Global Neurocognitive Performance Research Articles

The combination of donepezil and cognitive training for improving treatment outcomes for alcohol use disorder: Design of a randomized controlled trial

BackgroundThe development of alcohol use disorder (AUD) is a major concern in public health, and cognitive impairments caused by alcohol are involved in this process. Emerging neurobiological evidence suggests that donepezil, an anticholinesterase agent, may improve AUD treatment outcomes by enhancing neurocognitive functioning. Previous research has also suggested that cognitive remediation therapy (CRT) could potentially improve cognitive function and AUD treatment outcomes. We present the rationale and design of a trial to evaluate the combination of donepezil and cognitive remediation therapy (donepezil + CRT) as an intervention for AUD. MethodsWe propose a 13-week, randomized, double-blind, placebo-controlled, between-subjects trial comparing 4 groups (donepezil + CRT vs. donepezil alone vs. CRT alone vs. placebos) as an intervention for AUD. The main goal of the study is to evaluate if donepezil + CRT is superior to placebo in reducing heavy drinking days and improving neurocognitive functioning. A total of 160 patients (4 groups, 40 per each group) with AUD between the ages of 18–80 years will be recruited at Yale University and the VA Connecticut Healthcare System. Primary outcome measures include 1) heavy drinking by Timeline Follow Back (TLFB) over 13 weeks and 2) global neurocognitive functioning by a global index of neurocognitive function score at 7 and 13 weeks. DiscussionThis protocol paper describes the rationale and proposed methods for the randomized controlled trial for improving AUD treatment outcomes. This project has significant clinical potential to help patients suffering from AUD by improving their cognition and reducing alcohol consumption.Trial Registration:NCT05042102

Disparities in Metabolic Syndrome and Neurocognitive Function Among Older Hispanics/Latinos with Human Immunodeficiency Virus.

Neurocognitive impairment and metabolic syndrome (MetS) are prevalent in persons with HIV (PWH). We examined disparities in HIV-associated neurocognitive function between Hispanic and non-Hispanic White older PWH, and the role of MetS in explaining these disparities. Participants included 116 community-dwelling PWH aged 50-75 years enrolled in a cohort study in southern California [58 Hispanic (53% Spanish speaking) and 58 age-comparable non-Hispanic White; overall group: age: M = 57.9, standard deviation (SD) = 5.7; education (years): M = 13, SD = 3.4; 83% male, 58% AIDS, 94% on antiretroviral therapy]. Global neurocognition was derived from T-scores adjusted for demographics (age, education, sex, ethnicity, language) on a battery of 10 cognitive tests. MetS was ascertained via standard criteria that considered central obesity, and fasting elevated triglycerides, low high-density lipoprotein cholesterol and elevated glucose, or medical treatment for these conditions. Covariates examined included sociodemographic, psychiatric, substance use and HIV disease characteristics. Compared with non-Hispanic Whites, Hispanics showed worse global neurocognitive function (Cohen's d = 0.56, p < 0.05) and had higher rates of MetS (38% vs. 56%, p < 0.05). A stepwise regression model including ethnicity and significant covariates showed Hispanic ethnicity was the sole significant predictor of worse global neurocognition (B = -3.82, SE = 1.27, p < 0.01). A model also including MetS showed that both Hispanic ethnicity (B = -3.39, SE = 1.31, p = 0.01) and MetS (B = -2.73, SE = 1.31, p = 0.04) were independently associated with worse neurocognition. In conclusion, findings indicate that increased MetS is associated with worse neurocognitive function in both Hispanic and non-Hispanic White older PWH, but does not explain neurocognitive disparities. MetS remains an important target for intervention efforts to ameliorate neurocognitive dysfunction among diverse older PWH.

Clinical Manifestations.

Older adults may experience decreased social support, which has been linked to cognitive decline and increased risk of dementia. Immigrants may also experience more social isolation due to discrimination and fear of deportation. This study examined social networks, nativity status, and neurocognitive functioning(NC) in an ethnoculturally diverse sample of middle/older adults. Participants included 26 immigrants (Mage= 64.12, SD = 5.64) and 109 U.S.-born adults (Mage= 65.37, SD = 7.10). Participants completed a comprehensive NC battery and the Berkman-Syne Social Network Index(SNI; a well-validated self-reported questionnaire assessing close social support, where higher scores represent more social support). Demographically-adjusted norms were used to compute average global NC and domain T-scores. A series of hierarchical multiple regressions were computed to predict global and domain NC T-scores. SNI and age were entered at Step-One, the interaction term(age*SNI) was entered at Step-Two, and nativity status was entered at Step-Three. Results revealed that the omnibus model was significantly associated with Attention/Working Memory(A/WM) (R² = .13; ps = .009) and Processing Speed(PS) (R² = .20; ps = .002). Notably Step-Three of the model significantly contributed to the association of AWM (R²Δ= .11; ps<.05) and PS (R²Δ= .09; ps<.05) beyond Step-One and Step-Two. For A/WM, the interaction term, and nativity status (𝛽s = .04-6.96, respectively; ps<.05) were significantly associated with A/WM. For PS, SNI, the interaction term, and nativity status (𝛽s = -3.91-8.17; ps<.05) were significantly associated with PS. Such that, there is a main effect of nativity status with immigrants scoring lower on measures of A/WM by 6.96 and PS by 8.17 units. Overall, there is a negative association between age and A/WM and PS but as SNI increases the relation between age and NC becomes positive. Only nativity status (𝛽s = 5.99-8.23; ps<.05) significantly predicted Memory, Verbal Fluency, and Global NC functioning scores. Findings show that among middle/older adults, both SNI and nativity status are associated with A/WM and PS, suggesting that a larger SNI can serve as a protective factor against the effects of aging on NC functioning. Importantly, even when SNI and age were not significantly related to NC T-scores, nativity status was. Nativity status likely serves as a proxy for other risk factors (e.g., healthcare access), which should be explored in future studies.

41 Examining the independent and additive effects of family history of dementia and apolipoprotein e4 on neurocognitive performance among people with HIV

Objective:Among people with HIV (PWH), the apolipoprotein e4 (APOE-e4) allele, a genetic marker associated with Alzheimer’s disease (AD), and self-reported family history of dementia (FHD), considered a proxy for higher AD genetic risk, are independently associated with worse neurocognition. However, research has not addressed the potential additive effect of FHD and APOE-e4 on global and domain-specific neurocognition among PWH. Thus, the aim of the current investigation is to examine the associations between FHD, APOE-e4, and neurocognition among PWH.Participants and Methods:283 PWH (Mage=50.9; SDage=5.6) from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study completed comprehensive neuropsychological and neuromedical evaluations and underwent APOE genotyping. APOE status was dichotomized into APOE-e4+ and APOE-e4-. APOE-e4+ status included heterozygous and homozygous carriers. Participants completed a free-response question capturing FHD of a first- or second-degree relative (i.e., biologic parent, sibling, children, grandparent, grandchild, uncle, aunt, nephew, niece, half-sibling). A dichotomized (yes/no), FHD variable was used in analyses. Neurocognition was measured using global and domain-specific demographically corrected (i.e., age, education, sex, race/ethnicity) T-scores. t-tests were used to compare global and domain-specific demographically-corrected T-scores by FHD status and APOE-e4 status. A 2x2 factorial analysis of variance (ANOVA) was used to model the interactive effects of FHD and APOE-e4 status. Tukey’s HSD test was used to follow-up on significant ANOVAs.Results:Results revealed significant differences by FHD status in executive functioning (t(281)=-2.3, p=0.03) and motor skills (t(278)=-2.0, p=0.03) such that FHD+ performed worse compared to FHD-. Differences in global neurocognition by FHD status approached significance (t(281)=-1.8, p=.069). Global and domain-specific neurocognitive performance were comparable among APOE-e4 carriers and noncarriers (ps&gt;0.05). Results evaluating the interactive effects of FHD and APOE-e4 showed significant differences in motor skills (F(3)=2.7, p=0.04) between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups such that the FHD+/APOE-e4- performed worse than the FHD-/APOE-e4+ group (p=0.02).Conclusions:PWH with FHD exhibited worse neurocognitive performance within the domains of executive functioning and motor skills, however, there were no significant differences in neurocognition between APOE-e4 carriers and noncarriers. Furthermore, global neurocognitive performance was comparable across FHD/APOE-e4 groups. Differences between the FHD-/APOE-e4+ and FHD+/APOE-e4- groups in motor skills were likely driven by FHD status, considering there were no independent effects of APOE-e4 status. This suggests that FHD may be a predispositional risk factor for poor neurocognitive performance among PWH. Considering FHD is easily captured through self-report, compared to blood based APOE-e4 status, PWH with FHD should be more closely monitored. Future research is warranted to address the potential additive effect of FHD and APOE-e4 on rates of global and domain-specific neurocognitive decline and impairment over time among in an older cohort of PWH, where APOE-e4 status may have stronger effects.

39 Neurocognitive Function in People Living with HIV from Tijuana: a Comparison Between Norms for Latin-American Population and Norms for US-Mexico Border Region

Objective:Global neurocognitive impairment (NCI) has been reported in white people living with HIV/AIDS (PLWHA) in 40%. In Latino populations there have been variable rates described from 30 to 77%. This variation has to do with the lack of normative data for Latino population and the application of norms for English-speakers, increasing the probability of misidentification of NCI. Thus, recognizing which are the best norms available for the Mexican population is important for the accurate identification of NCI. The aim of the present study was to investigate the rate and pattern of HIV associated neurocognitive impairment (NCI) and to compare rates of NCI between rates calculated using norms for the Latin-American population (NLAP) and norms for the US-Mexico border region (NP-NUMBRS).Participants and Methods:CIOMS international ethical guidelines for the participation of human subjects in health research were followed. 82 PLWHA living in Tijuana (Mexico) participated in the study (Age: Mean=39.6, SD=10.9; 28.3% Female; Years of education: Mean=8.5, SD=3.6). PLWHA were recruited from the board-and-care home “Las Memorias” (73.4% on antiretroviral therapy; Years since HIV diagnosis: Mean=9.9, SD=7.1). Participants completed a neuropsychological test battery sensitive to detect HIV associated NCI that assessed four cognitive domains (verbal fluency, speed of information processing, executive function and learning/memory). Raw scores in these tests were transformed to percentiles using LAPN and transformed to T-scores using NP-NUMBRS. T-scores were averaged across tests to compute domain specific and global impairment scores. NCI was defined as percentile scores &lt;16 and T-scores &lt; 40. McNemar’s tests were used to compare the rate of NCI utilizing NLAP vs NP-NUMBRS.Results:According to NLAP, rates of global NCI were about 13.4%. Utilizing NP-NUMBRS rates of global NCI were about 34.1%. However, there is a positive and significant correlation between Global Neurocognitive Function score in PLWHA according to NLAP and NP-NUMBRS (r=0.66, p&lt;.05). Rates of global NCI in PLWHA were significantly lower when using LAP norms (McNemar Chi-Square=29.89; p&lt;.001). Regarding the pattern of NCI according both norms learning and memory was the most affected cognitive domain with 34% of impairment according to NLAP vs 51% of impairment according to NP-NUMBRs.Conclusions:Utilizing NP-NUMBRS, rates of NCI are consistent with findings of prior studies. Employing norms for LAP the rates of NCI are lower that the ones reported in the literature. This is an important finding since PLWHA included in the sample have several vulnerable factors such as deportation, prostitution, drug abuse and discrimination for sexual preference, factor that could impact cognition. The pattern of neurocognitive function was also similar to those of prior studies in HIV. To accurately make NCI diagnosis it is important to use norms that consider specific characteristics of the population. The diagnosis of NCI is important since these deficits present a strong risk of concurrent problems in a wide range of health behaviors like medication non-adherence in PLWHA.

Concordance Between Self-Reported Medical Diagnosis of Mild Cognitive Impairment/Dementia and Neurocognitive Function Among Middle-Aged and Older Hispanic/Latino Adults: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA).

Population-based studies typically rely on self-reported medical diagnosis (SRMD) of mild cognitive impairment (MCI)/dementia; however, links to objective neurocognitive function have not been established. Examine the association between SRMD of MCI/dementia and objective neurocognitive function among Hispanic/Latino adults. We conducted a case-control study using the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) baseline data and its ancillary SOL-Investigation of Neurocognitive Aging (SOL-INCA) at visit 2. Hispanic/Latino adults aged 50 years and older (n = 593) were administered neurocognitive tests: the Six-Item Screener (SIS), Brief-Spanish English Verbal Learning Test (B-SVELT Sum), B-SVELT Recall, Word Fluency Test (WF), Digit Symbol Substitution Test (DSS), and Trail Making Test A and B. Individual and global neurocognitive function scores were used for analyses. Propensity matching techniques and survey generalized linear regression models were used to compare SRMD of MCI/dementia with demographic, psychological, and cardiovascular risk matched controls. Complex survey design methods were applied. There were 121 cases of SRMD of MCI/dementia and 472 propensity matched controls. At baseline, compared to matched controls, cases showed no differences in neurocognitive function (p > 0.05). At SOL-INCA visit 2, cases had poorer scores in global neurocognitive function (p < 0.05), B-SEVLT Sum, B-SEVLT Recall, WF, DSS, and Trail A (p < 0.01). Observed differences in neurocognitive test scores between SRMD of MCI/dementia cases and matched controls were present at visit 2, but not at baseline in middle-aged and older Hispanic/Latino adults. These findings present initial evidence of the potential utility of SRMD of MCI/dementia in epidemiologic studies, where obtaining confirmation of diagnosis may not be feasible.

Immediate and Long-Term Effects of a Computerized Cognitive Rehabilitation Therapy on Cognitive Function in People Living with HIV in Iran: A Single-Blind Two-Arm Parallel Randomized Controlled Trial.

Up to 50% of people with HIV (PWH) experience neurocognitive impairments (NCIs) that can interfere with everyday functioning and reduce quality of life. To address this problem, this study examined the immediate and long-term efficacy of computerized cognitive rehabilitation therapy (CCRT) on cognitive function in PWH in Tehran, Iran. Thirty PWH with NCI engaged in 24 biweekly 90-min CCRT sessions. A control group of 30 PWH and NCI received treatment-as-usual, but no CCRT. The cognitive rehabilitation protocol focused on attention, visual memory, nonverbal learning, and planning. Pretest, posttest, and follow-up cognitive measurements showed that the designed CCRT protocol was effective in improving performance in selected cognitive domains along with the global neurocognitive performance scores of PWH. These findings suggest that this CCRT protocol be considered as part of a treatment plan to address cognitive impairment for PWH. Implications for clinical practice and research are provided.

HIV Antiretroviral Medication Neuropenetrance and Neurocognitive Outcomes in HIV+ Adults: A Review of the Literature Examining the Central Nervous System Penetration Effectiveness Score.

This literature review summarizes the existing research examining the CNS penetration effectiveness (CPE) score and neurocognitive outcomes (i.e., neuropsychological assessment and neurocognitive screening) in HIV+ individuals. Despite the effectiveness of Combined Antiretroviral Therapy (CART) in reducing mortality and morbidity in HIV and controlling viral replication, HIV often persists in the Central Nervous System (CNS), and rates of neurocognitive impairment remain higher than predicted in the post-CART era. The CPE score was developed to rank antiretroviral regimens on their ability to penetrate the CNS and potency in inhibiting the virus, and it has been examined in relation to neurocognitive functioning for over a decade. Based on the results of 23 studies, we conclude that CPE is not as strongly associated with neurocognitive outcomes as initially hypothesized, although higher CPE ARV regimens may be associated with modest, improved outcomes in global neurocognitive functioning, and to a lesser extent attention/working memory and learning/memory. Conclusions, however, are limited by the heterogeneity in study design and methods, and the lack of a more recent CPE metric update. It is recommended that future research in this area employ comprehensive, standardized neuropsychological test batteries and examine domain-level performance, and use the newer 2010 CPE metric, although an updated CPE ranking is urgently needed.

Prevalence, Demographic Correlates, and Medical Correlates of Cognitive Impairment Among Iranian People Living With HIV: A Cross-sectional Survey Study.

While taking antiretroviral therapy, 30%-60% of people living with HIV (PLWH) experience neurocognitive impairment (NCI). To determine NCI prevalence among Iranian PLWH, by the computerized Vienna Test System, 63 adults living without HIV and 63 Iranian PLWH aged 18-50 years ( M = 35.3, SD = 7.9) were assessed for cognitive function. NCI was determined by receiver operating characteristic curve cutoff points based on the adults living without HIV. Associations between demographics, HIV serostatus markers, and mean T-scores were investigated. Performance differences were tested by including significant covariates in an analysis of covariance. NCI prevalence rates were 57.14% in PLWH and 19.05% in adults living without HIV. Global neurocognitive performance and all cognitive domains were significantly different between the groups, except for visual memory and selective attention. In Iran, NCI prevalence parallels that reported in PLWH worldwide. There should be a strategy to screen Iranian PLWH for NCI.

Cognition and driving ability in isolated and symptomatic REM sleep behavior disorder.

To analyze cognitive deficits leading to unsafe driving in patients with REM Sleep Behavior Disorder (RBD), strongly associated with cognitive impairment and synucleinopathy-related neurodegeneration. Twenty isolated RBD (iRBD), 10 symptomatic RBD (sRBD), and 20 age- and education-matched controls participated in a prospective case-control driving simulation study. Group mean differences were compared with correlations between cognitive and driving safety measures. iRBD and sRBD patients were more cognitively impaired than controls in global neurocognitive functioning, processing speeds, visuospatial attention, and distractibility (p < .05). sRBD patients drove slower with more collisions than iRBD patients and controls (p < .05), required more warnings, and had greater difficulty following and matching speed of a lead car during simulated car-following tasks (p < .05). Driving safety measures were similar between iRBD patients and controls. Slower psychomotor speed correlated with more off-road accidents (r = 0.65) while processing speed (-0.88), executive function (-0.90), and visuospatial impairment (0.74) correlated with safety warnings in sRBD patients. Slower stimulus recognition was associated with more signal-light (0.64) and stop-sign (0.56) infractions in iRBD patients. iRBD and sRBD patients have greater selective cognitive impairments than controls, particularly visuospatial abilities and processing speed. sRBD patients exhibited unsafe driving behaviors, associated with processing speed, visuospatial awareness, and attentional impairments. Our results suggest that iRBD patients have similar driving-simulator performance as healthy controls but that driving capabilities regress as RBD progresses to symptomatic RBD with overt signs of cognitive, autonomic, and motor impairment. Longitudinal studies with serial driving simulator evaluations and objective on-road driving performance are needed.

A-107 Quantifying the Effect of Sleepiness and Mood on Gross Neuropsychological Functioning in a Forensic Population with a History of Traumatic Brain Injury

Abstract Objective Traumatic brain injury (TBI) is a serious public health concern. Furthermore, inmates and probationers are at a higher risk for TBI, as well as mental health issues and sleepiness. Both sleep and mood disturbance have been linked to poor cognitive performance. These state-dependent cognitive changes can undermine the evaluation of true cognitive ability and contaminate validity. This study examined the effects of sleep and mood on neurocognitive functioning and its impact on the validity of assessment results. Methods This study looked at retrospective Automated Neuropsychological Assessment Metrics (ANAM) core battery data. The sample included inmates and probationers (n = 419) with a history of TBI. A multiple linear regression was used to examine the relationship between self-reported sleepiness, mood state, and cognitive performance. Results All regression models were statistically significant, with negative mood being the most significant predictor of ANAM throughput scores (p = 0.000). Higher endorsement of negative mood states was related to lower cognitive performance overall (p = 0.003). Sleepiness predicted worse performance on at the end of the battery (p &amp;lt; 0.05), whereas positive mood predicted better performance at the beginning of the battery (p &amp;lt; 0.01). Conslusion The present study confirms that negative mood adversely affects global neurocognitive test performance in a forensic population. Examiners should be aware that sleepiness and mood states have an effect on test performance during even brief cognitive batteries. The current findings suggest that it is imperative to screen and identify sleepiness and negative mood symptoms as they may depress test results and threaten the validity or test interpretations and recommendations.

Evidence for neuropsychological health disparities in Black Americans with HIV disease

ABSTRACT Objective: Black Americans are at high risk for HIV disease and associated morbidity. The impact and clinical correlates of HIV-associated neurocognitive impairment among Black Americans is not fully understood. The current study uses a full factorial design to examine the independent and combined effects of race and HIV disease on neurocognitive functioning, including its associations with everyday functioning and clinical disease markers in Black and White persons with HIV (PWH). Method: Participants included 40 Black PWH, 83 White PWH, 28 Black HIV- and 64 White HIV- individuals. Neurocognition was measured by raw sample-based z-scores from a clinical battery. Everyday functioning was assessed using self- and clinician-rated measures of cognitive symptoms and activities of daily living. HIV-associated neurocognitive disorders were also classified using demographically adjusted normative standards and the Frascati criteria. Results: We observed a significant three-way interaction between HIV, race, and domain on raw neurocognitive z-scores. This omnibus effect was driven by medium and large effect size decrements in processing speed and semantic memory, respectively, in Black PWH compared to other study groups. Black PWH also demonstrated higher frequencies of HIV-associated neurocognitive disorders as compared to White PWH. Unexpectedly, global neurocognitive performance was negatively related to everyday functioning impairments for White PWH, but not for Black PWH. Conclusions: Systemic disadvantages for Black Americans may combine with HIV disease to compound some neurocognitive impairments in this under-served population. Prospective studies are needed to identify better ways to prevent, measure, diagnose, and manage HIV-associated neurocognitive disorders among Black Americans.

How cerebral cortex protects itself from interictal spikes: The alpha/beta inhibition mechanism.

Interactions between interictal epileptiform discharges (IEDs) and distant cortical regions subserve potential effects on cognition of patients with focal epilepsy. We hypothesize that “healthy” brain areas at a distance from the epileptic focus may respond to the interference of IEDs by generating inhibitory alpha and beta oscillations. We predict that more prominent alpha‐beta oscillations can be found in patients with less impaired neurocognitive profile. We performed a source imaging magnetoencephalography study, including 41 focal epilepsy patients: 21 with frontal lobe epilepsy (FLE) and 20 with mesial temporal lobe epilepsy. We investigated the effect of anterior (i.e., frontal and temporal) IEDs on the oscillatory pattern over posterior head regions. We compared cortical oscillations (5–80 Hz) temporally linked to 3,749 IEDs (1,945 frontal and 1,803 temporal) versus an equal number of IED‐free segments. We correlated results from IED triggered oscillations to global neurocognitive performance. Only frontal IEDs triggered alpha‐beta oscillations over posterior head regions. IEDs with higher amplitude triggered alpha‐beta oscillations of higher magnitude. The intensity of posterior head region alpha‐beta oscillations significantly correlated with a better neuropsychological profile. Our study demonstrated that cerebral cortex protects itself from IEDs with generation of inhibitory alpha‐beta oscillations at distant cortical regions. The association of more prominent oscillations with a better cognitive status suggests that this mechanism might play a role in determining the cognitive resilience in patients with FLE.

Higher Comorbidity Burden Predicts Worsening Neurocognitive Trajectories in People with HIV

Background: Comorbidities linked to aging such as diabetes mellitus, pulmonary disease and renal insufficiency accumulate at a faster rate in people with HIV (PWH) than in the general population. We evaluated whether the Charlson Index, a multimorbidity scale comprising 17 variables that has been validated in previous studies, predicted neurocognitive trajectories in PWH. Methods: Neurocognition was measured by averaging scaled scores from all assessments in a comprehensive neuropsychological battery. Multilevel modeling was used to examine between- and within-person predictors of global neurocognition. At the between-person level, average Charlson Index (averaged within each person across all their visits) was examined as a predictor of neurocognitive change over time, covarying for the effect of HIV disease characteristics (proportion of visits virally suppressed, average CD4). At the within-person level, Charlson Index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for visit-specific effects of viral load detectability and current CD4 count. Results: Participants were 1195 PWH (mean age at baseline = 43·0; SD 9·7) followed for an average of over 7·1 years (SD = 5·0; range = 0·5 to 20·5 years). Between persons, higher average Charlson index scores were associated with faster rates of global neurocognitive decline (standardized β = -0·050 [0·015], p = 0·001)· This global effect was driven by significant declines in the domains of executive functioning (p = 0·001) and working memory (p = 0·007). HIV disease characteristics did not predict trajectories of neurocognitive change (ps > 0·05). At the within-person level of the model, lower current CD4+ lymphocytes (β = 0·043 [0·009]; p < 0·001), detectable plasma HIV RNA (β = 0·018 [0·006]; p = 0·001), and higher Charlson Index score (β =-0·046 [0·015]; p = 0·003) independently predicted worse concurrent global neurocognitive performance. Time-lag analyses demonstrated that increasing comorbidities occurred concurrent with, not before, neurocognitive decline. Conclusion: The impact of comorbidities on trajectories of neurocognitive decline was greater than that of HIV disease factors and independent of chronological age. Although correlative, the temporal relationship between accumulating comorbidities and neurocognitive decline suggests that interventions to prevent or ameliorate a variety of comorbidities may improve neurocognitive prognosis for PWH. Funding Statement: This publication was made possible through funding by the NIMH and NINDS by the following grants: HIV Neurobehavioral Research Center (HNRC): P30 MH62512 Manhattan HIV Brain Bank (MHBB): U24MH100931 Texas NeuroAIDS Research Center (TNRC): U24MH100930 National Neurological AIDS Bank (NNAB): U24MH100929 California NeuroAIDS Tissue Network (CNTN): U24MH100928 Data Coordinating Center (DCC): U24MH100925 Translational Methamphetamine AIDS Research Center (TMARC): P50 DA026306 Declaration of Interests: None to declare. Ethics Approval Statement: UCSD's Human Research Protections Program (irb.ucsd.edu) approved all study procedures, and all participants provided written informed consent.

Glaucomatous visual fields and neurocognitive function are independently associated with poor lane maintenance during driving simulation

BackgroundDriving simulators are a safe alternative to on-road vehicles for studying driving behavior in glaucoma drivers. Visual field (VF) loss severity is associated with higher driving simulator crash risk, though mechanisms explaining this relationship remain unknown. Furthermore, associations between driving behavior and neurocognitive performance in glaucoma are unexplored. Here, we evaluated the hypothesis that VF loss severity and neurocognitive performance interact to influence simulated vehicle control in glaucoma drivers.MethodsGlaucoma patients (n = 25) and suspects (n = 18) were recruited into the study. All had > 20/40 corrected visual acuity in each eye and were experienced field takers with at least three stable (reliability > 20%) fields over the last 2 years. Diagnosis of neurological disorder or cognitive impairment were exclusion criteria. Binocular VFs were derived from monocular Humphrey VFs to estimate a binocular VF index (OU-VFI). Montreal Cognitive Assessment (MoCA) was administered to assess global and sub-domain neurocognitive performance. National Eye Institute Visual Function Questionnaire (NEI-VFQ) was administered to assess peripheral vision and driving difficulties sub-scores. Driving performance was evaluated using a driving simulator with a 290° panoramic field of view constructed around a full-sized automotive cab. Vehicle control metrics, such as lateral acceleration variability and steering wheel variability, were calculated from vehicle sensor data while patients drove on a straight two-lane rural road. Linear mixed models were constructed to evaluate associations between driving performance and clinical characteristics.ResultsPatients were 9.5 years older than suspects (p = 0.015). OU-VFI in the glaucoma group ranged from 24 to 98% (85.6 ± 18.3; M ± SD). OU-VFI (p = .0066) was associated with MoCA total (p = .0066) and visuo-spatial and executive function sub-domain scores (p = .012). During driving simulation, patients showed greater steering wheel variability (p = 0.0001) and lateral acceleration variability (p < .0001) relative to suspects. Greater steering wheel variability was independently associated with OU-VFI (p = .0069), MoCA total scores (p = 0.028), and VFQ driving sub-scores (p = 0.0087), but not age (p = 0.61).ConclusionsPoor vehicle control was independently associated with greater VF loss and worse neurocognitive performance, suggesting both factors contribute to information processing models of driving performance in glaucoma. Future research must demonstrate the external validity of current findings to on-road performance in glaucoma.

Randomized Trial Evaluating the Neurotoxicity of Dolutegravir/Abacavir/Lamivudine and Its Reversibility After Switching to Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide: GESIDA 9016.

BackgroundDespite evidence shown of dolutegravir (DTG)-related neurotoxicity, which may be more common when combined with abacavir (ABC), its reversibility has not been explored in a clinical trial.MethodsWe conducted a randomized, multicenter, open-label, pilot trial to evaluate the reversibility of patient-reported neuropsychiatric symptoms, developed or worsened on DTG/ABC/lamivudine (DTG/ABC/3TC), in virologically suppressed patients switched to cobicistat-boosted-elvitegravir/emtricitabine/tenofovir-alafenamide (EVG/COBI/FTC/TAF). Participants were randomized to immediate switch (baseline) or to defer switch (week 4), and then all completed 24 weeks of follow up on EVG/COBI/FTC/TAF. At each visit, participants completed Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression (HAD) scales and were interviewed about 11 neuropsychiatric symptoms potentially related with DTG through a questionnaire. At baseline and at the end of follow up, they also performed neurocognitive testing. Our primary objective was to compare changes in neuropsychiatric symptoms and PSQI and HAD scales between arms at week 4. Secondary objectives were to evaluate changes in neuropsychiatric symptoms and PSQI and HAD scales at weeks 4, 12, and 24 after switching to EVG/COBI/FTC/TAF and in neurocognitive performance and magnetic resonance imaging biomarkers at end of follow up.ResultsThirty-eight participants were included. Study arms were similar at baseline. At week 4, neuropsychiatric symptoms and PSQI and HAD scores remained unchanged in participants receiving DTG/ABC/3TC and improved significantly in participants receiving EVG/COBI/FTC/TAF. These significant improvements were also observed at weeks 4, 12, and 24 after all participants switched to EVG/COBI/FTC/TAF. In addition, global neurocognitive performance improved (NPZ-7) after switching to EVG/COBI/FTC/TAF.ConclusionsNeuropsychiatric symptoms in patients on DTG/ABC/3TC could resolve or improve after switching to EVG/COBI/FTC/TAF.

Depressive Symptoms Differentially Predict Neurocognition in Latinx and Non-Hispanic White People Living with HIV.

Depression is common in people living with HIV (PLWH) and can contribute to neurocognitive dysfunction. Depressive symptoms in PLWH are often measured by assessing only cognitive/affective symptoms. Latinx adults, however, often express depressive symptoms in a somatic/functional manner, which is not typically captured in assessments of depression among PLWH. Given the disproportionate burden of HIV that Latinx adults face, examining whether variations in expressed depressive symptoms differentially predict neurocognitive outcomes between Latinx and non-Hispanic white PLWH is essential. This cross-sectional study included 140 PLWH (71% Latinx; 72% male; mean (M) age = 47.1 ± 8.5 years; M education = 12.6 ± 2.9 years) who completed a comprehensive neurocognitive battery, Wechsler Test of Adult Reading (WTAR), and Beck Depression Inventory-II (BDI-II). Neurocognitive performance was measured using demographically adjusted T-scores. BDI-II domain scores were computed for the Fast-Screen (cognitive/affective items) score (BDI-FS) and non-FS score (BDI-NFS; somatic/functional items). Linear regressions revealed that the BDI-NFS significantly predicted global neurocognitive function and processing speed in the Latinx group (p < .05), such that higher physical/functional symptoms predicted worse performance. In the non-Hispanic white group, the cognitive/affective symptoms significantly predicted processing speed (p = .02), with more symptoms predicting better performance. Interaction terms of ethnicity and each BDI sub-score indicated that Latinx participants with higher cognitive/affective symptoms performed worse on executive functioning. Depressive symptoms differentially predict neurocognitive performance in Latinx and non-Hispanic white PLWH. These differences should be considered when conducting research and intervention among the increasingly culturally and ethnically diverse population of PLWH.

A Meta-Analysis of Neuropsychological Effort Test Performance in Psychotic Disorders.

Psychotic disorders are characterized by a generalized neurocognitive deficit (i.e., performance 1.5 SD below controls across neuropsychological domains with no specific profile of differential deficits). A motivational account of the generalized neurocognitive deficit has been proposed, which attributes poor neuropsychological testing performance to low effort. However, findings are inconsistent regarding effort test failure rate in individuals with psychotic disorders across studies (0-72%), and moderators are unclear, making it difficult to know whether the motivational explanation is viable. To address these issues, a meta-analysis was performed on data from 2205 individuals with psychotic disorders across 19 studies with 24 independent effects. Effort failure rate was examined along with moderators of effort test type, forensic status, IQ, positive symptoms, negative symptoms, diagnosis, age, gender, education, and antipsychotic use. The pooled weighted effort test failure rate was 18% across studies and there was a moderate pooled association between effort failure rate and global neurocognitive performance (r = .57). IQ and education significantly moderated failure rate. Collectively, these findings suggest that a nontrivial proportion of individuals with a psychotic disorder fail effort testing, and failure rate is associated with global neuropsychological impairment. However, given that effort tests are not immune to the effects of IQ in psychotic disorders, these results cannot attest to the viability of the motivational account of the generalized neurocognitive deficit. Furthermore, the significant moderating effect of IQ and education on effort test performance suggests that effort tests have questionable validity in this population and should be interpreted with caution.

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.

1144 Actigraphy-defined Sleep And Neurocognitive Decline In Middle-age Hispanic/Latino Adults

Abstract Introduction Few studies have evaluated objective sleep measures and longitudinal neurocognitive decline, particularly in middle-age or Hispanic/Latino adults. We evaluated prospective associations between actigraphy-defined sleep and 7-year neurocognitive change among Hispanic/Latino adults. We hypothesized that sleep duration would be associated with neurocognitive decline. Methods We analyzed data from 1,036 adults 45-64 years of age from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multi-center prospective cohort study of diverse community-dwelling Hispanic/Latino adults. At Visit 1 (2008-2011), participants underwent neurocognitive assessments, 7-days of actigraphy, home sleep testing, and sleep questionnaires (including the Insomnia Severity Index). Seven years later, participants repeated neurocognitive assessments. The neurocognitive battery included the Six-Item Screener, Brief Spanish-English Verbal Learning Test, phonemic word fluency test, and Digit Symbol Subtest. Survey linear regression was used to evaluate prospective associations between actigraphy-defined or self-reported sleep variables and neurocognitive change. Final models adjusted for objectively-defined variables (age, body-mass index, Field Center, and time between neurocognitive assessments), and self-reported variables (sex, education, Hispanic/Latino background, alcohol consumption, physical activity, heart failure, cerebrovascular events, depression and anxiety symptoms, and antidepressant use). Results At Visit 1, the sample was 55% female and mean age was 54.9±2.2 years. The mean sleep duration was 402.6±27.6 minutes, mean sleep-onset latency was 11.3±9.7 minutes, mean number of days with naps of ≥ 15 minutes duration was 1.1±0.7, and mean sleep-time per nap was 51±14.1 minutes. Increased sleep-onset latency was associated with 7-year declines in global neurocognitive function (β=-0.0026, p&amp;lt;0.01), verbal learning (β=-0.0028, p&amp;lt;0.001) and verbal memory (β=-0.036, p&amp;lt;0.05). Increased sleep-time per nap predicted better verbal memory (β=0.0038, p&amp;lt;0.05). In contrast, sleep duration, sleep fragmentation, and self-reported sleep measures were not associated with neurocognitive change. Conclusion Among middle-age adults, sleep-onset latency and nap duration were associated with neurocognitive change. These findings may serve as targets for intervention of neurocognitive decline. Support This work is supported by the National Institute on Aging: R01AG048642, RF1AG054548, R01AG061022, R21AG056952, and R21HL140437 (AR).