Davis, D.H.J. and Skelly, D.T. and Murray, C. and Hennessy, E. and Bowen, J. and Norton, S. and Brayne, C. and Rahkonen, T. and Sulkava, R. and Sanderson, D.J. and Rawlins, J.N.P. and Bannerman, D.M. and MacLullich, A.M.J. and Cunningham, C. (2015) 'Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium.', American journal of geriatric psychiatry., 23 (4). pp. 403-415.
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.
|Keywords:||Delirium, Dementia, Neurodegeneration, Neuropathology, Synaptic, Axonal, Thalamus, Hippocampus, Basal forebrain, Ageing, Cognitive decline, Systemic, Inflammation, Susceptibility, Neuroinflammation.|
|Full text:||(VoR) Version of Record|
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|Publisher Web site:||https://doi.org/10.1016/j.jagp.2014.08.005|
|Publisher statement:||Open Access funded by Wellcome Trust. This article is available under the terms of the Creative Commons Attribution License (CC BY). You may copy and distribute the article, create extracts, abstracts and new works from the article, alter and revise the article, text or data mine the article and otherwise reuse the article commercially (including reuse and/or resale of the article) without permission from Elsevier. You must give appropriate credit to the original work, together with a link to the formal publication through the relevant DOI and a link to the Creative Commons user license above. You must indicate if any changes are made but not in any way that suggests the licensor endorses you or your use of the work.|
|Date accepted:||08 August 2014|
|Date deposited:||28 August 2015|
|Date of first online publication:||April 2015|
|Date first made open access:||No date available|
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