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Pathophysiology of Alzheimer disease Alzheimer disease is characterized by severe neurodegeneration, neuroinflammation, and progressive loss of cognitive abilities. The diagnostic criteria for dementia released by the National Institute on Aging-Alzheimer's Association define dementia as the development of cognitive or behavioral symptoms associated with decline in the previous level of performance, involving several cognitive domains that may not be explained by delirium or psychiatric disorders. Recently, the guidelines also included biomarkers as diagnostic criteria, such as decreased levels of amyloid protein (by oligomerization) associated with increased total tau or phosphorylated tau protein in cerebrospinal fluid (CSF). Moreover, the ratio between total tau protein and amyloid protein may also be used as an adjunct in Alzheimer disease diagnosis. The main disorder involved in its pathophysiology is abnormal protein folding. It has marked neuropathological characteristics, such as: 1) accumulation of senile plaques formed by ampk of extracellular amyloid protein; 2) formation of intraneuronal neurofibrillary tangles of hyperphosphorylated tau protein.14, 15 These disorders induce oxidative stress, neuronal inflammation and dysfunction with eventual cell death. Loss of hemostasis from tau protein phosphorylation may result from deregulation of the kinases and phosphatases involved in this process. Environmental factors may also contribute to changes in signal transduction leading to loss of this balance and culminating in neurofibrillary degeneration and cell death. The amyloid hypothesis recognizes that deregulation between amyloid protein production and clearance leads to its accumulation. This hypothesis also contemplates that some forms of amyloid peptide are neurotoxic and contribute to tau protein abnormal phosphorylation. Ultimately, this cascade culminates in mitochondrial damage, calcium deregulation, apoptosis, and neurodegeneration. Biomarker studies have shown that CSF amyloid protein concentrations are inversely related to the degree of Alzheimer's disease. However, both amyloid plaques and amyloid protein declining can be found in the elderly without clinical signs of cognitive dysfunction, so amyloidosis alone appears to be insufficient for the development of dementia symptoms. Some neurotransmitters appear to play a role in the context of Alzheimer's dementia. Cholinergic dysfunction appears to be involved in the clinical symptoms of dementia. Alzheimer disease appears to be associated with loss of cholinergic neurons since acetylcholine modulates higher brain functions, such as attention, learning, and memory. Thus, the degree of cognitive dysfunction may be associated with the cholinergic deficit present, which raises the question about the potential role of acetylcholinesterase inhibitors. The attempt to relate environmental exposures such as anesthesia to Alzheimer disease development should be based on evidence between exposure and pathophysiological processes underlying the disease. In addition, surgery alone is considered to promote inflammatory stress response, which may promote the disease pathogenesis.
Animal models Several studies have found evidence that anesthetic agents may contribute to or even exacerbate neurodegenerative diseases such as Alzheimer's disease.22, 23 While some studies have shown changes in cytokine and tau protein levels in human CSF fluid following anesthesia/surgery, coinciding with the levels found in patients with this dementia, other studies did not find a significant contribution of anesthesia and surgery in its development.24, 25 The use of animal models allows the exploration of mechanisms through which anesthetics may be involved in the Alzheimer disease pathogenesis. A pilot in vitro study using a free cell model demonstrated that volatile anesthetics, such as halothane, isoflurane, and sevoflurane could potentiate the oligomerization and cytotoxicity of Alzheimer's disease-related amyloid peptides. It should be noted that amyloid protein oligomerization with halothane was dose-dependent and the doses used were high (∼4 MAC). The effect remained for hours after the volatile anesthetic washout. In vitro and animal studies have shown that the use of 1.4% isoflurane and 2.5% sevoflurane for 2h potentiates the processing of amyloid precursor protein into amyloid protein, increasing its brain levels in wild type mice (five months old), which leads to caspase-3 activation and causes neuronal apoptosis.27, 28 A recent study reported that anesthesia with 2.1% sevoflurane for 6h can induce caspase-3 activation and increase amyloid protein levels in brains of six-day naive mice and transgenic mice models of Alzheimer disease (mutation of amyloid precursor protein) which may be more vulnerable to neurotoxicity. Thus, it has been shown that certain mouse models have an increased risk for developing Alzheimer's disease.