Cerebrospinal fluid clearance impairment captured using stable isotope labeling kinetics (SILK) in normal pressure hydrocephalus
Leckey, C. A.; Giovannucci, T. A.; Murphy, E. C.; Moncur, E.; Tariq, K.; Aslanyan, A.; Scholl, M.; Srikrishna, M. A.; Coath, W.; Barker, S.; Esguerra, D. P.; Toma, A.; Watkins, L.; Thorne, L.; Lehmann, S.; Vialaret, J.; Wray, S.; Bateman, R. J.; Mills, K.; Elbert, D. L.; Pellegrini, L.; Paterson, R. W.
Show abstract
Normal pressure hydrocephalus is a common cause of gait and cognitive impairment in later life, characterised by accumulation of excessive cerebrospinal fluid (CSF). Clinical improvement can occur following CSF diversion. No biomarkers are available to mechanistically investigate fluid accumulation, support diagnosis or predict response to CSF diversion. We developed a stable isotope labeling kinetics (SILK) method to capture the function of the main site of production of CSF in humans, the choroid plexus (ChP), in vitro and in vivo. We captured ChP protein kinetics in human ChP organoids and the CSF of participants with suspected NPH undergoing CSF drainage (n=10) or controls (n=9). We found that transthyretin is abundantly secreted by ChP organoids, and we observe correlations with CSF transthyretin synthesis rates and volume of CSF production in vivo ({rho}=0.738; p<0.05). Clearance rates of transthyretin are [~]10 fold slower in NPH compared to controls, demonstrating impaired CSF clearance. ChP SILK is a novel clinical tool for interrogating CSF flow. One Sentence Summary: Using stable isotope labeling kinetics of choroid plexus proteins, in human choroid plexus organoids and in vivo, we find that synthesis and clearance of transthyretin is altered in normal pressure hydrocephalus.
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