Cognitive and Physiologic Reserve Independently Relate to Superior Neurocognitive Abilities in Adults Aging With HIV

Abstract

Background: To investigate joint contributions of cognitive and physiologic reserve to neurocognitive SuperAging in older persons with HIV (PWH).

Methods: Participants included 396 older PWH (age range: 50-69 years) who completed cross-sectional neuropsychological and neuromedical evaluations. Using published criteria, participants exhibiting global neurocognition within normative expectations of healthy 25-year-olds were classified as SuperAgers (SA; n = 57). Cognitively normal (CN; n = 172) and impaired (n = 167) participants were classified with chronological age-based norms. Cognitive reserve was operationalized with an estimate of premorbid verbal intelligence, and physiologic reserve was operationalized with a cumulative index of 39 general and HIV-specific health variables. Analysis of variance with confirmatory multinomial logistic regression examined linear and quadratic effects of cognitive and physiologic reserve on SA status, adjusting for chronological age, depression, and race/ethnicity.

Results: Univariably, SA exhibited significantly higher cognitive and physiologic reserve compared with CN and cognitively impaired ( d s ≥ 0.38, p s < 0.05). Both reserve factors independently predicted SA status in multinomial logistic regression; higher physiologic reserve predicted linear increases in odds of SA, and higher cognitive reserve predicted a quadratic "J-shaped" change in odds of SA compared with CN (ie, odds of SA > CN only above 35th percentile of cognitive reserve).

Conclusions: Each reserve factor uniquely related to SA status, which supports the construct validity of our SA criteria and suggests cognitive and physiologic reserve reflect nonoverlapping pathways of neuroprotection in HIV. Incorporation of proxy markers of reserve in clinical practice may improve characterization of age-related cognitive risk and resilience among older PWH, even among PWH without overt neurocognitive impairment.

Figure 1. SuperAgers exhibit higher cognitive and physiologic reserve compared to non-SuperAgers

Panel A) Raw and race/ethnicity-adjusted cognitive reserve (i.e., WRAT4 reading scores) by neurocognitive status. SuperAgers (SA) univariably exhibit higher cognitive reserve compared to cognitively impaired (CI) and cognitively normal (CN) individuals, and this relationship strengthens after adjusting for the influence of race/ethnicity on WRAT4 reading performance. Panel B) SA exhibit higher levels of physiologic reserve, or fewer health deficits, compared to CI and CN, whereas CI and CN do not differ on physiologic reserve. # = p<.10 * = p<.05 ** = p<.01 *** = p<.001

Figure 2. Association of physiologic reserve index components and SuperAging

Forest plot displaying the magnitude and precision (95% confidence intervals) of odds ratio effect size estimates reflecting the relationship between SuperAger (SA) status and individual health deficits comprising the cumulative physiologic reserve (PR) index. SA were less likely to meet criteria for the majority of individual index components compared to cognitively impaired (CI; panel A) and cognitively normal (CN; panel B) individuals, however almost all odds ratios reflecting these individual health deficit differences failed to reach statistical significance due to poor precision. Conversely, the odds ratio reflecting the relationship between SA and the cumulative PR index (dichotomized as low vs. high PR for purposes of analysis) exhibited sufficient magnitude and precision to reach statistical significance (95% confidence interval does not contain an odds ratio of 1). The prevalence of individual health deficits by neurocognitive status are provided in Table S1, Supplemental Digital Content. Abbreviations: ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; BMI = body mass index; BUN = blood urea nitrogen; COPD = chronic obstructive pulmonary disease; CVA = cerebrovascular accident; DNP = distal neuropathic pain; eGFR = estimated glomerular filtration rate; HCV = hepatitis C virus; HDL = high-density lipoprotein; MCHC = mean corpuscular hemoglobin concentration; MI = myocardial infarction; PR = physiologic reserve; SNP = sensory neuropathy; WBC = white blood cell

Figure 3. Quadratic associations between cognitive reserve and neurocognitive status

Cognitive reserve exhibited independent linear and quadratic effects on neurocognitive status in multinomial logistic regression analyses, accounting for age, depressive symptoms, race/ethnicity, and physiologic reserve. Higher cognitive reserve linearly increased odds of classification as SuperAger (SA) compared to cognitively impaired (CI; dotted line vs. solid line) across the full range of cognitive reserve. Higher cognitive reserve best discriminated SA from cognitively normal (CN; dotted line vs. dashed line) among individuals with scores above the 35^th percentile of cognitive reserve (WRAT4 >91.9). Conversely, higher cognitive reserve best discriminated CN from CI (dashed line vs. solid line) among individuals with scores below the 52^nd percentile of cognitive reserve (WRAT4 <96.4).