Disrupted cerebral metabolite levels and lower nadir CD4+ counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatmentpatients on stable treatment

Abstract

Cognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV + patients scanned with whole-brain MRI at 1.5 T (mean age: 48.6 ± 8.4 years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4 + count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4 +. Even so, brain volume measured by TBM showed no detectable association with current CD4 + count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage.

Diffusion Tensor and Volumetric Magnetic Resonance Measures as Biomarkers of Brain Damage in a Small Animal Model of HIV

“…We pursued volumetric imaging of this animal model based on brain volume loss being one of the earliest recognized abnormalities in HIV+ patients [24], [25]. This volume loss persisted in the post ART era with white matter and basal ganglia volume loss still demonstrable in virologically suppressed patients [5], [46], [47]. We also used DTI since this technique has been applied extensively in the evaluation of HIV+ patients, often with positive although not always consistent results [7], [28], [48]–[50]: generally decreased FA and increased MD [14], [22], [23].…”

White matter damage and effects of nadir CD4+ count on patients with asymptomatic HIV associated dementia complex–A DTI study

“…HIVassociated dementia (HAD), the most severe form of HIV induced CNS impairment, is clinically characterized by motor disorders, behavioral changes and cognitive dysfunction that in the absence of therapy may lead to seizures, coma and death within six months of onset. Conventional magnetic resonance imaging (cMRI) has revealed gray matter atrophy and white matter hyperintensities [1,2] in advanced HIV disease. In the early stages of HIV infection, however, white matter abnormalities are unreliably detected on structural MR.…”

The Effect of Central Nervous System Penetration Effectiveness of Highly Active Antiretroviral Therapy on Neuropsychological Performance and Neuroimaging in HIV Infected Individuals

“…This technique may provide valuable insights into the impact of CPE within the brain. Similar to prior neuropsychological studies, the effects of CPE on neuroimaging outcomes have been mixed, with some studies reporting no difference between high and low CPE regimens on brain volumetrics (Hua et al, 2013) and others reporting negative effects of high CPE (Gongvatana et al, 2009). To date, no study has analyzed the relationship between CPE and brain integrity using neuropsychological tests and brain volumetrics.…”