Acute systemic inflammation affects brain function, with detrimental consequences in aged individuals. These include delirium, an acute neuropsychiatric syndrome characterized by fluctuating disturbances in attention, perception and cognition. Delirium is associated with disrupted brain energy metabolism but our understanding of this during acute systemic inflammation is limited. Here we hypothesized that LPS-induced systemic inflammation would disrupt brain energy metabolism in aged C57BL6J mice and that the consequent functional impairments would be mitigated by ketone body utilization. We investigated ketone body effects in sickness behaviour, inflammation, energy metabolism and cognitive function. Real-time changes in utilisation of energy sources were quantified by indirect calorimetry and administration of radioisotope-labelled glucose and betahydroxybutyrate. Mass-spectrometry metabolomics was used to index severity of behavioural distrurbances to changes in hippocampal energy metabolism. LPS precipitated hypoglycemia and induced a whole-body switch from carbohydrate to lipid utilisation. Despite this, hippocampal insulin resistance and preserved brain glucose was observed while alternative carbohydrates, mannose and fructose, became depleted. Ketone ester treatment reversed insulin resistance, mitigated sickness behaviour and prevented delirium-like cognitive dysfunction without altering pro-inflammatory responses. Our results show that promoting ketone body usage mitigates systemic inflammation-induced brain energy disruption and prevents delirium-like cognitive deficits in aged mice.

Delirium is a highly prevalent neuropsychiatric syndrome characterised by acute inattention, altered arousal and impaired cognition. Cerebral energy insufficiency is hypothesised to drive delirium and both hypoglycaemia and hypoxia can directly precipitate functional deficits and EEG slowing. Here we review the evidence that disrupted energy metabolism may play a causative role in delirium across multiple settings. Neuromonitoring methods including near infrared resonance spectroscopy and Transcranial Doppler suggest an association between altered cerebral perfusion and delirium, albeit with a minority of studies demonstrating associations with hyperoxia or low brain oxygen extraction. Hyperglycaemia, hypoglycaemia, relative hypoglycaemia and large fluctuations in glucose show associations with delirium, dependent on the setting. Functional neuroimaging methodologies such as functional MRI and fluorodeoxyglucose-positron emission tomography, demonstrate regional rather than global changes in functional hyperaemia and hypometabolism and the networks across which these changes occur may be key drivers of the delirium phenotype. Whether those changes reflect regulated changes in activity, the development of insulin resistance or an impairment of neurovascular coupling in those circuits requires further research. Availability of glucose, the ability to take it up and use it are all important in maintaining normal brain function and the disruption of any or all of these could impair energy metabolism in the brain during acute illness and delirium. Optimising brain glucose utilisation is a rational goal towards reducing delirium. Clinical trials with intranasal insulin offer tentative indication that this might be tractable and alternative fuels also might mitigate delirium. Systematic experiments and clinical trials are necessary to assess whether restoring normal metabolism can protect against delirium in different clinical environments.

Encephalopathy is a common complication of sepsis, occurring in up to 70

BACKGROUND:Both low-grade systemic inflammation and acute inflammatory events may contribute to Alzheimer Disease (AD) progression. However, studies examining the prognostic utility of systemic inflammatory biomarkers in AD, and how systemic inflammatory events may contribute to clinical trajectories in AD, have yielded conflicting results. METHODS:We quantified plasma cytokines/chemokines in 333 individuals with mild-moderate AD at baseline, 12 and 18 months alongside baseline neurodegenerative biomarkers. AD severity was assessed using the Alzheimer Disease Assessment Scale (ADAS-Cog), Clinical Dementia Rating Scale (CDR-Sb) and Disability Assessment for Dementia (DAD). FINDINGS:Systemic inflammatory biomarkers were primarily associated with age/socio-demographic characteristics, remained strikingly stable over time, and were not associated with AD progression. Rather, higher baseline plasma p-tau217 was associated with greater yearly progression on both the ADAS-Cog (β: 2.82; 95% CI: 1.12, 4.52; nominal p = 0.001) and DAD (β: -2.34; 95% CI: -3.86, -0.82; nominal p = 0.003). Higher baseline GFAP was also associated with subsequent decline on both the CDR-Sb (β: 1.02; 95% CI: 0.38, 1.67; nominal p = 0.002) and DAD (β: 1.91; 95% CI: -3.45, -0.37; nominal p = 0.02). Experiencing one or more episodes of delirium was associated with accelerated decline on the CDR-Sb at 18-months (β: 2.63; 95% CI: 1.55, 3.71; adjusted p < 0.001). INTERPRETATION:Biomarkers of neuroinflammation (GFAP), neurodegeneration (p-tau217) and incident delirium, rather than systemic inflammatory biomarkers, were associated with clinically-significant decline in mild-moderate AD. FUNDING:European Commission (FP7 grant; 279093); Meath Foundation (MFRG 121/2021); Wellcome Trust (227946/Z/23/Z & 203930/B/16/Z); Health Research Board (203930/B/16/Z; ECSA-2024-003).

Epidemiological, PET imaging, genome-wide association and animal research suggests inflammation contributes to Alzheimer's disease (AD) and other dementias, however there is no consensus on its precise contribution. Human and animal studies show acute systemic inflammation, arising from infection, fracture or co-morbid inflammatory disease, accelerate dementia. ASCRIBED aimed to investigate the relationship between acute hip fracture, inflammation and brain injury in dementia. Participants were recruited with dementia and hip fracture, those with hip fractures but no dementia, and a control group of individuals with dementia but no acute illness or injury. Cerebrospinal fluid (CSF) and blood samples were collected to measure inflammatory markers and brain injury biomarkers. We recruited from 37 UK hospital sites, drawing CSF and blood from participants with dementia and hip fracture ( n  = 191), participants with no dementia and hip fracture ( n  = 218), participants with confusion and hip fracture ( n  = 80) and a Norwegian cohort of community-dwelling participants with dementia ( n  = 181). Most participants were women (68%) across the groups. APOE3/E3 was the commonest genotype in UK samples (mean 56%). Multi-morbidity as measured by the Charlson index was highest in the dementia fracture group. Despite the stable dementia group showing the expected CSF elevation in phosphoTau ( p  <0.001) and reduction in CSF Ab1-42 ( p  <0.001) compared to all other groups, the axonal damage marker neurofilament light chain (NFL) was significantly higher in those with hip fracture than in stable dementia and was highest in those with hip fracture and dementia ( p  <0.001). CSF NFL levels were correlated most strongly with blood CSF barrier permeability, as measured by Q albumin ( p  <0.001). Our findings show hip fracture leads to an increase in axonal injury, significantly beyond that observed in patients with stable dementia. This acute injury appears more severe in those with existing dementia. Additionally, NFL levels were correlated with blood CSF barrier permeability which may suggest a link between axonal damage and BBB disruption. Further research is needed to elucidate the underlying mechanisms of this acute brain injury and explore potential therapeutic interventions.

The measurement of choline as a biomarker for in vivo cholinergic neurotransmission is a valuable tool in the study of a range of CNS pathologies. However, the continuous detection of cholinergic neurotransmission in selective brain regions in the mouse brain remains challenging and underexploited. Here, we have refined an established choline oxidase (ChOx) microelectrochemical biosensor and validated its use for long-term recording in the freely moving mouse. Using a 75-μm diameter polymer-ChOx composite disc electrode, we have successfully monitored stable and reproducible chronic real-time changes in choline-induced amperometric currents in vivo. Local infusions of choline and acetylcholine resulted in an increase in biosensor current in the hippocampus, while the inhibition of endogenous acetylcholinesterase (with neostigmine) significantly attenuated the response to exogenous acetylcholine. Systemic administration of donepezil produced a pronounced decrease in current in both the prefrontal cortex and hippocampus, with scopolamine and amphetamine resulting in signal increases that were not observed in animals with selective saporin lesioning (murine-p75) of the cholinergic basal forebrain. Furthermore, continuous biosensor recording in both regions displayed diurnal oscillations across repetitive light-dark phases. All are consistent with successful monitoring of endogenous changes in cholinergic neurotransmission.

Delirium is a highly prevalent neuropsychiatric syndrome characterised by acute and fluctuating impairments in attention and cognition. Mechanisms driving delirium are poorly understood but it has been suggested that blood cytokines and chemokines cross the blood brain barrier during delirium, directly impairing brain function. It is not known whether these molecules reach higher brain levels when the blood cerebrospinal fluid barrier (BCSFB) is impaired. Here, in human hip-fracture patients, we tested the influence of BCSFB integrity on CSF levels of chemokines and assessed their association with delirium. CSF levels of IP-10, eotaxin, eotaxin 3 and TARC showed weak to moderate correlations with BCSFB permeability, as measured by the Qalbumin ratio, while MCP1, IL-8, MIP1α and MIP1β showed no significant correlation. Chemokines were not associated with delirium in univariate analysis or when stratified on dementia status, but exploratory analyses showed that elevated Eotaxin (CCL11) and MIP1α (CCL3) were associated with prevalent delirium. Modelling acute systemic inflammation, we used bacterial LPS (250 μg/kg) or sterile laparotomy surgery in mice to demonstrate de novo synthesis of chemokines at the choroid plexus (CP) and microvasculature. Gene expression data showed CP-enriched expression of Il1b, Tnfa, Cxcl1 and Ccl3 in both models and immunohistochemistry showed cytokine and chemokine synthesis in CP stromal (IL-1β, CCL2/MCP1) or epithelial cells (CXCL10/IP-10) cells and at the microvasculature. Larger studies are required to confirm these human findings on chemokine associations with BCSFB permeability and prevalent delirium. Preclinical studies are warranted to determine whether chemokines might play a role in the pathophysiology of delirium.

Falls are the commonest cause of accidental death in older people and the most frequent reason for their presentation to hospital. The Screening Tool of Older Persons Prescriptions in older adults with high falls risk (STOPPFall) facilitates deprescribing by providing a clear consensus on which medications are considered fall-risk-increasing drugs (FRIDs). This study aimed to determine the prevalence of STOPPFall FRIDs in inpatients referred to a falls and syncope service (FASS). Additionally, we aimed to analyse the impact of a dedicated FASS on deprescribing, both of FRIDs and of non-FRID medications. We conducted a retrospective observational study of all FASS inpatient consultations over a 6-month period (March–August 2021). Patients ≥ 65 years old were included. Medications on admission and discharge (following FASS assessment) were reviewed, with FRIDs identified using the STOPPFall deprescribing tool. The prevalence of FRIDs was defined as the proportion of patients who had at least one regular FRID prescribed on admission. In total, 162 patients were included for review: 54.94

Alterations in brain energy metabolism have long been proposed as one of several neurobiological processes contributing to delirium. This is supported by previous findings of altered CSF lactate and neuron-specific enolase concentrations and decreased glucose uptake on brain-PET in patients with delirium. Despite this, there are limited data on metabolic alterations found in CSF samples, and targeted metabolic profiling of CSF metabolites involved in energy metabolism has not been performed. The aim of the study was to investigate whether metabolites related to energy metabolism in the serum and CSF of patients with hip fracture are associated with delirium. The study cohort included 406 patients with a mean age of 81 years (standard deviation 10 years), acutely admitted to hospital for surgical repair of a hip fracture. Delirium was assessed daily until the fifth postoperative day. CSF was collected from all 406 participants at the onset of spinal anaesthesia, and serum samples were drawn concurrently from 213 participants. Glucose and lactate in CSF were measured using amperometry, whereas plasma glucose was measured in the clinical laboratory using enzymatic photometry. Serum and CSF concentrations of the branched-chain amino acids, 3-hydroxyisobutyric acid, acetoacetate and β-hydroxybutyrate were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). In total, 224 (55%) patients developed delirium pre- or postoperatively. Ketone body concentrations (acetoacetate, β-hydroxybutyrate) and branched-chain amino acids were significantly elevated in the CSF but not in serum among patients with delirium, despite no group differences in glucose concentrations. The level of 3-hydroxyisobutyric acid was significantly elevated in both CSF and serum. An elevation of CSF lactate during delirium was explained by age and comorbidity. Our data suggest that altered glucose utilization and a shift to ketone body metabolism occurs in the brain during delirium.

Age is a significant but heterogeneous risk factor for acute neuropsychiatric disturbances such as delirium. Neuroinflammation increases with aging but the determinants of underlying risk for acute dysfunction upon systemic inflammation are not clear. We hypothesised that, with advancing age, mice would become progressively more vulnerable to acute cognitive dysfunction and that neuroinflammation and neuronal integrity might predict heterogeneity in such vulnerability. Here we show region-dependent differential expression of microglial transcripts, but a ubiquitously observed primed signature: chronic Clec7a expression and exaggerated Il1b responses to systemic bacterial LPS. Cognitive frailty (vulnerability to acute disruption under acute stressors LPS and double stranded RNA; poly I:C) was increased in aged animals but showed heterogeneity and was significantly correlated with reduced myelin density, synaptic loss and severity of white matter microgliosis. The data indicate that white matter disruption and neuroinflammation may be key substrates of the progressive but heterogeneous risk for delirium in aged individuals.

Sepsis is characterised by dysregulated immune responses to infection, leading to multi-organ dysfunction and high rates of mortality. With increasing survival rates in recent years long-term neurological and psychiatric consequences have become more apparent in survivors. Many patients develop sepsis associated encephalopathy (SAE) which encompasses the profound but usually transient neuropsychiatric syndrome delirium but also new brain injury that emerges in the months and years post-sepsis. It is now clear that systemic inflammatory signals reach the brain during sepsis and that very significant neuroinflammation ensues. The major brain resident immune cell population, the microglia, has been implicated in acute and chronic cognitive dysfunction in animal models of sepsis based on a growing number of studies using bacterial endotoxin and in polymicrobial sepsis models such as cecal ligation and puncture. The current review explores the effects of sepsis on the brain, focussing on how systemic insults translate to microglial activation and neuroinflammation and how this disrupts neuronal function and integrity. We examine what has been demonstrated specifically with respect to microglial activation, revealing robust evidence for a role for neuroinflammation in sepsis-induced brain sequelae but less clear information on the extent of the specific microglial contribution to this, arising from findings using global knockout mice, non-selective drugs and treatments that equally target peripheral and central compartments. There is, nonetheless, clear evidence that microglia do become activated and do contribute to brain consequences of sepsis thus arguing for improved understanding of these neuroinflammatory processes toward the prevention and treatment of sepsis-induced brain dysfunction.

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.

Delirium is associated with the risk of future long-term cognitive impairment, but the degree to which markers of neuronal injury may be distinct or shared with dementia has yet to be comprehensively described. We investigated CSF biomarkers of dementia, astrocytosis and neuronal damage in a clinical cohort with persistent delirium, comparing them with an outpatient memory clinic sample. Our aim was to determine if different patterns of biomarker changes could implicate specific mechanisms for delirium-related neuronal injury over and above that attributable to comorbid dementia. We recruited 35 participants from the Prince of Wales Hospital, Sydney, Australia. We included inpatients with delirium persisting for at least 5 days (n = 15, 10 with underlying dementia) and participants from outpatient memory clinics (n = 20, 17 with dementia). CSF assays were as follows: amyloid-beta 42, amyloid-beta 40, phosphorylated tau181, neurofilament light chain and glial fibrillary acidic protein. We used propensity score matching to estimate effect sizes for each standardized CSF biomarker separately for persistent delirium (irrespective of underlying dementia) and dementia (irrespective of superimposed delirium). Compared with individuals without delirium, persistent delirium was associated with elevated glial fibrillary acidic protein (normalized coefficient per transformed standard deviation, beta = 0.85; 95% confidence interval: 0.03-1.68) and neurofilament light chain (beta = 1.1; 95% confidence interval: 0.5-1.6), but not phosphorylated tau181. Compared with individuals without dementia, glial fibrillary acidic protein, neurofilament light chain and phosphorylated tau181 were all increased to expected levels in dementia cases, with the former two biomarkers at levels comparable to those seen in persistent delirium [glial fibrillary acidic protein (beta = 1.54; 95% confidence interval: 1.05-2.0) and neurofilament light chain (beta = 0.65; 95% confidence interval: 0.24-1.1)]. Persistent delirium was linked with changes in CSF biomarkers not necessarily attributable to dementia. These findings support the potential that delirium is associated with direct neuronal injury independent of dementia pathophysiology. Whether this neuronal injury involves astrocyte dysfunction or direct axonal damage are both possibilities. Future work examining acute brain injury in delirium is needed. Persistent delirium poses risks for long-term cognitive impairment, but how neuronal injury markers relate to dementia remains unclear. Tsui et al. studied CSF biomarkers in medical admissions with persistent delirium and dementia, finding elevated glial fibrillary acidic protein and neurofilament light chain, suggesting direct neuronal injury beyond dementia-related changes. Graphical Abstract

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national longitudinal study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers and reduced anterior cingulate cortex volume one year after admission. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Treatment with corticosteroids during the acute phase appeared protective against cognitive deficits. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 is immune-mediated, and should guide the development of therapeutic strategies.

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies. A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.

Delirium is a common, morbid, and costly syndrome that is closely linked to Alzheimer's disease (AD) and AD-related dementias (ADRD) as a risk factor and outcome. Human studies of delirium have advanced our knowledge of delirium incidence and prevalence, risk factors, biomarkers, outcomes, prevention, and management. However, understanding of delirium neurobiology remains limited. Preclinical and translational models for delirium, while challenging to develop, could advance our knowledge of delirium neurobiology and inform the development of new prevention and treatment approaches. We discuss the use of preclinical and translational animal models in delirium, focusing on (1) a review of current animal models, (2) challenges and strategies for replicating elements of human delirium in animals, and (3) the utility of biofluid, neurophysiology, and neuroimaging translational markers in animals. We conclude with recommendations for the development and validation of preclinical and translational models for delirium, with the goal of advancing awareness in this important field.

Background Autism spectrum disorders (ASD) are predominantly neurodevelopmental and largely genetically determined. However, there are human data supporting the idea that fever can improve symptoms in some individuals, but those data are limited and there are almost no data to support this from animal models. We aimed to test the hypothesis that elevated body temperature would improve function in two animal models of ASD. Methods We used a 4 h whole-body hyperthermia (WBH) protocol and, separately, systemic inflammation induced by bacterial endotoxin (LPS) at 250 µg/kg, to dissociate temperature and inflammatory elements of fever in two ASD animal models: C58/J and Shank3B- mice. We used one- or two-way ANOVA and t-tests with normally distributed data and Kruskal–Wallis or Mann–Whitney with nonparametric data. Post hoc comparisons were made with a level of significance set at p < 0.05. For correlation analyses, data were adjusted by a linear regression model. Results Only LPS induced inflammatory signatures in the brain while only WBH produced fever-range hyperthermia. WBH reduced repetitive behaviours and improved social interaction in C58/J mice and significantly reduced compulsive grooming in Shank3B- mice. LPS significantly suppressed most activities over 5–48 h. Limitations We show behavioural, cellular and molecular changes, but provide no specific mechanistic explanation for the observed behavioural improvements. Conclusions The data are the first, to our knowledge, to demonstrate that elevated body temperature can improve behavioural signs in 2 distinct ASD models. Given the developmental nature of ASD, evidence that symptoms may be improved by environmental perturbations indicates possibilities for improving function in these individuals. Since experimental hyperthermia in patients would carry significant risks, it is now essential to pursue molecular mechanisms through which hyperthermia might bring about the observed benefits.