Neural Correlates of Working Memory Training for HIV Patients

描述（由申请人提供）：尽管有效的抗逆转录病毒治疗广泛可用，但高达50%的HIV感染者继续表现出较轻形式的HIV相关神经认知障碍（HAND）。随着艾滋病毒感染者的老龄化人口不断增加，他们患手足的风险更大，护理费用在未来20年可能会增加近一倍。合并症问题，如酒精，大麻或精神兴奋剂滥用，发生在艾滋病毒患者中的流行率要高得多，可以进一步加剧他们的认知缺陷。由于HAND的有效治疗和预防仍然缺乏，因此为这些患者开发有效的治疗或预防性治疗至关重要。工作记忆（WM）和注意力缺陷是常见的，可能是导致HAND的认知缺陷的基础。因此，我们建议评估一个自适应WM计算机为基础的培训计划，称为Cogmed的疗效。适应性WM训练的有效性在注意力缺陷多动障碍（ADHD）儿童和其他神经系统疾病的成人中得到了证实，但尚未在HIV阳性受试者中进行评估。WM缺陷也可能与神经炎症、额叶功能障碍或多巴胺能功能下降有关。因此，本提案的目的是：1）使用Cogmed进行双盲安慰剂对照研究，以确定强化适应性WM训练是否会导致WM和其他认知功能的更大改善（增益）。（转移增益）在HIV感染的个人和HIV血清阴性（SN）的控制比固定的低水平（安慰剂）的训练，在训练后一个月和六个月（增益保持）。2)为了评估WM训练的神经相关性：在训练后1个月和6个月，在WM和注意力期间，BOLD-fMRI上的大脑激活是否会改善。3)由于在先前的研究中，具有LMX 1A SNP（rs 4657412）的AA基因型的个体在言语WM中表现出更大幅度的训练相关增益，因此我们将评估我们的受试者在训练效果（增益和维持）上的这种等位基因变异。最后，我们将评估那些同意在训练前和训练后6个月进行腰椎穿刺的人的CSF中神经炎症标记物和单胺代谢物的变化，并评估这些CSF标记物、认知表现和训练效果以及脑激活fMRI之间的关系。虽然Cogmed”不是HAND的“治愈”方法，但该研究项目可能会发现一种新的有效的治疗方法，以改善认知功能，从而改善这些患者的日常生活和功能活动。我们的遗传学研究可以确定哪些人可能从WM训练中受益最大，因此有助于指导HIV感染者未来的治疗计划。最后， 我们也将了解到训练前后大脑激活、神经炎症和脑脊液单胺水平与WM功能的关系。

DESCRIPTION (provided by applicant): Despite the wide availability of potent antiretroviral therapy, up to 50% of HIV-infected individuals continue to demonstrate milder forms of HIV-associated neurocognitive disorders (HAND). With the increasing aging population of HIV-infected patients who are at greater risk for developing HAND, the cost of care may nearly double in the next two decades. Co-morbid issues such as alcohol, marijuana or psychostimulant abuse, which occur at much higher prevalence amongst HIV patients, can further exacerbate their cognitive deficits. Since effective treatment and preventions for HAND are still lacking, developing effective treatments or adjunctive therapy for these patients are critical. Working memory (WM) and attention deficits are common and may underlie cognitive deficits that lead to HAND. Therefore, we propose to evaluate the efficacy of an adaptive WM computer based training program called Cogmed. Effectiveness of adaptive WM training was shown in children with attention deficit and hyperactivity disorder (ADHD), and in adults with other neurological disorders, but has not been evaluated in HIV-positive subjects. WM deficits also may be related to neuroinflammation, frontal lobe dysfunction or decreased dopaminergic function. Therefore, the aims of this proposal are: 1) To perform a double blind placebo-controlled study using Cogmed" to determine whether the intensive adaptive WM training will lead to greater improvement (gain) on WM and other cognitive functions (transfer of gain) in HIV-infected individuals and in HIV-seronegative (SN) controls than fixed low level (placebo) training, at one-month and at six months after training (maintenance of gain). 2) To assess the neural correlates of WM training: Whether brain activation will improve, at 1-month and 6-months after the training, on BOLD-fMRI during WM and attention. 3) Since individuals with the AA genotype for the SNP (rs4657412) for LMX1A showed greater magnitudes of training-related gains in verbal WM in a prior study, we will assess our subjects for this allelic variation on thei training effects (gain and maintenance). Lastly, we will assess changes in neuroinflammatory markers and monoamine metabolites in the CSF of those who consent to lumbar punctures before and 6 months after training, and evaluate the relationships between these CSF makers, cognitive performance and training effects, as well as brain activation fMRI. Although Cogmed" is not a "cure" for HAND, this research project may identify a new and effective adjunctive therapy to improve cognitive function and hence these patients' activities of daily living and functioning. Our genetic study may identify individuals who might benefit the most from the WM training, and therefore help to guide future treatment plans for HIV-infected individuals. Finally, we will also learn how brain activation, neuroinflammation and CSF monoamine levels might relate to WM function before and after the training.