Large neutral amino acids levels in primate cerebrospinal fluid do not confirm competitive transport under baseline conditions

- Fasting large neutral amino acid levels were measured in serum and CSF.
- Modest serum / CSF correlations were not improved by taking transport competition into account.
- Serum levels of large neutral amino acids do not support quantitative estimates of CSF levels.

In rodents, transport of large neutral amino acids (LNAAs) across the blood brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier is mediated by high affinity carriers. Net brain LNAA levels are thought to be determined mainly by this competitive transport from plasma. Since the affinity for LNAA transport at the BBB in primates is considerably higher than in rodents, brain influx and by extension LNAA brain levels, should be even more dependent on competitive transport. Given that LNAA levels in CSF and brain interstitial fluid are usually similar, we analyzed serum and CSF of fasted subjects (n=24) undergoing spinal anesthesia and calculated brain influx and transporter occupancy using a conventional model of transport. Despite predicted near-full transporter saturation (99.7%), correlations between CSF levels and brain influx were modest, limited to tyrosine (r=0.60, p<0.002) and tryptophan (r=0.50, p<0.01) and comparable to correlations between CSF and serum levels. We also analyzed serum and CSF in (n=5) fasted vervet monkeys. Tyrosine and phenylalanine levels in CSF were positively correlated with those in serum, but correlations with calculated brain influx, which takes competition into account, were weaker or absent. We conclude that in primates i) baseline CSF LNAA levels do not confirm competitive transport, ii) brain LNAA levels should not be estimated on the basis of serum indices alone. This has implications for amino acid challenge studies and for neuropsychiatric disorders associated with dysregulated LNAA transport in which quantitative information about brain LNAA levels is needed.