**7. Cerebrospinal Fluid Ascorbic Acid, Cognition, and Alzheimer's Disease**

Examination of the AA in the CSF reflects nutrient content with direct access to the brain parenchyma. This proximal representation should be considered the gold standard of brain nutrition in living subjects [130]. Presumably owing to the more intrusive nature of the testing far fewer studies have reported CSF AA (Table 2).

Paraskevas *et al.* [131] report high variation in plasma AA levels in hospitalized groups of 17 AD, 19 amyotrophic lateral sclerosis and 15 control patients, but reasonably stable CSF levels. They conclude that maintenance of the plasma:CSF ratio must be due to appropriate action of the SVCT2 at the choroid plexus. Lack of data on dietary intakes and case classifications limit the full utility of this study. Quinn *et al*. [132] examined the cross-sectional differences in CSF and plasma AA between 10 AD cases *versus* 10 healthy controls. Another cross-sectional study conducted by Glaso *et al*. [133] examined the mean differences between plasma and CSF AA in women with and without dementia of AD type. In both of these studies mean plasma and CSF AA were less (although not significantly in [132]) and the CSF-to-plasma AA ratio was higher in AD *versus* controls.





Ideally, such studies would be prospective, with baseline and later AA levels taken of both plasma and CSF AA across at least one year, in addition to cognitive assessment. One such prospective analysis also included CSF Albumin Index to reflect blood-brain barrier integrity in living probable mild to moderate AD patients over a year [134]. However, a higher CSF-to-plasma AA ratio was associated with a slower rate of decline although neither plasma nor CSF AA alone was predictive. The relationship between CSF AA ratio and rate of decline was attenuated when CSF Albumin Index (a validated measure of BBB integrity) was added to the regression model. These findings suggest that maintenance of high CSF-to-plasma AA ratio may be important to preventing cognitive decline in AD and that BBB impairment unfavorably alters this ratio. This study was unable to distinguish whether transport mechanisms for AA (*i.e*., SVCT2) were disturbed as well as the integrity of the BBB since the CSF albumin index reflects only barrier disturbances to our knowledge. How much of this "barrier" impairment is accompanied by "carrier" dysfunction is one area for future research interest.

A recent study on dietary supplements examined the antioxidant effect of 1000 mg AA per day (two × 500 mg) plus 400 IU vitamin E in mild to moderate AD patients who were also taking cholinesterase inhibitors [135]. In this relatively small, open label study, one year of supplements did not have a direct effect on cognition. Nevertheless, the authors were able to successfully demonstrate that supplements led to higher AA and vitamin E in the CSF and also decreased lipid peroxidation in the CSF. Greater levels of oxidation were also associated with faster cognitive decline. Unfortunately CSF was only measured in the supplement group, and dietary intake, or baseline group differences were not accounted for (although none of the subjects was taking supplements at the start of the study). In an additional study supplementation for 16 weeks with 500 mg/d AA with 800 IU/d vitamin E and 900 mg/day alpha-lipoic acid in 24 mild to moderately affected AD patients screened to exclude cases of vascular disease, were compared to 18 controls [136]. The antioxidant mix was also found to decrease oxidative stress in the CSF (F2-isoprostanes), however, no effects were seen on CSF Aβ1-42, tau or *p*-tau. No improvements were seen in cognition, in fact this group appeared to suffer faster cognitive decline. Critically, all subjects in the study were allowed to continue taking their own vitamin supplements up to 200 mg/day AA, this included 52% of the antioxidant group and 43% of controls. AA levels at baseline or following treatment are not reported, and thus it is not possible to assess whether groups truly differ; 200 mg/day in a supplement plus a reasonable diet could permit AA repletion in the placebo group and mitigate the chance of seeing differences in cognition although the oxidative stress data clearly indicates benefits of the antioxidant cocktail. A recent review of several studies above concluded that CSF levels within normal range for AA (and folate and additional CSF proteins), despite lower plasma levels indicated preservation of choroid plexus function and AA transport into CSF [137]. However, they also discuss the lack of definitive data on potential for change in CSF volume or turnover.
