Human immunodeficiency virus infection in the CNS and decreased dopamine availability: relationship with neuropsychological performance

Abstract

Human immunodeficiency virus (HIV-1) infection in the central nervous system (CNS) is associated with a wide range of neurological, cognitive, and behavioral problems. HIV-1 enters the brain soon after the initial infection and is distributed in varying concentrations in different regions with specific affinity to the subcortical regions, particularly the basal ganglia, causing neurodegeneration of dopaminergic regions and resulting in the decreased availability of dopamine (DA) in the CNS. Although there are numerous reports on HIV-1-associated neuropsychological (NP) impairment, there is a paucity of studies showing a direct relationship between the decreased availability of dopamine in different regions of postmortem brains of HIV-1-infected individuals and the level of performance in different NP functions during life. Dopamine is the key neurotransmitter in the brain and plays a regulatory role for motor and limbic functions. The purpose of the present study was to investigate the relationship between the decreased availability of dopamine found in the postmortem brain regions (fronto-cortical regions, basal ganglia, caudate, putamen, globus pallidus, and substantia nigra) of individuals with HIV/AIDS and the antemortem level of performance (assessed as T scores) in different NP functions. The relationship between HIV-1 RNA levels in different brain regions and the level of performance in different NP domains was also investigated. We found that although DA concentrations were 2-53% lower in the brain regions of HIV-1-infected, HAART-treated individuals, compared with HIV-negative controls, a 45% decrease in DA levels in the substantia nigra (SN) of HIV-1-infected individuals was significantly correlated with the low level of performance (T scores) in the speed of information processing, learning, memory, verbal fluency, and average T scores across domains. In case of homovanillic acid (HVA), the variable changes in different regions, including the substantia nigra, basal ganglia, caudate, and putamen (compared to that in the HIV-negative individuals), were significantly correlated with the level of performance (T scores) in motor functions, speed of information processing, and attention/working memory. HIVRNA levels in the frontal cortex, caudate, and GP were significantly inversely correlated with abstract/executive function, motor, learning, verbal fluency, and attention/working memory. No significant correlations were found between HIVRNA in other brain regions and NP performance. These findings suggest that the decreased availability of dopamine in the SN (the main site of DA synthesis in the CNS), and changes in the levels of HVA in different brain regions are, in part, related with the lower level of performance in some of the NP functions in individuals with HIV/AIDS.

Time and time again: Temporal processing demands implicate perceptual and gating deficits in the HIV-1 transgenic rat

“…Significant reductions in DA markers, including DA levels in the substantia nigra (Kumar et al 2011), homovanillic acid (di Rocco et al 2000, and DA transporter (DAT) levels (Chang et al 2008;Wang et al 2004) have been correlated with poor performance on measures of learning, memory, and executive function in HIV-1-positive individuals. HIV-1 Tg rats also display alterations in the DA system, with significantly lower MAO-A levels than control animals, as well as lower levels of tyrosine hydroxylase after treatment with methamphetamine (Moran et al 2012).…”

“…We have observed a "flattening" of the ISI function in rats administered apomorphine (Moran et al, 2009), comparable to the ISI functions exhibited by the HIV-1 Tg rats in the present study. Although other neural systems may be involved, central DA system dysfunction often results from HIV-1 infection and is associated with subsequent cognitive deficits (Kumar et al 2011;diRocco et al 2000;Chang et al 2008;Wang et al 2004; for review, see Purohit et al 2011). The use of behavioral measures such as the ASR and PPI that can detect early neurological alterations, especially those of the DA system, may be instrumental in predicting the development of HAND and thus determining an appropriate course of treatment.…”

Cognitive impairment in HIV and HCV co-infected patients: a systematic review and meta-analysis

“…A possible explanation for greater impairment in the coinfected patients may be the higher risk of neurotoxicity due to CNS insults by both viruses in fronto-striatal areas. Particularly, high levels of HIV have been found in the basal ganglia (notably the substantia nigra) and fronto-cortical areas (Kumar, Borodowsky, Fernandez, Gonzalez, & Kumar, 2007), and it has been shown that fronto-striatal neuronal circuitry mediates processing speed (e.g., Fellows, Byrd, & Morgello, 2014;Kumar, Ownby, Waldrop-Valverde, Fernandez, & Kumar, 2011;Salthouse, 1996). Additionally, there is evidence that fronto-striatal circuits are rich in dopaminergic activity and it is hypothesised that dopamine depletion exacerbates processing speed impairment in HIV (Kumar et al, 2011).…”

Influence of dopamine receptor gene polymorphisms on circulating T lymphocytes: A pilot study in healthy subjects

“…Recently, an association has been reported in HIV+ subjects between sleep disturbances and lower CD4+ T cell count and decreased urinary levels of dopamine [34]. Remarkably, HIV+ subjects often exhibit deficiencies in subcortical dopamine which may result in deficits in fronto-striatal functioning and subsequent neurocognitive dysfunction [35,36].…”