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Objective  The present work evaluates the relationship between postoperative immune and neurovascular changes and the pathogenesis of surgery‐induced delirium superimposed on dementia.    Background and rationale  Postoperative delirium is a common complication in many older adults and in patients with dementia including Alzheimer's disease (AD). The course of delirium can be particularly debilitating, while its pathophysiology remains poorly defined.    Historical evolution  As of 2019, an estimated 5.8 million people of all ages have been diagnosed with AD, 97% of whom are >65 years of age. Each year, many of these patients require surgery. However, anesthesia and surgery can increase the risk for further cognitive decline. Surgery triggers neuroinflammation both in animal models and in humans, and a failure to resolve this inflammatory state may contribute to perioperative neurocognitive disorders as well as neurodegenerative pathology.    Updated hypothesis  We propose an immunovascular hypothesis whereby dysregulated innate immunity negatively affects the blood‐brain interface, which triggers delirium and thereby exacerbates AD neuropathology.    Early experimental data  We have developed a translational model to study delirium superimposed on dementia in APPSwDI/mNos2 −/−  AD mice (CVN‐AD) after orthopedic surgery. At 12 months of age, CVN‐AD showed distinct neuroimmune and vascular impairments after surgery, including acute microgliosis and amyloid‐β deposition. These changes correlated with attention deficits, a core feature of delirium‐like behavior.    Future experiments and validation studies  Future research should determine the extent to which prevention of surgery‐induced microgliosis and/or neurovascular unit dysfunction can prevent or ameliorate postoperative memory and attention deficits in animal models. Translational human studies should evaluate perioperative indices of innate immunity and neurovascular integrity and assess their potential link to perioperative neurocognitive disorders.    Major challenges for the hypothesis  Understanding the complex relationships between delirium and dementia will require mechanistic studies aimed at evaluating the role of postoperative neuroinflammation and blood‐brain barrier changes in the setting of pre‐existing neurodegenerative and/or aging‐related pathology.    Linkage to other major theories  Non‐resolving inflammation with vascular disease that leads to cognitive impairments and dementia is increasingly important in risk stratification for AD in the aging population. The interdependence of these factors with surgery‐induced neuroinflammation and cognitive dysfunction is also becoming apparent, providing a strong platform for assessing the relationship between postoperative delirium and longer term cognitive dysfunction in older adults.

Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia