Despite the small numbers of patients enrolled in this biomarker study, several observations are of interest. First, the standard, diagnostic measure of Alzheimer's disease, Aβ1-42
remained unchanged throughout the perioperative period. In Alzheimer's disease, this biomarker is lowered to 144 ± 41 pg/ml in the CSF,17
presumably due to sequestration into senile plaque, although there might also be less release into the extracellular space because of the synaptic destruction characteristic of this neurodegenerative process.19
Even mild cognitively impaired patients have CSF Aβ1-42
levels that are significantly lower than observed here at any time point (164 ± 55 pg/ml). Few studies on the effect of an acute intervention have been conducted however, so it is not clear whether any acute changes in CSF Aβ1-42
are to be expected even if the intervention were known to enhance Alzheimer's neurodegeneration.
On the other hand, the dramatic and progressive increase in CSF t-tau does suggest that an acute CNS injury of some sort has occurred. Tau is a microtubule associated protein that normally has an intracellular location. On hyperphosphorylation, it dissociates from microtubules, and can then aggregate to form paired helical filaments and when in excess, neurofibrillary tangles, a hallmark intracellular lesion of Alzheimer's disease. The appearance of tau in CSF is likely to reflect cellular damage and release rather than the more complex Aβ1-42
process, which involves proteolysis, release, oligomerization and extracellular plaque formation. This is consistent with the elevation in CSF S100B. Even though considered non-specific, there exists consensus that S100B elevation reflects CNS injury, most likely due to release from astrocytes, Schwann cells and other CNS cell types. While some may speculate that the anesthetic drug itself is responsible for the stress or cytotoxicity underlying the biomarkers, the similar changes observed with very different anesthetic approaches renders this somewhat less likely. It is perhaps more likely due to the surgery-induced inflammatory cascade, for which we provide ample biochemical evidence, as has been observed in brain tissue from wild type mice undergoing hepatectomy.7
We cannot rule out, however, that the changes in tau and S100B are due to local tissue damage caused by the surgeon in the vicinity of the CSF leak repair. This seems unlikely since tau and S100B are considered to have a CNS origin, and have a different time course after tissue injury than observed here.20
The ratio of t-tau to Aβ1-42
after 24h post-operatively approximates that seen in patients with diagnosed mild cognitive impairment.9
It is important to point out, however, that in the ADNI study, the progressive increase in this ratio is driven primarily by a larger decrease in Aβ1-42
and a smaller increase in t-tau. Since the increase in this ratio in our patients is driven almost entirely by an increase in t-tau, the significance with respect to Alzheimer neuropathology remains unclear.
Allthough smaller in magnitude than t-tau, the repeated measures ANOVA indicated a significant time effect in CSF p-tau181p
perioperatively (), with levels elevated over 20% at 6 and 24 h as compared to immediate post-operative samples. Tau phosphorylation is antecedent to microtubule detachment and destabilization, in addition to neurofibrillary tangle formation, a hallmark lesion of Alzheimer's disease. Increases in CSF p-tau181p
have been found to be the most sensitive predictor of cognitive decline in otherwise cognitively normal patients.10
Thus, CSF p-tau181p
should be considered as a potentially useful biomarker for postoperative cognitive decline in future studies, and perhaps risk stratification. Whether it can be considered a predictor of Alzheimer's dementia in these patients is unclear.
Our data clearly indicate that anesthesia and surgery initiate an acute pro-inflammatory event in the CNS, consistent with recent studies in both humans21
The pro-inflammatory cytokines IL-6 and tumor necrosis factor α were all elevated in the 24-48 h following surgery, and the “anti-inflammatory” IL-10 became modestly elevated. Surgical initiation of inflammatory cascades is well-known in the periphery,23
but has been less well documented in the CNS, where it would be considered “neuroinflammation”. Enhanced neuroinflammation is hypothesized to worsen Alzheimer neuropathology, and thus our results may indicate one mechanism by which the perioperative period might modulate ongoing neurodegeneration. Most interestingly, we detected a significant difference in IL-6 levels between anesthetic management approaches. Maintenance with the inhalational anesthetic sevoflurane was associated with significantly higher CSF IL-6 levels than maintenance with TIVA (propofol and reminfentanil). Although this finding is consistent with the repeated observation of inhaled anesthetic-induced neurotoxicity (usually isoflurane), it should be emphasized that few side-by-side comparisons with TIVA have been conducted, so it cannot yet be concluded that TIVA is less neurotoxic or neuroinflammatory than inhalational general anesthesia. Although the significance of an isolated CNS IL-6 change is not clear, the difference in IL-6 levels between these two approaches is not small, and may indicate either a more pro-inflammatory effect of sevoflurane or a more cytotoxic effect that secondarily triggers IL-6 release.
This biomarker study indicates that anesthesia and surgery evoke a robust neuroinflammatory response, and an injury response marked by large increases in t-tau and S100B. Limited evidence suggests that anesthetic management may modulate this inflammatory response. The lack of effect of anesthesia and surgery on Aβ1-42 suggests the lack of a specific interaction with amyloidopathy pathways, although a small effect on CSF p-tau181p suggest a potential interaction with tauopathy pathways. The relevance of these observations to long term consequences must be tempered by the fact that few biomarker studies after an acute intervention have been performed, and the evolution of biomarker changes remains unclear.