Global Neurocognitive Impairment Research Articles

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV

Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4 + T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA levels ≤ 200 copies/mL. All three noncoding EIF2AK3 SNVs were associated with GDS and NCI (all p < 0.05). Additionally, 30.9%, 30.9%, and 41.2% of participants had at least one risk allele for the coding SNVs rs1805165 (G), rs867529 (G), and rs13045 (A), respectively. Homozygosity for all three coding SNVs was associated with significantly worse GDS (p < 0.001) and more NCI (p < 0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II value > 13 were independently associated with GDS and NCI (p < 0.001) whereas the other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but present in multivariable analyses, raising the possibility of specific SNVs in EIF2AK3 as an important component of genetic vulnerability to neurocognitive complications in PWH.Graphical

Diagnostic utility of culture/language‐specific normative data on the Version 3 of the Uniform Data Set Neuropsychological Battery for differentiating stages of cognitive impairment among Latinos in the United States

AbstractBackgroundAccurate detection of neurocognitive disorders of aging among Latinos in the United States (U.S.) is an important step towards addressing disparities in Alzheimer’s disease and related dementias (ADRDs) and promoting health equity in this group. Federally‐funded Alzheimer’s Disease Research Centers (ADRCs) in the U.S. have utilized the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set Version 3 Neurobehavioral Battery (UDS3‐NB) since 2015. Normative data on this battery adjusted for age, education and sex were published for English‐speakers in 2018 (Weintraub et al., 2018) and expanded to consider differences among non‐Hispanics White and Black people in 2020 (Sachs et al., 2020). We aimed to determine whether the use of newly developed culture/language‐specific neuropsychological normative data for Spanish‐ and English‐speaking Latinos in the U.S. improved diagnostic accuracy of the UDS3‐NB in this group.MethodParticipants included 1,018 Latino adults age 50+ enrolled in ADRCs. Table 1 presents participant demographics by global Clinical Dementia Rating (CDR) score, as indicative of stage of neurocognitive impairment (0 = normal, 0.5 = questionable impairment, 1 = mild impairment, 2‐3 = moderate‐to‐severe impairment). Individual test raw scores were converted to demographically‐adjusted z scores utilizing normative data on the UDS3‐NB developed for Latinos and for other culture/language groups. Individual tests z scores were converted to deficit scores and averaged to compute global deficit scores and determine global neurocognitive impairment (NCI). Rates of NCI based on culture/language specific normative data were compared across the four CDR groups via Chi‐Square tests. Sensitivity and specificity were computed for differentiating participants with CDR = 0 (normal) and CDR = 1 (mild impairment) based on different sets of normative data.ResultsUtilizing culture/language‐specific normative data significantly differentiated CDR groups (p&lt;.001; Figure 1). These culture/language specific normative data performed better in differentiating between CDR = 0 and 1, than utilizing normative data developed for non‐Hispanic English speakers (Table 2).ConclusionCulture/language‐specific normative data improve diagnostic accuracy for neurocognitive impairment among Latinos in the U.S. relative to existing normative data developed for other groups. These culture/language‐specific norms can be used in research and clinical practice to enhance ADRD diagnosis among Latinos and represent an important step towards addressing ADRD disparities in this group.

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.

The association between benzodiazepine use and greater risk of neurocognitive impairment is moderated by medical burden in people with HIV

Benzodiazepine use is linked to neurocognitive impairment (NCI) in the general population and people with HIV (PWH); however, this relationship may depend on age-related factors such as medical comorbidities, which occur at an elevated rate and manifest earlier in PWH. We retrospectively examined whether chronological age or medical burden, a clinical marker for aging, moderated the relationship between benzodiazepine use and NCI in PWH. Participants were 435 PWH on antiretroviral therapy who underwent neurocognitive and medical evaluations, including self-reported current benzodiazepine use. A medical burden index score (proportion of accumulated multisystem deficits) was calculated from 28 medical deficits. Demographically corrected cognitive deficit scores from 15 neuropsychological tests were used to calculate global and domain-specific NCI based on established cut-offs. Logistic regressions separately modeled global and domain-specific NCI as a function of benzodiazepine x age and benzodiazepine x medical burden interactions, adjusting for current affective symptoms and HIV disease characteristics. A statistically significant benzodiazepine x medical burden interaction (p = .006) revealed that current benzodiazepine use increased odds of global NCI only among those who had a high medical burden (index score > 0.3 as indicated by the Johnson–Neyman analysis), which was driven by the domains of processing speed, motor, and verbal fluency. No age x benzodiazepine interactive effects on NCI were present. Findings suggest that the relationship between BZD use and NCI among PWH is specific to those with greater medical burden, which may be a greater risk factor for BZD-related NCI than chronological age.

Long-term neurocognitive, psychological, and return to work outcomes in meningioma patients.

This study aimed to investigate long-term neurocognitive, psychological, and return to work (RTW) outcomes in meningioma patients, and to explore whether neurocognitive and psychological factors influence RTW outcomes in this population. In this retrospective study, 61 meningioma patients completed in-depth clinical neuropsychological assessments. Of these participants, 42 were of working-age and had RTW information available following neuropsychological assessment. Seventy-one percent and 80% of patients received radiation and surgery, respectively, with 49% receiving both radiation and surgery. Associations between demographic, medical, neurocognitive, psychological, and RTW data were analyzed using multivariable logistic regression analyses. In our sample, 68% of patients exhibited global neurocognitive impairment, with the largest effect sizes found on tests of visual memory (d = 0.73), executive function (d = 0.61), and attention (d = 0.54). Twenty-seven percent exhibited moderate to severe levels of depressive symptoms. In addition, 23% and 30% exhibited clinically significant state and trait anxiety, respectively. Forty-eight percent of patients were unable to RTW. Younger age, faster visuomotor processing speed, and, unexpectedly, higher trait anxiety scores were associated with an increased likelihood of returning to work. Meningioma patients are at risk of experiencing neurocognitive deficits, psychological symptoms, and difficulties returning to work. Our results suggest that neurocognitive and psychological factors contribute to RTW status in meningioma patients. Prospective research studies are necessary to increase our understanding of the complexity of functional disability in this growing population.

Association between Veterans Aging Cohort Study (VACS) index and neurocognitive function among people living with HIV\u2013a cross sectional study in coastal South India

BackgroundHIV is an infectious disease affecting 36.7 million people worldwide. In recent times, Antiretroviral Therapy (ART) has become accessible to the majority of People Living with HIV (PLHIV) and this has transformed the course of infection to one that is chronic, characterized by fewer diseases pathognomonic of AIDS. In view of this, there is a pressing need for better markers, apart from the routine HIV indicators, to detect comorbidities such as Neurocognitive Impairment (NCI). The aim of this study was to find out the association between Veterans Aging Cohort Study (VACS) index and Neurocognitive function in HIV positive patients.MethodsIn our study, we included 97 HIV positive patients and their Neurocognitive function was assessed using a combination of Montreal Cognitive Assessment and Grooved Pegboard Test, while VACS index was calculated using the most recent laboratory values. Binomial Logistics Regression analyses, adjusting for potential confounding variables, was performed to determine the association between VACS score and Neurocognitive Impairment.ResultsWe found that a higher VACS Index was associated with global and domain-wise Neurocognitive impairment (p < 0.01), specifically in the domains of attention (p < 0.01) and fine motor skills (p = 0.01). Our study also showed that among all the VACS components, older age (p = 0.02) and lower hemoglobin (p < 0.01) values were associated with global NCI. After plotting an ROC curve, a VACS cut-off score of 11.00 was identified as it had good sensitivity (87.0%) and specificity (71.4%) in identifying Global NCI.ConclusionOur findings extend prior research on the use of VACS Index to predict global and domain-wise NCI in HIV-positive patients. However, further research with more comprehensive neurocognitive testing is required in our setting before VACS Index can be used as a tool to screen for neurocognitive dysfunction among PLHIV.

Mitochondrial DNA haplogroups and domain-specific neurocognitive performance in adults with HIV.

Neurocognitive (NC) impairment (NCI) is an important cause of morbidity in persons with HIV (PWH). In the high-energy environment of the central nervous system, mitochondria contribute to neuroinflammation and aging, which may ultimately drive the pathogenesis of neurodegenerative diseases. Mitochondrial DNA (mtDNA) haplogroups are associated with health outcomes in PWH. For example, we previously observed less global NCI in Hispanic ancestry PWH having mtDNA haplogroup B. Another study reported increased NCI among PWH having African subhaplogroup L2a. We therefore analyzed NC domains in relation to these haplogroups in CNS HIV Antiretroviral Therapy Effects Research (CHARTER), a multi-site observational neuro-HIV study. Haplogroups were assigned using mtDNA sequence in 1016 PWH. Outcomes were NCI, defined by domain deficit score and mean T-scores (TS) for seven NC domains. Ancestry-stratified analyses of NC performance included Wilcoxon rank sum, χ2, and Fisher's exact tests. Multivariable regression adjusted for NC comorbidity, antiretroviral therapy use, and nadir CD4+ T cells. Among 98 Hispanic ancestry PWH, executive function, learning, and recall performance were better with haplogroup B (N = 17) than other haplogroups. With adjustment for covariates, haplogroup B remained associated with better executive function (p = 0.04) and recall TS (p = 0.03). PWH with haplogroup B had fewer impaired domains than other haplogroups (p < 0.01). Subhaplogroup L2a (N = 89) was associated with greater NCI in learning, recall, and working memory among 478 PWH of African ancestry, and had more impaired domains than other subhaplogroups (p < 0.01). These findings may inform risk stratification for NCI and studies to define mechanisms by which mtDNA variation may influence NCI in PWH.

Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood.

This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age-adjusted z score < 10th percentile. Participants impaired on ≥3 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). A total of 1,598 survivors received CNS-directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2 to 4 conditions, stratified by CNS treatment. CNS-treated survivors performed worse than non-CNS-treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p < 0.001). After adjusting for demographic and treatment factors, there was a dose-response association between severity/burden score and global neurocognitive impairment, but only among CNS-treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.42-3.53; very high OR = 4.07, 95% CI = 2.30-7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS-treated but not non-CNS-treated survivors who were impacted by neurologic conditions. Reduced cognitive/brain reserve associated with CNS-directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534-545.

Entire duration of active psychosis and neurocognitive performance in first-episode non-affective psychosis.

To explore if the entire duration of active psychosis (DAP) is related to neurocognitive performance at baseline and at 3-year follow-up in patients with first episode psychosis (FEP). DAP was estimated for 481 FEP patients. A neuropsychological battery was administered to measure neurocognitive specific domains, and a global indicator of neurocognitive impairment (global deficits score, GDS) was calculated. According to the DAP quartiles, four subgroups were formed, and these were compared. In addition, a logistic regression analysis was carried out to predict neurocognitive impairment at 3-year follow-up. FEP patients with the longest DAP (more than 18.36 months) presented a more severe global neurocognitive impairment evidenced in their GDS, both at baseline (F=5.53; p˂ .01) and at 3-year follow-up (F=4.16; p˂ .01). Moreover, a subgroup of participants with DAP between 7.40 and 18.36 months showed a specific attentional decline over the 3-year follow-up (F=3.089; p˂ .05).The logistic regression model showed that sex (Wald=7.29, p < .010), premorbid adjustment (Wald=7.24, p < .010), attention (Wald=12.10, p < .001), verbal memory (Wald=16.29, p < .001) and visual memory (Wald=9.41, p < .010) were significant predictors of neurocognitive impairment 3 years after the FEP. The variables composing the DAP were not significant predictors in this model. DAP seems to be related to global neurocognitive impairment in FEP patients. These findings contribute in several ways to our understanding of the effects of active psychosis on the brain, and provide the basis for future research.

HIV, Vascular Risk Factors, and Cognition in the Combination Antiretroviral Therapy Era: A Systematic Review and Meta-Analysis.

Mounting evidence indicates that vascular risk factors (VRFs) are elevated in HIV and play a significant role in the development and persistence of HIV-associated neurocognitive disorder. Given the increased longevity of people living with HIV (PLWH), there is a great need to better elucidate vascular contributions to neurocognitive impairment in HIV. This systematic review and meta-analysis examine relationships between traditional VRFs, cardiovascular disease (CVD), and cognition in PLWH in the combination antiretroviral therapy era. For the systematic review, 44 studies met inclusion criteria and included data from 14,376 PLWH and 6,043 HIV-seronegative controls. To better quantify the contribution of VRFs to cognitive impairment in HIV, a robust variance estimation meta-analysis (N = 11 studies) was performed and included data from 2139 PLWH. In the systematic review, cross-sectional and longitudinal studies supported relationships between VRFs, cognitive dysfunction, and decline, particularly in the domains of attention/processing speed, executive functioning, and fine motor skills. The meta-analysis demonstrated VRFs were associated with increased odds of global neurocognitive impairment (odds ratio [OR ]= 2.059, p = .010), which remained significant after adjustment for clinical HIV variables (p = .017). Analyses of individual VRFs demonstrated type 2 diabetes (p = .004), hyperlipidemia (p = .043), current smoking (p = .037), and previous CVD (p = .0005) were significantly associated with global neurocognitive impairment. VRFs and CVD are associated with worse cognitive performance and decline, and neurocognitive impairment in PLWH. Future studies are needed to examine these relationships in older adults with HIV, and investigate how race/ethnicity, gender, medical comorbidities, and psychosocial factors contribute to VRF-associated cognitive dysfunction in HIV.

Single-suture craniosynostosis: is there a correlation between preoperative ophthalmological, neuroradiological, and neurocognitive findings?

In spite of literature data stating that children with single-suture craniosynostosis have an increased risk for neuropsychological deficits, no data are present clarifying the potential risk factors. All children with non-syndromic single-suture craniosynostosis operated on from January 2014 to January 2017 were enrolled. A comprehensive neurocognitive and neuro-ophthalmological evaluation was performed before surgery and 6months after surgery. A further neurocognitive evaluation was performed 12months after surgery. All children had a preoperative CT/MR study. One hundred forty-two patients were enrolled; 87 are affected by sagittal craniosynostosis, 38 by trigonocephaly, and 17 by plagiocephaly. A global neurocognitive impairment was documented in 22/87 children with scaphocephaly, 5/38 children with trigonocephaly, and 6/17 children with anterior plagiocephaly. There was a significant relationship between results of the ophthalmological evaluation, global IQ, and CT findings at diagnosis (r= 0.296, p< 0.001; r=0.187, p 0.05). Though a significant recovery was documented after surgery, a persistence of eye coordination deficits was present at 6months in 1 out of 3 children with abnormal preoperative exams. A significant correlation was found between pathological CT findings and persistence of below average neuro-ophthalmological and neurocognitive findings 6months after surgery, as well as between CT findings and neurocognitive scores at the 1year follow-up (r= 0.411; p< 0.01). The presence of neuroradiological abnormalities appears to be related to both ophthalmological and neurocognitive deficits at diagnosis. This relationship is maintained in spite of the surgical treatment in children who show the persistence of ophthalmological and neurocognitive deficits during the follow-up.

N400 event-related brain potential as an index of real-world and neurocognitive function in patients at clinical high risk for schizophrenia.

The N400 event-related potential is a neurophysiological index of cognitive processing of real-world knowledge. In healthy populations, N400 amplitude is smaller in response to stimuli that are more related to preceding context. This 'N400 semantic priming effect' is thought to reflect activation of contextually related information in semantic memory (SM). N400 semantic priming deficits have been found in schizophrenia, and in patients at clinical high risk (CHR) for this disorder. Because this abnormality in processing relationships between meaningful stimuli could affect ability to navigate everyday situations, we hypothesized it would be associated with real-world functional impairment in CHR patients. Second, we hypothesized it would correlate with global neurocognitive impairment in this group. We measured N400 semantic priming in 35 CHR patients who viewed prime words each followed by a related or unrelated target word, at stimulus-onset asynchrony (SOA) of 300 or 750 ms. We measured academic/occupational and social function with the global function (GF): Role and Social scales, and cognitive function with the MATRICS Consensus Cognitive Battery (MCCB). Decreased N400 semantic priming at the 300-ms SOA correlated with lower GF:Role scores. Decreased N400 semantic priming at the 750-ms SOA correlated with lower MCCB composite scores. Deficits in activating contextually related concepts in SM over short time intervals may contribute to functional impairment in CHR patients. Furthermore, N400 priming deficits over longer intervals may be a biomarker of global cognitive dysfunction in this population. Longitudinal studies are needed to determine whether these deficits are associated with schizophrenia risk within this population.

Neurocognitive impairment in Spanish-speaking Latinos living with HIV in the US: Application of the neuropsychological norms for the US–Mexico border region in Spanish (NP-NUMBRS)

Objective Latinos in the US are at increased risk for HIV-associated neurocognitive impairment (NCI). Most studies of US Latinos living with HIV have included primarily English-speakers only. We investigated the rate, pattern, and correlates of HIV-associated NCI in native Spanish-speaking Latinos living in the US near the Mexican border. Methods Participants included 407 native Spanish-speaking Latinos (Age: M = 37.65, SD = 10.0; Education: M = 10.75, SD = 4.1; 53% male): 153 persons living with HIV (PLWH; 56% AIDS) and 254 healthy controls. All participants completed comprehensive neuropsychological assessments in Spanish. Raw neuropsychological test scores from seven domains were converted to demographically-adjusted T-scores using norms developed with healthy controls. Global and domain NCI were defined per established criteria. Among PLWH we applied norms developed for non-Hispanic (NH) Whites and Blacks, and investigated correlates of global NCI, including HIV disease characteristics and psychiatric comorbidities. Results Utilizing population specific norms, rates of global NCI were significantly higher among PLWH (39%) than healthy controls (17%), comparable to previously published rates. In contrast, rates of global NCI in the same group of PLWH were significantly different when NH White norms (63%, p < 0.0001) and NH Black norms were used (18%, p < 0.0001). Among PLWH without a history of lifetime substance use disorder, more years of antiretroviral exposure were significantly associated with decreased rates of global NCI. Conclusions Present findings lend support to the validity of newly developed norms for native Spanish-speakers living near the US-Mexico border, and underscore the importance of utilizing appropriate norms to accurately identify HIV-associated NCI.

Operationalizing and evaluating the Frascati criteria for functional decline in diagnosing HIV-associated neurocognitive disorders in adults.

The Frascati criteria for HIV-associated neurocognitive disorders (HAND; Antinori et al. 2007) outlines a classification scheme for functional decline that-despite being over a decade old-has not heretofore been examined systematically. Participants included 307 HIV+ and 183 HIV- participants who completed self-report, clinician-rated, and performance-based measures of functional status, along with neurocognitive, psychiatric, and medical/laboratory assessments. Using the Frascati criteria, we classified participants with (1) no functional declines, (2) mild functional declines, or (3) major functional declines. A multivariable logistic regression showed that HIV serostatus was associated with higher rates of major (33.2 vs. 13.7%) but not mild (38.8 vs. 31.7%) Frascati-defined functional decline. Within the HIV+ group, individuals with global neurocognitive impairment and affective disorders were at highest risk of Frascati-defined functional decline. Findings provide some empirical support for the sensitivity and validity of the Frascati criteria for functional declines in the context of HAND. Future work is needed to determine the reliability, stability, cross-cultural validity, and downstream health-related consequences of the Frascati-defined functional classifications.

Neurocognitive Impairment in Spanish-Speaking Latinos Living with Human Immunodeficiency Virus in the United States: Validation of Neuropsychological Tests Norms

Abstract Objective Latinos in the US are at increased risk for HIV-associated neurocognitive impairment (NCI). Yet, most studies in this group have included English-speakers only. We investigated the rate and pattern of HIV-associated NCI in Spanish-speaking Latinos from the US-Mexico border region by utilizing newly developed norms for this group, and compared it to previously published norms for English-speaking non-Latino Whites and Blacks/African Americans. Participants and Method Participants included 153 HIV+ Spanish-speaking Latinos (Age: M = 38.2, SD = 9.7; Education: M = 10.9, SD = 3.6; 27% female; 56% AIDS) living in the greater San Diego area. Participants completed comprehensive neuropsychological, neuromedical and psychiatric assessments in Spanish. The neuropsychological test battery employed in this study - and used extensively in prior studies of HIV- assesses seven ability domains. Raw test scores were converted to demographically-adjusted T-scores using regional norms for Spanish-speakers, and for non-Latino Whites and Blacks. NCI was defined per established criteria. Results Rate of global NCI was 39% using norms for Spanish-speaking Latinos, compared to 64% with White norms and 18% with Black norms. Using norms for Spanish speakers, domain specific NCI among those impaired was highest in executive function (68%), speed of information processing (65%), learning (51%), and working memory (50%). The pattern of HIV associated NCI varied when norms developed for non-Latino Whites and Blacks were used. Conclusions HIV+ Spanish speakers showed similar rates of global NCI to those in other HIV+ populations, when norms developed for this group were used. In contrast, use of non-Latino White and Black norms resulted in misclassification of impairment. The pattern of NCI differed based on the norms used. Present findings highlight the importance of utilizing norms developed for Spanish-speakers in the US in order to obtain more precise and valid depictions of cognition in this population.

Brief Report: Body Mass Index and Cognitive Function Among HIV-1-Infected Individuals in China, India, and Nigeria.

Risk of cognitive impairment is increased among persons with high or low body mass index in HIV- and HIV+ populations in resource-rich settings. We examined this association among HIV+ patients in 3 resource-limited settings. This secondary analysis included data of 761 HIV+ volunteers pooled from 3 prospective cohort studies conducted in China (n = 404; 53%), India (n = 200; 26%), and Nigeria (n = 157; 21%). World Health Organization (WHO) weight classifications were based on body mass index. T scores, adjusted for demographics and practice effects, were derived from a 7-domain neuropsychological battery. Neurocognitive impairment (NCI) was defined as global deficit score of ≥0.5. Overall, prevalence of NCI at baseline was 27.7% (similar across all cohorts). The overweight/obese and underweight constituted 37.3% and 15.5% of the total participants, respectively. In a multivariable logistic regression of pooled longitudinal data, adjusting for clinical and demographic variables, the odds of global NCI were 38% higher among the overweight/obese as compared to normal weight participants [odds ratio: 1.38 (95% confidence interval: 1.1 to 1.72); P = 0.005]. Similarly, the odds of global NCI were 39% higher among the underweight as compared to normal weight participants [odds ratio: 1.39 (95% confidence interval: 1.03 to 1.87); P = 0.029]. NCI among HIV-1-infected patients was more prevalent in both overweight/obese and underweight than normal weight individuals in 3 resource-limited settings, confirming observations in resource-rich settings. Mechanisms underlying these associations are unclear but likely differ for underweight and overweight persons.

Sex differences in HIV-associated cognitive impairment

We determined whether there are sex differences in the prevalence and profile of HIV-associated neurocognitive impairment, and whether sex moderates the effect of HIV-serostatus on neurocognitive impairment among HIV-positive and HIV-negative individuals. Secondarily, we assessed whether differences were explained by greater biopsychosocial risk factors in HIV-positive women. An observational cohort study. Analyses included 1361 HIV-positive (204 women) and 702 HIV-negative (214 women) (ages = 18-79 years) participants from the UCSD HIV Neurobehavioral Research Program. Demographically corrected standardized T-scores from 15 neuropsychological tests were used to calculate domain-specific and global deficit scores (GDS). GDS at least 0.5 defined neurocognitive impairment. Biopsychosocial risk factors included low education, low reading level (education quality), lifetime substance use disorders, depressed mood (clinically significant depressive symptoms and/or current major depressive disorder) and a cumulative syndemic count (sum of biopsychosocial risk factors, range = 0-4). Race-stratified analyses were conducted. Analyses were adjusted for relevant demographic and clinical factors. HIV-associated neurocognitive impairment was more prevalent in women versus men; however, the difference was eliminated after adjustment for reading level. In sex-stratified logistic regressions, the association between HIV-seropositivity and higher likelihood of neurocognitive impairment was stronger in women versus men; however, the association was attenuated in women, but not men, after adjusting for reading level. These results in the overall sample were specific to blacks. Sex differences in the profile of HIV-associated neurocognitive impairment varied by race. Women, particularly black women, were most at-risk for HIV-associated neurocognitive impairment. Higher rates of HIV-associated neurocognitive impairment in women versus men may reflect differences in educational quality.

Resilience attenuates the association between neurocognitive functioning and everyday functioning in individuals aging with HIV in the Deep South.

Adults aging with HIV are at risk for poorer neurocognitive and daily functioning. Identifying factors to protect such outcomes is a significant research priority. The aim of this study was to explore the role of resilience in cognitive and everyday functioning in a largely African American and low socioeconomic status sample of adults and older adults with HIV in the Deep South. In this cross-sectional study 100 HIV+ middle-aged and older adults (range 40-73; 61% aged 50+) completed a comprehensive neurocognitive battery along with self-reported measures of resilience and everyday functioning. Higher resilience was associated with better global neurocognitive functioning (rho=0.31, P<0.01), as well as better functioning in all domains (verbal fluency, executive functioning, speed of information processing, learning, working memory) except recall and motor skills. Resilience was also significantly associated with instrumental activities of daily living (IADL) dependence, with lower resilience observed in those with IADL dependence compared with those who were IADL independent (P<0.01). In a multiple regression adjusting for data-driven covariates (verbal IQ, income, depression), and global neurocognitive impairment, resilience was the only significant (P=0.02) correlate of IADL dependence. A follow-up mediation showed that the direct relationship between neurocognitive functioning and IADL declines was fully attenuated after accounting for shared variance with resilience. Resilience is associated with better cognitive and functional outcomes in people aging with HIV. While further work is needed to understand these associations over time, results suggest interventions to build resilience may promote successful aging in this vulnerable population.

HPA-axis genes as potential risk variants for neurocognitive decline in trauma-exposed, HIV-positive females.

PurposePrevious studies have independently provided evidence for the effects of HIV infection, hypothalamic–pituitary–adrenal (HPA) axis dysfunction and early life trauma on neurocognitive impairment (NCI). This study examined the interaction between single-nucleotide polymorphisms (SNPs) of two HPA axis genes, corticotrophin-releasing hormone receptor 1 (CRHR1; rs110402, rs242924, rs7209436, and rs4792888) and corticotrophin-releasing hormone-binding protein (CRHBP; rs32897, rs10062367, and rs1053989), childhood trauma, and HIV-associated NCI.Patients and methodsThe sample comprised 128 HIV-positive Xhosa females of whom 88 (69%) had a history of childhood trauma. NCI was assessed using a battery of 17 measures sensitive to the effects of HIV, and the history of childhood trauma was assessed using the validated retrospective Childhood Trauma Questionnaire-Short Form. Generalized linear regression models were used to compare allelic distribution by trauma status and global NCI. The association between genotype, childhood trauma, and cognitive scores was also evaluated using generalized linear regression models, assuming additive models for the SNPs, and ANOVA.ResultsOf the seven polymorphisms assessed, only the rs10062367 variant of CRHBP was significantly associated with global NCI (P=0.034), independent of childhood trauma. This polymorphism was not significantly associated with z-scores on any specific cognitive domain. The interaction of childhood trauma and variants of CRHR1 was associated with poorer learning (rs110402) and/or recall (rs110402 and rs4792888).ConclusionThese findings suggest that CRHBP rs10062367 A allele is a possible risk variant for NCI in HIV, independent of childhood trauma. Furthermore, results show that the interaction of childhood trauma with variants of CRHR1, rs110402 and rs4792888, confer added vulnerability to NCI in HIV-infected individuals in cognitive domains that are known to be impacted by HIV. While these findings need independent replication in larger samples, it adds CRHBP and CRHR1 to the list of known genes linked to HIV- and childhood trauma-associated neurocognitive phenotypes.

Neurological Sequelae of Adult Meningitis in Africa: A Systematic Literature Review.

The high human immunodeficiency virus (HIV) prevalence in sub-Saharan Africa has markedly changed the epidemiology and presentation of adult meningitis. We conducted a systematic review using PubMed, Embase, Ovid, CENTRAL, and African Index Medicus to identify studies in Africa with data on neurological outcomes in adults after meningitis. We found 22 articles meeting inclusion criteria. From 4 studies with predominately pneumococcal meningitis, a median of 19% of survivors experienced hearing loss up to 40 days. Two studies of cryptococcal meningitis evaluated 6- to 12-month outcomes; in one, 41% of survivors had global neurocognitive impairment and 20% severe impairment at 1 year, and in a second 30% of survivors had intermediate disability and 10% severe disability at 6 months. A single small study of patients with tuberculosis/HIV found marked disability in 20% (6 of 30) at 9 months. Despite the high burden of meningitis in sub-Saharan Africa, little is known about neurological outcomes of patients with HIV-associated meningitides.