## 7 Limitations of the Study  
Although exclusion criteria involved diseases (stroke, head trauma, acute liver failure, hypertensive encephalopathy, HIV infection) that destroy the integrity and function of BBB [58; 59], other diseases that were an indication for lumbar puncture and CSF collection may also enhance BBB permeability. For instance, MS and diabetes mellitus were reported to increase BBB permeability [58]. Moreover, two patients suffered from meningitis and one from brain tumor, diseases which potentially induce BBB dysfunction. Thus one may suppose that our results concerning CA concentrations in CSF were higher than those in healthy subjects. On the other hand, 4 patients with mononeuropathy or polyneuropathy without coexisting diabetes mellitus and any pathology localized in the brain represented detectable CA in CSF. Systemic inflammation negatively affects BBB function [58]. The majority of studied patients (especially those with MS) had plasma CRP, a marker of intensity of inflammatory response within normal range. In addition, the lack of correlation between CSF and plasma concentrations of CA suggests that simple permeation was not the main mechanism of CA transportation through BBB. These indicate that our results were not significantly biased by the presence of neurological disorders in studied subjects. We used relatively nonspecific analytical methods (HPLC-UV-Vis and HPLC-ECD) for the measurement of phenolics in human CSF and matched plasma. An application of HPLC with mass spectrometric detection would probably give an opportunity to find more dietary phenolics in CSF. However, despite this, we achieved our goal. We describe for the first time the presence of CA in human CSF. Plasma and CSF samples were collected under fasting conditions after 15 h from the last meal. Maximal increase in CA plasma levels was observed within 0.5-1 h after consumption of 200 mL of red wine containing 1.8 mg of CA [60]. Similarly, an ingestion of 200 mL of instant coffee resulted in the maximal increase in chlorogenic acid plasma levels (an ester of caffeic acid and quinic acid) after 1 h, with a half-life time of about 0.3 h [34]. These suggest that non-fasting plasma and CSF samples could have considerably increased CA concentrations. On the other hand, studies with ileostomy patients revealed that almost all the ingested CA dose was absorbed in the small intestine, while in the case of chlorogenic acid it was only one third of the dose [61]. This indicates that the majority of chlorogenic acid from food could reach the colon and be hydrolyzed by colon microbiota into free CA, with its subsequent absorption into the blood. Thus, the absorption of CA can occur even after several hours from the last meal and the conditions of blood and CSF samples collection can have a rather moderate effect on CA measurement results. However, the considerable differences between CSF concentrations of CA and the remaining two phenolics (HVA and 3 HPAA) are in line with these data and support, to the same extent, the conclusion that the presence of caffeic acid in CSF results only from its passage through the blood-brain barrier. Other phenolic acids (e.g., ferulic acid, dihydrocaffe acid, 3,4-dihydroxybenzoic acid) are also rapidly absorbed in the small intestine and reach maximal plasma concentration, within 1 to 2 h after ingestion. Their elimination lasts about a few hours [60]. Similarly, hipuric acids (hippuric acid, 3-hydroxyhippuric, 4-hydroxyhippuric), which are metabolites of various polyphenols, are rapidly excreted with the urine [60]. Therefore, it is possible that the lack of detectable concentrations of these compounds in plasma and CSF samples could result from the relatively long fasting period preceding their collection. This is in line with our previous observations [29].