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疗法广泛可用，高达50%的艾滋病毒感染者继续表现出轻度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的老龄化人口增加，他们患HAND的风险更大，在未来20年内，护理费用可能会增加近一倍。酒精、大麻或精神兴奋剂滥用等共病问题在艾滋病毒患者中发病率更高，可进一步加剧他们的认知缺陷。由于仍然缺乏有效的治疗和预防措施，因此为这些患者开发有效的治疗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HAND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计算机训练计划的有效性。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系统疾病的成人中显示出有效性，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，本建议的目的是：1)使用Cogmed进行双盲安慰剂对照研究，以确定在训练后1个月和6个月，与固定低水平（安慰剂）训练相比，强化适应性WM训练是否会使hiv感染者和hiv血清阴性（SN）对照组的WM和其他认知功能（增益转移）得到更大的改善（增益）。2)评估WM训练的神经相关性：在训练后1个月和6个月，在WM和注意期间，BOLD-fMRI是否会改善大脑激活。3)由于LMX1A SNP （rs4657412）基因型为AA型的个体在先前的研究中表现出更大程度的口头语言能力训练相关增益，我们将评估该等位基因变异对其训练效果（增益和维持）的影响。最后，我们将评估训练前和训练后6个月同意腰椎穿刺的患者脑脊液中神经炎症标志物和单胺代谢物的变化，并评估这些脑脊液标志物、认知表现和训练效果以及脑激活fMRI之间的关系。虽然Cogmed不能“治愈”HAND，但该研究项目可能会发现一种新的有效的辅助治疗方法来改善认知功能，从而改善这些患者的日常生活和功能活动。我们的基因研究可以确定从WM培训中获益最多的个体，从而有助于指导艾滋病毒感染者未来的治疗计划。最后,

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.