Abstract
Post-operative delirium (POD) is the most common complication following major surgery in non-demented older (>65 y/o) patients. Patients experiencing POD show increased risk for future cognitive decline, including mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and, conversely, patients with cognitive decline at surgery show increased risk for POD. Here, we demonstrate that a previously established panel of AD-driven MCI (ADMCI) autoantibody (aAB) biomarkers can be used to detect prodromal AD pre-surgically in individuals admitted into the hospital for hip fracture repair (HFR) surgery. Plasma from 39 STRIDE (STRIDE: A Strategy to Reduce the Incidence of Postoperative Delirium in Elderly Patients) HFR patients and sera from 25 age- and sex-matched non-demented and non-surgical controls were screened using human protein microarrays to measure expression of a panel of 44 previously identified MCI aAB biomarkers. The predictive classification accuracy of the aAB biomarker panel was evaluated using Random Forest (RF). The ADMCI aAB biomarkers successfully distinguished 21 STRIDE HFR patients (CDR = 0.5) from 25 matched non-surgical controls with an overall accuracy of 91.3% (sensitivity = 95.2%; specificity = 88.0%). The ADMCI aAB panel also correctly identified six patients with preoperative CDR = 0 who later converted to CDR = 0.5 or >1 at one-year follow-up. Lastly, the majority of cognitively normal (CDR = 0) STRIDE HFR subjects that were positive for CSF AD biomarkers based on the A/T/N classification system were likewise classified as ADMCI aAB-positive using the biomarker panel. Results suggest that pre-surgical detection of ADMCI aAB biomarkers can readily identify HFR patients with likely early-stage AD pathology using pre-surgery blood samples, opening up the potential for early, blood-based AD detection and improvements in peri- and postoperative patient management.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease afflicting approximately 5.8 million people in the US, including almost half of those at 85 years and older [1–3]
Random Forest (RF) analysis of the resulting aAB profiles demonstrated that 20 of Clinical Dementia Rating (CDR) = 0.5 hip fracture repair (HFR) subjects and of 25 non-demented controls were correctly classified as mild cognitive impairment (MCI) and controls, respectively (Table 2), which translates into an overall accuracy of 91.3% (Table 3)
We asked if the panel of AD-driven MCI (ADMCI) aAB biomarkers could be used to identify cognitively normal individuals who are at high risk for progressing to MCI or dementia at one year follow-up based on aAB profiles obtained from their presurgical blood samples
Summary
AD is a progressive neurodegenerative disease afflicting approximately 5.8 million people in the US, including almost half of those at 85 years and older [1–3]. It is generally agreed that AD-related neuropathological changes can begin in the brain as early as 20 years before symptoms appear and can be evaluated for diagnosis and potential treatment [5–11]. This delay in emergence of symptoms after the onset of pathology makes it difficult to identify AD patients at earlier, preclinical (or pre-symptomatic) and prodromal (mild cognitive impairment, MCI) disease stages, i.e., at times when disease-modifying treatments would likely be most effective and beneficial. CSF levels of phosphorylated tau (p-tau) and total tau (t-tau), biomarkers of tau pathology and neurodegeneration or injury, respectively, have been used successfully together or in combination with Aβ42 as positive indicators of existing AD pathology [18, 25]
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