The early diagnosis of leptomeningeal disease is a challenge because it is an asymptomatic pathology in the early stages. Hence, it is highly relevant to identify a panel of biomarkers to help in the diagnosis and/or prognostic. For this purpose, we have explored a multipronged proteomics approaches, in cerebrospinal fluid, to determine a potential panel of biomarkers in cerebrospinal fluid. Thus, a systematic and exhaustive characterization of more than 347 CSF samples have been performed by an integrated LC-MS/MS (n 20) and functional proteomics (n 347) analysis to establish protein profiles which has been useful to develop a panel of biomarkers validated by in silico approaches.