In these 32 adults followed for one year with mild-to-moderate AD, we found that rates of cognitive decline were not explained by CSF or plasma AA independently, but the ratio of CSF: plasma AA did predict cognitive decline.
The absence of a relationship between rate of cognitive decline and CSF or plasma AA may be readily explained. Plasma AA levels are dependent on recent dietary intake, so they are not very reproducible and also not representative of long-term consumption, which is probably more relevant to neurologic outcome than short-term exposure. Plasma AA is also not in direct contact with the brain. On the other hand, CSF AA may be a better reflection of the AA that the brain “sees”, but the drive to maintain a homeostatic level of vitamin C is so strong that low variability of AA content in CSF may actually prevent detection of a relationship between AA and rate of cognitive decline. This notion is exemplified by observations in overt scurvy where brain levels of AA are relatively maintained through depletion of peripheral tissues [28
We consequently examined the relationship between CSF: plasma AA ratio and rate of decline in light of previous observations that CSF: plasma AA ratio discriminates AD patients from controls more reliably than CSF or plasma levels alone [12
]. We and others have noted that the CSF: plasma AA ratio is higher in AD patients than in controls and hypothesized that this was a reflection of the increased “consumption” of AA by the oxidatively stressed brain, leading to lower plasma levels. Based on this experience, we would predict that AD patients with higher CSF: plasma AA ratio would have more rapid rates of decline, but we observe the opposite in this sample where the slowest rates of cognitive decline are seen in subjects with the highest CSF: plasma AA ratio. This may be interpreted as evidence that either a high CSF: plasma AA ratio is causally related to rate of cognitive decline, or there is a non-causal correlation due to the fact that the ability to maintain a high CSF: plasma AA ratio is a marker of a “healthier” brain, more able to cope with the neurodegenerative process of AD. We argue that the latter explanation is more plausible, and we use data on BBB integrity to test this possibility. CSF Albumin Index, a marker of BBB integrity, attenuated the association of CSF: plasma AA ratio with cognitive outcomes, suggesting that the observed effect of CSF: plasma AA ratio on cognitive decline is partially attributed to underlying “barrier” function of the BBB. An inverse correlation between CSF: plasma AA ratio and CSF Albumin Index further supports the hypothesis that lower AA ratios in some patients may be due to BBB dysfunction, impairing the ability of the brain to maintain high CSF: plasma AA ratio due to diffusion of AA out of the CNS according to its concentration gradient.
To our knowledge, this is the first prospective study of cognitive decline in AD that quantifies CSF and plasma AA content and BBB integrity as modifiers of disease progression. Its strengths lie in its prospective design, consensus diagnosis of mild-to-moderate AD, and simultaneous collection of CSF and plasma AA and serum albumin. Its limitations are that CSF and plasma AA was measured only at baseline and our study population was relatively small (n = 32). Nevertheless, these findings support the hypothesis that BBB integrity is relevant to the progression of AD, and raise the possibility that BBB dysfunction accelerates the rate of degeneration not only by potentially exposing brain parenchyma to peripheral toxins, but by impairing the ability of the brain to concentrate AA and perhaps other nutrients with neuroprotective properties.