of neurocognitive impairment in HIV-infected individuals. We also examined circulating biomarkers, NF-L, sCD163, and sCD14, pertinent to identifying changes in the CNS that could indicate real-time changes in patient physiology. Lastly, we discuss future studies, such as exosomes and the microbiome, which could play a role in the HIV-induced neuroinflammation that eventually manifests as cognitive impairment.

Alterations in brain TREM2 and Amyloid-β levels are associated with neurocognitive impairment in HIV-infected persons on antiretroviral therapy.

Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-β, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aβ protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aβ levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aβ in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aβ and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Altered cerebro-cerebellum resting-state functional connectivity in HIV-infected male patients

In addition to the role of planning and executing movement, the cerebellum greatly contributes to cognitive process. Numerous studies have reported structural and functional abnormalities in the cerebellum for HIV-infected patients, but little is known about the altered functional connectivity of particular cerebellar subregions and the cerebrum. Therefore, this study aimed to explore the resting-state functional connectivity (rsFC) changes of the cerebellum and further analyze the relationship between the rsFC changes and the neuropsychological evaluation. The experiment involved 26 HIV-infected men with asymptomatic neurocognitive impairment (ANI) and 28 healthy controls (HC). We selected bilateral hemispheric lobule VI and lobule IX as seed regions and mapped the whole-brain rsFC for each subregion. Results revealed that right lobule VI showed significant increased rsFC with the anterior cingulate cortex (ACC) in HIV-infected subjects. In addition, the correlation analysis on HIV-infected subjects illustrated the increased rsFC was negatively correlated with the attention/working memory score. Moreover, significantly increased cerebellar rsFCs were also observed in HIV-infected patients related to right inferior frontal gyrus (IFG) and right superior medial gyrus (SMG) while decreased rsFC was just found between right lobule VI and the left hippocampus (HIP). These findings suggested that, abnormalities of cerebro-cerebellar functional connectivity might be associated with cognitive dysfunction in HIV-infected men, particularly working memory impairment. It could also be the underlying mechanism of ANI, providing further evidence for early injury in the neural substrate of HIV-infected patients.

Neurological soft signs as a marker of cognitive impairment severity in people living with HIV

HIV-associated neurocognitive disorders (HAND) include asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia. Early recognition of HAND is crucial, and usually requires thorough neuropsychological testing. Neurological soft signs (NSS), i.e. minor motor and sensory changes, a common feature in severe psychiatric disorders, may facilitate early diagnosis. NSS were examined using the Heidelberg NSS Scale in 18 patients with ANI, 21 with MND, 28 HIV positive patients without HAND, and 39 healthy controls matched for age, gender, and education. The highest NSS scores were obtained in the MND patients (13.3 ± 10.0, p < 0.0001) followed by those with ANI (11.7 ± 10.6), the HIV positive subjects without neurocognitive deficits (8.0 ± 4.1) and the healthy controls (3.8 ± 3.2). This result was confirmed when age and years of school education were entered as covariates. No significant correlations between NSS and CD4 counts or any other clinical variables were found among the HIV positive groups. Our results demonstrate that NSS are frequently found in both ANI and MND but not HIV positive patients without neurocognitive deficits. NSS may facilitate the screening of HIV positive patients for ANI and MND as an easier and less expensive clinical tool.

Axonal chronic injury in treatment-na\xefve HIV+ adults with asymptomatic neurocognitive impairment and its relationship with clinical variables and cognitive status

BackgroundHIV is a neurotropic virus, and it can bring about neurodegeneration and may even result in cognitive impairments. The precise mechanism of HIV-associated white matter (WM) injury is unknown. The effects of multiple clinical contributors on WM impairments and the relationship between the WM alterations and cognitive performance merit further investigation.MethodsDiffusion tensor imaging (DTI) was performed in 20 antiretroviral-naïve HIV-positive asymptomatic neurocognitive impairment (ANI) adults and 20 healthy volunteers. Whole-brain analysis of DTI metrics between groups was conducted by employing tract-based spatial statistics (TBSS), including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). DTI parameters were correlated with clinical variables (age, CD4+ cell count, CD4+/CD8+ ratio, plasma viral load and duration of HIV infection) and multiple cognitive tests by using multilinear regression analyses.ResultsDTI quantified diffusion alterations in the corpus callosum and corona radiata (MD increased significantly, P < 0.05) and chronic axonal injury in the corpus callosum, corona radiata, internal capsule, external capsule, posterior thalamic radiation, sagittal stratum, and superior longitudinal fasciculus (AD increased significantly, P < 0.05). The impairments in the corona radiata had significant correlations with the current CD4+/CD8+ ratios. Increased MD or AD values in multiple white matter structures showed significant associations with many cognitive domain tests.ConclusionsWM impairments are present in neurologically asymptomatic HIV+ adults, periventricular WM (corpus callosum and corona radiata) are preferential occult injuries, which is associated with axonal chronic damage rather than demyelination. Axonopathy may exist before myelin injury. DTI-TBSS is helpful to explore the WM microstructure abnormalities and provide a new perspective for the investigation of the pathomechanism of HIV-associated WM injury.

Global Perspective of Novel Therapeutic Strategies for the Management of NeuroAIDS.

Among Human immunodeficiency virus (HIV) infected individuals, around two-thirds of patients present with neuroAIDS, where HIV-associated neurocognitive disorders (HAND), and HIV-associated dementia (HAD) are the most prevailing neurological complications. The neuropathology of neuroAIDS can be characterized by the presence of HIV infected macrophages and microglia in the brain, with the formation of multinucleated giant cells. Global predominant subtypes of HIV-1 clade B and C infections influence the differential effect of immune and neuronal dysfunctions, leading to clade-specific clinical variation in neuroAIDS patient cohorts. Highly active antiretroviral therapy (HAART) enhances the survival rate among AIDS patients, but due to the inability to cross the Blood-Brain-Barrier (BBB), incidence of neuroAIDS during disease progression may be envisaged. The complex structure of blood-brain-barrier, and poor pharmacokinetic profile coupled with weak bio-distribution of antiretroviral drugs, are the principle barriers for the treatment of neuroAIDS. In the combined antiretroviral therapy (cART) era, the frequency of HAD has decreased; however the incidence of asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorder (MND) remains consistent. Therefore, several effective novel nanotechnology based therapeutic approaches have been developed to improve the availability of antiretroviral drugs in the brain for the management of neuroAIDS.

The association between asymptomatic and mild neurocognitive impairment and adherence to antiretroviral therapy among people living with human immunodeficiency virus.

BackgroundAsymptomatic cognitive impairment in human immunodeficiency virus (HIV)-infected patients has recently been recognised as part of HIV-associated neurocognitive disorders. This has been implicated as one of the causes of poor adherence to antiretroviral therapy (ART).ObjectiveTo assess the association between neurocognitive impairment (asymptomatic and mild forms) and adherence to ART.MethodsThis was a cross-sectional survey involving 218 participants consecutively sampled from those attending the HIV treatment clinic at Aga Khan University Hospital in Nairobi. Data collected included quantitative primary data on pre-defined baseline characteristics, neurocognitive assessment by Montreal Cognitive Assessment (MoCA) tool (Appendix 1), instrumental activities of daily living by Lawton score and objective and subjective adherence measures by medication possession ratio (MPR) and simplified medication adherence questionnaire (SMAQ) (see Appendix 2). Univariate and bivariate analyses were conducted to determine the strengths of association between predictor and the outcome variables.ResultsAmong the 218 participants in the study, a total of 69% had asymptomatic to mild neurocognitive impairment as assessed by the MoCA tool, while a total of 66% were determined as being adherent to ART by objective measures (by MPR) compared to subjective rates of 77% as assessed by SMAQ. However, no statistically significant association was observed between the presence of asymptomatic or mild neurocognitive impairment and likelihood of adherence to ART (p > 0.05).ConclusionEven though asymptomatic and mild forms of cognitive impairment are prevalent in the population studied, there was no significant association between cognitive impairment and adherence to treatment.

Association Between Frailty and HIV-Associated Neurodegenerative Disorders Among Older Adults Living with HIV.

The population of aging adults living with human immunodeficiency virus (HIV) is growing worldwide and evidence suggests that frailty occurs prematurely among them. In turn, frailty has been associated with cognitive decline. It is unknown, however, if people with both frailty and HIV infection have a higher risk of cognitive impairment compared with nonfrail HIV-infected persons. Therefore, the main objective of this study was to determine the association between the phenotype of frailty and HIV-associated neurocognitive disorders (HAND) among adults aged 50 years or older living with HIV/AIDS. A cross-sectional study was conducted on 206 adults living with HIV receiving care in a university-affiliated tertiary care hospital in Mexico City. Frailty was defined as per the Fried criteria. The presence of HAND was established according to the Antinori criteria: HIV-associated asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), or cognitively nonimpaired. Multinomial logistic regression models were used to test the independent association between frailty and HAND adjusting for potential confounders. Mean age of participants was 60.5 ± 6.3 years and 84.9% were male. Prevalence of HAND and frailty phenotype was 66.0% and 2.9%, respectively. The unadjusted analysis showed that both prefrail and frail statuses were associated with MND but not with ANI. However, after adjustment, the association with MND remained significant only among prefrail participants and no longer for frail persons (risk ratio [RR] = 5.7, 95% confidence intervals [CI] 1.09-29.82; p = .039 and RR = 18.3, 95% CI 0.93-362.6; p = .056, respectively). Prefrailty is associated with symptomatic neurocognitive disorders in older adults living with HIV. The spectrum of the frailty phenotype in this already vulnerable population should serve as an indicator of concomitant cognitive decline.

Association of age and time of disease with HIV-associated neurocognitive disorders: a Japanese nationwide multicenter study.

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥50years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥2 to <6years), then increased in the later stage [17.3% in ≥11years, p=0.001 (vs. ≥2 to <6years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for <2years and 17.4 vs. 3.1% for ≥2 to <6years, p=0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.

HIV-Associated Neurocognitive Disorders: A Global Perspective.

The present review on HIV-associated neurocognitive disorders (HAND) provides a worldwide overview of studies that have investigated the rate and neuropsychological (NP) profile of HAND research since the inception of the 2007 HAND diagnostic nomenclature. In the first part, the review highlights some of the current controversies around HAND prevalence rates. In the second part, the review critically assesses some solutions to move the field forward. In the third part, we present the cross-sectional NP profile in non-Western HIV+ cohorts and in relation to Western cohorts' findings. The adopted global perspective highlights the successful expansion of NP studies in HIV infection to culturally diverse low- to medium-income countries with high HIV burden. These studies have produced interestingly similar rates of HAND whether patients were naïve or treated and/or virally suppressed compared to the rich income countries where the NP research in NeuroHIV has originated. The perspective also demonstrates that globally, the group which is the most representative of the HIV epidemic, and thus at risk for HAND are persons with chronic HIV infection and survivors of past immunosuppression, while in relative terms, those who have been treated early with long-term viral suppression represent a minority. In the last part, we present a review of the naturalistic longitudinal NP global studies in HIV+cohorts, discuss the role of longitudinal design in solving issues around the question of asymptomatic neurocognitive impairment, and the question of biomarker discovery. Finally, we conclude by calling for greater methods and data harmonization at a global level. (JINS, 2017, 23, 860-869).

HIV-associated neurocognitive disorder in a KwaZulu-Natal HIV clinic: A prospective study.

IntroductionHIV-associated neurocognitive disorder (HAND) is a consequence of HIV infection of the central nervous system. The prevalence ranges between 15% and 60% in different settings.ObjectivesThis prospective study determined the prevalence of HAND at a peri-urban HIV clinic in KwaZulu-Natal. Factors associated with HAND were examined, alternate neurocognitive tools were tested against the international HIV dementia scale (IHDS) score and an association between HAND and non-adherence to antiretroviral therapy (ART) was explored.MethodsBetween May 2014 and May 2015, 146 ART-naïve outpatients were assessed for HAND. IHDS score ≤ 10 established a diagnosis of HAND. Functional capacity was assessed using Eastern Cooperative Oncology Group (ECOG) score. Chi-squared test was used to identify risk factors for HAND. The get-up-and-go test (GUGT) and Center for Epidemiological Studies Depression scale – revised (CESD-r) were tested against the IHDS. HIV viral load done six months after initiating ART was used as a surrogate marker for adherence to ART.ResultsThe prevalence of HAND was 53%. In total, 99.9% of patients with HAND had no functional impairment. Age > 50 years old was associated with HAND (p = 0.003). There was no correlation between the GUGT, CESD-r and the IHDS score. HAND was not associated with non-adherence (p = 0.06).ConclusionsWhile the prevalence of HAND is high, it is not associated with functional impairment which suggests that asymptomatic neurocognitive impairment is prevalent. Age > 50 years old is a risk factor for HAND. The GUGT and CESD-r are not useful diagnostic tools for HAND. The relationship between HAND and non-adherence should be further explored.

16 Prevalence and risk factors for hiv-associated neurocognitive impairment (hand) amongst adults aged 50 and over attending a hiv clinic in northern tanzania

Objective HIV infection is a major cause of disease burden and disability across sub-Saharan Africa (SSA). HIV-associated neurocognitive impairment (HAND) is estimated to affect 8 million people with HIV infection across the continent and is associated with increased mortality and morbidity. As a result of demographic transition and increased coverage of combination antiretroviral therapy (cART) the proportion of people aged 50 and over living with HIV infection in SSA is predicted to triple (to over 9 million people by 2040). Despite this, few published data exist on the prevalence of, or risk factors for, HAND in older individuals in SSA. We aimed to estimate prevalence and risk factors for HAND in a stable population of HIV positive individuals under long term follow up at a government clinic in Northern Tanzania, one of the pioneer sites for cART in SSA. Method A systematic sample of individuals aged 50 and over attending a HIV care and treatment centre for routine follow up were assessed for HAND using a locally normed neuropsychological battery adapted to a low literacy setting. All participants subsequently underwent a clinical interview, neurological examination, informant history for functional impairment and standardised psychiatric screening questionnaire. HAND was defined according the American Academy of Neurology (AAN) 2007 criteria for Asymptomatic Neurocognitive Impairment, Minor Neurocognitive Disorder (MND) and HIV-associated Dementia (HAD). General and HIV-specific risk factors for symptomatic HAND were examined using univariable and multivariable logistic regression. Results Complete data were available for 227 participants (162 (71%) female, median age 57.9 years) of whom 35% had 4 years formal education or fewer. Median Cd4 count was 500/µl and 95.5% of participants were on cART. Preliminary data indicate that the overall prevalence of HAND was 61.2% (ANI 35.2%, MND 23.8%, HAD 2.2%) and of symptomatic HAND (MND and HAD) 25%. Presence of symptomatic HAND was not related to current or nadir Cd4 count, or time since HIV diagnosis, but was independently associated with older age, illiteracy, living alone and greater number of depression symptoms. Conclusion HAND was very prevalent in this stable outpatient cohort of older adults most of whom were on cART. Initial results suggest that in this cohort of older adults in SSA, risk factors for symptomatic neurocognitive impairment appeared to be less related to HIV infection and more similar to factors commonly associated with neurodegenerative dementias in both high income and low income country settings.

Predictors and Impact of Self-Reported Suboptimal Effort on Estimates of Prevalence of HIV-Associated Neurocognitive Disorders.

Prevalence estimates of HIV-associated neurocognitive disorders (HAND) may be inflated. Estimates are determined via cohort studies in which participants may apply suboptimal effort on neurocognitive testing, thereby inflating estimates. Additionally, fluctuating HAND severity over time may be related to inconsistent effort. To address these hypotheses, we characterized effort in the Multicenter AIDS Cohort Study. After neurocognitive testing, 935 participants (525 HIV- and 410 HIV+) completed the visual analog effort scale (VAES), rating their effort from 0% to 100%. Those with <100% then indicated the reason(s) for suboptimal effort. K-means cluster analysis established 3 groups: high (mean = 97%), moderate (79%), and low effort (51%). Rates of HAND and other characteristics were compared between the groups. Linear regression examined the predictors of VAES score. Data from 57 participants who completed the VAES at 2 visits were analyzed to characterize the longitudinal relationship between effort and HAND severity. Fifty-two percent of participants reported suboptimal effort (<100%), with no difference between serostatus groups. Common reasons included "tired" (43%) and "distracted" (36%). The lowest effort group had greater asymptomatic neurocognitive impairment and minor neurocognitive disorder diagnosis (25% and 33%) as compared with the moderate (23% and 15%) and the high (12% and 9%) effort groups. Predictors of suboptimal effort were self-reported memory impairment, African American race, and cocaine use. Change in effort between baseline and follow-up correlated with change in HAND severity. Suboptimal effort seems to inflate estimated HAND prevalence and explain fluctuation of severity over time. A simple modification of study protocols to optimize effort is indicated by the results.

The Presence of Human Immunodeficiency Virus-Associated Neurocognitive Disorders Is Associated With a Lower Adherence to Combined Antiretroviral Treatment.

BackgroundHuman immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are defined according to their diagnostic degrees as follows: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. Because high adherence to combined antiretroviral therapy (cART) is required to maintain viral suppression among HIV-infected patients, it is important to investigate the impact of HAND on medication adherence. Our study hypothesis was that patients with HAND had a lower medication adherence than patients who did not have HAND.MethodsThis was an observational, exploratory, 2-center pilot study of patients who had a state-of-the-art neurocognitive assessment performed between January 2011 and June 2015 while also being followed at their respective adherence clinics. Adherence was measured with electronic monitors. Patients’ sociodemographic characteristics, HIV viral load, and CD4 counts were retrieved from the Swiss HIV Cohort Study database. At each time t, adherence was computed as the proportion of patients taking medication as prescribed at that time.ResultsWe included 59 patients, with a median (Q1, Q3) age of 53 years (47–58) and 39 (66%) were male participants. Twenty-two patients (35%) had no neurocognitive deficits, 16 (27%) patients had HAND, and 21 (35%) patients had non-HAND (mostly depression). Implementation over 3 years showed a significant decline (50%) in medication adherence among patients diagnosed with HAND in comparison with patients who had a normal neuropsychological status or a non-HIV-related cognitive deficit (implementation stayed 90% during follow-up).ConclusionsOur findings support the hypothesis that HAND is associated with reduced cART adherence.

HMGB1/anti-HMGB1 antibodies define a molecular signature of early stages of HIV-Associated Neurocognitive Disorders (HAND)

BackgroundHIV-associated neurocognitive disorders (HAND) persist in the post-HAART era, characterized by asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorders (MND). High mobility group box 1 (HMGB1) is a non-histone chromosomal protein widely expressed in the nucleus of all eukaryotic cells, including brain cells, which acts as a potent proinflammatory cytokine when actively secreted from immune cells. Recent reports suggested that HMGB1 acts on microglial cells to promote neuroinflammation. In this study, our aim was to determine whether HMGB1 is involved in HAND, but also to identify early new markers of neurological impairment in HIV-infected patients.MethodsCSF and serum were collected from 103 HIV-1-infected patients enrolled in Neuradapt, a prospective study of the prevalence of HAND in HIV-1 infected patients at Nice University Hospital. Stored fluids were assessed for immunological, virological, and brain metabolite parameters. In addition to HIV RNA and DNA measurements, expression of T-cell surface markers of activation (CD38 and HLA-DR) was analyzed on whole blood. Concentration of 27 cytokines and chemokines was measured using multiplex bead assays on serum and CSF. Concentration of HMGB1 and anti-HMGB1 IgG autoantibodies were also measured on the same samples. Changes in cerebral metabolites N-acetyl aspartate (NAA), Choline (Cho) and creatinine (Cr) were assessed by magnetic resonance microscopy (MRS).ResultsClinical, virological and immunological characteristics were comparable between HAND (n = 30) and no HAND (n = 73) patients, except the absolute numbers of CD8+ T cells, which were higher in patients with HAND. Among the 29 molecules tested, only 4 of them were significantly upregulated in the CSF from HAND patients as compared to healthy donors i.e. HMGB1, anti-HMGB1 IgG antibodies, IP-10 and MCP1. CSF HMGB1 levels were positively correlated with HIV-1 DNA in aviremic HAND patients, suggesting a positive impact of HMGB1 on HIV reservoirs. Moreover, in contrast to NAA/Cr and Cho/NAA ratios, circulating anti-HMGB1 IgG antibody levels could discriminate patients with no HAND from patients with no HAND and a single deficit (average ROC-AUC = 0.744, p = 0.03 for viremic patients), thus enabling the identification of a very early stage of neurocognitive impairment,ConclusionWe report that brain injury in chronically HIV-infected patients on stable HAART is strongly associated with persistent CNS inflammation, which is correlated with increased levels of HMGB1 and anti-HMGB1 IgG in the CSF. Moreover, we identified circulating anti-HMGB1 IgG as a very early biomarker of neurological impairment in patients without HAND. These results might have important implication for the identification of patients who are at high risk of developing neurological disorders.

Screening for neurocognitive impairment in HIV-positive adults aged 50 years and older: Montreal Cognitive Assessment relates to self-reported and clinician-rated everyday functioning

ABSTRACTAs the HIV+ population ages, the risk for and need to screen for HIV-associated neurocognitive disorders (HAND) increases. The aim of this study is to determine the utility and ecological validity of the Montreal Cognitive Assessment (MoCA) among older HIV+ adults. A total of 100 HIV+ older adults aged 50 years or over completed a comprehensive neuromedical and neurocognitive battery, including the MoCA and several everyday functioning measures. The receiver operating characteristic curve indicates ≤26 as the optimal cut-off balancing sensitivity (84.2%) and specificity (55.8%) compared to “gold standard” impairment as measured on a comprehensive neuropsychological battery. Higher MoCA total scores are significantly (p < .01) associated with better performance in all individual cognitive domains except motor abilities, with the strongest association with executive functions (r = −0.49, p < .01). Higher MoCA total scores are also significantly (p <.01) associated with fewer instrumental activities of daily living declines (r = −0.28), fewer everyday cognitive symptoms (r = −0.25), and better clinician-rated functional status (i.e., Karnofsky scores; r = 0.28); these associations remain when controlling for depressive symptoms. HIV+ individuals who are neurocognitively normal demonstrate medium-to-large effect size differences in their MoCA performance compared to those with asymptomatic neurocognitive impairment (d = 0.85) or syndromic HAND (mild neurocognitive disorder or HIV-associated dementia; d = 0.78), while the latter two categories do not differ. Although limited by less than optimal specificity, the MoCA demonstrates good sensitivity and ecological validity, which lends support to its psychometric integrity as a brief cognitive screening tool among older HIV+ adults.

Concordance Between Self-Report and Performance-Based Measures of Everyday Functioning in HIV-Associated Neurocognitive Disorders.

Self-report is typically used to differentiate between asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) in the assessment of HIV-associated neurocognitive disorders (HAND). Yet, it is unclear whether the lack of self-reported functional impairments in individuals with ANI is indicative of a genuine absence of functional impairment, or of inaccurate self-reports. In the present study, we examined the relationship between previously validated self-report (patient's assessment of own functioning inventory; instrumental activities of daily living inventory) and performance-based (the Texas Functional Living Scale) measures of functional abilities in 112 virologically-controlled HIV-infected, and 40 well-matched, HIV-uninfected participants. Participants with symptomatic cognitive impairment (CI) had significantly lower overall scores and higher rates of impairment on a performance-based measure of everyday functioning as compared to participants with either asymptomatic CI or normal cognitive performance (WNL [within normal limits]; all p<0.05), while asymptomatic CI and WNL participants had comparable rates of impairment and performance within the average range on the performance-based measure. The concordance between self-report and performance-based measures of everyday functioning in asymptomatic and symptomatic CI provide support for ANI and MND as clinically distinct diagnostic entities, and support the use of self-reports as appropriate measures of everyday functioning in the diagnosis of HAND.

MoCA Utility as a Quick Testing Tool for Neurocognitive Disorders in HIV Patients: Analysis of a Prospective Cohort

Background Since the introduction of highly active antiretroviral therapy, asymptomatic and mild neurocognitive impairment are the main clinical manifiestations of HIV associated neurocognitive disorders (HAND), compromising adherence to treatment, daily performance, quality of life, and even increasing the risk of mortality. We do not have validated screening tools for early detection of HAND applicable to the routine medical visit. The Montreal Cognitive Assessment test (MoCA) is a simple questionnaire used in Alzheimer’s disease, but its utility as a screening tool for HAND remains controversial.Methods We designed a prospective study to establish MoCA´s usefulness as a rapid and sensitive tool for the detection of HAND, compared with a gold-standard test (GST) that includes Mini-mental State Examination (MMSE) and a battery of assays that evaluate several neurological domains. Adult patients with HIV infection attending our institution were included. The MoCA test was performed by infectious diseases specialists, and the GST by neurologists. History of recent stroke, neurological disease, opportunistic central nervous system infection, major depression, schizophrenia, bipolar disorder, substance abuse or dependence on alcohol, were exclusion criteria. We analized demographic and clinical variables.ResultsFifty HIV-infected patients were enrolled, 94% males, with a mean age of 45.6 years (range 20–75), and an average of 14.8 years of education (range 3–26). The mean CD4 cell count was 596 cells/ml (range 65–1130), and 70% of the patients had undetectable viral load (≤20 copies/mL) at the time of the evaluation. Compared with GST, MoCA had a sensibility (S) of 94.12% (CI 71.3–99.8), specificity (E) 78.79% (CI 61.09–91.02), positive predictive value (PPV) 69.57% (CI 47–86.79) and negative predictive value (NPV) 96.3 (CI 81–99.9). In contrast, the MMSE presented S 11.76% (CI 1.46–36.44), E 100% (CI 89.4–100), PPV 100% (CI 15.8–100) and NPV 68.75% (CI 53.7–81.3). Cohen’s kappa coefficient between MoCA and GST was 0.67 (95% CI 0.46–0.87), reflecting an adequate agreement.Conclusion MoCA’s performance as a screening test was adequate compared with GST and far superior to MMSE for early detection of HAND. Although specifity could be optimized, MoCA test remains a valuable screening tool in the routine medical visit in our HIV population.Disclosures All authors: No reported disclosures.

Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda.

In the USA, increased cerebrospinal fluid (CSF) inflammatory cytokines have been observed in antiretroviral therapy (ART)-naive, HIV-seropositive individuals with HIV-associated neurocognitive disorder (HAND). We characterized the relationship between HAND and CSF biomarker expression in ART-naive, HIV-seropositive individuals in Rakai, Uganda. We analyzed CSF of 78 HIV-seropositive, ART-naive Ugandan adults for 17 cytokines and 20 neurodegenerative biomarkers via Luminex multiplex assay. These adults underwent neurocognitive assessment to determine their degree of HAND. We compared biomarker concentrations between high and low CD4 groups and across HAND classifications, adjusting for multiple comparisons. Individuals with CD4 <200 cells/μL (N=38) had elevated levels of CSF Interleukin (IL)-2, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, matrix metalloproteinase (MMP)-1, MMP-7, and S100 calcium-binding protein B (S100B) and lower levels of amyloid β42. Individuals with CD4 351-500 cells/μL (N=40) had significantly higher CSF levels of interleukin (IL)-1β, amyloid β42, and soluble receptor for advanced glycation end products (sRAGE). Increasing levels of S100B, platelet-derived growth factor-AA (PDGF-AA), brain-derived neurotrophic factor (BDNF), and sRAGE were associated with decreased odds of mild neurocognitive disorder (n=22) or HIV-associated dementia (n=15) compared with normal function (n=30) or asymptomatic neurocognitive impairment (n=11). Increased levels of interferon (IFN)-γ were associated with increased odds of mild neurocognitive impairment or HIV-associated dementia relative to normal or asymptomatic neurocognitive impairment. Proinflammatory CSF cytokines, chemokines, and neurodegenerative biomarkers were present in increasing concentrations with advanced immunosuppression and may play a role in the development of HAND. The presence of select CNS biomarkers may also play a protective role in the development of HAND.

Validation of the International HIV Dementia Scale as a Screening Tool for HIV-Associated Neurocognitive Disorders in a German-Speaking HIV Outpatient Clinic.

BackgroundHIV-associated neurocognitive disorders (HAND) are widely present among people living with HIV. Especially its milder forms, asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), remain highly prevalent worldwide. Diagnosing these conditions is subject to a time and resource consuming neuropsychological assessment. Selecting patients at a higher risk of cognitive impairment by using a simple but effective screening tool helps to organise access to further neuropsychological diagnosis. The International HIV Dementia Scale (IHDS) has until now been a well-established screening tool in African and American countries, however these populations’ demographics defer significantly from ours, so using the same parameters could be ineffective.ObjectivesTo calculate the prevalence of this condition among people attending an HIV outpatient clinic in Berlin and to validate the use of the IHDS as a screening tool for HAND in a German-speaking population.MethodsWe screened 480 HIV-infected patients using the IHDS, 89% of them were on a stable antiretroviral treatment. Ninety of them completed a standardised neuropsychological battery of tests and a specific cognitive complaints questionnaire. The same procedure was applied to a control group of 30 HIV-negative participants. HAND diagnosis was established according to the Frascati criteria.ResultsThe overall prevalence of HAND in our cohort was 43% (20% ANI, 17% MND and 6% HIV-associated dementia). The optimal cut-off on the IHDS for detecting HAND cases was set at 11 and achieved both a sensitivity and a specificity of 80%. When specifically screening for the more severe form of HAND, HIV-associated dementia, a cut-off value of 10 offered an increase in both sensitivity (94%) and specificity (86%). The Youden Index for diagnostic accuracy was 0.6 and 0.8, respectively.ConclusionsThe prevalence of HAND was comparable to the reported by recent studies performed in countries with a similar economic development. The study confirms the IHDS to be a useful HAND screening tool in primary care settings and establishes new recommendations for its use in German-speaking countries.