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

HAND 的神经生理学标志物和衰老的影响：来自 MEG 的证据

• 批准号: 8790180
• 负责人: Tony W Wilson
• 金额: $ 48.22万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790180
• 关键词: Adult; Affect; Age; Aging; Aging-Related Process; Anti-Retroviral Agents; Area; Biological Markers; Brain; Brain Neoplasms; Brain imaging; Chronic; Clinical; Cognitive; Cognitive deficits; Complex; Consensus; Data; Dementia; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Drug toxicity; Emerging Technologies; Encephalitis; Evaluation; Evolution; Exclusion; Exhibits; Functional disorder; Funding; General Population; Goals; HIV; HIV diagnosis; High Prevalence; Human; Image; Impaired cognition; Impairment; Knowledge; Laboratories; Life; Life Expectancy; Location; Longitudinal Studies; Magnetic Resonance Imaging; Magnetoencephalography; Malignant Neoplasms; Maps; Measures; Mental disorders; Methods; Metric; Microglia; Monitor; Motor; Motor Cortex; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Nature; Neurocognitive; Neurologic; Neurons; Neuropsychological Tests; Opportunistic Infections; Participant; Patients; Performance; Persons; Physiology; Prefrontal Cortex; Prevalence; Protocols documentation; Recommendation; Relative (related person); Research; Research Personnel; Research Priority; Residual state; Resolution; Risk; Sensory; Series; Staging; Targeted Research; Task Performances; Terminal Disease; Testing; Therapeutic; Time; Viral Load result; Virus Diseases; Virus Replication; Visit; age effect; age group; antiretroviral therapy; association cortex; base; cognitive function; density; excitotoxicity; falls; frontal eye fields; high risk; macrophage; millisecond; neuroimaging; neurophysiology; neuropsychological; programs; public health relevance; relating to nervous system; research study; response; spatiotemporal; trend

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.

描述（由申请人提供）： 抗逆转录病毒疗法（CART）已将HIV感染的性质从最终疾病转变为慢性可管理状况，预期寿命接近一般人群。然而，感染的患者仍然有显着增加与HIV相关神经认知疾病（手）的风险，其中35-70％的所有患者（接受治疗和未经治疗）至少在神经心理学功能方面表现出微妙的障碍。该修订后的R01提案来自早期研究者（ESI）将检查手的神经生理基础，识别手进展的标志物，并确定慢性HIV感染如何调节衰老对认知性能和脑生理学的正常作用。在过去的两年中，我的实验室通过使用磁脑摄影（MEG）的一系列成像研究评估了CART处理的HIV感染对神经活动和神经心理学（NP）功能的影响。 MEG是对神经元活性的无创和直接度量，具有毫秒的时间分辨率和良好的空间精度（3-5 mm）。使用MEG，我们已经证明了额叶眼田，背外侧前额叶皮层和其他关联皮层的神经生理异常，以及一级运动皮层的缺陷。最常见的是，我们发现相对于未感染对照的患者的原发性感觉和运动区域的缔合性皮质和低激活性过度激活。我们还表明，特定大脑区域的激活指标与NP测试的评分相关，并且与对照组相比，衰老对神经元活性和认知功能的影响遵循HIV感染的患者的独特轨迹。在这些广泛的初步发现的基础上，我们提出MEG成像对手的病理生理学和进展非常敏感，以及HIV感染和衰老对神经元功能的添加作用。为此，我们将检查162名成年人，81名HIV感染患者和81个人口统计学匹配的对照，分为三个特定年龄的组（即22-38、39-55岁，超过55年）。所有参与者将在一系列认知任务中进行高密度录制，完成多个MRI/DTI方案，并执行一系列NP评估，以遵守Frascati共识的建议[7]。为了评估手的进展，将以1。5年的间隔纵向遵循一部分参与者（感染和未感染）。该项目的具体目的是：（1）通过将受损的艾滋病毒感染的患者与未受影响的患者进行比较，确定手的神经生理基础； （2）通过对对照组和受损患者的短期纵向研究确定手进展的神经元标记，他们将以1.5年的间隔进行重复的MEG和NP测试课程； （3）确定衰老如何调节患者和对照组中的NP功能和神经元活性，并确定HIV感染对这些参数的独立作用。我们预计，关键脑网络中的衰老过程会极大地加剧与HIV感染相关的认知和神经缺陷。