Cortical Synaptic Density is Reduced in Mild to Moderate Human Immunodeficiency Virus Neurocognitive Disorder

Abstract

Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)‐related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante‐mortem levels of cognitive performance in AIDS patients. Three‐dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin‐immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life. It is concluded that a combination of factors including synaptic damage, specific neuronal loss and increasing viral load underlies HIV‐associated cognitive impairment. As synaptic damage is potentially reversible, early diagnosis and treatment of mild cogntive disorders may improve functioning and prevent the progression of brain disease.

HIV-1 infection and AIDS: consequences for the central nervous system

“…44,45 In contrast, increased numbers of microglia, 44 elevated TNF-a mRNA in microglia and astrocytes, 46 evidence of excitotoxins, [47][48][49] decreased synaptic and dendritic density, 45,50 and selective neuronal loss 51,52 constitute the pathologic features most closely associated with the clinical signs of HAD. Furthermore, signs of neuronal apoptosis have been linked to HAD, [53][54][55] although this finding is not clearly associated with viral burden 53 or a history of dementia.…”

Neurocognitive characterizations of Russian heroin addicts without a significant history of other drug use

“…Patients with Axis II disorders were not excluded, however, as this would reduce the subject pool significantly, limiting the feasibility of recruiting a sufficient number of patients. Also, given that AIDS has adverse effects on neurocognitive function, those known to be infected (as per LRCA records) were excluded (Everall et al, 1999).…”

Voltage-gated Potassium Channels in Human Immunodeficiency Virus Type-1 (HIV-1)-associated Neurocognitive Disorders

“…Although the incidence of HAD has decreased from an estimated 30% to ~10% in the era of HAART, it remains a significant complication of HIV-1 infection as patients with acquired immunodeficiency syndrome (AIDS) live longer, antiretroviral drugs remain unable to effectively cross the blood brain barrier, and HIV-1 resistance grows due to viral strain mutation. It is widely believed HAD cognitive impairments are associated with the number of immune competent and HIV-1-infected MP (Glass et al 1995), diminished synaptic and dendritic density Everall et al 1999), and selective neuronal loss (Masliah et al 1992;Fox et al 1997). However, not all HAD patients exhibit profound neuronal loss (Seilhean et al 1993) and improvements in cognitive function have been observed after HAART (Ferrando et al 1998;Gendelman et al 1998;Tozzi et al 1999;Robertson et al 2004).…”