The neuroinflammatory hypothesis of delirium

Delirium is a neuropsychiatric syndrome characterized by a sudden and global impairment in consciousness, attention and cognition. It is particularly frequent in elderly subjects with medical or surgical conditions and is associated with short- and long-term adverse outcomes. The pathophysiology of delirium remains poorly understood as it involves complex multi-factorial dynamic interactions between a diversity of risk factors. Several conditions associated with delirium are characterized by activation of the inflammatory cascade with acute release of inflammatory mediators into the bloodstream. There is compelling evidence that acute peripheral inflammatory stimulation induces activation of brain parenchymal cells, expression of proinflammatory cytokines and inflammatory mediators in the central nervous system. These neuroinflammatory changes induce neuronal and synaptic dysfunction and subsequent neurobehavioural and cognitive symptoms. Furthermore, ageing and neurodegenerative disorders exaggerate microglial responses following stimulation by systemic immune stimuli such as peripheral inflammation and/or infection. In this review we explore the neuroinflammatory hypothesis of delirium based on recent evidence derived from animal and human studies

The Stress Response to Surgery and Postoperative Delirium: Evidence of Hypothalamic—Pituitary—Adrenal Axis Hyperresponsiveness and Decreased Suppression of the GH/IGF-1 Axis

Introduction: The aim of this study is to determine whether postoperative delirium is associated with dysregulation of hypothalamic—pituitary—adrenal and growth hormone/insulin-like growth factor 1 (GH/IGF-1) responses following acute systemic inflammation. Methods: Plasma levels of cortisol, IGF-1, C-reactive protein, interleukin (IL)-6, IL-8, and IL-10 were measured before and after surgery in 101 patients 60 years without dementia undergoing elective hip arthroplasty. Participants were assessed with confusion assessment method and Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision; DSM-IV-TR) postoperatively and 37 patients fulfilled the DSM-IV-TR criteria for delirium. Results: Preoperative plasma cortisol levels were similar in delirium and nondelirium groups (405.37+189.04 vs 461.83+219.39; P ¼ .22). Participants with delirium had higher postoperative cortisol levels (821.67 + 367.17 vs 599.58 + 214.94; P ¼ .002) with enhanced postoperative elevation in relation to baseline (1.9- vs 1.5-fold; P ¼ .004). The plasma levels of IGF1 did not differ in delirium and nondelirium groups before (18.12 + 7.58 vs 16.8 + 7.86; P ¼ .477) and following surgery (13.39 + 5.94 vs 11.12 + 6.2; P ¼ .639), but the levels increased in relation to baseline more frequently in patients who developed delirium (24.3% vs 7.8%; P ¼ .034). The magnitude of postoperative cortisol elevation correlated with DIL-6 (P ¼ .485; P ¼ .002), DIL-8 (P ¼ .429; P ¼ .008), and DIL-10 (P ¼ .544; P < .001) only in patients with delirium. Conclusions: Hypothalamic—pituitary—adrenal axis hyperresponsiveness and a less frequent suppression of the GH/IGF-1 axis in response to acute stress are possibly involved in delirium pathophysiology

Low preoperative plasma cholinesterase activity as a risk marker of postoperative delirium in elderly patients.

BACKGROUND: delirium is a frequent neuropsychiatric syndrome affecting medical and surgical elderly patients. Cholinergic dysfunction has been implicated in delirium pathophysiology and plasmatic acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities are suppressed in patients with delirium. In this cohort study, we investigated whether these changes emerge during delirium or whether they are present before its onset. METHODS: plasma activities of AChE and BuChE were measured pre- and postoperatively in consecutive patients ≥60 years old undergoing elective total hip replacement surgery. In addition to a comprehensive clinical and demographic baseline evaluation, venous blood samples were collected from each subject in the morning of hospital admission's day and in the morning of the first postoperative day. Delirium was screened daily with confusion assessment method (confirmed with diagnostic and statistical manual of mental disorders (DSM-IV)-TR). RESULTS: preoperatively, plasma esterase activity was significantly lower in patients who developed delirium compared with the remaining subjects. Following surgery BuChE activity was lower in the delirium group but this difference disappeared after controlling for preoperative values. Plasma cholinesterase activity correlated positively with calcium and haemoglobin and negatively with total bilirubin and international normalised ratio. CONCLUSION: plasma cholinesterase activity can be a useful candidate biomarker to identify subjects at greater risk of developing postoperative delirium

The Cholinergic System and Inflammation: Common Pathways in Delirium Pathophysiology

OBJECTIVES: To investigate whether delirium is associated with an unbalanced inflammatory response or a dysfunctional interaction between the cholinergic and immune systems. DESIGN: Cohort observational study. SETTING: General hospital orthopedic ward. PARTICIPANTS: One hundred one individuals aged 60 and older with no previous cognitive impairment undergoing elective arthroplasty. MEASUREMENTS: Incidence of postoperative delirium, plasma cholinesterase activity (acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE)) and inflammatory mediators (C-reactive protein (CRP), interleukin (IL)-1 beta, tumor necrosis factor alpha, IL-6, IL-8, IL-10) before and after surgery. RESULTS: Thirty-seven participants developed postoperative delirium and had greater production of CRP and proinflammatory to anti-inflammatory ratio after surgery. In participants with delirium, but not in controls, preoperative levels of plasma cholinesterase activity correlated with ΔCRP (AChE: ρ = 0.428, P = .008 and BuChE: ρ = 0.423, P = .009), ΔIL-6 (AChE: ρ = 0.339, P = .04), and ΔP/A ratio (AChE: ρ = 0.346, P = .04). CONCLUSION: Delirium was associated not only with an unbalanced inflammatory response, but also with a dysfunctional interaction between the cholinergic and immune systems. Comprehensive understanding of the relationship between the cholinergic and immune systems is crucial to developing new insights into delirium pathophysiology and novel therapeutic intervention

Tubulin and Tubulin Posttranslational Modifications in Alzheimer’s Disease and Vascular Dementia

Copyright \ua9 2021 Santiago-Mujika, Luthi-Carter, Giorgini, Kalaria and Mukaetova-Ladinska. Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common forms of dementia in older people. Although these two dementia types differ in their etiology, they share many pathophysiological and morphological features, including neuronal loss, which is associated with the microtubule (MT) destabilization. Stabilization of MTs is achieved in different ways: through interactions with MT binding proteins (MTBP) or by posttranslational modifications (PTMs) of tubulin. Polyglutamylation and tyrosination are two foremost PTMs that regulate the interaction between MTs and MTBPs, and play, therefore, a role in neurodegeneration. In this review, we summarize key information on tubulin PTMs in relation to AD and VaD and address the importance of studying further the tubulin code to reveal sites of potential intervention in development of novel and effective dementia therapy

Binding of multiple features in memory by high-functioning adults with autism spectrum disorder

Diminished episodic memory and diminished use of semantic information to aid recall by individuals with autism spectrum disorder (ASD) are both thought to result from diminished relational binding of elements of complex stimuli. To test this hypothesis, we asked high-functioning adults with ASD and typical comparison participants to study grids in which some cells contained drawings of objects in non-canonical colours. Participants were told at study which features (colour, item, location) would be tested in a later memory test. In a second experiment, participants studied similar grids and were told that they would be tested on object-location or object-colour combinations. Recognition of combinations was significantly diminished in ASD, which survived covarying performance on the Color Trails Test (D'Elia et al. Color trails test. Professional manual. Psychological Assessment Resources, Lutz, 1996), a test of executive difficulties. The findings raise the possibility that medial temporal as well as frontal lobe processes are dysfunctional in ASD