Regional cerebral hypometabolism on 18F-FDG PET/CT scan in delirium is independent of acute illness and dementia.

INTRODUCTION: Delirium is associated with new onset dementia and accelerated cognitive decline; however, its pathophysiology remains unknown. Cerebral glucose metabolism previously seen in delirium may have been attributable to acute illness and/or dementia. We aimed to statistically map cerebral glucose metabolism attributable to delirium. METHODS: We assessed cerebral glucose metabolism using 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) in sick, older patients with and without delirium, all without clinical dementia (N = 20). Strict exclusion criteria were adopted to minimize the effect of established confounders on FDG-PET. RESULTS: Patients with delirium demonstrated hypometabolism in the bilateral thalami and right superior frontal, right posterior cingulate, right infero-lateral anterior temporal, and left superior parietal cortices. Regional hypometabolism correlated with delirium severity and performance on neuropsychological testing. DISCUSSION: In patients with acute illness but without clinical dementia, delirium is accompanied by regional cerebral hypometabolism. While some hypometabolic regions may represent preclinical Alzheimer's disease (AD), thalamic hypometabolism is atypical of AD and consistent with the clinical features that are unique to delirium.

Persistent delirium in older hospital patients: an updated systematic review and meta-analysis.

Introduction: Delirium is associated with future dementia progression. Yet whether this occurs subclinically over months and years, or persistent delirium merges into worsened dementia is not understood. Our objective was to estimate the prevalence of persistent delirium and understand variation in its duration. Methods: We adopted an identical search strategy to a previous systematic review, only including studies using a recognised diagnostic framework for ascertaining delirium at follow-up (persistent delirium). Studies included hospitalised older patients outside critical and palliative care settings. We searched MEDLINE, EMBASE, PsycINFO and the Cochrane Database of Systematic Reviews on 11th January 2022. We applied risk of bias assessments based on Standards of Reporting of Neurological Disorders criteria and assessed strength of recommendations using the grading of recommendation, assessment, development and evaluation (GRADE) approach. Estimates were pooled across studies using random-effects meta-analysis, and we estimated associations with follow-up duration using robust error meta-regression. Results: We identified 13 new cohorts, which we added to 10 from the previous systematic review (23 relevant studies, with 39 reports of persistent delirium at 7 time-points in 3186 individuals admitted to hospital care (mean age 82 years and 41% dementia prevalence). Studies were mainly at moderate risk of bias. Pooled delirium prevalence estimates at discharge were 36% (95% CI 22% to 51%, 13 studies). Robust error meta-regression did not show variation in prevalence of persistent delirium over time (-1.6% per month, 95% CI -4.8 to 1.6, p=0.08). Margins estimates for this model indicate a prevalence of persistent delirium of 16% (95% CI 6% to 25%) at 12 months. Conclusions: This systematic review emphasises the importance of delirium as a persistent and extensive problem (GRADE certainty = moderate), raising questions on chronic delirium as a clinical entity and how it might evolve into dementia. Addressing persistent delirium will require a whole-system, integrated approach to detect, follow-up and implement opportunities for recovery across all healthcare settings.

Intranasal insulin for treatment of delirium in older hospitalised patients: study protocol for a randomised controlled trial.

INTRODUCTION: Delirium is one of the most common conditions diagnosed in hospitalised older people and is associated with numerous adverse outcomes, yet there are no proven pharmacological treatments. Recent research has identified cerebral glucose hypometabolism as a pathophysiological mechanism offering a therapeutic target in delirium. Insulin, delivered via the intranasal route, acts directly on the central nervous system and has been shown to enhance cerebral metabolism and improve cognition in patients with mild cognitive impairment and dementia. This trial will determine whether intranasal insulin can reduce the duration of delirium in older hospitalised patients. METHODS AND ANALYSIS: This is a prospective randomised, placebo-controlled, double-blind study with 6 months follow-up. One hundred patients aged 65 years or older presenting to hospital with delirium admitted under geriatric medicine will be recruited. Participants will be randomised to intranasal insulin detemir or placebo administered twice daily until delirium resolves, defined as Confusion Assessment Method (CAM) negative for 2 days, or discharge from hospital. The primary outcome measure will be duration of delirium using the CAM. Secondary outcome measures will include length of hospital stay, severity of delirium, adherence to treatment, hospital complications, new admission to nursing home, mortality, use of antipsychotic medications during hospital stay and cognitive and physical function at 6 months postdischarge. ETHICS AND DISSEMINATION: This trial has been approved by the South Eastern Sydney Human Research and Ethics Committee. Dissemination plans include submission to a peer-reviewed journal for publication and presentation at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12618000318280.

Current Challenges in the Recognition and Management of Delirium Superimposed on Dementia.

Delirium occurring in a patient with preexisting dementia is referred to as delirium superimposed on dementia (DSD). DSD commonly occurs in older hospitalized patients and is associated with worse outcomes, including higher rates of mortality and institutionalization, compared to inpatients with delirium or dementia alone. This narrative review summarizes the screening, diagnosis, management, and pathophysiology of DSD and concludes by highlighting opportunities for future research. Studies were identified via Medline and PsycINFO keyword search, and handsearching reference lists. Conceptually, DSD could be considered an "acute exacerbation" of dementia precipitated by a noxious insult akin to an acute exacerbation of heart failure or acute on chronic renal failure. However, unlike other organ systems, there are no established biomarkers for delirium, so DSD is diagnosed and monitored clinically. Because cognitive dysfunction is common to both delirium and dementia, the diagnosis of DSD can be challenging. Inattention, altered levels of arousal, and motor dysfunction may help distinguish DSD from dementia alone. An informant history suggestive of an acute change in cognition or alertness should be investigated and managed as delirium until proven otherwise. The key management principles include prevention, identifying and treating the underlying precipitant(s), implementing multicomponent interventions to create an ideal environment for brain recovery, preventing complications, managing distress, and monitoring for resolution. Informing and involving family members or caregivers throughout the patient journey are essential because there is significant prognostic uncertainty, including the risk of persistent cognitive and functional decline following DSD and relapse. Furthermore, informal carers can provide significant assistance in management. Emerging evidence demonstrates that increased exposure to delirium is associated with neuronal injury and worse cognitive outcomes although the mechanisms through which this occurs remain unclear. Given the clinical overlap between delirium and dementia, studying shared pathophysiological pathways may uncover diagnostic tests and is an essential step in therapeutic innovation.

Delirium in older adults is associated with development of new dementia: a systematic review and meta-analysis.

OBJECTIVES: Observational studies have examined the association between delirium and development of new dementia. However, no recent review has collectively assessed the available evidence quantitatively and qualitatively. We systematically reviewed and critically evaluated the literature regarding the association between delirium and dementia, and calculated the odds of developing new dementia after having delirium. METHODS: This systematic review and meta-analysis was conducted according to Preferred reporting items for systematic reviews and meta-analyses guidelines. MEDLINE, EMBASE and PsycINFO, were searched for English-language articles that compared the incidence of new dementia in older adult (≥65) inpatients with delirium, to inpatients without delirium. A random effects model was used for meta-analysis, and overall effect size was calculated using reported raw data of event counts. The Newcastle-Ottawa Quality Assessment scale assessed risk of bias. RESULTS: Six observational studies met eligibility criteria, with follow-up times ranging from six months to five years. Four looked at hip fracture surgical patients; one was on cardiac surgery patients and one examined geriatric medical patients. All studies excluded patients with pre-existing dementia. Pooled meta-analysis revealed that older adult inpatients who developed delirium had almost twelve times the odds of subsequently developing new dementia compared to non-delirious patients (OR = 11.9 [95% CI: 7.29-19.6]; p < 0.001). CONCLUSIONS: Older adult inpatients who develop delirium are at significant risk of subsequently developing dementia. This emphasises the importance of delirium prevention and cognitive monitoring post-delirium. The included studies mainly examined post-surgical patients-further research on medical and intensive care unit cohorts is warranted. Future studies should assess whether delirium duration, severity and subtype influence the risk of developing dementia.

A call to action for delirium research: Meta-analysis and regression of delirium associated mortality.

BACKGROUND: Delirium is an extremely common hospital complication. No study to date has assessed whether a priori defined covariates; type of hospital setting and year of study publication, influence the relationship between delirium and mortality. This is also the first study to examine the longitudinal trend of delirium-associated mortality over recent decades, to analyse the trajectory of our efforts in combating this disease. METHODS: MEDLINE, EMBASE and PsycINFO, were searched from January 1981 to May 2018 for English-language primary articles. Rigorous title and abstract screen and full-text screen were conducted independently by two reviewers. This paper adhered to MOOSE guidelines. Data was extracted independently by one reviewer using standardised data-collection sheets, with a separate reviewer verifying for accuracy. The quality of included studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Unadjusted effect sizes and event counts were analysed with a random effects model in primary meta-analysis and meta-regression, whereas a mixed effect model was used in secondary sub-group analysis. Mortality data at longest follow-up and cumulative mortality (hospital mortality combined with mortality at longest follow-up) data were analysed. RESULTS: As part of a larger project, 446 of 6790 articles were retrieved, including 71 studies that measured mortality. Our results demonstrate that elderly inpatients with delirium had significantly greater odds of mortality (OR 3.18 [95%CI: 2.73, 3.70]) compared to non-delirious controls. Patients with delirium in the ICU had the highest odds for mortality (OR: 7.09 [95%CI: 3.60, 14.0]); double the risk compared to the average. Curiously, despite advancements in delirium research, delirium associated in-hospital odds of mortality has not changed in 30 years. CONCLUSION: This is the largest meta-analysis to confirm the association between delirium and mortality, in older (age ≥ 65) hospital inpatients. The current meta-analysis highlights the significant odds of mortality after an episode of delirium, and these odds are much higher for ICU patients. However, in contrast to other medical conditions that have seen a decrease in associated mortality over the past few decades, delirium associated mortality remains unchanged. These findings underscore the urgent need for better delirium treatments. PROSPERO Registration Number: CRD42018098627, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=98627.

A systematic review of neuroimaging in delirium: predictors, correlates and consequences.

OBJECTIVE: Neuroimaging advances our understanding of delirium pathophysiology and its consequences. A previous systematic review identified 12 studies (total participants N = 764, delirium cases N = 194; years 1989-2007) and found associations with white matter hyperintensities (WMH) and cerebral atrophy. Our objectives were to perform an updated systematic review of neuroimaging studies in delirium published since January 2006 and summarise the available literature on predictors, correlates or outcomes. METHODS: Studies were identified by keyword and MeSH-based electronic searches of EMBASE, MEDLINE and PsycINFO combining terms for neuroimaging, brain structure and delirium. We included neuroimaging studies of delirium in adults using validated delirium assessment methods. RESULTS: Thirty-two studies (total N = 3187, delirium N = 1086) met the inclusion criteria. Imaging included magnetic resonance imaging (MRI; N = 9), computed tomography (N = 4), diffusion tensor imaging (N = 3), transcranial Doppler (N = 5), near infrared spectroscopy (N = 5), functional-MRI (N = 2), single photon emission computed tomography (N = 1), proton MRI spectroscopy (N = 1), arterial spin-labelling MRI (N = 1) and 2-13 fluoro-2-deoxyglucose positron emission tomography (N = 1). Despite heterogeneity in study design, delirium was associated with WMH, lower brain volume, atrophy, dysconnectivity, impaired cerebral autoregulation, reduced blood flow and cerebral oxygenation and glucose hypometabolism. There was evidence of long-term brain changes following intensive care unit delirium. CONCLUSIONS: Neuroimaging is now used more widely in delirium research due to advances in technology. However, imaging delirious patients presents challenges leading to methodological limitations and restricted generalisability. The findings that atrophy and WMH burden predict delirium replicates findings from the original review, while advanced techniques have identified other substrates and mechanisms that warrant further investigation.