Diagnostic and prognostic biomarkers for HAND

Abstract

In 2007, the nosology for HIV-1-associated neurocognitive disorders (HAND) was updated to a primarily neurocognitive disorder. However, currently available diagnostic tools lack the sensitivity and specificity needed for an accurate diagnosis for HAND. Scientists and clinicians, therefore, have been on a quest for an innovative biomarker to diagnose (i.e., diagnostic biomarker) and/or predict (i.e., prognostic biomarker) the progression of HAND in the post-combination antiretroviral therapy (cART) era. The present review examined the utility and challenges of four proposed biomarkers, including neurofilament light (NFL) chain concentration, amyloid (i.e., sAPPα, sAPPβ, amyloid β) and tau proteins (i.e., total tau, phosphorylated tau), resting-state functional magnetic resonance imaging (fMRI), and prepulse inhibition (PPI). Although significant genotypic differences have been observed in NFL chain concentration, sAPPα, sAPPβ, amyloid β, total tau, phosphorylated tau, and resting-state fMRI, inconsistencies and/or assessment limitations (e.g., invasive procedures, lack of disease specificity, cost) challenge their utility as a diagnostic and/or prognostic biomarker for milder forms of neurocognitive impairment (NCI) in the post-cART era. However, critical evaluation of the literature supports the utility of PPI as a powerful diagnostic biomarker with high accuracy (i.e., 86.7-97.1%), sensitivity (i.e., 89.3-100%), and specificity (i.e., 79.5-94.1%). Additionally, the inclusion of multiple CSF and/or plasma markers, rather than a single protein, may provide a more sensitive diagnostic biomarker for HAND; however, a pressing need for additional research remains. Most notably, PPI may serve as a prognostic biomarker for milder forms of NCI, evidenced by its ability to predict later NCI in higher-order cognitive domains with regression coefficients (i.e., r) greater than 0.8. Thus, PPI heralds an opportunity for the development of a brief, noninvasive diagnostic and promising prognostic biomarker for milder forms of NCI in the post-cART era.

Keywords: Diagnostic biomarker; HIV-1-associated neurocognitive disorders; Prepulse inhibition; Prognostic biomarker.

FIGURE 1.

The diagnostic utility of measures of prepulse inhibition (PPI) and gap prepulse inhibition (gap-PPI) is illustrated as a function of genotype (i.e., HIV-1 transgenic (Tg) vs Control) using both discriminant function analyses (DFA) and receiver-operating curves (ROC; inset). In the HIV-1 Tg rat, cross-modal PPI and/or gap-PPI accurately diagnoses the presence of the HIV-1 transgene with high accuracy, high sensitivity and high specificity across multiple ages. ROC analyses were conducted based on the discriminant scores. ROC area under the curve (AUC) is utilized as a single measure of overall accuracy for the ROC. A: In pre-weanling animals (i.e., Postnatal Day 14–21), a DFA selected 6 PPI variables, exhibiting 97.1% accuracy, 100% sensitivity, and 93.8% specificity. An AUC of 1.0 was observed when an ROC analysis was conducted. Adapted from McLaurin et al., 2017c. B: In adolescent/young adult animals (i.e., PD 30-PD 180), 4 PPI variables best discriminated between HIV-1 Tg and control animals in a DFA, displaying 90.8% accuracy, 100% sensitivity, and 79.5% specificity. An AUC of 0.986 was observed when a ROC analysis was conducted. Adapted from McLaurin et al., 2016. C: In adult animals (i.e., PD 240-PD 480), a DFA selected 3 PPI variables, exhibiting 86.7% accuracy, 89.3% sensitivity, and 84.4% specificity. An AUC of 0.951 was observed when an ROC analysis was conducted. Reanalysis of data presented in McLaurin et al., 2018b. D: In older adult animals (i.e., PD 540), a 5 PPI variables best discriminated between HIV-1 Tg and control animals in a DFA, exhibiting 96.8% accuracy, 100% sensitivity and 94.1% specificity. An AUC of 0.995 was observed when an ROC analysis was conducted. Reanalysis of data presented in McLaurin et al. 2018d.

FIGURE 2.

The utility of early (i.e., Postnatal Day (PD) 30 and PD 60)) prepulse inhibition (PPI) assessments to accurately predict later (i.e., PD 540) neurocognitive impairment in higher order cognitive processes (i.e., sustained attention, flexibility, and inhibition) was assessed in HIV-1 Tg animals. Regression assessments were conducted independently by sex due to sex-dependent expression of the HIV-1 transgene at an advanced age. Specifically, male HIV-1 Tg animals exhibited greater impairments in sustained attention (i.e., 18 Month Acquisition), while female HIV-1 Tg animals displayed greater impairments in flexibility and inhibition (i.e., Reversal; McLaurin et al., 2018c). A trimmed means regression analysis was conducted. A: For HIV-1 Tg males, regressing auditory PPI at PD 30 and PD 60 on the number of errors in 18 month acquisition (i.e., a challenging signal detection task tapping sustained attention) revealed a regression coefficient (r) of 0.81. Therefore, in male HIV-1 Tg animals, auditory PPI explained 65.8% of the variance in the number of errors in 18 months acquisition. B: For HIV-1 Tg females, regressing auditory PPI at PD 30 and PD 60 on the number of errors in an operant reversal task at 18 months of age, tapping flexibility and attention, exhibited a regression coefficient (r) of 0.83. Thus, in female HIV-1 Tg animals, auditory PPI explained 68.9% of the variance in the number of errors in a reversal task, tapping flexibility and inhibition, at 18 months of age. Reanalysis of data presented in McLaurin et al., 2018c. C: Regression Analysis.