Human Alzheimer and Inflammation Biomarkers after Anesthesia and Surgery

Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Anesthesiology (Impact Factor: 5.88). 08/2011; 115(4):727-32. DOI: 10.1097/ALN.0b013e31822e9306
Source: PubMed


The prevalence of postoperative cognitive disturbance, coupled with growing in vitro, cell, and animal evidence suggesting anesthetic effects on neurodegeneration, calls for additional study of the interaction between surgical care and Alzheimer neuropathology. The authors studied human cerebrospinal fluid (CSF) biomarkers during surgery.
Eleven patients undergoing idiopathic nasal CSF leak correction were admitted to this Institutional Review Board-approved study. Lumbar subarachnoid catheters were placed before the procedure. Anesthesia was total intravenous propofol or remifentanil or inhalational sevoflurane, depending on provider choice. CSF samples were taken after catheter placement (base), at procedure end (0 h), and then at 6, 24, and 48 h. CSF was analyzed using xMAP Luminex immunoassay (Luminex, Austin, TX).
Of the 11 patients (age range, 53 ± 6 yr), 8 were women; 4 received intravenous anesthesia, 6 sevoflurane, and 1 mixed. Procedures lasted 6.4 ± 2 h. Mean CSF amyloid-β(1-42) remained unchanged, but total-tau and phosphorylated-tau181P increased progressively until at least 48 h. Total-tau, phosphorylated-tau, or amyloid-β(1-42) concentrations were not different between anesthetic groups. CSF interleukin-10, S100Beta, and tumor necrosis factor α were increased similarly in both anesthetic groups at 24 h, but interleukin-6 was increased more in the inhalational group.
These data indicate a robust neuroinflammatory response, including not only the usual markers (interleukin-6, tumor necrosis factor α, interleukin-10), but also S100Beta and tau, markers of injury. The total-tau/amyloid-β(1-42) ratio increased in a pattern consistent with Alzheimer disease, largely because of an increase in total-tau rather than a decline in amyloid-β(1-42). The differences in CSF interleukin-6 concentrations suggest that anesthetic management may make a difference in neuroinflammatory response.

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Available from: Maryellen F Eckenhoff, Feb 03, 2015
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    • "Tissue damage due to surgery leads to local inflammation. This local inflammatory response is paralleled by systemic and brain inflammation (Beloosesky et al., 2007; Cibelli et al., 2010; Tang et al., 2011). Interestingly , (neuro)inflammation has been associated with changes in cognition, affective behavior and fatigue (Capuron and Miller, 2011; Lotrich et al., 2011; Yirmiya and Goshen, 2011). "
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    ABSTRACT: Elderly patients may experience impairments in cognition or mood following surgery. To study the development and underlying mechanisms of these postoperative behavioral changes, young (3months) and aged (18-20months) male rats were subjected to abdominal surgery followed by behavioral testing during a period of 6weeks. Microglia activation (IBA-1) and neurogenesis (DCX) were immunohistochemically determined. In separate experiments, the effects of anesthesia and the cytokine response (IL-6) following surgery were evaluated. Increased age was associated with changes in affective behavior, decreased cognitive flexibility and increased microglia activation as well as increased weight loss and plasma IL-6 following surgery. No effects of surgery on cognition were observed at either age. However, aged rats displayed long-term changes in affective behavior and had increased microgliosis in the CA1 hippocampal region following surgery. Microglia activation following surgery was positively correlated to parameters of behavior and spatial learning. These findings support the hypothesis that elderly patients have an increased behavioral and (neuro)inflammatory response to surgery and these factors may be related.
    Full-text · Article · Jul 2013 · Experimental gerontology
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    • "Propofol, a commonly used intravenous anesthetic for GA, was demonstrated to produce less delayed cognitive impairment than inhalational anesthetics in older rats [46] [47]. Tang and colleagues [48] showed that GA with total IV drugs (propofol or remifentanil) had fewer neurotoxic or neuroinflammatory effects than inhalational anesthetics in human subjects. These studies suggest that inhalational anesthetics may have sustained effects on learning or memory, whereas others, such as IVGA anesthetics, have transient or milder effects. "
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    ABSTRACT: Dementia, which leads to disability, is one of the important diseases occurring among older populations. However, the exact mechanism of the disease remains unknown. The potential risk factor of general anesthesia (GA) in the development of dementia is a controversial topic. Therefore, this study aimed to evaluate the association between previous exposure to different GA types and the incidence of dementia. Using the claims data of 1 million insured residents covered by Taiwan's universal health insurance from 2005 to 2009, 5345 newly diagnosed dementia patients older than 50 years were eligible for the study group. The control group, which consisted of 21,380 individuals without dementia, was matched for age, gender, and index date. GA was categorized into three subtypes: endotracheal tube intubation general anesthesia (ETGA), intravenous injection general anesthesia (IVGA) or intramuscular injection general anesthesia (IMGA), and heavy sedation. The multiple logistic regression model was used for analyses. Individuals exposed to surgery under ETGA (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.25-1.44) and those exposed to surgery under IVGA or IMGA (OR, 1.28; 95% CI, 1.14-1.43) were at significantly higher risk of dementia in a dose-response relationship (P < .0001), whereas surgery under heavy sedation was not associated with increased risk of dementia (OR, 1.04; 95% CI, 0.68-1.59). The dementia risk for subjects with diabetes mellitus who received surgery under ETGA (OR, 1.59; 95% CI, 1.42-1.78), hypertension (OR, 1.98; 95% CI, 1.78-2.21), atherosclerosis (OR, 1.35; 95% CI, 1.22-1.50), or after having experienced a stroke (OR, 3.52; 95% CI, 3.13-3.97), but no interaction was found between surgery under ETGA and depression for the risk of dementia. A history of previous exposure to surgery under GA might be associated with an increased risk of dementia, particularly in subjects who have undergone repeated exposure to GA. In addition, subjects who had received surgery under ETGA with comorbidities such as stroke, hypertension, diabetes mellitus, and atherosclerosis could have a potential relationship with dementia risk.
    Full-text · Article · Jul 2013 · Alzheimer's & dementia: the journal of the Alzheimer's Association
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    • "These investigators measured levels of total tau and tau phosphorylated at Thr 181 in patients undergoing surgery for idiopathic cerebrospinal fluid leak correction, and observed that both total tau and phospho-Thr 181 steadily increased until at least 48 h, which was the last sampling time point. As the authors noted, the increase in phospho- Thr 181 postoperatively is particularly interesting, as increased levels of phosphorylation at this epitope in CSF has been observed to be the most sensitive indicator of cognitive decline in normal patients (Tang et al., 2011a). As noted above, it is not possible to dissociate the effects of anesthesia and surgery in patients. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia and remains a growing worldwide health problem. As life expectancy continues to increase, the number of AD patients presenting for surgery and anesthesia will steadily rise. The etiology of sporadic AD is thought to be multifactorial, with environmental, biological and genetic factors interacting together to influence AD pathogenesis. Recent reports suggest that general anesthetics may be such a factor and may contribute to the development and exacerbation of this neurodegenerative disorder. Intra-neuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated and aggregated tau protein are one of the main neuropathological hallmarks of AD. Tau pathology is important in AD as it correlates very well with cognitive dysfunction. Lately, several studies have begun to elucidate the mechanisms by which anesthetic exposure might affect the phosphorylation, aggregation and function of this microtubule-associated protein. Here, we specifically review the literature detailing the impact of anesthetic administration on aberrant tau hyperphosphorylation as well as the subsequent development of neurofibrillary pathology and degeneration.
    Full-text · Article · Mar 2013 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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