Acetylcholinesterase activity measurement and clinical features of delirium

Aims: Cholinergic deficiency is commonly implicated in the pathophysiology of delirium. We aimed to investigate the relationship between directly measured serum AChE activity and (1) clinical features of delirium and (2) outcomes, among older hospital patients with delirium. Methods: Hospitalized patients with delirium were recruited and delirium motor subtype, severity and duration of delirium were measured. Serum AChE activity was measured using a colorimetric assay. Results: The mean AChE activity for the whole sample was 2.46 μmol/μml/min (SD 1.75). Higher AChE activity was associated with increased likelihood of hypoactive delirium rather than the hyperactive or mixed subtype (OR 1.98, CI 1.10-3.59). Conclusion: Higher AChE activity was associated with hypoactive delirium, but did not predict outcomes. Simple enhancement of cholinergic neurotransmission may not be sufficient to treat deliriu

Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium

Background: Delirium 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. Methods: Humans 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. Results: In 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. Conclusions: A 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

Association of delirium with cognitive decline in late life: A neuropathologic study of 3 population-based cohort studies

Importance Delirium is associated with accelerated cognitive decline. The pathologic substrates of this association are not yet known, that is, whether they are the same as those associated with dementia, are independent, or are interrelated. Objective To examine whether the accelerated cognitive decline observed after delirium is independent of the pathologic processes of classic dementia. Design, Setting, and Participants Harmonized data from 987 individual brain donors from 3 observational cohort studies with population-based sampling (Vantaa 85+, Cambridge City Over-75s Cohort, Cognitive Function and Ageing Study) performed from January 1, 1985, through December 31, 2011, with a median follow-up of 5.2 years until death, were used in this study. Neuropathologic assessments were performed with investigators masked to clinical data. Data analysis was performed from January 1, 2012, through December 31, 2013. Clinical characteristics of brain donors were not different from the rest of the cohort. Outcome ascertainment was complete given that the participants were brain donors. Exposures Delirium (never vs ever) and pathologic burden of neurofibrillary tangles, amyloid plaques, vascular lesions, and Lewy bodies. Effects modeled using random-effects linear regression and interactions between delirium and pathologic burden were assessed. Outcomes Change in Mini-Mental State Examination (MMSE) scores during the 6 years before death. Results There were 987 participants (290 from Vantaa 85+, 241 from the Cambridge City Over-75s Cohort, and 456 from the Cognitive Function and Ageing Study) with neuropathologic data; mean (SD) age at death was 90 (6.4) years, including 682 women (69%). The mean MMSE score 6 years before death was 24.7 points. The 279 individuals with delirium (75% women) had worse initial scores (−2.8 points; 95% CI, −4.5 to −1.0; P < .001). Cognitive decline attributable to delirium was −0.37 MMSE points per year (95% CI, −0.60 to −0.13; P < .001). Decline attributable to the pathologic processes of dementia was −0.39 MMSE points per year (95% CI, −0.57 to −0.22; P < .001). However, the combination of delirium and the pathologic processes of dementia resulted in the greatest decline, in which the interaction contributed an additional −0.16 MMSE points per year (95% CI, −0.29 to −0.03; P = .01). The multiplicative nature of these variables resulted in individuals with delirium and the pathologic processes of dementia declining 0.72 MMSE points per year faster than age-, sex-, and educational level–matched controls. Conclusions and Relevance Delirium in the presence of the pathologic processes of dementia is associated with accelerated cognitive decline beyond that expected for delirium or the pathologic process itself. These findings suggest that additional unmeasured pathologic processes specifically relate to delirium. Age-related cognitive decline has many contributors, and these findings at the population level support a role for delirium acting independently and multiplicatively to the pathologic processes of classic dementia

The Delirium Interview as a new reference standard in studies on delirium assessment tools.

BACKGROUND: The reference standard in studies on delirium assessment tools is usually based on the clinical judgment of only one delirium expert and may be concise, unstandardized, or not specified at all. This multicenter study investigated the performance of the Delirium Interview, a new reference standard for studies on delirium assessment tools allowing classification of delirium based on written reports. METHODS: We tested the diagnostic accuracy of our standardized Delirium Interview by comparing delirium assessments of the reported results with live assessments. Our reference, the live assessment, was performed by two delirium experts and one well-trained researcher who registered the results. Their delirium assessment was compared to the majority vote of three other independent delirium experts who judged the rapportage of the Delirium Interview. Our total pool consisted of 13 delirium experts with an average of 13 ± 8 years of experience. RESULTS: We included 98 patients (62% male, mean age 69 ± 12 years), of whom 56 (57%) intensive care units (ICUs) patients, 22 (39%) patients with a Richmond Agitation Sedation Scale (RASS) < 0 and 26 (27%) non-verbal assessments. The overall prevalence of delirium was 28%. The Delirium Interview had a sensitivity of 89% (95% confidence interval [CI]: 71%-98%) and specificity of 82% (95% CI: 71%-90%), compared to the diagnosis of an independent panel of two delirium experts and one researcher who examined the patients themselves. Negative and positive predictive values were 95% (95% CI: 86%-0.99%), respectively, 66% (95% CI: 49%-80%). Stratification into ICU and non-ICU patients yielded similar results. CONCLUSION: The Delirium Interview is a feasible reference method for large study cohorts evaluating delirium assessment tools since experts could assess delirium with high accuracy without seeing the patient at the bedside