THE EFFECTS OF AGE AND HIGHLY ACTIVE ANTIRETROVIRAL THERAPY ON BRAIN FUNCTION

描述(申请人提供)：由于高效抗逆转录病毒疗法(HAART)，感染人类免疫缺陷病毒(HIV)的患者现在寿命更长。到2015年，超过50%的艾滋病毒感染者的年龄将超过50岁。然而，HAART并没有降低HIV感染患者中神经系统疾病的患病率。老年艾滋病毒感染患者患神经疾病的风险更大，对照顾者来说是一个巨大的负担。此外，关于HAART的总体疗效也存在争议，因为更好的脑穿透方案(NeuroHAART)可能会控制大脑中的病毒，但会导致神经毒性。目前对艾滋病毒引起的神经认知障碍的评估需要进行漫长的神经心理测试，这可能对神经元功能障碍的早期迹象不敏感。当务之急是确定早期症状前生物标志物，以测试预防艾滋病毒感染患者发展神经认知功能障碍的干预措施。一种有希望的新方法是对静息状态的大脑功能连接进行非侵入性神经成像。这项技术已经识别了默认模式网络--参与组织记忆和为未来事件做准备的一系列大脑区域。我们的初步结果表明，艾滋病毒使这个网络中大脑功能连接的完整性降低了40%。艾滋病毒还放大了老龄化的影响，因为老年感染患者的大脑网络连接相当于年长15-20岁的血清阴性患者。我们假设，HIV诱导的默认模式网络内神经元连接性的下降将先于神经心理测试的差异。该提案将：1)衡量艾滋病毒对大脑功能连接的影响；2)调查艾滋病毒是否会加速大脑网络的老化；3)评估神经HAART对大脑连接的影响。这些结果将帮助护士和临床医生决定何时开始HAART，并帮助他们评估定制的辅助神经保护疗法的疗效。 与公共卫生相关：高效抗逆转录病毒疗法(HAART)改变了艾滋病毒的面貌，但神经并发症仍然存在。这项建议：1)利用非侵入性神经成像生物标记物来识别艾滋病毒引起的大脑网络的早期变化2)评估艾滋病毒是否加速大脑老化3)评估更好的脑穿透药物(“神经HAART”)是否具有神经毒性。这项建议将帮助护士和临床医生决定启动HAART的适当时机，并帮助他们评估量身定制的辅助治疗的疗效。

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) infected patients are now living longer due to highly active antiretroviral therapy (HAART). More than 50% of all HIV infected patients will be > 50 years old by 2015. However, HAART has not decreased the prevalence of neurological disorders in HIV infected patients. Older HIV infected patients are at greater risk for developing neurological disorders and are a significant burden to caregivers. In addition, debate also exists concerning the overall efficacy of HAART as better brain penetrating regimens (neuroHAART) may control the virus in the brain but cause neurotoxicity. Current assessment of neurocognitive disorders due to HIV entails lengthy neuropsychological testing which may not be sensitive to early signs of neuronal dysfunction. It is imperative that an early presymptomatic biomarker is identified to test interventions that prevent HIV infected patients from developing neurocognitive impairment. One promising new approach is non-invasive neuroimaging of resting state brain functional connections. This technique has identified the default mode network- a series of brain areas involved in organizing memories and preparing for the future events. Our preliminary results demonstrate that HIV diminishes the integrity of brain functional connections within this network by 40%. HIV also amplifies the effects of aging as older infected patients have brain network connections equivalent to seronegative subjects who are 15-20 years older. We hypothesize that HIV-induced decreases in neuronal connectivity within the default mode network will precede neuropsychological testing differences. The proposal will: 1) measure the effects of HIV on brain functional connections; 2) investigate if HIV accelerates aging of brain networks; 3) evaluate the effects of neuroHAART on brain connections. These results will assist nurses and clinicians in deciding when to initiate HAART and help them evaluate the efficacy of tailored adjunctive neuroprotective therapies. PUBLIC HEALTH RELEVANCE: Highly active anti-retroviral therapy (HAART) has changed the face of HIV but neurological complications still remain. This proposal: 1) utilizes a non-invasive neuroimaging biomarker to identify early changes in brain networks due to HIV 2) assesses if HIV acclerates brain aging 3) evaluates if better brain penetrating medications ("neuroHAART") is neurotoxic. This proposal will assist nurses and clinicians in deciding the appropriate timing for initiating HAART and help them evaluate the efficacy of tailored adjunctive therapies.