MOLECULAR NEUROIMAGING OF AIDS DEMENTIA--ANIMAL MODELS

我们研究的目的是了解感染HIV后的关键神经发病事件及其时间过程。在我们最初两年的工作中，我们通过开发和实施MRS的进展，以及应用成熟的神经病理学和病毒学技术来研究SIV的猕猴模型，取得了重要的成果。通过这一横断面方法，我们发现，在SIV感染后的几天内，NAA发生了显著的、但可逆的下降，而在感染SIV后的两年内，NAA明显地出现了大量的、不可逆转的损失。我们还发现了SIV感染猕猴突触树突损伤的证据，以及NAA的丢失与脑突触素和钙结合蛋白减少有关的迹象。也许我们最具挑衅性的结果是，NAA的丢失可能是累积的，并随着时间的推移而进展，无论是否患有脑炎。最后，我们发现慢性SIV感染可能引发严重的异质性星形细胞增多症，主要影响深部灰质结构和小脑。我们的结果支持HIV感染后神经元损伤的间接机制的存在。基于这些结果，我们的新假设是：a)SIV会导致整个感染过程中神经元的累积损伤；b)NAA的丢失直接与SIV感染过程中早期遭受的突触树突损伤以及后来观察到的神经元丢失有关；c)脑损伤的位置是不同的；以及d)我们在SIV猕猴模型中观察到的代谢和病理异常与SIV感染在大脑中的存在直接相关。为了验证我们的假设，我们将进行以下研究努力：特定目标1.将在SIV感染的不同阶段对SIV感染猕猴体内NAA和其他代谢物的区域分布、模式和变化程度进行磁共振波谱检查；特定目标2.SIV脑中观察到的代谢变化的细胞病理学将通过对神经元含量、突触和树突密度以及星形细胞的定量研究来确定；以及特定目标3.脑内病毒感染与随后观察到的代谢和病理异常的关系将被确定。

The goal of our research is to gain an understanding of critical neuropathogenesis events and their time course after infection with HIV. We achieved important gains during our initial two years of work by developing and implementing advances in MRS, as well as applying well established techniques of neuropathology and virology, to investigate a macaque model of SIV. Through this cross-sectional approach, we showed that a significant, but reversible decrease in NAA occurs within days of SIV infection, while a large, irreversible loss of NAA is evident two years thereafter. We also found evidence of synaptodendritic injury in the SIV infected macaque, along with indications that loss of NAA is related to decreases in brain synaptophysin and calbindin. Perhaps our most provocative result was that loss of NAA may be cumulative and progress over time, with or without encephalitis. Finally, we discovered that chronic SIV infection may incite severe, heterogeneous astrocytosis, primarily affecting deep gray structures and cerebellum. Our results support the existence of indirect mechanisms of neuronal injury after HIV infection. Based on these results, our new hypotheses are that: a) SIV results in cumulative neuronal injury throughout the duration of infection; b) Loss of NAA is directly related to synaptodendritic injury sustained early in the course of SIV infection, and to the neuronal loss observed later; c) Brain injury is heterogeneous with respect to location; and d) the metabolic and pathologic abnormalities we observe in the SIV macaque model are directly related to the presence of SIV infection in the brain. To test our hypotheses, we will undertake the following research efforts: Specific Aim 1. MR spectroscopic examinations of the regional distribution, pattern and extent of changes in NAA and other metabolites in the SIV infected macaque will be performed throughout different stages of SIV infection; Specific Aim 2. Cellular pathology underlying metabolic alterations observed in the SIV brain will be identified through quantitative studies of neuronal content, synaptic and dendritic density, and astrocytosis; and Specific Aim 3. The relationship of viral infection in the brain to metabolic and pathological abnormalities subsequently observed will be determined.