Association of postoperative delirium with markers of neurodegeneration and brain amyloidosis: a pilot study

Abstract

The aim of the study was to investigate the association between postoperative delirium (POD) and in vivo markers of Alzheimer's disease pathology in nondemented hip fracture surgery patients. POD was assessed with the Confusion Assessment Method. Amyloid load was quantified on ¹⁸F-Flutemetamol positron emission tomography images as standardized uptake value ratio. Secondary outcome measures were gray matter volumes, white matter integrity, and functional connectivity at rest. All the patients with POD (POD+, N = 5) were amyloid negative (standardized uptake value ratio <0.59), whereas 6 out of 11 patients without POD (POD−) showed brain amyloid positivity. POD+ compared to POD− displayed: lower gray matter volumes in the amygdala (p = 0.003), in the middle temporal gyrus and in the anterior cingulate cortex (p < 0.001), increased diffusivity in the genu of the corpus callosum and in the anterior corona radiata (p < 0.05), and higher functional connectivity within the default mode network (p < 0.001). POD patients showed altered gray and white matter integrity in the fronto-limbic regions in absence of brain amyloidosis. Based on this preliminary investigation, delirium pathophysiology might be independent of Alzheimer's disease. Future studies on larger samples are needed to confirm this hypothesis.

Introduction

Delirium is a neurocognitive disorder characterized by acute and fluctuating disturbance in attention and awareness with additional changes in other cognitive domains (American Psychiatric Association, 2013), and it is commonly reported in elderly patients after major surgery (Inouye et al., 2014). Although delirium is defined by its acute onset, it is now clear that it is associated with subsequent loss of independence, increased risk of mortality, and long-term cognitive decline and dementia, even in the absence of presurgery cognitive impairment (Bellelli et al., 2014, Gleason et al., 2015). The multifactor theory for postoperative delirium (POD) etiology in elderly postulates that vulnerable brain could be less resilient to various stressors, leading to acute brain dysfunctions and to further inability to return to the previous levels of functioning (Inouye et al., 2014). However, the specific nature of brain vulnerabilities increasing the risk of POD in elderly and leading to the subsequent long-term cognitive impairment has to be discovered.

Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by extracellular deposition of beta amyloid and intracellular accumulation of tau protein in the brain. These pathophysiological processes can be detected in vivo by surrogate markers using positron emission tomography (PET) or cerebrospinal fluid (CSF) (Scheltens et al., 2016). AD patients furthermore showed impaired structural and functional connectivity within the default mode network (DMN), which involves brain areas early affected by AD pathology such as the posterior cingulate and the precuneus, the parietal cortex, the hippocampus, and the medial prefrontal cortex (Pievani et al., 2014). Amyloid may be present in the brain up to 10–20 years before the onset of clinical symptoms (Villemagne et al., 2013), and around 30% of cognitively normal older individuals show amyloid burden (Sperling et al., 2009); therefore, the presence of cortical amyloidosis in nondemented elderly could represent a major cause of poor brain resiliency. Few studies investigating the predictive value of CSF beta amyloid for POD onset in hip fracture surgery patients led to contrasting results (Witlox et al., 2011, Xie et al., 2014). Furthermore, very recent postmortem studies in oldest-old suggested that the relationship between history of delirium and dementia was not mediated by the typical neuropathological hallmarks of classic dementia, with delirium independently and additively affecting the rate of cognitive decline (Davis et al., 2017). Studies prospectively evaluating the relationship between in vivo AD pathophysiology and POD are needed, in order to improve our understanding of delirium pathophysiology and to further ameliorate the management of patients with cognitive impairment after POD.

Recently, presurgery gray matter (GM) volume decrease in temporal and limbic lobes (Shioiri et al., 2015) and reduced white matter (WM) integrity (Cavallari et al., 2016) were found to increase vulnerability to POD in elective surgery patients. Elective surgery is an ideal approach to investigate the brain vulnerabilities predisposing to POD, since it allows neuroimaging examinations to be performed before surgery. However, individuals after nonelective surgery were a more frail population with increased risk of delirium and adverse long-term outcomes compared to the elective surgery ones, deserving further investigations (Rizk et al., 2016).

The primary aim of the present study was to use in vivo estimation of brain amyloid load and neurodegenerative processes to investigate the association between AD pathology and POD in hip fracture surgery elderly patients. Moreover, we explored the association of markers of brain structural and functional connectivity disruption with POD.