Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2019 Feb;25(1):32-41.
doi: 10.1007/s13365-018-0682-9. Epub 2018 Oct 5.

White matter damage, neuroinflammation, and neuronal integrity in HAND

Aljoharah Alakkas  1 , Ronald J Ellis  2 , Caitlin Wei-Ming Watson  2 , Anya Umlauf  2 , Robert K Heaton  2 , Scott Letendre  2 , Ann Collier  3 , Christina Marra  3 , David B Clifford  4 , Benjamin Gelman  5 , Ned Sacktor  6 , Susan Morgello  7 , David Simpson  7 , J Allen McCutchan  2 , Asha Kallianpur  8 , Sara Gianella  2 , Thomas Marcotte  2 , Igor Grant  2 , Christine Fennema-Notestine  2 ; CHARTER Group
Affiliations
Multicenter Study

White matter damage, neuroinflammation, and neuronal integrity in HAND

Aljoharah Alakkas et al. J Neurovirol. 2019 Feb.

Abstract

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

Keywords: HAND; MRI.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Structural MRI alterations associated with neurocognitive impairment (NCI = all HAND categories). a In all participants and b only in individuals with undetectable plasma HIV RNA. Adjusted binary logistic regression models were used to estimate the odds (95% CI) of HAND for each 1 standard deviation (SD) increase in log-transformed values of structural MRI volumes (mm3). Values less than 1.0 indicate that HAND was associated with smaller structural volumes, while values greater than 1.0 indicate that HAND was associated with larger volumes. *p < .05
Fig. 2
Fig. 2
Structural MRI alterations associated with HAND classifications. a In all participants and b only in individuals with undetectable plasma HIV RNA. Adjusted multinomial logistic regression models predicting whether individuals were NU, ANI, MND, or HAD. The odds ratio and 95% CI for the effect of the measure is reported. The OR represents effect size per 1 SD increase in log-transformed values of structural MRI. ****p < .001; ***p < .005; **p < .01; *p < .05
Fig. 3
Fig. 3
Probability of cognitive impairment (any HAND) plotted against amount of a abnormal white matter (log10 mm3) and b BG-NAA (unit-less absolute values derived using water scaling), after adjusting for nadir CD4 cell count, HIV RNA level count, age, scanner and supratentorial cranial vault size in SMRI and proportion of relevant tissue within each voxel in MRS. The probability curves shown were obtained by setting the covariates to their average values. p values for both relationships were significant (see text)
Fig. 4
Fig. 4
MRS alterations associated with neurocognitive impairment (NCI = all HAND categories). a In all participant and b in individuals with undetectable plasma HIV RNA. Adjusted binary logistic regression models predicting whether individuals were impaired or not. The odds ratio and 95% CI for the effect of the MRS measure is reported. *p < .05
Fig. 5
Fig. 5
MRS alterations associated with HAND classifications. a In all participant and b only in individuals with undetectable plasma HIV RNA. Adjusted multinomial logistic regression models predicting whether individuals were NU, ANI, MND, or HAD. The odds ratio and 95% CI for the effect of the measure is reported. ****p < .001; ***p < .005; **p < .01; *p < .05
See this image and copyright information in PMC

References

    1. Akay C, et al. Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neuro-Oncol. 2014;20(1):39–53. - PMC - PubMed
    1. Ances BM, Ortega M, Vaida F, Heaps J, Paul R. Independent effects of HIV, aging, and HAART on brain volumetric measures. J Acquir Immune Defic Syndr. 2012;59(5):469–477. - PMC - PubMed
    1. Anderson AM, et al. CSF biomarkers of monocyte activation and chemotaxis correlate with magnetic resonance spectroscopy metabolites during chronic HIV disease. J Neuro-Oncol. 2015;21(5):559–567. - PMC - PubMed
    1. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789–1799. - PMC - PubMed
    1. Archibald SL, Masliah E, Fennema-Notestine C, Marcotte TD, Ellis RJ, McCutchan JA, Heaton RK, Grant I, Mallory M, Miller A, Jernigan TL. Correlation of in vivo neuroimaging abnormalities with postmortem human immunodeficiency virus encephalitis and dendritic loss. Arch Neurol. 2004;61(3):369–376. - PubMed

Publication types

MeSH terms