Patients with AIDS develop neurological complications ranging from minimal cognitive dysfunction to dementia, motor alterations and seizures. During the course of funding for the HNRC Neuropathology Core we found that in HIVE there is substantial selective neuronal damage that could be responsible for specific cognitive and motor deficits, and that distribution and degree of damage to neuronal populations correlates with brain viral burden. Better understanding of the relationship between selective neuronal damage and cognitive impairment will help establish the structural basis of behavioral and motor alterations in HIVE. For the renewal we propose the following: 1. Perform postmortem studies and coordinate the diagnosis, processing and distribution of brain tissue. Blocks from frontal cortex, basal ganglia and hippocampus will be utilized for neuropathological analysis and confocal microscopy to assess neuron damage and immunochemical and PCR analysis to assess viral burden and neuropathological staging. The right hemibrain will be utilized for Magnetic Resonance Imaging by Dr. Jernigan of Project 2. 2. Determine the extent of the neurodegenerative process during the progression of HIVE. Extent of damage to pyramidal neurons will be determined in cresyl violet-stained sections with the Quantimet 570C, and synaptic and dendritic quantification will be done by confocal microscopy. The extent of damage to interneurons will be evaluated by Quantimet 570C in sections immunolabeled with antibodies against ChAT parvalbumin, calbindin, and somatostatin. These more sensitive assays to determine the extent of neurodegenerative process will serve as basis for correlations with neurobehavioral, neurovirological, and neuroimagnig data. We hypothesize that: a) severity of global cognitive dysfunction will be correlated with severity of dendritic damage to pyramidal neurons, b) selective loss of cholinergic interneurons in the basal ganglia will be correlated with impaired perceptual-motor test performance and c) damage to hippocampal and neocortical calbindin-positive neurons will be correlated with impaired priming and memory recognition. 3. Determine if in HIVE, altered growth-factor expression correlates with neurodegeneration. Sections will be immunolabeled with antibodies against platelet-derived growth factor (PDGF), amyloid precursor protein (APP), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF). These data will be correlated with total cell counts, measurements of synaptic and dendritic area, and counts of parvalbumin-, calbindin-,and somatostatin- and ChAT- positive cells. We hypothesize that PDGF and APP levels will be altered in pyramidal neurons susceptible to HIV-1 (Nef), while levels of NGF and BDNF will be associated with degeneration of interneurons and high levels of HIV-1 (Tat). Understanding the neuronal basis of the cognitive alterations in HIVE and of the mechanisms of neurodegeneration will help to develop new animal models of this disease for discovery and testing of novel therapeutic approaches.
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