ObjectiveWe aimed to evaluate the effectiveness of an adaptive working memory (WM) training (WMT) program, the corresponding neural correlates, and LMX1A‐rs4657412 polymorphism on the adaptive WMT, in human immunodeficiency virus (HIV) participants compared to seronegative (SN) controls.MethodsA total of 201 of 206 qualified participants completed baseline assessments before randomization to 25 sessions of adaptive WMT or nonadaptive WMT. A total of 74 of 76 (34 HIV, 42 SN) completed adaptive WMT and all 40 completed nonadaptive WMT (20 HIV, 20 SN) and were assessed after 1 month, and 55 adaptive WMT participants were also assessed after 6 months. Nontrained near‐transfer WM tests (Digit‐Span, Spatial‐Span), self‐reported executive functioning, and functional magnetic resonance images during 1‐back and 2‐back tasks were performed at baseline and each follow‐up visit, and LMX1A‐rs4657412 was genotyped in all participants.ResultsAlthough HIV participants had slightly lower cognitive performance and start index than SN at baseline, both groups improved on improvement index (>30%; false discovery rate [FDR] corrected p < 0.0008) and nontrained WM tests after adaptive WMT (FDR corrected, p ≤ 0.001), but not after nonadaptive WMT (training by training type corrected, p = 0.01 to p = 0.05) 1 month later. HIV participants (especially LMX1A‐G carriers) also had poorer self‐reported executive functioning than SN, but both groups reported improvements after adaptive WMT (Global: training FDR corrected, p = 0.004), and only HIV participants improved after nonadaptive WMT. HIV participants also had greater frontal activation than SN at baseline, but brain activation decreased in both groups at 1 and 6 months after adaptive WMT (FDR corrected, p < 0.0001), with normalization of brain activation in HIV participants, especially the LMX1A‐AA carriers (LMX1A genotype by HIV status, cluster‐corrected‐p < 0.0001).InterpretationAdaptive WMT, but not nonadaptive WMT, improved WM performance in both SN and HIV participants, and the accompanied decreased or normalized brain activation suggest improved neural efficiency, especially in HIV‐LMX1A‐AA carriers who might have greater dopaminergic reserve. These findings suggest that adaptive WMT may be an effective adjunctive therapy for WM deficits in HIV participants. ANN NEUROL 2017;81:17–34

HIV-infection is associated with neuroinflammation and greater psychopathological symptoms, which may be mediated by imbalances in the kynurenic pathway (KP). Two key KP enzymes that catabolize kynurenine include kynurenine-aminotransferase II (KATII), which yields antioxidative kynurenine acid [KYNA] in astrocytes, and kynurenine-3-monooxygenase (KMO), which produces neurotoxic metabolites in microglia. The relationships between polymorphisms in KMO and KATII, psychopathological symptoms, and cerebrospinal fluid (CSF) [KYNA] were evaluated in subjects with and without HIV-infection. Seventy-two HIV-positive and 72-seronegative (SN) participants were genotyped for KATII-rs1480544 and KMO-rs1053230. Although our participants were not currently diagnosed with depression or anxiety, they were assessed for psychopathological distress with Center for Epidemiologic Studies-Depression scale and Symptom Checklist-90-Revised. CSF-[KYNA] was also measured in 100 subjects (49 HIV/51 SN). HIV-participants had more psychopathological distress than SN, especially for anxiety. KATII-by-HIV interactions were found on anxiety, interpersonal sensitivity and obsessive compulsivity; KATII-C-carriers had lower scores than TT-carriers in SN but not in HIV. In contrast, the KMO-polymorphism had no influence on psychopathological symptoms in both groups. Overall, CSF-[KYNA] increased with age independently of HIV-serostatus, except KATII-TT-carriers tended to show no age-dependent variations. Therefore, the C-allele in KATII-rs1480544 appears to be protective against psychopathological distress in SN but not in HIV individuals, who had more psychopathological symptoms and likely greater neuroinflammation. The age-dependent increase in CSF-[KYNA] may reflect a compensatory response to age-related inflammation, which may be deficient in KATII-TT-carriers. Targeted treatments that decrease neuroinflammation and increase KYNA in at risk KATII-TT-carriers may reduce psychopathological symptoms in HIV.

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