Improving Cognitive Predictors and Everyday Outcomes in Adults with HIV

As adults age with HIV, they may encounter challenges with cognitive impairments. Perhaps, the neurobiological effects of HIV, subtle lifestyle changes, and the aging process may negatively influence cognitive functioning. Some cognitive impairments may interfere with everyday functioning and even compromise quality of life. In this dissertation, three articles were presented which focused on the overall theme of HIV and cognition. Article 1, a review of literature published in the Neurobiology of Disease, focused on how HIV affects the brain independently and the synergistic effects of HIV and aging on cognitive health. Also, the article closed with a section on cognitive interventions and future directions for novel cognitive interventions (e.g., transcranial direct current stimulation). Article 1 provided extensive literature that supports the relationship between HIV and cognition, which leads to Article 2 that examined the impact of HIV-related cognitive functioning on everyday outcomes such as proactive coping. Article 2, which was published in the Journal of Neuroscience for Nursing, examined the role of cognitive functioning in predicting proactive coping in middle-aged and older adults with HIV. Given some adults with HIV may incur cognitive damage to prefrontal areas, such damage may negatively influence their executive functioning ability which is necessary to engage in proactive coping behaviors such as planning and problem solving. In this study of 98 adults with HIV, spirituality/religiosity rather than cognitive functioning was found to be a significant predictor of proactive coping. Implications for research and nursing practice are provided. In addition, other everyday outcomes such as sleep quality has shown to be affected in older adults with HIV. Using data from two pilot studies, Article 3 examined the effects of a low current brain stimulation known as transcranial direct current stimulation (tDCS) and speed of processing (SOP) training on sleep quality in older adults (50+) with HIV (n = 33) and without HIV (n = 33). Participants were randomized to receive either tDCS with SOP training or sham tDCS with SOP training. At baseline, adults with HIV had significantly poorer sleep quality and worse performance on the Letter Comparison Test compared to adults without HIV. tDCS or sham tDCS with SOP training did not improve sleep quality in any of the groups; therefore, this finding must be considered when using tDCS in combination with cognitive training to ameliorate sleep quality. Performance on Useful Field of View, a measure of visual SOP and divided attention, improved across all training groups. Perhaps, novel cognitive interventions to improve cognitive functioning may in turn improve everyday outcomes for the growing HIV population, especially as more of them age with the disease

Effects of Diversity and Neuropsychological Performance in an NFL Cohort

Objective: The aim of this study was to examine the effect of ethnicity on neuropsychological test performance by comparing scores of white and black former NFL athletes on each subtest of the WMS. Participants and Methods: Data was derived from a de-identified database in South Florida consisting of 63 former NFL white (n=28, 44.4%) and black (n=35, 55.6%) athletes (Mage= 50.38; SD= 11.57). Participants completed the following subtests of the WMS: Logical Memory I and II, Verbal Paired Associates I and II, and Visual Reproduction I and II. Results: A One-Way ANOVA yielded significant effect between ethnicity and performance on several subtests from the WMS-IV. Black athletes had significantly lower scores compared to white athletes on Logical Memory II: F(1,61) = 4.667, p= .035, Verbal Paired Associates I: F(1,61) = 4.536, p = .037, Verbal Paired Associates: II F(1,61) = 4.677, p = .034, and Visual Reproduction I: F(1,61) = 6.562, p = .013. Conclusions: Results suggest significant differences exist between white and black athletes on neuropsychological test performance, necessitating the need for proper normative samples for each ethnic group. It is possible the differences found can be explained by the psychometric properties of the assessment and possibility of a non-representative sample for minorities, or simply individual differences. Previous literature has found white individuals to outperform African-Americans on verbal and non-verbal cognitive tasks after controlling for socioeconomic and other demographic variables (Manly & Jacobs, 2002). This highlights the need for future investigators to identify cultural factors and evaluate how ethnicity specifically plays a role on neuropsychological test performance. Notably, differences between ethnic groups can have significant implications when evaluating a sample of former athletes for cognitive impairment, as these results suggest retired NFL minorities may be more impaired compared to retired NFL white athletes

The Effect of Ethnicity on Neuropsychological Test Performance of Former NFL Athletes

Objective: To investigate the effect of ethnicity on neuropsychological test performance by specifically exploring differences between white and black former NFL athletes on subtests of the WAIS-IV. Participants and Methods: Data was derived from a de-identified database in Florida consisting of 63 former NFL athletes (Mage=50.38; SD=11.57); 28 white and 35 black. Participants completed the following subtests of the WAIS-IV: Block Design, Similarities, Digit Span, Matrix Reasoning, Arithmetic, Symbol Search, Visual Puzzles, Coding, and Cancellation. Results: One-Way ANOVA yielded a significant effect between ethnicity and performance on several subtests. Black athletes had significantly lower scaled scores than white athletes on Block Design F(1,61)=14.266, p\u3c.001, Similarities F(1,61)=5.904, p=.018, Digit Span F(1,61)=8.985, p=.004, Arithmetic F(1,61)=16.07, p\u3c.001 and Visual Puzzles F(1,61)=16.682, p\u3c .001. No effect of ethnicity was seen on performance of Matrix Reasoning F(1,61)=2.937, p=.092, Symbol Search F(1,61)=3.619, p=.062, Coding F(1,61)=3.032, p=.087 or Cancellation F(1,61)=2.289, p=.136. Conclusions: Results reveal significant differences between white and black athletes on all subtests of the WAIS-IV but those from the Processing Speed Scale and Matrix Reasoning. These findings align with previous literature that found white individuals to outperform African-Americans on verbal and non-verbal tasks after controlling for socioeconomic and demographic variables (Manly & Jacobs, 2002). These differences may also be a reflection of the WAIS-IV’s psychometric properties and it is significant to consider the normative sample used may not be appropriate for African-Americans. This study highlights the need for future research to identify how ethnicity specifically influences performance, sheds light on the importance of considering cultural factors when interpreting test results, and serves as a call to action to further understand how and why minorities may not be accurately represented in neuropsychological testing

SuperAging in Adults with HIV Disease: Biopsychosocial Predictors of Neurocognitive Aging Trajectories

Deficit models that predominate neuroHIV research describe adverse, synergistic effects of HIV and older age on neurocognitive impairment, yet many older persons with HIV (PWH) exhibit unimpaired neurocognition. HIV-seronegative studies have identified a subgroup of elders with youthful neurocognition, termed SuperAgers (SA). SA demonstrate stable neurocognitive trajectories and robust neurobiological integrity, consistent with models of cognitive and physiological reserve (CR and PR). However, the construct validity of SuperAging in HIV, including its prevalence, trajectory, and biopsychosocial correlates, is unknown. This three-paper dissertation: 1) established classification criteria for SuperAging in PWH; 2) examined the joint influence of CR and PR on SuperAging; and 3) characterized longitudinal trajectories of SuperAging. All three studies used archival data from older PWH (age range: 50-69) enrolled in studies coordinated by the HIV Neurobehavioral Research Program. Study 1 (N=724, Saloner et al., 2018). Individuals with intact global neurocognition based on normative standards for healthy 25 year-olds were classified as SA (n=124 [17.1%]). SA had similar HIV disease severity but better real-world outcomes (e.g., functional independence) than cognitively normal but non-super (CN) and cognitively impaired (CI) individuals. Study 2 (N=394, Saloner et al., 2022). CR was operationalized as estimated premorbid verbal intelligence (i.e., WRAT4 Reading subtest) and PR was operationalized with a validated disease burden index composed of 39 health variables. Higher PR predicted linear increases in odds of SA (vs. CN and CI) and higher CR predicted a quadratic ‘J-shaped’ change in odds of SA compared to CN (i.e., odds of SA>CN only above 35th percentile of CR). Study 3 (N=184, Saloner et al., 2021). Growth mixture modeling identified a 3-class solution that included Class 1Stable Elite (n=31 [16.8%], a latent class defined by stable and elite global neurocognition across a 5-year longitudinal period. Higher CR, PR, and SA status at baseline increased odds of Class 1Stable Elite membership. Findings support SuperAging in HIV as a construct reflecting neurocognitive resilience that converges with markers of robust biopsychosocial health. Replication of methodology in even older PWH (i.e., 70+ years) may improve characterization of cognitive risk and resilience, particularly among PWH without overt neurocognitive impairment

The Influence of Psychosocial and Physiological Factors on Cognitive Outcomes in Older Adults

This three-manuscript dissertation examined the influence of psychosocial and physiological stressors on cognitive functioning in older adults in the Health and Retirement Study (HRS). Manuscripts 1 and 2 evaluated the influence of loneliness and social isolation on four measures of cognitive functioning (Immediate Word Recall, Delayed Word Recall, Serial 7s, Backward Count) in the context of metabolic syndrome (MetS) using linear and logistic regression. Cross-sectional data came from the 2016 HRS core and Venous Blood Study data. Loneliness was inversely associated with Delayed Word Recall outcomes (manuscript 1; n=2,143), while social isolation (manuscript 2, n=1,341) was inversely associated with Immediate Word Recall scores after adjusting for demographic covariates and depression. Neither loneliness nor social isolation interacted with MetS to influence cognitive functioning. Outcomes support prior research indicating a link between cognitive function and loneliness and social isolation but do not suggest a moderating role for these psychosocial stressors on cognitive functioning in middle-aged and older adults living with MetS. vii Manuscript 3 examined whether sleep disturbance moderated relations between loneliness and cognition functioning and cognitive status over a 12-year period (n=1,093) using mixed effects regression modeling. Loneliness was inversely associated with Immediate Word Recall scores and cognitive status. After controlling for demographic covariates and depression, sleep disturbance inversely correlated with Delayed Word Recall outcomes and cognitive status and moderated relations between loneliness and Immediate Word Recall and Serial 7s outcomes. Findings suggest that sleep disturbance may exacerbate the negative physiological effects of loneliness on episodic memory and executive functioning in late middle-aged and older adults

Regional Cerebral Blood Flow Patterns in Children vs. Adults with ADHD Combined and Inattentive Types: A SPECT Study

Objective: The current study sought to determine whether ADHD Combined Type (ADHD-C) and ADHD Primarily Inattentive Type (ADHD-PI) showed differential regional cerebral blood flow (rCBF) patterns in children vs. adults. Participants and Methods: The overall sample (N=1484) was effectively split into four groups: adults with ADHD-PI (n=519), adults with ADHD-C (n=405), children with ADHD-PI (n=192), children with ADHD-C (n=368). All participants were void of bipolar, schizophrenia, autism, neurocognitive disorders, and TBI. The data were collected from a de-identified archival database of individuals who underwent SPECT scans at rest. Results: Using αConclusions: Overall, the current study suggested that children may show rCBF differences between different ADHD subtypes, but adults may not. The current study did not find significance in any of the 17 brain regions examined when comparing adults with ADHD-C to adults with ADHD-PI. All significant findings were attributed to the children with ADHD-C group showing aberrant blood flow rate than at least one other group. Previous research has supported that the differentiation of these subtypes as distinctive disorders is difficult to make in adults (Sobanski et al., 2006). Other research has indicated the potential of imaging techniques to differentiate the two in children (Al-Amin, Zinchenko, & Geyer, 2018). The current findings support nuanced ways in which rCBF patterns of ADHD-C and ADHD-PI differ between children and adults

The Interactive Effects of Brain-Derived Neurotrophic Factor (BDNF) Polymorphisms and Posttraumatic Stress Disorder on Neurocognitive Functioning in U.S. Military Veterans

Posttraumatic Stress Disorder (PTSD) is associated with mild-to-moderate deficits in neurocognitive functioning. Single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, namely, the Met allele, may also be associated with mild deficits in neurocognitive functioning. However, findings are inconsistent and may be sensitive to environmental epigenetic moderators such as psychopathology. The current study analyzed data from European-American U.S. military veterans (n = 1,244) who participated in the 2011 National Health and Resilience in Veterans Study (NHRVS). Multivariate analyses of covariances were conducted to evaluate the unique and interactive effects of the Met allele and probable PTSD on objective and subjective neurocognitive functioning. Significant (p ≤ .001) interactions between Met allele carrier status and probable PTSD were observed in objective (ηp2 = .028) and subjective neurocognitive functioning (ηp2 = .029). In individuals without PTSD (n = 1113), the Met allele was not significantly associated with objective neurocognitive functioning (p = .01, ηp2 = .013) or subjective neurocognitive functioning (p = .17, ηp2 = .009). In individuals with PTSD (n = 131), the Met allele was significantly (p \u3c .01) associated with poorer objective (ηp2 = .179) and subjective neurocognitive functioning (ηp2 = .237). These findings suggest that associations between the Met allele and neurocognitive functioning are dependent on the presence of PTSD

Family history of dementia and APOE e4 status predict neurocognitive trajectories among persons with HIV

Rationale: HIV and aging are associated with an increased risk for HIV-associated neurocognitive disorders (HAND) and Alzheimer’s disease (AD). Cross-sectional research among people with HIV (PWH) has shown that the apolipoprotein e4 (APOE-e4) allele and family history of dementia (FHD+) are independently associated with worse neurocognition. However, these cross-sectional data do not address the potential additive effect of FHD and APOE-e4 on rates of global and domain-specific neurocognitive decline among older PWH.Design: This study utilized longitudinal data from the CNS HIV Antiretroviral Therapy Effects Research programs (N=283 PWH; ages 45-69). Aim 1 used a 2x2 factorial analysis of covariance to model independent and interactive effects of FHD and APOE-e4 status. Aim 2 used linear mixed-effects modeling to examine global- and domain-specific neurocognitive trajectories (average follow-up = 7.0 visits over 5.4 years) in the four FHD/APOE-e4 groups linearly and non-linearly. The exploratory aim examined if demographic, neuropsychiatric, substance use, daily functioning factors, comorbidities, and HIV disease characteristics impact neurocognitive trajectories by FHD and APOE-e4 status, using linear mixed-effects modeling. Results: Cross-sectional analyses revealed lower executive functioning (p = .03) and motor skills (p = .04) T-scores among FHD+. Global T-scores trended towards significance (p = .07), with lower scores among FHD+. Mean differences in motor skills trended towards significance by APOE-e4 status (p = .08), with worse scores among APOE-e4 carriers. Longitudinal analyses revealed significant and trend-level differences in curvilinear trajectories between the FHD-/APOE-e4- and FHD+/APOE-e4+ groups in global performance (p = .01), executive functioning (p = .08), learning (p = .02), delayed recall (p = .07), and motor skills (p = .004). Lastly, demographics, depression, substance use history, cardiovascular conditions, and HIV-disease characteristics significantly predicted poorer neurocognitive outcomes, with worse global- and domain-specific trajectories in the FHD+/APOE-e4+ compared to the FHD-/APOE-e4- group. Conclusions: FHD+ and APOE-e4 jointly heighten risk of cognitive decline among middle-to-older age PWH with compounding medical and psychiatric burdens. Additional research is needed to clarify whether domain-specific differences in curvilinear cognitive trajectories between FHD+/APOE-e4+ and FHD-/APOE-e4- reflect HAND or early-stages of AD, considering there were limited sample sizes in follow-up visits and the possibility that cohorts may have been too young to detect expected neurocognitive decline.

Redefining Aging in HIV Infection Using Phenotypes

Purpose of review: This article critically reviews the utility of “phenotypes” as behavioral descriptors in aging/HIV research that inform biological underpinnings and treatment development. We adopt a phenotypic redefinition of aging conceptualized within a broader context of HIV infection and of aging. Phenotypes are defined as dimensions of behavior, closely related to fundamental mechanisms, and, thus, may be more informative than chronological age. Primary emphasis in this review is given to comorbid aging and cognitive aging, though other phenotypes (i.e., disability, frailty, accelerated aging, successful aging) are also discussed in relation to comorbid aging and cognitive aging. Recent findings: The main findings that emerged from this review are as follows: (1) the phenotypes, comorbid aging and cognitive aging, are distinct from each other, yet overlapping; (2) associative relationships are the rule in HIV for comorbid and cognitive aging phenotypes; and (3) HIV behavioral interventions for both comorbid aging and cognitive aging have been limited. Summary: Three paths for research progress are identified for phenotype-defined aging/HIV research (i.e., clinical and behavioral specification, biological mechanisms, intervention targets), and some important research questions are suggested within each of these research paths