Casting light on the links between delirium, infection, and dementia risk
Authors: Colum P Dunne, Suzanne Shine Dunne
Journal: The Lancet Healthy Longevity (2024)

The study by Sarah Pendlebury and colleagues1Pendlebury ST Luengo-Fernandez R Seeley A et al.Infection, delirium, and risk of dementia in patients with and without white matter disease on previous brain imaging: a population-based study.Lancet Healthy Longev. 2024; 5: e131-e140Summary Full Text Full Text PDF Google Scholar merits comment. The authors have addressed the challenge of determining whether there might be a direct association between incidence of delirium or infection and dementia risk in the context of white matter disease. Working with a high-quality dataset, the authors have provided credible evidence that, as found in previous studies,2Goldberg TE Chen C Wang Y et al.Association of delirium with long-term cognitive decline: A meta-analysis.JAMA Neurol. 2020; 77: 1373-1381Crossref PubMed Scopus (196) Google Scholar, 3Tsui A Searle SD Bowden H et al.The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study.Lancet Healthy Longev. 2022; 3: e232-e241Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 4Sipilä PN Heikkilä N Lindbohm JV et al.Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort.Lancet Infect Dis. 2021; 21: 1557-1567Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar the presence of preceding delirium or infection increases subsequent risk of dementia. However, this study contributes new insight by showing that that the effects of delirium and infection on dementia risk were independent of one another, as well as showing the modifying role of white matter disease. Another key contribution of the study is demonstrating the differentiation of the impacts of delirium and infection for older patients (≥80 years) and those who are younger. In particular, the increased dementia risk after delirium was driven mainly by older patients, while the increased risk of dementia after infection was driven by younger patients. In light of the data provided, specific to these modifiable contributing factors for dementia, it is reasonable to conclude that mechanisms mediating dementia in older and younger patients might be entirely disparate or at least sufficiently distinct to warrant further investigation. Building on previous work,5Pendlebury ST Thomson RJ Welch SJV Kuker W Rothwell PM Utility of white matter disease and atrophy on routinely acquired brain imaging for prediction of long-term delirium risk: population-based cohort study.Age Ageing. 2022; 51afab200 Crossref Scopus (2) Google Scholar the authors correctly emphasise that prevention of vascular dementia in patients with white matter disease should focus on post-infection care. Of note, in performing the study, Pendlebury and colleagues have made considerable efforts to work within a well-defined scope of small vessel disease, accessing data for more than 1360 patients. This is no small feat, as the authors have, in effect, mitigated potential confounding by variability in white matter hyperintensities. This report poses interesting questions for future work while also highlighting challenges associated with current care provided, specifically, for the elderly. The authors show that delirium increased dementia risk irrespective of the presence of white matter disease. It is widely accepted that delirium alters patients’ cognitive trajectories, perhaps most acutely in patients with Alzheimer's disease,6Fong TG Jones RN Shi P et al.Delirium accelerates cognitive decline in Alzheimer disease.Neurology. 2009; 72: 1570-1575Crossref PubMed Scopus (363) Google Scholar and it also increases the risk of dementia following stroke.7Pendlebury ST Rothwell PM Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis.Lancet Neurol. 2009; 8: 1006-1018Summary Full Text Full Text PDF PubMed Scopus (1240) Google Scholar Both findings suggest that delirium might influence neurodegenerative and vascular pathology. However, in this study Pendlebury and colleagues do not define delirium sufficiently to determine potential distinct effects of severity, duration, or forms of cognitive confusion, including subsyndromal delirium, on subsequent dementia. There is, clearly, a need to investigate how delirium progression8Sepulveda E Leonard M Franco JG et al.Subsyndromal delirium compared with delirium, dementia, and subjects without delirium or dementia in elderly general hospital admissions and nursing home residents.Alzheimers Dement (Amst). 2016; 7: 1-10Google Scholar, 9Leonard M McInerney S McFarland J et al.Comparison of cognitive and neuropsychiatric profiles in hospitalised elderly medical patients with delirium, dementia and comorbid delirium-dementia.BMJ Open. 2016; 6e009212 Crossref PubMed Scopus (23) Google Scholar influences patient physiology and biochemistry in the context of detectable cognitive decline, comorbidities, and administered medicines, as suggested previously.10Dunne SS Coffey JC Konje S et al.Biomarkers in delirium: A systematic review.J Psychosom Res. 2021; 147110530 Crossref PubMed Scopus (27) Google Scholar Here, Pendlebury and colleagues report that most delirium-related admissions occurred in the absence of infection, suggesting a role for non-infective mechanisms linked to other mediators (eg, constipation, dehydration, metabolic derangement, medication, environmental factors, and occult acute cerebrovascular events). They suggest, in fact, that future studies could aim to establish whether it is the delirium itself that elevates dementia risk or, perhaps, whether shared factors underlie both delirium and future dementia risk. However, in suggesting this enquiry, it is possible that the authors underestimate the potential involvement of inflammation and associated circulating biomarkers on cognitive dysfunction, particularly delirium. Infection is a broad term and the authors, understandably due to the design of the study, underemphasise variation in infectious agents involved and their putative effects, which range from none to severe inflammation, systemic immunology, and host response. As reported previously,10Dunne SS Coffey JC Konje S et al.Biomarkers in delirium: A systematic review.J Psychosom Res. 2021; 147110530 Crossref PubMed Scopus (27) Google Scholar these effects can impact not only general physiology but also cognition, ranging from headaches to severe impairment. For instance, even the use of antimicrobials (some of which have known psychotropic effects) can contribute to potential enduring cognitive effects on patients. All that said, this study by Pendlebury and colleagues is substantial. It represents considerable work based on a longitudinal population-based design using multiple means of follow-up and covariates. Indeed, the authors show restraint in their conclusions while using two-sided tests of significance despite well acknowledged relationships between delirium, infection, and dementia risks. In that context, the clinical implications of the study merit merit attention as they infer a use for prophylactic antimicrobial treatment or prioritising vaccination before surgery or other invasive procedures that are linked with known cognitive impairment. We hope that this study provides some impetus for change. We declare no competing interests. Infection, delirium, and risk of dementia in patients with and without white matter disease on previous brain imaging: a population-based studyThe increased risk of dementia after delirium is unrelated to the presence of WMD, whereas infection increases risk only in patients with WMD, suggesting differences in underlying mechanisms and in potential preventive strategies. Full-Text PDF Open Access