INTRODUCTION

In Chapter 2: Pathogenesis of Mental Disorders in HIV, Chana et al. provide an overview of the structural biology, replication and neurotoxic effects of HIV infection, as well as the potential impact of comorbid conditions on the presentation of HIV-related central nervous system (CNS) infection. The neurologic impact of HIV infection contributes to HIV-associated neurocognitive disorders (HAND) that may be exacerbated by co-occurring conditions including methamphetamine abuse, hepatitis C virus (HCV) coinfection, psychiatric disorders and normal ageing. As the authors note, even in the current era of antiretroviral therapy (ART), which has led to reduced viral replication, improved immune function and increased life expectancy, CNS involvement remains prevalent. The early entrance of HIV into the CNS, inevitably occurring prior to treatment, may result in neuronal and axonal damage in the context of chronic inflammation [1]. HIV infection can be particularly destructive to the white matter because of the infiltration of HIV-infected monocytes and macrophages [2], and the inflammatory response may be chronic, occurring during continued low-level infection, or episodic in nature, perhaps even during immune recovery [1]. Neuroimaging studies may identify sensitive, non-invasive biomarkers to monitor treatment and identify individuals at risk for CNS decline to guide future therapeutic initiatives.

NEUROIMAGING EVIDENCE OF WHITE MATTER AND BASAL GANGLIA DAMAGE

Magnetic resonance imaging (MRI) findings support white matter and basal ganglia damage in HIV-infected individuals, even those on ART [3456789]. Structural morphometry consistently reveals white matter volume loss, which is often associated with detectable HIV cerebrospinal fluid (CSF) RNA viral load and lower nadir CD4 [345]. Even HIV-infected individuals on ART demonstrate continued white matter loss over time, particularly when CD4 counts are low [5]. In support of pathological findings [2], white matter abnormalities (e.g. hyperintensities on T₂-weighted MRI) are also a common feature of the HIV-related neuroimaging phenotype that have been associated with lower nadir CD4 [4] and, of particular interest, with HIV encephalitis and the extent of dendritic loss as assessed by the analysis of microtubule-associated protein 2 immunoreactivity [10]. These white matter alterations may reflect inflammation and tissue loss, owing to loss or shrinkage of axons, demyelination, reactive gliosis and increased extracellular fluid. The basal ganglia are also affected in HIV infection, with greater volume loss in individuals on therapy who have higher viral load [3, 5, 11, 12]. The same mechanisms of white matter neuropathogenesis may affect the basal ganglia because of the greater vascular and white matter composition of these nuclei.

Further evidence of white matter damage comes from diffusion tensor imaging (DTI) studies that quantify the molecular motion of water molecules along and across white matter fibre tracts. Measures of mean diffusivity and the strength of directional diffusivity (fractional anisotropy) estimate the effects of inflammation, demyelination and gliosis. Altered white matter diffusivity has been reported in HIV infection, including increased mean diffusivity and altered fractional anisotropy, and these effects have been associated with current CD4 and HIV viral load [7, 8, 13, 14]. Furthermore, diffusion abnormalities were correlated with elevated levels of monocyte chemoattractant protein-1 (MCP-1), which has been linked to the presence of inflammation [8]. Single voxel magnetic resonance spectroscopy (MRS) studies of brain metabolites also support the presence of inflammation as well as neuronal injury in the frontal grey and white matter regions and the basal ganglia of HIV-infected individuals. Increased choline, a measure of cell membrane degradation and lipid changes, and myo-inositol, a possible indicator of glial proliferation, as well as reduced N-acetylaspartate (NAA), a putative marker of neuronal integrity, are often associated with current CD4 count [1, 6, 13].

NEUROPATHOGENESIS AND HAND

HIV-related neuropathogenesis likely contributes to the continued presence of HAND [11, 15], and variations in immune response or ART may result in dynamic changes in impairment status. Consistent with fronto-striatal and white matter alterations, HAND is marked by deficits in executive functions, memory and psychomotor speed [16]. Neurocognitive impairment has been associated with neuroimaging measures of tissue damage, particularly within the white matter [9, 13, 14] and basal ganglia [3, 9], and is correlated with post-mortem measures of HIV RNA viral load levels in the basal ganglia [11].