Neurophysiological markers of HAND and the impact of aging: Evidence from MEG

描述(由申请人提供)： 联合抗逆转录病毒疗法(CART)极大地改变了艾滋病毒感染的性质，从绝症转变为慢性可控状态，预期寿命接近普通人群。然而，受感染的患者患艾滋病毒相关神经认知障碍(HAND)的风险仍然显著增加，所有患者(治疗和未治疗)中有35%-70%至少表现出轻微的神经心理功能障碍。这项由早期研究人员(ESI)提出的修订后的R01提案将检查手的神经生理学基础，识别手进展的标志，并确定慢性艾滋病毒感染如何调节衰老对认知表现和脑生理的正常影响。在过去的两年里，我的实验室通过使用脑磁图(MEG)进行的一系列成像研究，评估了CART治疗HIV感染对神经活动和神经心理(NP)功能的影响。脑磁图是一种无创、直接测量神经元活动的方法，具有毫秒级的时间分辨率和良好的空间精度(3-5 mm)。使用脑磁图，我们发现了额叶眼区、背外侧前额叶皮质和其他联合皮质的神经生理学异常，以及初级运动皮质的缺陷。最常见的是，我们发现与未感染的对照组相比，患者的联合皮质过度激活，而初级感觉和运动区的激活不足。我们还表明，特定大脑区域的激活指标与NP测试的分数相关，而且与对照组相比，衰老对艾滋病毒感染患者神经活动和认知功能的影响遵循不同的轨迹。基于这些广泛的初步发现，我们认为脑磁图成像对手部的病理生理学和进展，以及艾滋病毒感染和衰老对神经功能的附加影响是唯一敏感的。为此，我们将检查162名成年人、81名艾滋病毒感染者和81名人口统计学上匹配的对照组，他们平均分为三个特定年龄组(即22-38岁、39-55岁和55岁以上)。所有参与者将在一系列认知任务期间接受高密度脑磁图记录，完成几个MRI/DTI方案，并执行一系列符合Frascati共识建议的NP评估[7]。为了评估手部的进展，将每隔1.5年对一部分参与者(感染和未感染)进行纵向跟踪。该项目的具体目的是：(1)通过比较按Frascati标准受损的艾滋病毒感染患者和未受损的艾滋病毒感染患者，确定手的神经生理学基础；(2)通过对对照和受损患者进行短期纵向研究，确定手部进展的神经元标志物，这些患者将每隔1.5年接受一次重复的脑磁图和NP检测；(3)确定衰老如何调节患者和对照组的NP功能和神经元活动，并确定艾滋病毒感染对这些参数的独立影响。我们预计，与艾滋病毒感染相关的认知和神经缺陷将因关键大脑网络的老化过程而显著加剧。

DESCRIPTION (provided by applicant): Combination antiretroviral therapy (cART) has dramatically shifted the nature of HIV-infection from a terminal illness to a chronic manageable condition, with a life expectancy close to that of the general population. However, infected patients remain at a significantly increased risk of developing HIV-associated neurocognitive disorders (HAND), with 35-70% of all patients (treated and untreated) exhibiting at least subtle impairments in neuropsychological function. This revised R01 proposal from an early-stage investigator (ESI) will examine the neurophysiological bases of HAND, identify markers of HAND progression, and determine how chronic HIV- infection modulates the normal effects of aging on cognitive performance and brain physiology. Over the past two years, my laboratory has evaluated the impact that cART treated HIV-infection has on neural activity and neuropsychological (NP) function through a series of imaging studies using magnetoencephalography (MEG). MEG is a noninvasive and direct measure of neuronal activity with millisecond temporal resolution and good spatial precision (3-5 mm). Using MEG, we have demonstrated neurophysiological abnormalities in the frontal eye fields, dorsolateral prefrontal cortex, and other association cortices, as well as deficits in the primary motor cortex. Most commonly, we have found hyper-activation in association cortices and hypo-activation in primary sensory and motor areas of patients relative to uninfected controls. We have also shown that activation metrics in specific brain areas correlate with scores on NP tests, and that the effects of aging on neuronal activity and cognitive function follow a distinct trajectory in HIV-infected patients compared with controls. Anchored by these extensive preliminary findings, we propose that MEG imaging is uniquely sensitive to the pathophysiology and progression of HAND, and to the additive effects that HIV-infection and aging have on neuronal function. To this end, we will examine 162 adults, 81 HIV-infected patients and 81 demographically-matched controls, divided equally into three age-specific groups (i.e., 22-38, 39-55, and over 55 years). All participants will undergo high- density MEG recording during a series of cognitive tasks, complete several MRI/DTI protocols, and perform a battery of NP assessments that adheres to the recommendations of the Frascati consensus [7]. To evaluate the progression of HAND, a subset of participants (infected and uninfected) will be followed longitudinally at 1.5-year intervals. The Specific Aims of this project are to: (1) Determine the neurophysiological bases of HAND by comparing HIV-infected patients who are impaired, according to the Frascati criteria, to those who are unimpaired; (2) Identify neuronal markers of HAND progression through a short-term longitudinal study of controls and impaired patients, who will undergo repeated MEG and NP testing sessions at 1.5 year intervals; (3) Determine how aging modulates NP function and neuronal activity in patients and controls, and identify the independent effect of HIV-infection on these parameters. We expect that the cognitive and neural deficits associated with HIV-infection will be significantly exacerbated by the aging process in critical brain networks.