Robert K. Heaton

Background: Age-related comorbidities accumulate faster in people with HIV (PWH) than in those without HIV. We evaluated whether a validated multimorbidity scale, the Charlson index, predicted neurocognitive trajectories in PWH. Methods: Scaled scores of a comprehensive neuropsychological battery were averaged across all visits. Multilevel modeling examined between- and within-person predictors of global neurocognition. At the between-person level, averaged Charlson scores were examined as a predictor of neurocognitive change rate, covarying for HIV disease characteristics. Within-persons, visit-specific Charlson index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for disease measures. Results: Participants were 1195 PWH (mean baseline age: 43.0; SD: 9.7 years) followed for a mean of 7.1 years (range: 0.5–20.5). At the between-person level, more rapid neurocognitive worsening correlated with higher (worse) average Charlson scores (standardized β: −0.062; SE: 0.015; P = .001) and lower CD4 nadir (standardized β: 0.055; SE: 0.021; P = .011), but not viral suppression or average CD4+ lymphocytes (P > .05). At the within-person level, poorer visit-specific neurocognition was related to worse concurrent, but not preceding, Charlson scores (standardized β: −0.046; SE: 0.015; P = .003), detectable HIV viral load (standardized β: 0.018; SE: 0.006; P = .001), and higher CD4+ (standardized β: 0.043; SE: 0.009; P < .001). Conclusions: The impact of comorbidities on neurocognitive decline exceeded that of HIV disease factors. Although correlative, the temporal relationships suggested that treatment of comorbidities might improve neurocognitive prognosis for PWH.

This study evaluated whether a history of lifetime methamphetamine (MA) use disorder increases risk for poor sleep quality in people with or without HIV infection (HIV+/HIV−). Participants (n = 313) were stratified into four groups based on HIV status and lifetime MA use disorder diagnosis [HIV+/MA+ (n = 84); HIV+/MA− (n = 141); HIV−/MA+ (n = 16); and HIV−/MA− (n = 72)] and compared on global sleep outcomes using the Pittsburgh Sleep Quality Index (PSQI). Significant differences on global sleep were observed between HIV+/MA+ and HIV+/MA− groups, but not between the HIV− groups. Follow-up multiple regression analyses within the HIV+ subgroups examined global sleep scores as a function of MA status and clinical covariates, including those related to HIV disease and demographics. HIV+ individuals with a history of MA use disorder evidenced significantly poorer sleep quality and were more likely to be classified as problematic sleepers than those without a lifetime disorder. This was independent of depressed mood, body mass index, and viral suppression while on treatment. Poorer reported sleep quality among HIV+/MA+ was associated also with multiple adverse functional outcomes, including greater objective cognitive impairment, unemployment, clinical ratings of functional impairment, and self-reported cognitive difficulties, decreased independence in activities of daily living, and poorer overall life quality. Interventions to avoid or curtail MA use in HIV+ individuals may help protect sleep quality and improve functioning.

Objective: Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.Method: Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.Results: When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.Conclusions: The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.

National Institutes of Health Toolbox Emotion Battery for English- and Spanish-speaking adults: normative data and factor-based summary scores Ida Babakhanyan,1,2 Benjamin S McKenna,2 Kaitlin B Casaletto,3 Cindy J Nowinski,4 Robert K Heaton2 1Defense and Veteran’s Brain Injury Center, Camp Pendleton, 2Department of Psychiatry, University of California, San Diego, La Jolla, 3Department of Neurology, University of California, San Francisco, San Francisco, CA, 4Department of Medical Social Sciences, Northwestern University, Chicago, IL, USA Background: The National Institutes of Health Toolbox Emotion Battery (NIHTB-EB) is a “common currency”, computerized assessment developed to measure the full spectrum of emotional health. Though comprehensive, the NIHTB-EB’s 17 scales may be unwieldy for users aiming to capture more global indices of emotional functioning. Methods: NIHTB-EB was administered to 1,036 English-speaking and 408 Spanish-speaking adults as a part of the NIH Toolbox norming project. We examined the factor structure of the NIHTB-EB in English- and Spanish-speaking adults and developed factor analysis-based summary scores. Census-weighted norms were presented for English speakers, and sample-weighted norms were presented for Spanish speakers. Results: Exploratory factor analysis for both English- and Spanish-speaking cohorts resulted in the same 3-factor solution: 1) negative affect, 2) social satisfaction, and 3) psychological well-being. Confirmatory factor analysis supported similar factor structures for English- and Spanish-speaking cohorts. Model fit indices fell within the acceptable/good range, and our final solution was optimal compared to other solutions. Conclusion: Summary scores based upon the normative samples appear to be psychometrically supported and should be applied to clinical samples to further validate the factor structures and investigate rates of problematic emotions in medical and psychiatric populations. Keywords: emotional functioning, NIH Toolbox Emotion Battery, factor analyses, summary scores, normative data

The structure of neurocognition is explored by examining the neurocognitive domains underlying comprehensive neuropsychological assessment of cognitively healthy individuals. Exploratory factor analysis was conducted on the adult normative dataset of an expanded Halstead-Reitan Battery (eHRB), comprising Caucasian and African American participants. The factor structure contributions of the original HRB, eHRB expansion, and Wechsler intelligence scales were compared. Demographic effects were examined on composite factor scores calculated using confirmatory factor analysis. The full eHRB had an eight-factor structure, with latent constructs including: ‘working memory’, ‘fluency’, ‘verbal episodic memory’, ‘visuospatial cognition’ (visuospatial memory and problem solving), ‘perceptual-motor speed’ (speed for processing visual/tactile material and hand-motor execution), ‘perceptual attention’ (attention to sensory-perceptual information), ‘semantic knowledge’ (knowledge acquired through education and culturally-based experiences), and ‘phonological decoding’ (grapheme-phoneme processing essential for sounding-out words). ‘Perceptual-motor speed’ and ‘perceptual attention’ were most negatively associated with age, whereas ‘semantic knowledge’ and ‘phonological decoding’ were most resistant to aging. ‘Semantic knowledge’ showed the greatest dependence on demographic background, including education and ethnicity. Gender differences in cognitive performances were negligible across all domains except ‘phonological decoding’ with women slightly outperforming men. The original HRB contributed four neurocognitive domains, the eHRB expansion three domains, and the Wechsler scales one additional domain but with restructuring of verbal factors. Eight neurocognitive domains underlie performance of healthy cognitive individuals during comprehensive neuropsychological assessment. These domains serve as framework for understanding the constructs measured by commonly-used neuropsychological tests and may represent the structure of neurocognition.

Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression. CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment. CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection.

The criteria for differentiating symptomatic from asymptomatic HIV-associated neurocognitive disorder require evaluation of (1) cognitive impairment, (2) daily functioning declines, and (3) whether the functional declines are attributable to cognitive versus physical problems. Many providers rely only on self-report to evaluate these latter criteria. However, the accuracy of patient-provided information may be limited. This study evaluated the validity of self-assessment for HIV-associated neurocognitive disorder (HAND) diagnoses by comparing objective findings with self-report of criteria 2 and 3 above. Self-reports were used to stratify 277 cognitively impaired HIV+ individuals into functionally dependent (n = 159) and independent (n = 118) groups, followed by group comparisons of objective functional problems. The dependent group was then divided into those who self-attributed their functional dependence to only cognitive (n = 80) versus only physical (n = 79) causes, for further comparisons on objective findings. The functionally dependent group was significantly worse than the independent group on all objective disability characteristics except severity of cognitive impairment, while those who attributed their dependence to physical (versus cognitive) factors were similar on all objective physical, cognitive, and functioning variables. Of note, 28 % of physical attributors showed no physical abnormalities on neuromedical examinations. Results suggest that patient report is consistently associated with objective measures of functional loss; in contrast, patient identification of physical versus cognitive causes is poorly associated with objective criteria. These findings caution against relying solely on patient self-report to determine whether functional disability in cognitively impaired HIV+ individuals can be attributed to strictly physical causes.

Abstract: Background: Both family history of dementia (FHD) and lower levels of Aβ-42 are indepentently associated with worse neurocognitive functioning in HIVinfected patients. Objective: To examine the relationships between cerebrospinal fluid (CSF) Aβ-42 and FHD with HIV-associated neurocognitive disorders (HAND). Methods: One hundred eighty-three HIV+ adults underwent neuropsychological and neuromedical assessments, and determination of CSF Aβ-42 concentration and FHD (defined as a self-reported first or second-degree relative with a dementia diagnosis). Univariate analyses and multivariable logistic regressions were used. Results: FHD was not associated with HAND (p = 0.24); however, CSF Aβ-42 levels were lower (p = 0.03) in the HAND group, but were not associated with FHD (p = 0.89). Multivariable models showed a main effect of CSF Aβ-42 (p = 0.03) and a trend-level (p = 0.06) interaction between FHD and CSF Aβ-42, such that lower CSF Aβ-42 was associated with HAND in those with FHD (p Conclusion: FHD moderates the relationship between of CSF Aβ-42 and HAND. The findings highlight the complexities in interpreting the relationships between biomarkers of age-related neurodegeneration and HAND.