Diagnostic Cerebrospinal Fluid Biomarker Discovery and Validation in Patients with Central Nervous System Infections

Abstract

Word counts: Abstract: 245, text: 2760 2 7 Keywords: Meningitis, central nervous system infections, mass-spectrometry, lipocalin 2, 2 8 biomarkers 2 9Running title: Diagnostic biomarker discovery in central nervous system infected patients 3 0 ABSTRACT 1 Background: Central nervous system (CNS) infections are common causes of morbidity and 2 mortality worldwide. Rapid, accurate identification of the likely cause is essential for clinical 3 management and the early initiation of antimicrobial therapy, which potentially improves clinical 4 outcome. 5Methods: We applied liquid chromatography tandem mass-spectrometry on 45 cerebrospinal 6 fluid (CSF) samples from a cohort of adults with/without CNS infections to discover potential 7 diagnostic protein biomarkers. We then validated the diagnostic performance of a selected 8 biomarker candidate in an independent cohort of 364 consecutively treated adults with CNS 9 infections admitted to a referral hospital in southern Vietnam. 0Results: In the discovery cohort, we identified lipocalin 2 (LCN2) as a potential biomarker of 1 1 bacterial meningitis. The analysis of the validation cohort showed that LCN2 could discriminate 1 2 bacterial meningitis from other CNS infections, including tuberculous meningitis, cryptococcal 1 3 meningitis and viral/antibody-mediated encephalitis (sensitivity: 0.88 (95% confident interval 1 4 (CI): 0.77-0.94), specificity: 0.91 (95%CI: 0.88-0.94) and diagnostic odd ratio: 73.8 (95%CI: 1 5 31.8-171.4)). LCN2 outperformed other CSF markers (leukocytes, glucose, protein and lactate) 1 6 commonly used in routine care worldwide. The combination of LCN2 and these four routine 1 7 CSF markers resulted in the highest diagnostic performance for bacterial meningitis (area under 1 8 receiver-operating-characteristic-curve 0.96; 95%CI: 0.93-0.99).1 9Conclusions: Our results suggest that LCN2 is a sensitive and specific biomarker for 2 0 discriminating bacterial meningitis from a broad spectrum of CNS infections. A prospective 2 1 study is needed to further assess the diagnostic utility of LCN2 in the diagnosis and management 2 2 of CNS infections. 2 3 1 Central nervous system (CNS) infections cause significant mortality and morbidity worldwide, 2 but especially in low-and middle-income countries (1). Common CNS infections include 3 bacterial meningitis (BM), viral encephalitis, tuberculous meningitis (TBM) and cryptococcal 4 meningitis (2), but there are >100 documented infectious causes of CNS infections (3). 5 Additionally, over the last decade, antibody-mediated causes of encephalitis (e.g. anti-N-methyl-6 D-aspartate receptor (anti-NMDAR) encephalitis) have been recognized (4), which further 7 challenges routine diagnostics. 8 Clinical features are often insufficient to discriminate the likely cause and standard laboratory 9 investigations identify the causative agent in <60% of cases (5, 6). Critically, the clinical We thank Le 1 logistic support, and Dr Nguyen Thi Hoang Mai for her help with material collection. We are 2 indebted to patients for the...

A minimally-invasive method for serial cerebrospinal fluid collection and injection in rodents with high survival rates

“…(Fig. 1c) 4. Secure a 1-mL syringe without needle (#1) to a portable holder and connect the syringe to the Luer connector of the tubing containing a bent needle.…”

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Cerebrospinal fluid (CSF) is a clear fluid surrounding and nourishing the brain and spinal cord.Molecular profiling of the CSF is a common diagnostic approach for central nervous system (CNS) diseases, including infectious diseases, autoimmune disorders, brain hemorrhage and traumatic brain injury, CNS tumors, and Alzheimer's disease [1][2][3][4][5][6][7][8][9][10] . Rodent models are critical for investigating CNS disease mechanisms and therapeutics, however, both collecting CSF and injecting materials into CSF in small animals are technically challenging and often result in high rates of postoperative mortality.

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A Minimally-Invasive Method for Serial Cerebrospinal Fluid Collection and Injection in Rodents with High Survival Rates

“…Diagnosing central nervous system (CNS) diseases is an ongoing challenge in biomedicine. Molecular profiling of the cerebrospinal fluid (CSF) is a common diagnostic approach for diseases of the central nervous system (CNS), including infectious diseases, autoimmune disorders, brain hemorrhage and traumatic brain injury, CNS tumors, and Alzheimer’s disease [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. The CSF provides an important window and sample source for discovering potential biomarkers to indicate the pathophysiological states of the CNS.…”