Anesthesia, surgery, illness and Alzheimer's disease

Abstract

Patients and their families have, for many decades, detected subtle changes in cognition subsequent to surgery, and only recently has this been subjected to scientific scrutiny. Through a combination of retrospective human studies, small prospective biomarker studies, and experiments in animals, it is now clear that durable consequences of both anesthesia and surgery occur, and that these intersect with the normal processes of aging, and the abnormal processes of chronic neurodegeneration. It is highly likely that inflammatory cascades are at the heart of this intersection, and if confirmed, this suggests a therapeutic strategy to mitigate enhanced neuropathology in vulnerable surgical patients.

Keywords: 3xTgAD; ADNI; ADRC; ARDS; Alzheimer Disease Neuro Imaging; Alzheimer Disease Research Center; Alzheimer transgenic mice; Biomarkers; CABG; CSF; Cytokines; IL-10; IL-4; IL-6; Interleukin-10; Interleukin-4; Interleukin-6; LFA-1α; MCI; NSAID; Neuroinflammation; POCD; Peripheral inflammation; SAE; TGFβ; TNFα; Tumor Necrosis Factor-α; WT; adult respiratory distress syndrome; cerebrospinal fluid; coronary artery bypass surgery; leukocyte functional antigen-1α; mild cognitive impairment; non-steroidal anti-inflammatory drugs; post-operative cognitive decline; sepsis associated encephalopathy; transforming growth factor-β; triple transgenic mouse model of Alzheimer disease; wild type.

Fig. 1

A simplified conceptual model for what might be happening subsequent to anesthesia, surgery and/or illness in both the normal and the vulnerable brain. The presumed immediate effect of surgery is peripheral inflammation, the magnitude of which might be modulated by the anesthetic choice (indicated by the “?”). The peripheral inflammatory mediators (or neural afferents), cross the blood brain barrier (BBB), and activate microglia. Depending on the prior state of these immune cells, the response could be appropriate and balanced, as indicated for the normal brain, or amplified and unbalanced in the vulnerable Alzheimer (AD) brain. Presumably, the microglia in the vulnerable brain have already been activated, or “primed”, by disease-related proteins, like amyloid-β. Structural injury in the vulnerable brain may include the BBB, which further enhances inflammatory mediator entry. The degree and duration of cognitive loss will depend on the degree of inflammation-induced structural (synaptic) injury.