Global Deficit Score Research Articles

Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV.

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.

Cognitive Outcomes Among Patients with Hematological Cancer with Access to Computerized Cognitive Training: Results from a Feasibility Study

Objective: Cancer-related cognitive impairment can affect patients after treatment of hematological cancers, but evidence of the effect of cognitive training interventions in this population is limited. The objective of this study was to explore cognitive outcomes among a sample of patients with hematological cancer who were given access to an online computerized cognitive training program after treatment completion.Methods: Patients who had completed primary treatment for lymphoma, or autologous stem cell transplant for either lymphoma or multiple myeloma were recruited to test the feasibility of an 8-week computerized cognitive training intervention. All participants were assigned to receive the intervention, which was self-administered by participants at home and consisted of online brain training exercises designed to enhance information processing abilities. As part of the study, cognitive outcomes were assessed before (T1) and after (T2) the 8-week intervention, comprised of a standardized battery of neuropsychological tests, a self-report questionnaire of cognitive symptoms, and a functional assessment of medication management ability. Raw scores on neuropsychological tests were converted to T-scores based on demographically-adjusted norms (for age, sex, and education, where applicable), which were used for analysis. Composite T-scores representing performance in four cognitive domains (learning efficiency/memory, information processing speed/psychomotor efficiency, working memory, executive functioning) were computed at each time point. Wilcoxon's sum rank test was used to assess the differences in outcomes at times 1 and 2.Results: 14 patients (12 lymphoma, 2 multiple myeloma) completed cognitive measures at T1 and T2. Participants were a median 48.5 years of age (range 24-70) and a median 53.5 days from treatment completion (range 28 - 490). At baseline, 7 participants met the criteria for overall cognitive impairment based on a Global Deficit Score (GDS) ≥0.5. After 8 weeks of access to the online computerized cognitive training program, there was a statistically significant improvement in the domains of information processing speed/psychomotor efficiency (MD = 4.18, std =4.55, p=0.0042) and working memory (MD = 2.09, std = 2.74, p=0.0127). Effect sizes (d) for changes in information speed/psychomotor efficiency and working memory were 0.92 and 0.76, respectively, suggesting large effects by Cohen's d classification. There was no sufficient evidence of a difference in learning efficiency/memory, executive functioning, cognitive symptoms or medication management ability.Conclusion: Cognitive functioning in the domains of information processing speed/psychomotor efficiency and working memory were improved over the course of participation in an online self-administered computerized cognitive training program in this small sample of participants treated for hematological cancers. Post-hoc analyses to explore dose-response and factors associated with training time are forthcoming. Adequately powered studies with the inclusion of a control condition are required to determine treatment efficacy in this growing group of cancer survivors. DisclosuresKuruvilla:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria; Janssen: Consultancy; Hoffman LaRoche: Consultancy; Seattle Genetics: Consultancy, Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Lundbeck: Honoraria; Merck: Honoraria; Karyopharm: Research Funding; Roche: Research Funding; Celgene: Honoraria, Research Funding. Chen:Amgen: Honoraria; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

The effect of selective serotonin reuptake inhibitors on cognitive impairment in patients with depression: A prospective, multicenter, observational study

Whether selective serotonin reuptake inhibitors (SSRIs) can improve cognitive function in depressed patients remains unclear. We aimed to explore the effect of SSRIs on cognitive function and the influencing factors in patients with major depressive disorder (MDD) with impaired cognitive function. We used a neurocognitive test battery to assess five cognitive domains, namely, attention/vigilance, learning, memory, processing speed and executive functioning, and calculated the Global Deficit Score (GDS). A GDS≥0.5 indicated overall cognitive impairment. The changes in the cognitive domains and overall cognitive function were analyzed in MDD patients with a baseline GDS≥0.5 who completed 8 weeks of SSRI treatment. We divided the patients into the cognitive remission and nonremission groups to explore the associated factors. In total, 160 patients (mean age 37.6 ± 10.8 years, 30.6% male) were included in the final analysis. The median (quartiles) of baseline GDS and HRSD17 were 1.4 (0.8, 1.9) and 19.5 (17.0, 23.0), respectively. All five cognitive domains improved after the treatment, while only 41 (25.6%) patients achieved cognitive remission. Recurrence and a higher baseline GDS were risk factors for cognitive nonremission. More aggressive interventions may be needed to promote cognitive remission in clinical practice, especially for patients with severe cognitive impairment and recurrent episodes.

Predicting occupational outcomes from neuropsychological test performance in older people with HIV.

The ability to work is amongst the top concerns of people living with well treated HIV. Cognitive impairment has been reported in many otherwise asymptomatic persons living with HIV and even mild impairment is associated with higher rates of occupational difficulties. There are several classification algorithms for HIV-associated neurocognitive disorder (HAND) as well as overall scoring methods available to summarize neuropsychological performance. We asked which method best explained work status and productivity. Participants (N = 263) drawn from a longitudinal Canadian cohort underwent neuropsychological testing. : Several classification algorithms were applied to establish a HAND diagnosis and two summary measures (NPZ and Global Deficit Score) were computed. Self-reported work status and productivity was assessed at each study visit (four visits, 9 months apart). The association of work status with each diagnostic classification and summary measure was estimated using logistic regression. For those working, the value on the productivity scale was regressed within individuals over time, and the slopes were regressed on each neuropsychological outcome. The application of different classification algorithms to the neuropsychological data resulted in rates of impairment that ranged from 28.5 to 78.7%. Being classified as impaired by any method was associated with a higher rate of unemployment. None of the diagnostic classifications or summary methods predicted productivity, at time of testing or over the following 36 months. Neuropsychological diagnostic classifications and summary scores identified participants who were more likely to be unemployed, but none explained productivity. New methods of assessing cognition are required to inform optimal workforce engagement.

Rates of Cognitive and Functional Impairments in Older Adults Residing in a Continuing Care Senior Housing Community.

The current cross-sectional study examined cognition and performance-based functional abilities in a continuing care senior housing community (CCSHC) that is comparable to other CCSHCs in the US with respect to residents' demographic characteristics. Participants were 110 older adult residents of the independent living unit. We assessed sociodemographics, mental health, neurocognitive functioning, and functional capacity. Compared to normative samples, participants performed at or above expectations in terms of premorbid functioning, attention span and working memory, processing speed, timed set-shifting, inhibitory control, and confrontation naming. They performed below expectation in verbal fluency and verbal and visual learning and memory, with impairment rates [31.4% (>1 SD below the mean) and 18.49% (>1.5 SD below the mean)] well above the general population (16% and 7%, respectively). Within the cognitive test battery, two tests of delayed memory were most predictive of a global deficit score. Most cognitive test scores correlated with performance-based functional capacity. Overall, results suggest that a subset of older adults in the independent living sector of CCSHCs are cognitively and functionally impaired and are at risk for future dementia. Results also argue for the inclusion of memory tests in abbreviated screening batteries in this population. We suggest that CCSHCs implement regular cognitive screening procedures to identify and triage those older adults who could benefit from interventions and, potentially, a transition to a higher level of care.

Impact of Plasma IP-10/CXCL10 and RANTES/CCL5 Levels on Neurocognitive Function in HIV Treatment-Naive Patients

Immune activation, which is accompanied by the production of proinflammatory cytokines, is a strong predictor of disease progression in HIV infection. Inflammation is critical in neuronal damage linked to HIV-associated neurocognitive disorders. We examined the relationship between plasma cytokine levels and deficits in neurocognitive function. Multiplex profiling by Luminex® technology was used to quantify 27 cytokines/chemokines from 139 plasma samples of people living with HIV (PLWH). The relationship of plasma cytokine markers, clinical parameters, and cognitive impairment, was assessed using Spearman correlations. Partial least squares regression and variable importance in projection scores were used for further evaluation of the association. Forty-nine (35.3%) participants exhibited neurocognitive impairment based on a global deficit score (GDS) of at least 0.5 and 90 (64.7%) were classified as nonimpaired. Twenty-three (16.5%) initiated on combination antiretroviral therapy for 4 weeks before cognitive assessment and 116 (83.5%) were not on treatment. We identified five proinflammatory cytokines that were significant predictors of GDS namely, IP-10 (β = 0.058; p = .007), RANTES (β = 0.049; p = .005), IL-2 (β = 0.047, p = .006), Eotaxin (β = 0.042, p = .003), and IL-7 (β = 0.039, p = .003). IP-10 and RANTES were the strongest predictors of GDS. Both cytokines correlated with plasma viral load and lymphocyte proviral load and were inversely correlated with CD4+ T cell counts. IP-10 and RANTES formed a separate cluster with highest proximity. Study findings describe novel associations among IP-10, RANTES, cognitive status, plasma viral load, and cell-associated viral load.

Improvement of HIV-associated neurocognitive disorders after antiretroviral therapy intensification: the Neuro+3 study

Despite the effectiveness of antiretroviral (ARV) therapy to control HIV infection, HIV-associated neurocognitive disorders (HAND) remain frequent. The Neuro+3 study assessed the cognitive improvement associated with ARV intensification based on increased CNS penetration effectiveness (CPE) scoring ≥+3 and total CPE score ≥9. Thirty-one patients, aged 18-65 years, with confirmed diagnosis of HAND and effective ARV therapy were included. The cognitive improvement was measured using Frascati three-stage classification and global deficit score (GDS) after 48 and 96 weeks of ARV intensification. Ultrasensitive HIV-RNA, neopterin, soluble CD14, CCL2, CXCL10, IL6, IL8 and NF-L were measured in plasma and cerebrospinal fluid at Day 0 (baseline), Week 48 (W48) and W96. The intensified ARV was associated with a median (IQR) CPE score increase from 6 (4-7) at baseline to 10 (9-11). From baseline to W96, the median (IQR) GDS decreased from 1.4 (0.8-2.2) to 1.0 (0.6-2.0) (P = 0.009); HAND classification improved from 2 to 1 HIV-associated dementia, 22 to 8 mild neurocognitive disorders, 7 to 17 asymptomatic neurocognitive impairment and 0 to 5 patients without any neurocognitive alterations (P = 0.001). In multivariable linear regression analysis, GDS improvement at W96 was significantly associated with CPE score ≥9 after intensification (P = 0.014), CD4 lymphocyte increase at W48 (P < 0.001) and plasma CXCL10 decrease at W96 (P = 0.001). In patients with HAND, a significant cognitive improvement was observed after the ARV intensification strategy, with a higher CPE score. Cognitive improvement was more often observed in the case of a switch of two drug classes, arguing for better control of CNS HIV immune activation.

Examining Test-Retest Reliability and Reliable Change for Cognition Endpoints for the CENTER-TBI Neuropsychological Test Battery.

Objective: Seven candidate cognition composite scores have been developed and evaluated as part of a research program designed to validate a cognition endpoint for traumatic brain injury (TBI) research and clinical trials, but these composites have yet to be examined longitudinally. This study examined test-retest reliability and methods for determining reliable change for these seven candidate composite scores, using the neuropsychological test battery from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI).Methods: Participants (18–59 years-old) with mild TBI (n = 124), orthopedic trauma without head injury (n = 67), and healthy community controls (n = 63) from the Trondheim MTBI follow-up study completed the CENTER-TBI neuropsychological test battery at 2 weeks and 3 months after injury. The battery included both traditional paper-and-pencil tests and computerized tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Seven composite scores were calculated for the paper-and-pencil tests, the CANTAB tests, and all tests combined (i.e., 21 composites in total on each assessment): the overall test battery mean (OTBM); global deficit score (GDS); neuropsychological deficit score-weighted (NDS-W); low score composite (LSC); and the number of scores ≤5th percentile, ≤16th percentile, or <50th percentile. The OTBM was calculated by averaging T scores for all tests. The other composite scores were deficit-based scores, assigning different weights to low scores.Results: All composites revealed better cognitive performance at the 3-month assessment compared to the 2-week assessment and the magnitude of improvement was similar across groups. Differences, in terms of effect sizes, were largest on the OTBMs. In the combined composites, the test-retest correlation was highest for the OTBM (Spearman's rho = 0.87, in the community control group) and lowest for the number of scores ≤5th percentile (rho = 0.41).Conclusion: The high test-retest reliability of the OTBM appears to favor its use in TBI research; however, future studies are needed to examine these candidate composite scores in participants with more severe TBIs and cognitive deficits and the association of the composites with functional outcomes.

Asymptomatic neurocognitive impairment is a risk for symptomatic decline over a 3-year study period.

To examine whether persons with asymptomatic neurocognitive impairment (ANI) were more likely to show progression to mild neurocognitive disorder or HIV-associated dementia than those who were neuropsychologically normal (NP-N). Longitudinal observational cohort study. Study sample included 720 HIV-1 seropositive persons (317 with ANI and 403 NP-N) receiving care in Toronto, Canada [83% were on antiretroviral treatment; 71% had undetectable (<50 copies/ml) plasma HIVRNA]. Neuropsychological assessments were conducted at 12 months intervals for a median follow-up time of 34 months. Neuropsychological data were corrected for age, education, sex, and race/ethnicity, and corrected for practice effect at follow-ups. Progression to mild neurocognitive disorder and HIV-associated dementia at each time point was determined using the Global Deficit Score and presence of cognitive symptoms. Over the follow-up period, 170 individuals (24%) progressed to symptomatic HIV-associated neurocognitive disorders (HAND). Persons with ANI were more likely to progress to symptomatic HAND than persons with NP-N after adjusting for baseline and time-varying confounders (adjusted hazards ratio: 1.88; 95% confidence interval: 1.37-2.60; P < 0.001). Female sex, depression, and cigarette smoking were associated with higher risk of progression to symptomatic HAND, but traditional HIV markers and antiretroviral treatment were not. ANI is associated with a two-fold increased risk of progression to symptomatic HAND in a cohort with universal healthcare access. This represents the largest replication of comparable US results. Reproducibility of these findings indicate that routine monitoring of persons with ANI and exploration of clinical interventions to prevent or delay progression to symptomatic HAND are imperative. HIV, HAND, HIV-associated dementia, cohort study, replicability, reproducibility.

Prevalence of HIV-associated neurocognitive disorder (HAND) in Turkey and assessment of Addenbrooke's Cognitive Examination Revised (ACE-R) test as a screening tool.

We aimed to assess the Addenbrooke's Cognitive Examination Revised (ACE-R) and three questions (3Qs, European Aids Clinical Society Guidelines) as potential screening tools for HIV-associated neurocognitive disorder (HAND). In addition, we tried to determine the prevalence and associated factors for HAND among people living with HIV (PLWH) in Turkey. Persons living with HIV were enrolled from two teaching hospitals between March 2018 and September 2018. Participants underwent screening tools, a neuropsychological test battery (NTB) and an assessment of activities of daily living. HAND was diagnosed according to Frascati's criteria and applying the Global Deficit Score (GDS) approach. A receiver operating characteristic (ROC) curve analysis was performed to compare the predictive accuracy of ACE-R to that of the NP test battery. Factors associated with HAND were evaluated using multivariate logistic regression analysis. The study sample included 162 participants (94% male). The HAND prevalence was 45.7% [asymptomatic neurocognitive impairment (ANI), 37.7%; mild neurocognitive disorder (MND), 7.4%; HIV-associated dementia (HAD), 0.6%] according to the Frascati criteria and 31.5% (ANI, 25.9%; MND, 4.9%; HAD, 0.6%) using the GDS. In the ROC analysis, the ACE-R showed an area under the curve of 0.68 at a cut-off score of 89. The sensitivity, specificity and correct classification rate of screening tests for HAND diagnosis were as follows: ACE-R (62.2%, 67%, 64.8%) and 3Qs (10.8%, 88.6%, 53%). In multivariate analysis, only education level (adjusted odds ratio [aOR] = 0.84, 95% CI: 0.76-0.92, P≤0.001) was an independent risk factor for HAND. HAND is a common comorbidity in PLWH in Turkey. The sensitivities and specificities of 3Qs and the ACE-R as screening tools are lower than desired.

Impact of Latent Tuberculosis Infection on Neurocognitive Functioning and Inflammation in HIV-Infected and Uninfected South Indians.

HIV-associated neurocognitive disorder persists in some people living with HIV despite optimal antiretroviral therapy. Latent tuberculosis infection (LTBI) may cause systemic inflammation and immune activation that may impair brain function. We assessed cognition and biomarkers of inflammation in both HIV+ and HIV- South Indians with and without LTBI. Adults (≥18 years old) with and without HIV infection were screened for LTBI by interferon-gamma release assays, completed comprehensive neurocognitive assessments, and underwent measurement of serum inflammatory biomarker levels. The participants (n = 119) were HIV+/LTBI+ (n = 15), HIV+/LTBI- (n = 50), HIV-/LTBI+ (n = 26), and HIV-/LTBI- (n = 28). HIV+ participants, regardless of LTBI status, had more impaired global deficit scores than HIV- participants (odds ratio = 3.42, P = 0.028, adjusted for sex and education differences). Neither global deficit scores nor impairment rates differed in the LTBI+ group compared with the LTBI- group (P = 0.79 and P = 0.41, respectively). The mean log10 interleukin (IL)-6 and monocyte chemoattractant protein-1 values were significantly higher and high sensitivity C-reactive protein lower in the LTBI+ group than the LTBI- group (P = 0.044, 0.023, and 0.03, respectively, adjusting for HIV status and sex). In this cross-sectional study of South Indians, HIV infection, but not LTBI, was associated with increased neurocognitive impairment. Proinflammatory biomarkers (IL-6 and monocyte chemoattractant protein-1, but not tumor necrosis factor-α) were elevated in the LTBI+ groups compared with the LTBI- groups. Biomarkers of immune activation (interferon-γ, macrophage inflammatory protein-1β, IL-2, interferon gamma inducible protein-10, RANTES, and IL-22) did not differ between these groups. Larger longitudinal studies should be conducted to confirm our findings that the effect of LTBI on systemic inflammation or neurocognitive impairment is likely small.

Peripheral blood lymphocyte proviral DNA predicts neurocognitive impairment in clade C HIV

It is not known if proviral DNA in the periphery corresponds to cognitive status in clade C as it does in clade B and recombinant forms. A cross-sectional study was conducted on participants investigated for HIV-associated neurocognitive impairment in South Africa. HIV-1 proviral DNA was quantified using a PCR assay targeting a highly conserved HIV-1 LTR-gag region. Fifty-four (36.7%) participants were cognitively impaired and 93 (63.3%) were not impaired. Forty-three (79.6%) of the cognitively impaired participants were female and 11 (20.4%) were male. There was no significant age difference between cognitively impaired and unimpaired participants (p = 0.42). HIV-1 DNA in cognitively impaired PLWH was significantly higher than in cognitively normal individuals (p = .016). Considering impaired participants, lymphocyte HIV-1 DNA was significantly higher in males than females (p = 0.02). There was a modest positive correlation between lymphocyte HIV-1 DNA and global deficit scores (GDS) r = 0.176; p = 0.03). The two measures of viral load, lymphocyte HIV-1 DNA copies/million and plasma RNA copies/ml, were positively correlated (r = 0.39; p < .001). After adjusting for other covariates, age, sex, treatment status, and the interactions between impairment and treatment, the multivariate regression showed association between proviral load and neurocognitive impairment; omega effect size was 0.04, p value = 0.010. The burden of HIV-1 peripheral blood lymphocyte proviral DNA corresponds to neurocognitive impairment among individuals infected with clade C disease. Therefore, therapeutic strategies to reduce the HIV-1 proviral DNA reservoir in lymphocytes may improve neurocognitive outcomes in PLWH.

Developing Cognition Endpoints for the CENTER-TBI Neuropsychological Test Battery.

Background: Measuring cognitive functioning is common in traumatic brain injury (TBI) research, but no universally accepted method for combining several neuropsychological test scores into composite, or summary, scores exists. This study examined several possible composite scores for the test battery used in the large-scale study Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI).Methods: Participants with mild traumatic brain injury (MTBI; n = 140), orthopedic trauma (n = 72), and healthy community controls (n = 70) from the Trondheim MTBI follow-up study completed the CENTER-TBI test battery at 2 weeks after injury, which includes both traditional paper-and-pencil tests and tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Seven composite scores were calculated for the paper and pencil tests, the CANTAB tests, and all tests combined (i.e., 21 composites): the overall test battery mean (OTBM); global deficit score (GDS); neuropsychological deficit score-weighted (NDS-W); low score composite (LSC); and the number of scores ≤5th percentile, ≤16th percentile, or <50th percentile.Results: The OTBM and the number of scores <50th percentile composites had distributional characteristics approaching a normal distribution. The other composites were in general highly skewed and zero-inflated. When the MTBI group, the trauma control group, and the community control group were compared, effect sizes were negligible to small for all composites. Subgroups with vs. without loss of consciousness at the time of injury did not differ on the composite scores and neither did subgroups with complicated vs. uncomplicated MTBIs. Intercorrelations were high within the paper-and-pencil composites, the CANTAB composites, and the combined composites and lower between the paper-and-pencil composites and the CANTAB composites.Conclusion: None of the composites revealed significant differences between participants with MTBI and the two control groups. Some of the composite scores were highly correlated and may be redundant. Additional research on patients with moderate to severe TBIs is needed to determine which scores are most appropriate for TBI clinical trials.

4400 Low CD4 nadir linked to widespread cortical thinning in adults with HIV

OBJECTIVES/GOALS: The history of immune suppression, especially CD4 nadir, has been shown to be a strong predictor of HIV-associated neurocognitive disorders (HAND). However, the potential mechanism of this association is not well understood. This study examined the relationship between CD4 nadir and brain atrophy. METHODS/STUDY POPULATION: Fifty-nine people with HIV participated in the cross-sectional study (mean age, 56.5 ± 5.8; age range, 41-69; 15 females; 46 African-Americans). High resolution structural MRI images were obtained using a 3T Siemens scanner. From a comprehensive 7-domain neuropsychological test battery, a global deficit score (GDS) and HAND diagnoses were determined for each participant. The correlation between CD4 nadir (the lowest ever lymphocyte CD4 count) and cortical thickness was investigated using a vertex-wise non-parametric approach with a conservative statistical threshold of p &lt; 0.05 (FWE-corrected). RESULTS/ANTICIPATED RESULTS: Out of the 59 participants, 12 met standard Frascati criteria for asymptomatic neurocognitive impairment (ANI) and two met the criteria for mild neurocognitive disorder (MND). Across all participants, low CD4 nadir was associated with widespread cortical thinning, especially in the frontal and temporal regions. Higher GDS (indicating worse global neurocognitive function) was associated with bilateral frontal cortical thinning, and the association largely persisted in the subset of participants who did not meet HAND criteria. DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that the low CD4 nadir may be associated with widespread neural injury in the brain, especially in the frontal and temporal regions. This spatial profile might contribute to the prevalence/phenotypes of HAND in the cART era, such as the frequently observed deficits in the executive domain.

Genome Wide Association Study (GWAS) of cognitive impairment after blood or marrow transplantation (BMT) for hematologic malignancy.

1536 Background: Cognitive impairment is prevalent in hematologic malignancy patients treated with BMT (autologous: 18.7%; allogeneic: 35.7%; Sharafeldin JCO; 2018). Given the inter-individual variability in risk of cognitive impairment in this population, we investigated the role of genetic susceptibility using a genome-wide single nucleotide polymorphism (SNP) array platform to identify novel genetic associations. Methods: Discovery: Cognitive function was assessed objectively in 239 adult BMT recipients at pre-specified timepoints: pre-BMT and at 6 mo, 1y, 2y, and 3y post-BMT. A global deficit score (GDS - a summary score of 14 standardized neuropsychological tests) was computed for each patient; a higher score indicated greater cognitive impairment. SNPs passing standard quality control filters ( &gt; 1.4M) were used for analysis. Linear mixed effects models used GDS as the outcome, adjusted for age, sex, BMT type, baseline cognitive reserve, and the first four principal components. We used additive, codominant, and genotype models and an adjusted genome-wide significance threshold of 1.25 x 10−8. Replication: An independent cohort of 544 BMT survivors (192 cases with self-endorsed cognitive problems and 352 controls without) was used for replication. Results: Discovery: Median age at BMT was 51.3y; primary diagnoses: 47% leukemia, 32% lymphoma, 21% multiple myeloma; 57% males; 69% non-Hispanic whites: 50% allogeneic BMT, median GDS score = 0.22 (range 0-2). Forty-four SNPs were significantly associated with increased GDS (additive model: 3 SNPs; codominant model: 20 SNPs; genotype model: 21 SNPs). Estimates ranged from increase in GDS score by 0.28 points for each additional copy of risk allele, p = 1.07 x 10−8 to increase in GDS score by 1.82 points for two copies of risk allele, p = 2.3 x 10−11. Replication: Median age at BMT was 44y; primary diagnoses: 32% leukemia, 49% lymphoma, 19% multiple myeloma; 54% males; 80% non-Hispanic whites: 34% allogeneic BMT. Three SNPs were successfully replicated: rs116334183 resides within lncRNA-SEMA6D-2, which facilitates neuronal migration; rs13286152 86kb downstream of TLE-1, which promotes neuronal survival; and rs12486041 0.36Mb downstream from lncRNA-SPTSSB-1, which regulates sphingolipid production in neuronal axons and 0.36Mb upstream from TOMM22P6 linked to neural repair. Conclusions: In this first GWAS of cognitive impairment post-BMT, we identify 3 SNPs with plausible links to genes implicated in neuronal integrity. Functional studies are currently underway.

Hepatitis C Virus Cure in Human Immunodeficiency Virus Coinfection Dampens Inflammation and Improves Cognition Through Multiple Mechanisms.

Chronic inflammation in human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection increases cognitive impairment. With newer, direct-acting antiviral therapies for HCV, our objective was to determine whether chronic inflammation would be decreased and cognition improved with HCV sustained viral response (SVR) in coinfection. We studied 4 groups longitudinally: 7 HCV-monoinfected and 12 HIV/HCV-coinfected persons before and after treatment for HCV, 12 HIV-monoinfected persons, and 9 healthy controls. We measured monocyte activation and gene expression, monocyte-derived exosome micro-ribonucleic acid (miRNA) expression, plasma inflammation, and cognitive impairment before and after therapy. Plasma soluble CD163 and neopterin were decreased in HCV mono- and coinfected persons. Blood CD16+ monocytes were decreased in coinfection after HCV treatment. Global deficit score improved 25% in coinfection with the visual learning/memory domain the most improved. Hepatitis C virus SVR decreased monocyte interferon genes MX1, IFI27, and CD169 in coinfection and MX1, LGALS3BP, and TNFAIP6 in HCV monoinfection. Monocyte exosomes from coinfected persons increased in microRNA (miR)-19a, miR-221, and miR-223, all of which were associated with decreasing inflammation and nuclear factor-κB activation. Hepatitis C virus cure in coinfection brings monocyte activation to levels of HIV alone. Cognitive impairment is significantly improved with cure but not better than HIV infection alone, which strong suggests that cognitive impairment was driven by both HIV and HCV.SummaryHCV cure in HIV coinfection improves monocyte and plasma activation markers and increases cognitive function in the visual learning/memory domain.

Assessing Cognitive Functioning in People Living With HIV (PLWH): Factor Analytic Results From CHARTER and NNTC Cohorts.

Single summary scores, such as the Global Deficit Score, are often used to classify overall performance on neuropsychological batteries. The factor structure of test scores that underlie Global Deficit Score in studies of people living with HIV (PLWH) was assessed to determine whether individual test scores loaded onto a unitary factor to summarize performance. Secondary data analysis on baseline data of PLWH from National NeuroAIDS Tissue Consortium and CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Study. Primary analyses included testing model structure and fit of neuropsychological test scores with confirmatory and exploratory factor analyses. Secondary analyses involved receiver operating characteristic curves, and associations with psychosocial and medical variables. Participants with confounds were excluded, leading to 798 (National NeuroAIDS Tissue Consortium) and 1222 (CHARTER) cases. When confirmatory factor analysis models were structured to be consistent with theoretically-based cognitive domains, models did not fit adequately. Per exploratory factor analyses, tests assessing speeded information processing, working memory, and executive functions loaded onto a single factor and explained the most variance in both cohorts. This factor tended to be associated with age, estimated premorbid ability, and aspects of substance use history. Its relation to age, in context of demographically corrected neuropsychological scores, suggested accelerated aging. Results indicate that individual neuropsychological tests did not load exactly onto expected domains, suggesting another framework for future analyses of cognitive domains. The possibility of a new index, and its use to assess cognitive impairment in PLWH, is suggested for further diagnostic and prognostic purposes.

Cognition and functional capacity following traumatic brain injury in veterans.

Performance-based tests of functional capacity are rarely used in research on mild to moderate traumatic brain injury (TBI), but they may function as a link between cognitive impairment and real-world functioning. We sought to examine the relationship between cognitive functioning and performance-based functional capacity, as measured by the University of California San Diego Performance-Based Skills Assessment-Brief (UPSA-B), in Veterans with TBI histories. A total of 50 unemployed Operation Enduring Freedom/Operation Iraqi Freedom Veterans with mild to moderate TBI histories completed assessments of neuropsychological performance and functional capacity (UPSA-B total, financial subscale, and communication subscale scores). All participants were impaired in at least 1 neuropsychological domain on a prior clinical neuropsychological evaluation. A global deficit score was calculated based on neuropsychological performance on assessments of attention/working memory, processing speed, learning, delayed recall, prospective memory, and executive functioning. Deficit scores were also calculated for the executive-functioning domain and the processing-speed domain. Neuropsychological deficit scores were then correlated with UPSA-B performances. Correlation coefficients indicated that worse global neuropsychological performance was related to worse overall functional capacity (rs = -.28, p = .046) and communication capacity (rs = -.34, p = .016). Worse executive functioning was related to worse functional capacity, r = -.37, p = .008, particularly in the domain of communication, r = -.44, p ≤ .001. Processing-speed performance was not related to functional capacity. Executive functioning was moderately associated with both communication and overall everyday functioning capacity. Improvement in executive-functioning deficits may improve functional capacity, specifically in communication tasks. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Cannabis Exposure is Associated With a Lower Likelihood of Neurocognitive Impairment in People Living With HIV.

Aging and HIV have adverse effects on the central nervous system, including increased inflammation and neural injury and confer risk of neurocognitive impairment (NCI). Previous research suggests the nonacute neurocognitive effects of cannabis in the general population are adverse or null. However, in the context of aging and HIV, cannabis use may exert beneficial effects due to its anti-inflammatory properties. In the current study, we examined the independent and interactive effects of HIV and cannabis on NCI and the potential moderation of these effects by age. Participants included 679 people living with HIV (PLHIV) and 273 people living without HIV (HIV-) (18-79 years old) who completed neurocognitive, neuromedical, and substance use assessments. NCI was defined as a demographically corrected global deficit score ≥ 0.5. Logistic regression models examined the effects of age, HIV, cannabis (history of cannabis substance use disorder and cannabis use in past year), and their 2-way and 3-way interactions on NCI. In logistic regression models, only a significant interaction of HIV X cannabis was detected (P = 0.02). Among PLHIV, cannabis was associated with a lower proportion of NCI (odds ratio = 0.53, 95% confidence interval = 0.33-0.85) but not among HIV- individuals (P = 0.40). These effects did not vary by age. Findings suggest cannabis exposure is linked to a lower odds of NCI in the context of HIV. A possible mechanism of this result is the anti-inflammatory effect of cannabis, which may be particularly important for PLHIV. Further investigations are needed to refine the effects of dose, timing, and cannabis compound on this relationship, which could inform guidelines for cannabis use among populations vulnerable to cognitive decline.

Measurement of executive functioning with the National Institute of Health Toolbox and the association to anxiety/depressive symptomatology in childhood/adolescence

ABSTRACT Introduction Despite preliminary research, there remain inconsistent findings with regard to the role of executive functioning (EF) deficits in childhood anxiety and depression. This report examined the association of The National Institute of Health (NIH) Toolbox to clinical neuropsychological measures and to childhood, anxiety/depressive symptomatology. Methods: One-hundred eight children and adolescents completed the three EF measures from the NIH Toolbox (List Sorting Working Memory Test [LSWMT], Dimensional Change Card Sorting Test [DCCST], and Flanker Test of Attention and Inhibition [Flanker]) in an outpatient neuropsychology program. These tests were compared to established measures of EF in terms of linear correlations and detection of impairment. Heaton’s Global Deficit Score (GDS) was utilized to calculate impairment. The Toolbox-EF measures were paired with parent-reported EF symptoms (Behavior Rating Inventory of Executive Function [BRIEF2]) to identify the role of EF in childhood anxiety/depressive symptomatology. Results Toolbox-EF measures displayed medium sized correlations with their clinically comparable counterparts, and generally did not differ in their detection of impairment. Toolbox-GDS was associated with depression diagnosis and clinically significant child-reported anxiety and depressive symptoms. Together, Toolbox/BRIEF2 accounted for 26.8–30.9% of elevated depressive symptom variance, but only 13.2-14% of elevated anxiety symptom variance. Further, EF impairment was associated with depression across self report, parent report, and clinical diagnosis. Discussion The NIH Toolbox-EF measures display comparable psychometric properties to clinically available EF measures in a pediatric (primarily psychiatric) neuropsychology setting. The Toolbox appears to display an appropriate ability to detect EF deficits secondary to self-reported depression in childhood.