Worsening Cognitive Impairment and Neurodegenerative Pathology Progressively Increase Risk for Delirium

Abstract

BackgroundDelirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk.MethodsHumans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 μg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry.ResultsIn the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology.ConclusionA human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology.

The interface between delirium and dementia in elderly adults

“…The acute insult triggers acute, transient 81 and fluctuating 87 cognitive deficits during T-maze testing, and further neurodegeneration 78 and acceleration of disease trajectory is observed. 77 Other studies using this model have shown microglia express cyclo-oxygenase (COX) 1 and synthesise prostaglandins.…”

“…88 Inflammation was sufficient, but microglial priming was not essential, for similar deficits reproduced in cholinergic-deficient mice, which could be blocked by donepezil. 80 This suggests an important interplay between acetylcholine deficiency and systematic inflammation but the observation that worsening neurodegeneration makes animals progressively more susceptible to the cognitively disrupting effects of LPS 87 implicates several different neuronal networks.…”

Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration

“…The evidence that systemic inflammation has more robust effects on the frail or degenerating brain is accumulating in rodent studies (Barrientos et al, 2006, Buchanan et al, 2008, Field et al, 2012, Murray et al, 2012) and this is consistent with inflammatory triggering of human disorders such as delirium, which is a profound and acute cognitive impairment that frequently occurs during acute medical illness or after inflammatory traumas such as orthopedic fracture and surgery (Cunningham and Maclullich, 2013, Inouye et al, 2014). Existing cognitive impairment and neurodegenerative pathology are the key risk factors for delirium incidence and it has been shown that the risk of delirium is proportional to the extent of underlying pathology/baseline cognitive impairment (Davis et al, 2015). It is significant that in this model of acute systemic inflammation TNF-α alone is sufficient to induce acute dysfunction in a cognitive task reliant on attentional and working memory function, two key cognitive domains impaired in delirium.…”

Quantifying the Severity of a Delirium Episode Throughout Hospitalization: the Combined Importance of Intensity and Duration

“…1,4 Other studies examined delirium at discharge and cognitive change as severity indicators. 22,23 Thus, we chose to examine nine individual measures of delirium episode severity that were classified into four groups of measures requiring: 1) delirium intensity only (based on the 10-item CAM-S long form measurement), 2) delirium intensity and duration, 3) measures requiring information on delirium duration and delirium at discharge, and 4) a measure of cognitive change. We considered two measures that require delirium intensity (peak CAM-S score and mean CAM-S score), along with three measures that require delirium intensity plus delirium duration (sum of all CAM-S scores; sum of all CAM-S scores, only on delirium days; and peak CAM-S score × delirium days).…”