Affects of cannulation on CSF biomarker composition and consistency in Sprague-Dawley rats

Abstract

Cerebral spinal fluid (CSF) is commonly used for assessing biomarkers of drug efficacy and/or disease progression in the central nervous system. Studies of CSF from pre-clinical species can identify and characterize biomarkers for use in clinical trials. However, obtaining CSF from pre-clinical species, particularly rodents can be challenging due to small body sizes and the consequent low volumes of CSF. Surgical cannulation of rats is commonly used to allow for CSF withdrawal from the cisterna magna. However, CSF biomarkers may be affected by cannulation, thus introducing potential problems in translating the biomarkers to the clinic. Cannulated and non-cannulated rats were purchased from Charles River Labs. The cannulated rats were surgically implanted with catheters accessing the cisterna magna. CSF was collected from the non-cannulated rats by inserting a 25 or 27 gauge butterfly needle into the cisterna magna. Daily CSF withdrawals were attempted from individual rats using each model type. Using ELISA, protein biomarkers and albumin and other biomarkers were measured in the CSF from dozens of rats representing cannulated or non-cannulated methods. CSF from cannulated rats differs from that of non-cannulated rats in its protein composition. Of the biomarkers examined, including albumin, cannulated rat CSF biomarker levels were higher relative to non-cannulated rats. The variation in biomarker levels observed in CSF from cannulated rats was also greater than that observed from non-cannulated rats. In addition, multiple CSF collections from the same rats were more successful when the non-cannulated rats were used. Intracisternal-cannulation of rats may affect the biomarker composition of the CSF. Thus biomarker assessment using CSF from cannulated rats may not provide data representative of naive animals and may contribute confounding factors to biomarker identification and development for clinical use. Studies that utilize non-cannulated rats may provide data that is more biologically relevant than those conducted on cannulated rats, and ultimately may provide critical data on biomarkers that can be more readily translated to the clinic.