A Characterization of Neurology Consults for Inpatients with SARS-CoV-2 Infection Compared to Other Respiratory Viruses.

Introduction: Neurological consultation for patients infected with SARS-CoV-2 is common; it is currently unknown whether the neurologist's approach to inpatient consultation of patients with SARS-CoV-2 should differ from the paradigm used to evaluate hospitalized patients with similar respiratory viruses. The goal of the present study is to determine if the preponderance of new neurologic diagnoses differs between inpatients with SARS-CoV-2 and similar non-SARS-CoV-2 respiratory viruses for whom neurology is consulted. Methods: We performed a retrospective chart analysis of inpatient neurologic consultations at three major Philadelphia-based hospitals. We compared the final neurologic diagnosis of 152 patients infected with SARS-CoV-2 to 54 patients with a similar ubiquitous non-SARS-CoV-2 respiratory virus (influenza A, influenza B, respiratory syncytial virus, rhinovirus, or adenovirus, the most commonly tested respiratory viruses at our institution). Secondary metrics included age, sex, level of care, prior neurologic diagnoses, and mortality. A multinomial logistic regression model was utilized to evaluate the relative difference between diagnostic category groups on all metrics. Results: The proportion of patients with seizure who were infected with SARS-CoV-2 admitted to an intensive care unit (ICU) was significantly higher than those who were admitted to a medical-surgical floor. SARS-CoV-2 was also associated with increased risk for ICU admission compared to other common respiratory viruses. SARS-CoV-2 inpatients requiring neurologic consultation were also more likely to be older and female as compared to the non-SARS-CoV-2 cohort. In other domains, the proportion of neurologic diagnoses between SAR-CoV-2 and non-SARS-CoV-2 respiratory viruses showed no significant difference. Conclusion: Patients requiring inpatient neurologic consultation with a diagnosis of SARS-CoV-2 infection or another respiratory virus were found to be remarkably similar in terms of their ultimate neurologic diagnosis, with the exception of a larger preponderance of seizure in critical-care-level patients with SARS-CoV-2 infection. Our study suggests that the neurological approach to patients hospitalized with SARS-CoV-2 should be similar to that for patients with similar common respiratory infections, noting that seizure was seen more frequently in critically ill patients infected with SARS-CoV-2.

Transmitted/founder SHIV.D replicates in the brain, causes neuropathogenesis, and persists on combination antiretroviral therapy in rhesus macaques.

A biologically relevant non-human primate (NHP) model of HIV persistence in the central nervous system (CNS) is necessary. Most current NHP/SIV models of HIV infection fail to recapitulate viral persistence in the CNS without encephalitis or fail to employ viruses that authentically represent the ongoing HIV-1 pandemic. Here, we demonstrate viral replication in the brain and neuropathogenesis after combination antiretroviral therapy (ART) in rhesus macaques (RMs) using novel macrophage-tropic transmitted/founder (TF) simian-human immunodeficiency virus SHIV.D.191,859 (SHIV.D). Quantitative immunohistochemistry (IHC) and DNA/RNAscope in situ hybridization (ISH) were performed on three brain regions from six SHIV.D-infected RMs; two necropsied while viremic, two during analytical treatment interruptions, and two on suppressive ART. We demonstrated myeloid-mediated neuroinflammation, viral replication, and proviral DNA in the brain in all animals. These results demonstrate that TF SHIV.D models native HIV-1 CNS replication, pathogenesis, and persistence on ART in rhesus macaques.

Dimethyl Fumarate as Potential Treatment for Alzheimer's Disease: Rationale and Clinical Trial Design.

Alzheimer's Disease (AD) is a debilitating disease that leads to severe cognitive impairment and functional decline. The role of tau hyperphosphorylation and amyloid plaque deposition in the pathophysiology of AD has been well described; however, neuroinflammation and oxidative stress related to sustained microglial activation is thought to play a significant role in the disease process as well. NRF-2 has been identified in modulating the effects of inflammation and oxidative stress in AD. Activation of NRF-2 leads to an increased production of antioxidant enzymes, including heme oxygenase, which has been shown to have protective effects in neurodegenerative disorders such as AD. Dimethyl fumarate and diroximel fumarate (DMF) have been approved for the use in relapsing-remitting multiple sclerosis. Research indicates that they can modulate the effects of neuroinflammation and oxidative stress through the NRF-2 pathway, and as such, could serve as a potential therapeutic option in AD. We propose a clinical trial design that could be used to assess DMF as a treatment option for AD.

Mechanisms, Effects, and Management of Neurological Complications of Post-Acute Sequelae of COVID-19 (NC-PASC).

With a growing number of patients entering the recovery phase following infection with SARS-CoV-2, understanding the long-term neurological consequences of the disease is important to their care. The neurological complications of post-acute sequelae of SARS-CoV-2 infection (NC-PASC) represent a myriad of symptoms including headaches, brain fog, numbness/tingling, and other neurological symptoms that many people report long after their acute infection has resolved. Emerging reports are being published concerning COVID-19 and its chronic effects, yet limited knowledge of disease mechanisms has challenged therapeutic efforts. To address these issues, we review broadly the literature spanning 2020-2022 concerning the proposed mechanisms underlying NC-PASC, outline the long-term neurological sequelae associated with COVID-19, and discuss potential clinical interventions.

Behavioral and histological assessment of a novel treatment of neuroHIV in humanized mice.

Neurocognitive deficits are prevalent among people living with HIV, likely due to chronic inflammation and oxidative stress in the brain. To date, no pharmaceutical treatments beyond antiretroviral therapy (ARV) has been shown to reduce risk for, or severity of, HIV-associated neurocognitive disorder. Here we investigate a novel compound, CDDO-Me, with documented neuroprotective effects via activation of the nrf2 and inhibition of the NFkB pathways. Methods: We conducted three studies to assess the efficacy of CDDO-Me alone or in combination with antiretroviral therapy in humanized mice infected with HIV; behavioral, histopathological, and immunohistochemical. Results: CDDO-Me in combination with ARV rescued social interaction deficits; however, only ARV was associated with preserved functioning in other behaviors, and CDDO-Me may have attenuated those benefits. A modest neuroprotective effect was found for CDDO-Me when administered with ARV, via preservation of PSD-95 expression; however, ARV alone had a more consistent protective effect. No significant changes in antioxidant enzyme expression levels were observed in CDDO-Me-treated animals. Only ARV use seemed to affect some antioxidant levels, indicating that it is ARV rather than CDDO-Me that is the major factor providing neuroprotection in this animal model. Finally, immunohistochemical analysis found that several cellular markers in various brain regions varied due to ARV rather than CDDO-Me. Conclusion: Limited benefit of CDDO-Me on behavior and neuroprotection were observed. Instead, ARV was shown to be the more beneficial treatment. These experiments support the future use of this chimeric mouse for behavioral experiments in neuroHIV research.

Examining virtual driving test performance and its relationship to individuals with HIV-associated neurocognitive disorders.

Significance: Existing screening tools for HIV-associated neurocognitive disorders (HAND) are often clinically impractical for detecting milder forms of impairment. The formal diagnosis of HAND requires an assessment of both cognition and impairment in activities of daily living (ADL). To address the critical need for identifying patients who may have disability associated with HAND, we implemented a low-cost screening tool, the Virtual Driving Test (VDT) platform, in a vulnerable cohort of people with HIV (PWH). The VDT presents an opportunity to cost-effectively screen for milder forms of impairment while providing practical guidance for a cognitively demanding ADL. Objectives: We aimed to: (1) evaluate whether VDT performance variables were associated with a HAND diagnosis and if so; (2) systematically identify a manageable subset of variables for use in a future screening model for HAND. As a secondary objective, we examined the relative associations of identified variables with impairment within the individual domains used to diagnose HAND. Methods: In a cross-sectional design, 62 PWH were recruited from an established HIV cohort and completed a comprehensive neuropsychological assessment (CNPA), followed by a self-directed VDT. Dichotomized diagnoses of HAND-specific impairment and impairment within each of the seven CNPA domains were ascertained. A systematic variable selection process was used to reduce the large amount of VDT data generated, to a smaller subset of VDT variables, estimated to be associated with HAND. In addition, we examined associations between the identified variables and impairment within each of the CNPA domains. Results: More than half of the participants (N = 35) had a confirmed presence of HAND. A subset of twenty VDT performance variables was isolated and then ranked by the strength of its estimated associations with HAND. In addition, several variables within the final subset had statistically significant associations with impairment in motor function, executive function, and attention and working memory, consistent with previous research. Conclusion: We identified a subset of VDT performance variables that are associated with HAND and assess relevant functional abilities among individuals with HAND. Additional research is required to develop and validate a predictive HAND screening model incorporating this subset.

Developments in Neuroprotection for HIV-Associated Neurocognitive Disorders (HAND).

PURPOSE OF REVIEW: Reducing the risk of HIV-associated neurocognitive disorders (HAND) is an elusive treatment goal for people living with HIV. Combination antiretroviral therapy (cART) has reduced the prevalence of HIV-associated dementia, but milder, disabling HAND is an unmet challenge. As newer cART regimens that more consistently suppress central nervous system (CNS) HIV replication are developed, the testing of adjunctive neuroprotective therapies must accelerate. RECENT FINDINGS: Successes in modifying cART regimens for CNS efficacy (penetrance, chemokine receptor targeting) and delivery (nanoformulations) in pilot studies suggest that improving cART neuroprotection and reducing HAND risk is achievable. Additionally, drugs currently used in neuroinflammatory, neuropsychiatric, and metabolic disorders show promise as adjuncts to cART, likely by broadly targeting neuroinflammation, oxidative stress, aerobic metabolism, and/or neurotransmitter metabolism. Adjunctive cognitive brain therapy and aerobic exercise may provide additional efficacy. Adjunctive neuroprotective therapies, including available FDA-approved drugs, cognitive therapy, and aerobic exercise combined with improved cART offer plausible strategies for optimizing the prevention and treatment of HAND.

Dimethyl Fumarate, an Approved Multiple Sclerosis Treatment, Reduces Brain Oxidative Stress in SIV-Infected Rhesus Macaques: Potential Therapeutic Repurposing for HIV Neuroprotection.

Dimethyl fumarate (DMF), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, induces antioxidant enzymes, in part through transcriptional upregulation. We hypothesized that DMF administration to simian immunodeficiency virus (SIV)-infected rhesus macaques would induce antioxidant enzyme expression and reduce oxidative injury and inflammation throughout the brain. Nine SIV-infected, CD8+-T-lymphocyte-depleted rhesus macaques were studied. Five received oral DMF prior to the SIV infection and through to the necropsy day. Protein expression was analyzed in 11 brain regions, as well as the thymus, liver, and spleen, using Western blot and immunohistochemistry for antioxidant, inflammatory, and neuronal proteins. Additionally, oxidative stress was determined in brain sections using immunohistochemistry (8-OHdG, 3NT) and optical redox imaging of oxidized flavoproteins containing flavin adenine dinucleotide (Fp) and reduced nicotinamide adenine dinucleotide (NADH). The DMF treatment was associated with no changes in virus replication; higher expressions of the antioxidant enzymes NQO1, GPX1, and HO-1 in the brain and PRDX1 and HO-2 in the spleen; lower levels of 8-OHdG and 3NT; a lower optical redox ratio. The DMF treatment was also associated with increased expressions of cell-adhesion molecules (VCAM-1, ICAM-1) and no changes in HLA-DR, CD68, GFAP, NFL, or synaptic proteins. The concordantly increased brain antioxidant enzyme expressions and reduced oxidative stress in DMF-treated SIV-infected macaques suggest that DMF could limit oxidative stress throughout the brain through effective induction of the endogenous antioxidant response. We propose that DMF could potentially induce neuroprotective brain responses in persons living with HIV.

Robot-Based Assessment of HIV-Related Motor and Cognitive Impairment for Neurorehabilitation.

There is a pressing need for strategies to slow or treat the progression of functional decline in people living with HIV. This paper explores a novel rehabilitation robotics approach to measuring cognitive and motor impairment in adults living with HIV, including a subset with stroke. We conducted a cross-sectional study with 21 subjects exhibiting varying levels of cognitive and motor impairment. We tested three robot-based tasks - trajectory tracking, N-back, and spatial span - to assess if metrics derived from these tasks were sensitive to differences in subjects with varying levels of executive function and upper limb motor impairments. We also examined how well these metrics could estimate clinical cognitive and motor scores. The results showed that the average sequence length on the robot-based spatial span task was the most sensitive to differences between various cognitive and motor impairment levels. We observed strong correlations between robot-based measures and clinical cognitive and motor assessments relevant to the HIV population, such as the Color Trails 1 (rho = 0.83), Color Trails 2 (rho = 0.71), Digit Symbol - Coding (rho = 0.81), Montreal Cognitive Assessment - Executive Function subscore (rho = 0.70), and Box and Block Test (rho = 0.74). Importantly, our results highlight that gross motor impairment may be overlooked in the assessment of HIV-related disability. This study shows that rehabilitation robotics can be expanded to new populations beyond stroke, namely to people living with HIV and those with cognitive impairments.

Robot-based assessment of HIV-related motor and cognitive impairment for neurorehabilitation.

There is a pressing need for strategies to slow or treat the progression of functional decline in people living with HIV. This paper explores a novel rehabilitation robotics approach to measuring cognitive and motor impairment in adults living with HIV, including a subset with stroke. We conducted a cross-sectional study with 21 subjects exhibiting varying levels of cognitive and motor impairment. We developed three robot-based tasks trajectory tracking, N-back, and spatial span - to assess if metrics derived from these tasks were sensitive to differences in subjects with varying levels of executive function and upper limb motor impairments. We also examined if these metrics could estimate clinical cognitive and motor scores. The results showed that the average sequence length on the robot-based spatial span task was the most sensitive to differences between subjects' cognitive and motor impairment levels. We observed strong correlations between robot-based measures and clinical cognitive and motor assessments relevant to the HIV population, such as the Color Trails 1 (rho = 0.83), Color Trails 2 (rho = 0.71), Digit Symbol - Coding (rho = 0.81), Montreal Cognitive Assessment - Executive Function subscore (rho = 0.70), and Box and Block Test (rho = 0.74). Importantly, our results highlight that gross motor impairment may be overlooked in the assessment of HIV-related disability. This study shows that rehabilitation robotics can be expanded to new populations beyond stroke, namely to people living with HIV and those with cognitive impairments.

Neuroinflammation associates with antioxidant heme oxygenase-1 response throughout the brain in persons living with HIV.

Previous studies showed that persons living with HIV (PLWH) demonstrate higher brain prefrontal cortex neuroinflammation and immunoproteasome expression compared to HIV-negative individuals; these associate positively with HIV levels. Lower expression of the antioxidant enzyme heme oxygenase 1 (HO-1) was observed in PLWH with HIV-associated neurocognitive impairment (HIV-NCI) compared to neurocognitively normal PLWH. We hypothesized that similar expression patterns occur throughout cortical, subcortical, and brainstem regions in PLWH, and that neuroinflammation and immunoproteasome expression associate with lower expression of neuronal markers. We analyzed autopsied brains (15 regions) from 9 PLWH without HIV-NCI and 7 matched HIV-negative individuals. Using Western blot and RT-qPCR, we quantified synaptic, inflammatory, immunoproteasome, endothelial, and antioxidant biomarkers, including HO-1 and its isoform heme oxygenase 2 (HO-2). In these PLWH without HIV-NCI, we observed higher expression of neuroinflammatory, endothelial, and immunoproteasome markers in multiple cortical and subcortical regions compared to HIV-negative individuals, suggesting a global brain inflammatory response to HIV. Several regions, including posterior cingulate cortex, globus pallidus, and cerebellum, showed a distinct pattern of higher type I interferon (IFN)-stimulated gene and immunoproteasome expression. PLWH without HIV-NCI also had (i) stable or higher HO-1 expression and positive associations between (ii) HO-1 and HIV levels (CSF, plasma) and (iii) HO-1 expression and neuroinflammation, in multiple cortical, subcortical, and brainstem regions. We observed no differences in synaptic marker expression, suggesting little, if any, associated neuronal injury. We speculate that this may reflect a neuroprotective effect of a concurrent HO-1 antioxidant response despite global neuroinflammation, which will require further investigation.

Regional Brain Recovery from Acute Synaptic Injury in Simian Immunodeficiency Virus-Infected Rhesus Macaques Associates with Heme Oxygenase Isoform Expression.

Brain injury occurs within days in simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) infection, and some recovery may occur within weeks. Inflammation and oxidative stress associate with such injury, but what drives recovery is unknown. Chronic HIV infection associates with reduced brain frontal cortex expression of the antioxidant/anti-inflammatory enzyme heme oxygenase-1 (HO-1) and increased neuroinflammation in individuals with cognitive impairment. We hypothesized that acute regional brain injury and recovery associate with differences in regional brain HO-1 expression. Using SIV-infected rhesus macaques, we analyzed multiple brain regions through acute and chronic infection (90 days postinfection [dpi]) and quantified viral (SIV gag RNA), synaptic (PSD-95; synaptophysin), axonal (neurofilament/neurofilament light chain [NFL]), inflammatory, and antioxidant (enzymes, including heme oxygenase isoforms [HO-1, HO-2]) markers. PSD-95 was reduced in the brainstem, basal ganglia, neocortex, and cerebellum within 13 dpi, indicating acute synaptic injury throughout the brain. All areas except the brainstem recovered. Unchanged NFL was consistent with no acute axonal injury. SIV RNA expression was highest in the brainstem throughout infection, and it associated with neuroinflammation. Surprisingly, during the synaptic injury and recovery phases, HO-2, and not HO-1, progressively decreased in the brainstem. Thus, acute SIV synaptic injury occurs throughout the brain, with spontaneous recovery in regions other than the brainstem. Within the brainstem, the high SIV load and inflammation, along with reduction of HO-2, may impair recovery. In other brain regions, stable HO-2 expression, with or without increasing HO-1, may promote recovery. Our data support roles for heme oxygenase isoforms in modulating recovery from synaptic injury in SIV infection and suggest their therapeutic targeting for promoting neuronal recovery.IMPORTANCE Brain injury induced by acute simian (or human) immunodeficiency virus infection may persist or spontaneously resolve in different brain regions. Identifying the host factor(s) that promotes spontaneous recovery from such injury may reveal targets for therapeutic drug strategies for promoting recovery from acute neuronal injury. The gradual recovery from such injury observed in many, but not all, brain regions in the rhesus macaque model is consistent with the possible existence of a therapeutic window of opportunity for intervening to promote recovery, even in those regions not showing spontaneous recovery. In persons living with human immunodeficiency virus infection, such neuroprotective treatments could ultimately be considered as adjuncts to the initiation of antiretroviral drug therapy.

Heme oxygenase-1 promoter (GT) n polymorphism associates with HIV neurocognitive impairment.

OBJECTIVE: To determine whether regulatory variations in the heme oxygenase-1 (HO-1) promoter (GT) n dinucleotide repeat length could identify unique population genetic risks for neurocognitive impairment (NCI) in persons living with HIV (PLWH), we genotyped 528 neurocognitively assessed PLWH of European American and African American descent and linked genotypes to cognitive status. METHODS: In this cross-sectional study of PLWH (the CNS HIV Antiretroviral Therapy Effect Research cohort), we determined HO-1 (GT) n repeat lengths in 276 African Americans and 252 European Americans. Using validated criteria for HIV-associated NCI (HIV NCI), we found associations between allele length genotypes and HIV NCI and between genotypes and plasma markers of monocyte activation and inflammation. For comparison of HO-1 (GT) n allele frequencies with another population of African ancestry, we determined HO-1 (GT) n allele lengths in African PLWH from Botswana (n = 428). RESULTS: PLWH with short HO-1 (GT) n alleles had a lower risk for HIV NCI (OR = 0.63, 95% CI: 0.42-0.94). People of African ancestry had a lower prevalence of short alleles and higher prevalence of long alleles compared with European Americans, and in subgroup analyses, the protective effect of the short allele was observed in African Americans and not in European Americans. CONCLUSIONS: Our study identified the short HO-1 (GT) n allele as partially protective against developing HIV NCI. It further suggests that this clinical protective effect is particularly relevant in persons of African ancestry, where the lower prevalence of short HO-1 (GT) n alleles may limit induction of HO-1 expression in response to inflammation and oxidative stress. Therapeutic strategies that enhance HO-1 expression may decrease HIV-associated neuroinflammation and limit HIV NCI.

Stroke and HIV in Botswana: A prospective study of risk factors and outcomes.

OBJECTIVE: HIV is associated with an increased risk of stroke, but there are sparse data on risk factors for stroke in people living with HIV in Sub-Saharan African. The goal of this study was to identify HIV-specific stroke characteristics and risk factors among adults in Botswana. METHODS: We conducted a prospective cohort study in Gaborone, Botswana from June 2015 to June 2017 comparing risk factors and outcomes among adults with and without HIV admitted for acute stroke. In addition, we conducted a case-control study comparing patients with HIV and stroke to outpatients with HIV and no history of stroke. RESULTS: A total of 52 patients with imaging-confirmed acute stroke were enrolled. Stroke patients with HIV were younger than those without HIV (median age 40 vs 54, p = .005). Hypertension was the most common risk factor identified in both HIV+ and HIV- groups, but was more common in patients without HIV (81% vs. 55%, p = .04). Patients with HIV were significantly more likely to have a small-vessel lacunar syndrome compared to patients without HIV (67% vs. 29%, p = .02). In the case-control analysis, patients with HIV and stroke were more likely to have hypertension than stroke-free controls (53% vs. 16%; OR 7.2, 95% CI 1.5-33.8, p = .01), and were more likely to drink alcohol (53% vs. 21%, OR 3.7, 95% CI 1.1-12.1, p = .03). CONCLUSIONS: Individuals with HIV present with strokes at younger ages than individuals without HIV. Among those with HIV, hypertension and alcohol use are significant risk factors for stroke.

Characteristics of Motor Dysfunction in Longstanding Human Immunodeficiency Virus.

BACKGROUND: Cognitive dysfunction in human immunodeficiency virus (HIV) has decreased, but milder forms of HIV-associated neurocognitive disorders (HAND) persist along with motor dysfunction. The HIV Motor Scale (HMS) is a validated tool that captures motor abnormalities on routine neurologic examination and which is associated with cognitive impairment in HIV. In this study, we applied a modified HMS (MHMS) to a nationwide cohort of people with longstanding HIV to characterize and understand the factors contributing to motor dysfunction. METHODS: The National NeuroAIDS Tissue Consortium is a nationwide longitudinal cohort study. Participants undergo regular assessments including neurological examination, neuropsychological testing, and immunovirologic data collection. Data from examinations were used to calculate the MHMS score, which was then correlated with history of AIDS-related central nervous system (CNS) disorders (ARCD; eg, prior CNS opportunistic infection), cerebrovascular disease (CVD), and HAND. RESULTS: Sixty-nine percent of participants showed an abnormality on the MHMS, with 27% classified as severe. Results did not vary based on demographic or immunologic variables. The most common abnormalities seen were gait (54%), followed by coordination (39%) and strength (25%), and these commonly co-occurred. CVD (P = .02), history of ARCD (P = .001), and HAND (P = .001) were all associated with higher (ie, worse) HMS in univariate analyses; CVD and ARCD persisted in multivariate analyses. CVD was also marginally associated with symptomatic HAND. CONCLUSIONS: Complex motor dysfunction remains common in HIV and is associated with CVD, ARCD, and to a lesser extent, HAND. Future studies are needed to understand the longitudinal trajectory of HIV-associated motor dysfunction, its neural substrates, and impact on quality of life.

Frailty in medically complex individuals with chronic HIV.

OBJECTIVES: Multimorbidity and frailty are consequences of aging with HIV, yet not everyone with medical disease is frail. Our objective was to identify factors associated with frailty in a multimorbid HIV-infected cohort. DESIGN: Analysis of a prospective, observational, longitudinal cohort. METHODS: Three hundred and thirty-two participants in the medically advanced National NeuroAIDS Tissue Consortium (NNTC) study were categorized as frail, prefrail, or robust with the Fried Frailty Index. A series of logistic regression analyses (first univariate, then multivariable) were conducted to determine whether medical comorbidities, immunologic and virologic parameters, and/or neuropsychiatric variables predicted increased odds of frailty. RESULTS: The mean number of medical comorbidities per participant was 2.7, mean CD4 T-cell count was 530 cells/µl, and 77% had undetectable HIV RNA in blood. Twenty-two percent were frail, 55% prefrail, and 23% robust. Significant predictors of frailty in multivariable analysis were cognitive diagnosis rendered by Frascati criteria, depressive symptoms, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and sex. Men were less likely to be frail than women. Higher odds of frailty were seen with: symptomatic, but not asymptomatic, cognitive impairment (compared with cognitive normals); more depressive symptoms; diabetes mellitus; and COPD. CONCLUSION: Neuropsychiatric illness increased odds of being frail on a predominantly physical/motoric measure, but only when symptomatic. Lack of association with asymptomatic impairment may reflect the importance of functional limitation to frailty, or possibly a unique resilience phenotype. Understanding why sex and symptomatic neuropsychiatric illness are associated with frailty will be important in managing HIV-associated morbidity in aging populations.