Neural Correlates of Working Memory Training for HIV Patients

描述(由申请人提供)：尽管可以广泛获得有效的抗逆转录病毒治疗，但高达50%的艾滋病毒感染者继续表现出较轻形式的艾滋病毒相关神经认知障碍(HAND)。随着艾滋病毒感染患者日益老龄化，他们患上手部疾病的风险更大，在未来20年内，护理成本可能会增加近一倍。酒精、大麻或精神刺激药物滥用等共病问题在艾滋病毒患者中的患病率要高得多，可能会进一步加剧他们的认知缺陷。由于目前尚缺乏有效的手部治疗和预防措施，因此为这些患者开发有效的治疗方法或辅助治疗至关重要。工作记忆(WM)和注意力缺陷是常见的，可能是导致手部疾病的认知缺陷的基础。因此，我们建议评估一种名为Cogmed的自适应WM计算机培训计划的效果。适应性WM训练在患有注意力缺陷和多动障碍(ADHD)的儿童以及患有其他神经疾病的成年人中显示出有效性，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，这项建议的目的是：1)使用Cogmed进行一项双盲安慰剂对照研究，以确定强化适应性西医训练是否会导致HIV感染者和HIV血清阴性(SN)对照的WM和其他认知功能(收益转移)比固定低水平(安慰剂)训练更大的改善(收益)，在训练后一个月和六个月(保持收益)。2)评估西医训练的神经相关性：在训练后1个月和6个月，在西医训练和注意力训练过程中，进行BOLD-fMRI检查，以确定大脑的激活程度是否有所改善。3)由于在先前的研究中，携带LMX1A基因SNP(Rs4657412)AA基因型的个体在言语工作记忆中表现出更大的训练相关收益，我们将评估受试者的这种等位基因变异对他们的训练效果(收益和维持)的影响。最后，我们将评估那些同意腰椎穿刺者在训练前和训练6个月后脑脊液中神经炎性标志物和单胺代谢产物的变化，并评价这些脑脊液标志物与认知表现和训练效果之间的关系，以及脑激活功能磁共振成像。虽然“Cogmed”不是治愈手部疾病的“良方”，但这项研究项目可能会找到一种新的、有效的辅助疗法来改善认知功能，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能确定谁可能从西医培训中受益最大，从而帮助指导未来艾滋病毒感染者的治疗计划。最后， 我们还将学习训练前后大脑激活、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.