Observational Study

. 2023 Jun 13;100(24):e2466-e2476.

doi: 10.1212/WNL.0000000000207339. Epub 2023 Apr 27.

Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy

Cynthia McMahan¹, Devon K Dietrich¹, Elizabeth F Horne¹, Erin Kelly¹, Katrina Geannopoulos¹, Peter Selim Siyahhan Julnes¹, Lillian Ham¹, Ulisses Santamaria¹, Chuen-Yen Lau¹, Tianxia Wu¹, Hsing-Chuan Hsieh¹, Anuradha Ganesan¹, Catherine Berjohn¹, Suad Kapetanovic¹, Daniel S Reich¹, Govind Nair¹, Joseph Snow¹, Brian K Agan¹, Avindra Nath¹, Bryan R Smith²

Affiliations

¹ From the Section of Infections of the Nervous System (C.M., D.K.D., E.F.H., E.K., K.G., P.S.S.J., A.N., B.R.S.), Office of the Clinical Director (T.W.),, and Translational Neuroradiology Section (D.S.R., G.N.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; University of Pittsburgh School of Medicine (C.M.), PA; Duke University School of Medicine (E.F.H.), Durham, NC; Virginia Commonwealth University School of Medicine (E.K.), Richmond; Department of Neurology (K.G.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; Department of Psychiatry (P.S.S.J.), Washington University School of Medicine, St. Louis, MO; Office of the Clinical Director (L.H., J.S.), National Institute of Mental Health, NIH, Bethesda, MD; San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology (L.H.); Leidos Biomedical Research (U.S.), Frederick, MD; HIV Dynamics and Replication Program (C.-Y.L.), NCI, NIH, Bethesda, Infectious Diseases Clinical Research Program (H.-C.H., A.G., B.K.A.), Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda,; The Henry M. Jackson Foundation for the Advancement of Military Medicine (H.-C.H., A.G., B.K.A.), Bethesda,; Department of Medicine (A.G., B.K.A.), Uniformed Services University, Bethesda, MD; Division of Infectious Diseases (C.B.), Naval Medical Center San Diego, CA; and Department of Psychiatry and the Behavioral Sciences (S.K.), University of Southern California Keck School of Medicine, Los Angeles.
² From the Section of Infections of the Nervous System (C.M., D.K.D., E.F.H., E.K., K.G., P.S.S.J., A.N., B.R.S.), Office of the Clinical Director (T.W.),, and Translational Neuroradiology Section (D.S.R., G.N.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; University of Pittsburgh School of Medicine (C.M.), PA; Duke University School of Medicine (E.F.H.), Durham, NC; Virginia Commonwealth University School of Medicine (E.K.), Richmond; Department of Neurology (K.G.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; Department of Psychiatry (P.S.S.J.), Washington University School of Medicine, St. Louis, MO; Office of the Clinical Director (L.H., J.S.), National Institute of Mental Health, NIH, Bethesda, MD; San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology (L.H.); Leidos Biomedical Research (U.S.), Frederick, MD; HIV Dynamics and Replication Program (C.-Y.L.), NCI, NIH, Bethesda, Infectious Diseases Clinical Research Program (H.-C.H., A.G., B.K.A.), Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda,; The Henry M. Jackson Foundation for the Advancement of Military Medicine (H.-C.H., A.G., B.K.A.), Bethesda,; Department of Medicine (A.G., B.K.A.), Uniformed Services University, Bethesda, MD; Division of Infectious Diseases (C.B.), Naval Medical Center San Diego, CA; and Department of Psychiatry and the Behavioral Sciences (S.K.), University of Southern California Keck School of Medicine, Los Angeles. bryan.smith5@va.gov.

PMID: 37105760
PMCID: PMC10264056
DOI: 10.1212/WNL.0000000000207339

Observational Study

Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy

Cynthia McMahan et al. Neurology. 2023.

. 2023 Jun 13;100(24):e2466-e2476.

doi: 10.1212/WNL.0000000000207339. Epub 2023 Apr 27.

Authors

Affiliations

¹ From the Section of Infections of the Nervous System (C.M., D.K.D., E.F.H., E.K., K.G., P.S.S.J., A.N., B.R.S.), Office of the Clinical Director (T.W.),, and Translational Neuroradiology Section (D.S.R., G.N.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; University of Pittsburgh School of Medicine (C.M.), PA; Duke University School of Medicine (E.F.H.), Durham, NC; Virginia Commonwealth University School of Medicine (E.K.), Richmond; Department of Neurology (K.G.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; Department of Psychiatry (P.S.S.J.), Washington University School of Medicine, St. Louis, MO; Office of the Clinical Director (L.H., J.S.), National Institute of Mental Health, NIH, Bethesda, MD; San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology (L.H.); Leidos Biomedical Research (U.S.), Frederick, MD; HIV Dynamics and Replication Program (C.-Y.L.), NCI, NIH, Bethesda, Infectious Diseases Clinical Research Program (H.-C.H., A.G., B.K.A.), Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda,; The Henry M. Jackson Foundation for the Advancement of Military Medicine (H.-C.H., A.G., B.K.A.), Bethesda,; Department of Medicine (A.G., B.K.A.), Uniformed Services University, Bethesda, MD; Division of Infectious Diseases (C.B.), Naval Medical Center San Diego, CA; and Department of Psychiatry and the Behavioral Sciences (S.K.), University of Southern California Keck School of Medicine, Los Angeles.
² From the Section of Infections of the Nervous System (C.M., D.K.D., E.F.H., E.K., K.G., P.S.S.J., A.N., B.R.S.), Office of the Clinical Director (T.W.),, and Translational Neuroradiology Section (D.S.R., G.N.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD; University of Pittsburgh School of Medicine (C.M.), PA; Duke University School of Medicine (E.F.H.), Durham, NC; Virginia Commonwealth University School of Medicine (E.K.), Richmond; Department of Neurology (K.G.), Case Western Reserve University/University Hospitals Cleveland Medical Center, OH; Department of Psychiatry (P.S.S.J.), Washington University School of Medicine, St. Louis, MO; Office of the Clinical Director (L.H., J.S.), National Institute of Mental Health, NIH, Bethesda, MD; San Diego State University/University of California San Diego Joint Doctoral Program in Clinical Psychology (L.H.); Leidos Biomedical Research (U.S.), Frederick, MD; HIV Dynamics and Replication Program (C.-Y.L.), NCI, NIH, Bethesda, Infectious Diseases Clinical Research Program (H.-C.H., A.G., B.K.A.), Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda,; The Henry M. Jackson Foundation for the Advancement of Military Medicine (H.-C.H., A.G., B.K.A.), Bethesda,; Department of Medicine (A.G., B.K.A.), Uniformed Services University, Bethesda, MD; Division of Infectious Diseases (C.B.), Naval Medical Center San Diego, CA; and Department of Psychiatry and the Behavioral Sciences (S.K.), University of Southern California Keck School of Medicine, Los Angeles. bryan.smith5@va.gov.

PMID: 37105760
PMCID: PMC10264056
DOI: 10.1212/WNL.0000000000207339

Abstract

Background and objectives: Neurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses.

Methods: Participants underwent comprehensive neuropsychological testing and completed standardized questionnaires measuring depressive symptoms, perceptions of own functioning, and activities of daily living as part of an observational study. Brain MRI and lumbar puncture were optional. Coarsened Exact Matching was used to reduce between-group differences in age and sex, and weighted linear/logistic regression models were used to assess the effect of HIV on outcomes.

Results: Data were analyzed from 155 PWH on ART for at least 15 years and 100 HIV-negative controls. Compared with controls, PWH scored lower in the domains of attention/working memory (PWH least square mean [LSM] = 50.4 vs controls LSM = 53.1, p = 0.008) and motor function (44.6 vs 47.7, p = 0.009) and a test of information processing speed (symbol search 30.3 vs 32.2, p = 0.003). They were more likely to self-report a higher number of cognitive difficulties in everyday life (p = 0.011). PWH also reported more depressive symptoms, general anxiety, and use of psychiatric medications (all with p < 0.05). PWH had reduced proportions of subcortical gray matter on MRI (β = -0.001, p < 0.001), and CSF showed elevated levels of neurofilament light chain (664 vs 529 pg/mL, p = 0.01) and tumor necrosis factor α (0.229 vs 0.156 ng/mL, p = 0.0008).

Discussion: PWH, despite effective ART for over a decade, displayed neurocognitive deficits and mood abnormalities. MRI and CSF analyses revealed reduced brain volume and signs of ongoing neuronal injury and neuroinflammation. As the already large proportion of virologically controlled PWH continues to grow, longitudinal studies should be conducted to elucidate the implications of cognitive, psychiatric, MRI, and CSF abnormalities in this group.

Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.

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Conflict of interest statement

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Age Distributions by Group, Before and After Coarsened Exact Matching**

**Figure 2. Cytokine/Biomarker Levels in CSF by Group**
CSF outcomes were box-cox transformed for linear regression analysis. Back-transformed means and 95% CIs are plotted. Age, sex, and race were included as independent variables in each model along with HIV status. NfL = neurofilament light chain; ns = p value not significant; TNF = tumor necrosis factor.

See this image and copyright information in PMC

References

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Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy

Affiliations

Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Medical

Research Materials