Progressive cerebral injury in the setting of chronic HIV infection and antiretroviral therapy

Abstract

Background Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet whether neurological injury can progress in this setting remains uncertain. Methods Magnetic resonance spectroscopy, neurocognitive and clinical assessments were performed over two years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol (MI), and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM) and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function. Results HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95%), Cho (2.61%) in the FWM; NAA (1.89%), Cr (1.84%), Cho (2.19%) and Glx (6.05%) in the MFC; and Glx (2.80%) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG. Conclusions Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study.

Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients

“…For instance, increased glucose uptake in striatum has been suggested as an early indicator of subclinical neurological involvement [66], but studies in antiretroviral-treated individuals with undetectable viral loads have found varying degrees of reduced glucose uptake in the medial frontal gyrus [67], and evidence for a small but consistent age-related reduction of glucose uptake in the anterior cingulate cortex, but not in other brain regions [68]. Likewise, creatine, choline, N- acetylaspartate, glutamate-containing and glutamine-containing compounds appear to show annual decreases in multiple brain regions of HIV-infected patients on stable cART [69,70]. Neurocognitive decline appears to be specifically associated with reduced glutamate and glutamine containing compounds in multiple brain regions including frontal white and grey matter, basal ganglia and parietal grey matter [69,70].…”

“…Likewise, creatine, choline, N- acetylaspartate, glutamate-containing and glutamine-containing compounds appear to show annual decreases in multiple brain regions of HIV-infected patients on stable cART [69,70]. Neurocognitive decline appears to be specifically associated with reduced glutamate and glutamine containing compounds in multiple brain regions including frontal white and grey matter, basal ganglia and parietal grey matter [69,70]. These disease associated decreases in glutamate and glutamine were correlated with deficits in executive function, motor and psychomotor speed, attention and working memory [14].…”

Neuroimaging of HIV-associated neurocognitive disorders (HAND)

“…However, most MRS studies have been cross-sectional and have primarily focused on specific regions of interest. Additional longitudinal studies that focus on HIV+ patients as they transition across different disease states are needed [29]. …”

Glutamate metabolism and HIV-associated neurocognitive disorders

“…Glutamate transmission and metabolism are affected in many neurological diseases, including Alzheimer’s disease (Ferrarese et al , 2001), Parkinson’s disease (Plaitakis et al , 2010), amyotrophic lateral sclerosis, epilepsy (Eid et al , 2013a; Eid et al , 2013b), and HIV-1–associated neurocognitive disorders (Cohen et al , 2010; Gongvatana et al , 2013; Lentz et al , 2009). Whether glutamate levels in CSF or plasma represents a useful indicator of HIV-associated excitotoxicity remains unclear.…”