Integrating Biomarkers in the Diagnosis of Neurological and Neurocognitive Disorders in People Living with HIV

HIV is able to enter the CNS soon after systemic infection. In the absence of virological control HIV-associated dementia and CNS opportunistic infections (OIs) are common. Despite combination antiretroviral treatment (cART) is able to control viral replication and increase CD4 cell count, neurocognitive impairment (defined as HIV-associated NCI or HAND) is common with prevalence rates between 20 and 50% of people living with HIV (PLWH) receiving cART. Performance-based evaluations and symptomatic criteria are generally descriptive and lack the precision and accuracy needed for monitoring the disease's diagnosis, progression, and response to treatment when compared to objective and quantifiable laboratory-based biological markers, known as biomarkers. Aim of this study is to assess whether cerebrospinal fluids (CSF) or serum biomarkers of CNS involvement could be used to differentiate Neurological and Neurocognitive Disorders in PLWH. We performed a cross-sectional observational study that included PLWH enrolled in neurocognitive studies at the Infectious Diseases Unit, Amedeo di Savoia Hospital, in Turin. Demographic, clinical and viro-immunological data were recorded, as well as CSF and blood samples analysis results. Lumbar puncture was performed between 10:00 and 12:00 to reduce intra- and inter-subject daily variability of circulation and CSF flow. The samples were tested for Neopterin, T-tau, P-tau, Amyloid-β 1-42 (Aβ42) and Amyloid-β 1-40 (Aβ40), Neurofilament light chain (NFL) and S100-Beta protein. The samples were analyzed through ELISA or, more recently, through SIMOA. Data are described as number (percentage) and mean (standard deviation). Binary logistic multivariate analysis (using variable identified at univariate analysis and adding either CSF or serum biomarkers) were used to assess the potential role of biomarkers in the differential diagnosis. The population of the study included 931 patients, from which 72.7% were male, mostly of European ancestry (85.9%). Mean CD4 cell count (cell/mm3) and HIV RNA (Log10 copies/mL) were 342 and 2.9 respectively. The most common diagnosis were: HAND (n=353, 37.9%), Asymptomatic (n=178, 19.1%), Neurocognitive weakening (n=90, 9.7%) and CNS opportunistic infections (n=84, 9%). Average CSF biomarker levels were (all in pg/mL with the exception of neopterin in ng/mL): T-tau 266.3 (±211.4), P-tau 39 (±18.9), Beta1-42 953.3 (±390.4), Beta1-40 10527.4 (±4939), S100 Beta 175.6 (±188.2), Neopterin 3.12 (±5.56) and NFL 1635 (±5836). At multivariate analysis HAND was predicted by age (p<0.001) and serum HIV RNA levels (p=0.035) while including serum biomarkers identified and serum Tau levels (p=0.006) as statistically significant (beyond age effect). CNS OIs were predicted by CD4 cell count (p=0.012) and CSF Tau levels (p=0.021); including serum biomarkers showed that serum NFL level (p=0.013) was an independent predictor. Biomarkers of CNS involvement may be particularly useful in PLWH given the wide differential diagnosis and sometimes overlapping pathogenesis. Higher serum NFL and CSF tau were associated with a diagnosis of CNS opportunistic infections: this may be beneficial, once confirmed, for patients with a low a priori probability such as those with high CD4 cell count or for those ones presenting highly prevalent confounding conditions (such as cerebrovascular disorders or psychiatric disorders). For assessing neurocognitive impairment a promising role emerged for higher serum tau concentrations (besides older age and serum HIV RNA levels): this non-invasive test need to be tested in larger and more homogeneous patients’ groups before being adopted in clinical practice.