Among the most common and debilitating neurological complications of HIV infection is HIV associated dementia (HAD) or AIDS dementia complex (ADC). The exact pathogenesis of this disorder remains a conundrum, but trafficking of HIV-infected peripheral macrophages across the blood-brain barrier (BBB) appears to be an important route of entry of HIV, and the rate at which this occurs may be a determinant of HAD onset and/or progression. BBB breakdown is known to increase the rate of macrophage trafficking into CNS, and there is evidence for microvascular abnormalities, including increased regional blood volume (RCBV) and BBB disruption in HIV seropositive and particularly in HAD patients. Indeed preliminary results suggest that the severity of these microvascular changes is correlated with the severity of HAD. Zidovudine monotherapy and, more recently, highly active anti-retroviral therapy (HAART) may reduce the incidence of HAD. Furthermore, zidovudine or HAART may arrest or even reverse the dementing process, at least temporarily, in many but not all patients. The means by which HAART might slow the progression of HAD is unclear, but may include reduced trafficking of infected and/or activated macrophage into the CNS both as a result of a reduced serum viral load, and also by reversing the damage to the BBB. In this study employing patients with HAD of varying severity, carefully studied by clinical examination, neuropsychological test battery, and contrast-enhanced magnetic resonance imaging (MRI), we propose to test the over-arching hypothesis that disruption of cerebral microvascular integrity is a key event in progression to HAD, (with the severity of HAD correlated with the degree of microvascular disruption) and that therapies which reverse these microvascular defects lead to improvement in RAD.
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| Berger, Joseph R; Avison, Malcolm (2004) The blood brain barrier in HIV infection. Front Biosci 9:2680-5 |
