Meta-analysis of ICU Delirium Biomarkers and Their Alignment With the NIA-AA Research Framework

Abstract

Background Between 30% and 80% of survivors of critical illness experience cognitive impairment, but the underlying mechanisms remain unknown. Objective To determine whether intensive care unit (ICU) delirium biomarkers align with the National Institute on Aging–Alzheimer’s Association (NIA-AA) research framework for diagnostic biomarkers for Alzheimer disease and other related dementias (ADRD). Methods Ovid MEDLINE, PsycInfo, Embase, and the Cochrane Library were systematically searched for articles published between January 1, 2000, and February 20, 2020, on the relationship between delirium and biomarkers listed in the NIA-AA framework. Only studies that addressed delirium in the ICU setting and fluid biomarkers were included in these analyses. Results Of 61 256 records screened, 38 studies met inclusion criteria, 8 of which were suitable for meta-analysis. In pooled analysis, significant associations were found between ICU delirium and amyloid β-peptide 1-40 (standard mean difference [SMD], 0.42; 95% CI, 0.09-0.75), interleukin (IL)-1 receptor antagonist (SMD, 0.58; 95% CI, 0.21-0.94), and IL-6 (SMD, 0.31; 95% CI, 0.06-0.56). No significant association was observed in pooled analyses between ICU delirium and the other biomarkers. Few studies have examined ICU delirium and pathologic tau or neurodegeneration biomarkers. Conclusions Inflammatory biomarkers and amyloid β are associated with ICU delirium and point to potential overlapping mechanisms between delirium and ADRD. Critical care providers should consider integrating diagnostic approaches used in ADRD in their assessment of post–ICU cognitive dysfunction.

Comparison of serum neurodegenerative biomarkers among hospitalized COVID‐19 patients versus non‐COVID subjects with normal cognition, mild cognitive impairment, or Alzheimer's dementia

“…54,55 A large meta-analysis of non-COVID survivors of critical illness has also identified associations of delirium with Aβ40, IL-6, and IL-1R antagonist. 56 Our study is unique in that we identified elevations across a spectrum of CNS specific markers, including neuronal (t-tau, UCHL1), and astrocytic/glial markers (GFAP), as well as AD-related markers (p-tau181).…”

“…Furthermore, elevations in NfL have been associated with worse cognitive and functional outcomes in post‐operative patients and patients with septic encephalopathy 54,55 . A large meta‐analysis of non‐COVID survivors of critical illness has also identified associations of delirium with Aβ40, IL‐6, and IL‐1R antagonist 56 . Our study is unique in that we identified elevations across a spectrum of CNS specific markers, including neuronal (t‐tau, UCHL1), and astrocytic/glial markers (GFAP), as well as AD‐related markers (p‐tau181).…”

Perivascular spaces visible on magnetic resonance imaging predict subsequent delirium in older patients

“…Abnormal protein aggregation (e.g., β-amyloid) can block the upstream within the cortical arteries and impair the external drainage of interstitial fluid in the deep white matter, thus contributing to the retrograde enlargement of PVS in CS ( Gouveia-Freitas and Bastos-Leite, 2021 ), and the relationship between β-amyloid accumulation and CS-PVS has been demonstrated in previous studies ( Roher et al, 2003 ; Charidimou et al, 2015 ). Furthermore, the impaired perivascular pathway may cause a vicious feed-forward cycle, further prompting PVS dysfunction and β-amyloid deposition in the vascular wall and brain ( Gouveia-Freitas and Bastos-Leite, 2021 ; Bown et al, 2022 ), which may exacerbate neurovascular dysfunction, neuroinflammation, and neurodegeneration ( Carrano et al, 2012 ; Parodi-Rullan et al, 2021 ), making the brain vulnerable to delirium ( Idland et al, 2017 ; Maldonado, 2018 ; Chan et al, 2021 ).…”

“…BG-PVS, basal ganglia perivascular space; CS-PVS, centrum semiovale perivascular space; CI, confidence interval. cause a vicious feed-forward cycle, further prompting PVS dysfunction and β-amyloid deposition in the vascular wall and brain (Gouveia-Freitas and Bastos-Leite, 2021;Bown et al, 2022), which may exacerbate neurovascular dysfunction, neuroinflammation, and neurodegeneration (Carrano et al, 2012;Parodi-Rullan et al, 2021), making the brain vulnerable to delirium (Idland et al, 2017;Maldonado, 2018;Chan et al, 2021).…”

Identification of Risk Factors for Delirium, Cognitive Decline, And Dementia After Cardiac Surgery (FINDERI - Find Delirium Risk Factors): A Study Protocol of A Prospective Monocentric Observational Pilot Trial

“…It has recently been shown that surgery, in particular cardiac surgery, is associated with increased markers for neuronal damage and neurodegeneration, such as total-Tau and neuro lament light chain (NFL) [14][15][16][17]. In fact, these effects, including hypoxemia and disruption of the blood-brain barrier, seem to be caused by the entire procedure and not solely by inhalational anesthesia, as discussed earlier [18].…”