A growing body of evidence suggests that neuroinflammation plays a role in the development of neurodegeneration in patients with Alzheimer’s disease. Modulation of neuroinflammation may be possible early in the pathogenesis, though less so once cognitive symptoms appear. In particular, events during the perioperative period can modulate neuroinflammatory pathways and thereby impact the pathogenesis of Alzheimer’s disease. Such perioperative events include the anesthetic, surgery, pain, and sepsis (1).
Inflammation in the central nervous system (CNS) is mediated by cellular and humoral mechanisms which primarily involve the microglial cell. Derived from myeloid precursors in the bone marrow, microglia evenly distribute throughout the brain and perform several age-dependent functions, including brain development, synaptic plasticity, immune surveillance, and repair (2). In response to stressors – such as ischemia, trauma, and pathogens – microglia become activated and migrate to the affected areas. Subsequently, microglia undergo morphological changes that cause them to resemble macrophages, the phagocytic cells of the immune system (2). This morphological change heralds the production of cytokines, chemokines, growth factors, and reactive oxygen species, as well as the initiation of phagocytosis.
Migroglia activation during a neuroinflammatory response can be both beneficial and harmful (3). On the one hand, microglia clear apoptotic cells, dysfunctional synapses, and amyloid-β plaque, as well as promote repair by secreting neurotrophic factors and producing anti-inflammatory cytokines, such as interleukin-10. On the other hand, microglia activation is accompanied by a pro-inflammatory response mediated by interleukin-beta, interleukin-6, tumor necrosis factor, and reactive oxygen species, resulting in synaptic, neuronal, and ultimately cognitive dysfunction. Although the precise mechanisms remain unclear, neuroinflammation is a hallmark of Alzheimer’s disease. For example, researchers observed that patients taking anti-inflammatory drugs, e.g. for arthritis, displayed a lower incidence and later onset of Alzheimer symptoms (4). Based on such observations, randomized trials were performed, which confirmed the protective effects of anti-inflammatory drugs, such as ibuprofen, on the development of Alzheimer’s disease (5). Additional studies show increased levels of activated microglia and pro-inflammatory proteins (e.g. interleukin-6 and tumor necrosis factor) in patients with neurodegenerative diseases (6). That said, it remains unclear whether Alzheimer’s disease is primarily due to amyloidopathy (i.e. accumulation of amyloid), the brain’s inflammatory response, or dysfunctional microglial responses.
In the perioperative period, both anesthesia and surgery can modulate inflammation and cognition. For example, there is substantial evidence for the anti-inflammatory properties of local anesthetics, namely lidocaine (7). Furthermore, some studies demonstrate that isoflurane attenuates peripheral and central inflammatory markers (e.g. interleukin-beta, interleukin-6, tumor necrosis factor, and microglia), albeit other studies provide conflicting data (8-9). The possible mechanisms for anesthetic effects on inflammation include alterations in the blood brain barrier permeability (10), alterations in monocyte recruitment (11), and direct interactions with signaling molecules, such as integrins (12).
It is also well established that surgery plays a role in the inflammatory response, with the magnitude of inflammation roughly proportional to the amount of tissue damage (13). However, robust peripheral responses attenuate before manifesting in the CNS, likely due to the short-lived nature of humoral factors, as well as the blood brain barrier. Nevertheless, cytokines may enter the CNS in the event of blood brain barrier damage or by active transport across epithelial cells (14). Upon entering the CNS, these signals may activate microglia and initiate the neuroinflammatory response – though administration of a variety of anti-inflammatory drugs can prevent such events.
Much of the evidence supporting an interaction between surgery, inflammation, postoperative cognitive dysfunction, and Alzheimer’s disease comes from animal studies. For example, in young WT mice, surgery but not anesthesia led to neuroinflammation and acute cognitive losses (15). Overall, the current literature suggests that anesthesia alone causes only a modest neuroinflammatory response, while surgery causes a robust peripheral inflammatory response that is attenuated in the CNS. However, few studies examine the long term consequences of anesthesia and surgery on the pathology of Alzeihmer’s disease. Considering that many patients with cognitive complaints undergo surgery each year, there is ample opportunity to further study this complex issue in humans.
References
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