CROI 2019 Abstract eBook
of neurons in real time. NDE carry proteins that can serve as new and more accurate biomarkers of cognitive impairment. Methods: We obtained 80 plasma specimens from NIH-sponsored tissue banks, that included 8 groups of 10 persons with various neurocognitive diagnoses, HIV positive and negative, 51 women and 29 men, with 4 groups ≤ 45yo and 4 groups ≥50yo. All had extensive epidemiology, clinical and neurocognitive data. We isolated NDE from plasma using a 2-step procedure and L1CAM, a neuron specific antibody. We performed mass spectrometry (M/S) on 10 NDE samples. ELISA was used to quantify several proteins of interest. Proximity extension analysis (PEA) for 184 neural-associated proteins was performed on 48 samples. Results: Neuronal enrichment of NDE was confirmed with elevated synaptophysin as well as over 100 neuronal proteins identified by M/S. HMGB1 and neurofilament light (NF-L) proteins were significantly increased in NDE from cognitively impaired men but not for women. NDE from HIV+men had decreased p-T181-tau, a positive marker for Alzheimer’s disease, compared to no difference in women. Using PEA, 25 proteins were significantly differentially expressed in HIV infection alone. Eleven proteins significantly identified cognitive impairment, both asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND), in HIV+ women; 2 were also markers for MND in men. NDE frommen and women had statistically significant divergent results with ezrin, an axonal protein and SCARA5, a scavenger protein in neurons. NDE fromwomen had significantly increased cathepsin S, tau, neuronal cell adhesion molecule and granzyme A, in ANI. Conclusion: These findings show that NDE are from a neuronal source and that HIV infection alone causes neuronal dysfunction. There are several significantly differentially expressed NDE proteins that can separate ANI fromMND in women and some can identify cognitive impairment in men compared to women. These results may explain variability in previous findings for HIV cognitive impairment biomarkers when men and women are grouped together. The results suggest possible mechanistic gender differences to therapy associated with cognitive impairment. 412 REDUCED SCYLLO-INOSITOL CORRELATES WITH NEUROCOGNITIVE IMPAIRMENT IN HIV+ INDIVIDUALS Kalpana J. Kallianpur 1 , Cecilia M. Shikuma 1 , Anna Wang 2 , Liangjie Lin 2 , Robert Paul 3 , Lindsay Kohorn 1 , Michelle L. D’Antoni 1 , Louie Mar A. Gangcuangco 1 , Peter B. Barker 2 1 University of Hawaii at Manoa, Honolulu, HI, USA, 2 Johns Hopkins University School of Medicine, Baltimore, MD, USA, 3 University of Missouri St Louis, St Louis, MO, USA Background: Biochemical mechanisms underlying HIV-associated neurocognitive disorder (HAND) and the depressive symptoms seen in many HIV+ individuals are unclear. In Alzheimer’s disease, scyllo-inositol (sI) treatment has ameliorated cognitive deficits in transgenic mice and in clinical trials has decreased cerebrospinal fluid amyloid-β42 and increased brain sI. However, sI has been little studied in HIV. We examined sI and other metabolites as potential biomarkers of neuropsychiatric measures in an HIV+ population. Methods: HIV+ individuals on stable antiretroviral therapy > 1 year and diagnosed with mild-to-moderate neuropsychological (NP) impairment at screening underwent cross-sectional magnetic resonance spectroscopy (MRS) and NP testing. The Beck Depression Inventory (BDI)-II was administered. We computed global and 8 domain-specific NP z-scores (working memory [NPZwm], language [NPZlang], motor [NPZmotor], etc.). Single-voxel 1H-MRS at 3T (PRESS sequence with TE/TR=35/2000 ms) quantified metabolites including sI (concentrations; ratios to total creatine [tCr]) using ‘LCModel’ analysis in left frontal white matter (FWM) and basal ganglia (BG). Multi-voxel magnetic resonance spectroscopic imaging yielded ratios of N-acetylaspartate (NAA) to choline (Cho) in bilateral regions. Pearson (R) or Spearman (ρ) correlation and bootstrapped 95% confidence intervals assessed metabolite relationships to NP and BDI-II scores. Results: We evaluated 30 HIV patients [26 males; age 57± 7 years; 90%with plasma HIV RNA < 20 copies/mL; median current and nadir CD4 count 594 and 165 cells/µL]. Decreased FWM sI and sI/Cr related to NP deficits (Table); e.g., sI/ Cr correlated with NPZlang (ρ=0.59, p=0.003). Total NAA (tNAA) in FWM and BG also showed significant positive associations with NP z-scores. Lower gamma- aminobutyric acid (GABA) in BG related to slower psychomotor speed (ρ=0.41, p=0.033). Frontal, temporal and BG tNAA/Cho correlated positively with NP performance. Reduced GABA and glycerophosphocholine (GPC) in BG were linked to higher BDI-II (ρ~−0.4, p~0.03). Among NP z-scores, only NPZmotor
related to BDI-II (ρ=−0.40, p=0.028). Nadir CD4 correlated with FWM sI (ρ=0.58, p=0.006) and sI/tCr (ρ=0.48, p=0.029) but not NP z-scores. Conclusion: Scyllo-inositol in FWM of HIV+ individuals may provide a biomarker of NP functioning not mediated by mood. Reduced sI may reflect NP effects of past HIV disease. The role of sI in HAND warrants further study, as do GABA and GPC in relation to HIV-associated depression.
413 LEGACY EFFECTS ON COGNITIVE FUNCTIONS AMONG HIV-INFECTED MEN Yang Qu 1 , Zheng Wang 1 , Yu Cheng 1 , Lawrence Kingsley 1 , Andrew Levine 2 , Eileen Martin 3 , Cynthia Munro 4 , Ann B. Ragin 5 , Leah H. Rubin 4 , Ned Sacktor 4 , Eric C. Seaberg 4 , James T. Becker 1 , for the Neuropsychology Working Group of the Multicenter AIDS Cohort Study 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 University of California Los Angeles, Los Angeles, CA, USA, 3 Rush University Medical Center, Chicago, IL, USA, 4 Johns Hopkins University, Baltimore, MD, USA, 5 Northwestern University, Chicago, IL, USA Background: Prior to the use of combination antiretroviral therapy (cART), HIV-infected subjects were at high risk for developing significant neurological and neuropsychological dysfunction. However, such risk has declined after using cART, while the rate of milder forms of impairment has remained relatively unaffected. It is unclear from existing data how cognitive functions in HIV-infected subjects changed after beginning cART and the extent to which impairment prior to cART is associated with subsequent cognitive functions (i.e., legacy effect). This report aims to describe trajectories of cognitive functions in HIV-infected subjects over 15 years following the use of cART. Methods: We matched HIV-infected subjects from the Multicenter AIDS Cohort Study who had used cART with uninfected men using propensity scores computed with demographics and baseline cognitive functions (measured in 1996). These matched pairs were aligned such that time T0 corresponded to the first cART use visit by the HIV-infected men. We applied the Multivariate Normative Comparison method to all six NP domain scores to detect any abnormality in cognitive functions. We coded subjects as having prior impairment if there were any cognitive abnormalities at any visit prior to T0. We plotted the LOWESS trajectories of cognitive functions from T-5 to T+15 separated as a function of HIV and cognitive status prior to cART. Results: 537 matched pairs were utilized in the study. 121 of the infected men and 100 of the uninfected controls were found to have prior impairment. We did not observe significant differences between HIV-infected and uninfected men in trajectories of cognitive functions regarding executive processing, speed of information processing, learning and memory, working memory, and attention. However, faster decline in motor speed and coordination was observed among HIV-infected subjects without prior impairment approximately 10 years after the start of cART. Overall, subjects without prior impairment had higher scores in all six NP domains compared with subjects with prior impairments. Cognitive functions of HIV-infected men with prior impairment did not improve after beginning cART. Conclusion: By matching HIV-infected subjects with uninfected controls we were able to evaluate the relative cognitive decline among the infected men after they began using cART. The trajectories suggest that cognitive functions remain largely stable and that any prior impairments in cognition have a lasting effect over follow-up.
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