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Postoperative delirium is one of the most common postoperative complications in elderly patients. It has been shown that postoperative delirium has independent adverse effects on short and long-term mortality and morbidity, including poor functional recovery, postoperative cognitive dysfunction, deterioration in quality of life, and increased costs[3-6] (reviewed in refs. [7, 8]). However, at the present time, postoperative delirium is a clinical phenomenon, and its neuropathogenesis remains unknown. This gap in knowledge has become a barrier that limits further studies, including the development of potential interventions for postoperative delirium.
β-Amyloid protein (Aβ), including Aβ40 and Aβ42, is the key component of senile plaques in Alzheimer's disease (AD) patients. Tau is the major protein component of intraneuronal neurofibrillary tangles. Both Aβ and Tau are hallmark features of AD neuropathogenesis (reviewed in ref. ).
Lower levels of cerebrospinal fluid (CSF) Aβ42 have been found to be associated with higher brain amyloid amounts,[10-13] and appear in AD patients as compared to normal controls.[14, 15] Higher levels of CSF Tau are associated with elevated brain Tau levels,[13, 16] and with the progression of AD.[17-19] Therefore, higher CSF Tau to Aβ42 ratio or lower CSF Aβ42 to Tau ratio can distinguish AD patients from healthy controls and predict the development of AD (reviewed in ref. ). In addition to Aβ42, Aβ40 has been shown to induce neurotoxicity[23-25] and is associated with cognitive dysfunction and dementia.[26-28] Moreover, we recently published a study that reported that both CSF Aβ40/Tau ratio and Aβ42/Tau ratio were associated with postoperative cognitive changes, although each ratio was associated with changes in different cognitive domains. We, therefore, used the CSF Aβ/Tau ratio, not the mathematically different but scientifically equivalent CSF Tau/Aβ ratio, in the studies, and assessed whether human CSF Aβ40/Tau or Aβ42/Tau ratio would be associated with postoperative delirium.
Therefore, we performed a prospective investigation in patients who had elective total hip/knee replacement under spinal anesthesia to assess whether there were associations between preoperative human CSF Aβ40/Tau or Aβ42/Tau ratio and the incidence and severity of postoperative delirium. The current proof of concept study was performed in 153 participants. The primary hypothesis in this study was that lower preoperative CSF Aβ42/Tau ratio would be associated with greater severity of postoperative delirium. Our secondary hypotheses were that preoperative CSF Aβ40/Tau ratio would be also associated with postoperative delirium severity, and that both CSF Aβ42/Tau ratio and Aβ40/Tau ratio would be associated with the incidence of postoperative delirium. We chose the severity of postoperative delirium in the current research because there have been no studies to determine the association between the human CSF biomarkers and the severity of postoperative delirium. Moreover, given our anticipated relatively small sample size, using the continuous outcome of delirium severity maximizes statistical power, which is appropriate for this hypothesis generating study. The outcomes from this study mainly served to establish a system and to generate a concept that Aβ and/or Tau might contribute to the neuropathogenesis of postoperative delirium, which would promote more studies to further investigate the neuropathogenesis of postoperative delirium.
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We assessed the association between preoperative CSF Aβ40/Tau or CSF Aβ42/Tau ratio and the incidence and severity of postoperative delirium in this prospective study of 153 older adults who had total hip and knee replacement under spinal anesthesia. Aβ40, Aβ42, and Tau have been reported to contribute to neurotoxicity, cognitive dysfunction, dementia, and postoperative cognitive changes[14, 15, 17-19, 23-29] (reviewed in ref. ), and dementia is a risk factor of delirium.[4, 34] Therefore, we chose Aβ40, Aβ42, and Tau in the studies to determine whether these proteins may also contribute to postoperative delirium.
We found that the patients in the lowest quartile of CSF Aβ40/Tau and CSF Aβ42/Tau ratios (consistent with the AD biomarker) had the highest incidence of delirium (Fig. 2) and more severe symptoms of delirium represented by higher MDAS scores (Fig. 3). We also found that lower CSF Aβ40/Tau and CSF Aβ42/Tau ratios were significantly associated with greater postoperative delirium severity represented by a higher MDAS score (Table 2). Collectively, these findings suggest that Aβ and Tau may contribute to the neuropathogenesis of postoperative delirium, pending further studies.
Delirium incidence is a dichotomous outcome; therefore, we did not use linear models to analyze the incidence of postoperative delirium. Preoperative CSF Aβ/Tau ratio was not significantly associated with the postoperative delirium incidence, but was associated with the severity of postoperative delirium. We believe this difference is explained primarily by issues of statistical power. It is notable that lower preoperative CSF Aβ/Tau ratio is associated with both higher incidence and greater symptom severity of postoperative delirium, which is demonstrated in Figures 2, 3, respectively.
The postoperative delirium incidence depends on type of surgery, varying from 12% (otolaryngological surgery) up to 50% (major abdominal surgery) (reviewed in ref. ). The postoperative delirium incidence in the patients who have total joint replacement has been reported to be from 3.6% to 41%[35-39] (reviewed in ref. ). The incidence of postoperative delirium after total joint replacement in all ages of patients is 9–15% (reviewed in ref. ), and this incidence of postoperative delirium will be higher in older adults. The variation in the postoperative delirium incidence could be due to the influence of perioperative factors, including sedation levels, cognitive status, history of central nervous system disease, and postoperative pain levels. Therefore, the postoperative delirium incidence (20%) in this study was consistent with the incidence reported in other studies of total knee and hip replacement, demonstrating validity to our delirium assessment methods.
In a prospective cohort study in older adults with hip fracture, Witlox et al. found that CSF Aβ42, Tau, and phosphorylated Tau were not associated with postoperative delirium. However, the studies by Witlox et al. did not assess the association of preoperative CSF Aβ/Tau ratio with the postoperative delirium. In the current studies, we did not find the association between preoperative CSF Aβ40, Aβ42, or Tau with the incidence or severity of postoperative delirium either (data not shown). However, we investigated the association between the preoperative CSF Aβ40/Tau or Aβ42/Tau ratio and the incidence and severity of postoperative delirium, and we found an inverse association. Also of note, the subject population in the studies by Witlox et al. (patients who had surgical repair for acute hip fracture) was different from the participants in the current studies (patients who had elective total hip or total knee replacement). Taken together, the cohort and the variables measured were different between the studies by Witlox et al. and our current studies, which might explain the different findings and conclusions.
Lower levels of CSF Aβ42 and higher levels of CSF Tau are associated with the progression of AD.[14, 15, 17-19] Therefore, CSF Tau/Aβ42 ratio has been used for the diagnosis of AD dementia and prediction of its progress. The higher the CSF Tau/Aβ42 ratio or the lower CSF Aβ42 to Tau ratio, the worse the cognitive function in AD patients (reviewed in ref. ). Consistently, the current findings showed that the lower preoperative CSF Aβ40/Tau or Aβ42/Tau ratio might also predict postoperative delirium and suggested that more severe postoperative delirium symptoms may occur. Dementia is known as the most consistent risk factor of delirium.[4, 34] Taken together, these findings suggest that some AD neuropathogenesis, for example, accumulation of Aβ in the brain, could also be part of the neuropathogenesis of postoperative delirium. The future studies to further test this hypothesis are warranted.
Moreover, low CSF Aβ level represents high brain Aβ amounts, owing to the sequestration of Aβ into brain amyloid plaques,[16, 44] and CSF Tau levels represent brain Tau levels.[16, 44] Therefore, the findings that a lower CSF Aβ/Tau ratio is associated with higher incidence and greater severity of postoperative delirium also suggest that elevated brain Aβ levels may be associated with postoperative delirium. This hypothesis is supported by the fact that age is a risk factor of delirium, and aging is associated with elevated levels of Aβ in the brain. Further studies are needed to test this hypothesis by determining whether the amount of amyloid in the brain is associated with the incidence and severity of postoperative delirium, for example, by using positron emission tomographic imaging (PET) for amyloid.
We previously demonstrated that preoperative CSF Aβ40/Tau or CSF Aβ42/Tau ratio was associated with certain domains of postoperative cognitive change, and this study showed that the preoperative CSF Aβ40/Tau or CSF Aβ42/Tau ratio was associated with the incidence and severity of postoperative delirium symptoms. These results suggest that changes in the levels of Aβ and Tau in CSF and brain may be a common neuropathogenesis underlying both postoperative delirium and postoperative cognitive dysfunction. This hypothesis is further supported by the findings that postoperative delirium is associated with a significant decline in cognitive ability during the first year after cardiac surgery. Collectively, these results would promote further studies to determine the potential association, neuropathologically and behaviorally, among postoperative delirium, postoperative cognitive dysfunction, and dementia.
Postoperative delirium has been suggested to relate to neuroinflammation. However, although all patients may have a surgery-induced increase in proinflammatory cytokines in the blood that can enter the brain through the blood brain barrier[48, 49] to induce neuroinflammation, not every patient develops postoperative delirium. Thus, it is plausible that patients who develop postoperative delirium have other changes in the brain that facilitate neuroinflammation. The findings from the current studies that lower CSF Aβ/Tau ratio is associated with higher incidence and greater severity of postoperative delirium symptoms suggest that Aβ or Tau could be one of these changes.
It has been reported that there are large variations in the levels of CSF Aβ and Tau between the different studies, which could be caused by the differences in analytical procedures and the analytical kits. The values of Aβ and Tau in our current studies might also be different from those of the other studies. However, the CSF Aβ and Tau levels in the current studies were measured using the same methods by the same person, who had ample experience with the assays (Y.D.). Therefore, although the absolute values of CSF Aβ and Tau may differ from those reported in other studies, the relative differences in the CSF Aβ and Tau levels between the subjects are consistent. Moreover, the intra-assay coefficient of variations of CSF Aβ40 (21.8%), Aβ42 (18.7%), and Tau (6.8%) were still in the acceptable to good range, and within the range reported elsewhere in the literature (13–36%). Finally, there was no significant difference among the repeated values of CSF Aβ40, Aβ42, and Tau obtained in different measurements of our current studies. Taken together, we believe the results provide strong evidence that the associations between the CSF Aβ/Tau ratio and the postoperative delirium incidence and severity in the current studies are valid.
This study has several limitations. First, the majority of the participants were white and had education beyond high school. It remains unknown whether the association between CSF Aβ/Tau ratio and postoperative delirium would still exist in nonwhite participants with lower education levels. Second, we did not determine the preoperative cognitive function (e.g., MMSE) in this study, therefore, it remains unknown whether the relationship between preoperative CSF Aβ/Tau ratio and postoperative delirium remains significant after adjusting for measured preoperative cognitive function. However, the primary goal of the current studies was not to validate the CSF Tau/Aβ ratio as an independent predictive biomarker for delirium, but rather to assess a concept that Aβ and Tau might contribute to the neuropathogenesis of delirium. Therefore, we did not want to adjust for MMSE because low preoperative cognitive function (measured by MMSE) would be on the causal pathway between Aβ and Tau effects and delirium. However, given we did not perform baseline cognitive function, we could have missed some (milder) cases of dementia. Third, we did not assess whether patients had preoperative delirium. However, the patients all came to hospital by themselves for elective surgery, and they were assessed, including mental function examination, by both nurses and anesthesiologists before surgery. Therefore, the likelihood of participants having preoperative delirium is low. Finally, the spectrum of delirium was mild in this study as the MDAS score was relatively low. The observation could be due to the fact that the population of this study was relatively healthy and, it is possible that MDAS scores might represent mild reversible cognitive impairment. Nevertheless, our findings with delirium severity complement and extend the findings with CAM-defined postoperative delirium.
In conclusion, we have found that the patients who have lower preoperative CSF Aβ40/Tau or Aβ42/Tau ratio, particularly those in the lowest quartile, are more likely to develop postoperative delirium and have more severe symptoms. These findings have established a system and generated a concept for the future studies. If confirmed and extended in future studies, these findings may shed light on the currently undefined neuropathogenesis of postoperative delirium. These studies will hopefully promote the development of more targeted interventions to prevent and treat postoperative delirium, ultimately leading to safer surgery care and better postoperative outcomes for patients.