The Vaccine Adjuvant Chitosan Promotes Cellular Immunity via DNA Sensor cGAS-STING-Dependent Induction of Type I Interferons.

The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation. Additionally, this process was dependent on mitochondrial reactive oxygen species and the presence of cytoplasmic DNA. Chitosan-mediated enhancement of antigen specific Th1 and immunoglobulin G2c responses following vaccination was dependent on both cGAS and STING. These findings demonstrate that a cationic polymer can engage the STING-cGAS pathway to trigger innate and adaptive immune responses.

Impaired glucose utilization in the brain of patients with delirium following hip fracture.

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 ß-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, ß-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.

Extremes of baseline cognitive function determine the severity of delirium: a population study.

Although delirium is a significant clinical and public health problem, little is understood about how specific vulnerabilities underlie the severity of its presentation. Our objective was to quantify the relationship between baseline cognition and subsequent delirium severity. We prospectively investigated a population-representative sample of 1510 individuals aged ≥70 years, of whom 209 (13.6%) were hospitalized across 371 episodes (1999 person-days assessment). Baseline cognitive function was assessed using the modified Telephone Interview for Cognitive Status, supplemented by verbal fluency measures. We estimated the relationship between baseline cognition and delirium severity [Memorial Delirium Assessment Scale (MDAS)] and abnormal arousal (Observational Scale of Level of Arousal), adjusted by age, sex, frailty and illness severity. We conducted further analyses examining presentations to specific hospital settings and common precipitating aetiologies. The median time from baseline cognitive assessment to admission was 289 days (interquartile range 130 to 47 days). In admitted patients, delirium was present on at least 1 day in 45% of admission episodes. The average number of days with delirium (consecutively positive assessments) was 3.9 days. Elective admissions accounted for 88 bed days (4.4%). In emergency (but not elective) admissions, we found a non-linear U-shaped relationship between baseline global cognition and delirium severity using restricted cubic splines. Participants with baseline cognition 2 standard deviations below average (z-score = -2) had a mean MDAS score of 14 points (95% CI 10 to 19). Similarly, those with baseline cognition z-score = + 2 had a mean MDAS score of 7.9 points (95% CI 4.9 to 11). Individuals with average baseline cognition had the lowest MDAS scores. The association between baseline cognition and abnormal arousal followed a comparable pattern. C-reactive protein ≥20 mg/l and serum sodium <125 mM/l were associated with more severe delirium. Baseline cognition is a critical determinant of the severity of delirium and associated changes in arousal. Emergency admissions with lowest and highest baseline cognition who develop delirium should receive enhanced clinical attention.

Update of the European Society of Anaesthesiology and Intensive Care Medicine evidence-based and consensus-based guideline on postoperative delirium in adult patients.

Postoperative delirium (POD) remains a common, dangerous and resource-consuming adverse event but is often preventable. The whole peri-operative team can play a key role in its management. This update to the 2017 ESAIC Guideline on the prevention of POD is evidence-based and consensus-based and considers the literature between 01 April 2015, and 28 February 2022. The search terms of the broad literature search were identical to those used in the first version of the guideline published in 2017. POD was defined in accordance with the DSM-5 criteria. POD had to be measured with a validated POD screening tool, at least once per day for at least 3 days starting in the recovery room or postanaesthesia care unit on the day of surgery or, at latest, on postoperative day 1. Recent literature confirmed the pathogenic role of surgery-induced inflammation, and this concept reinforces the positive role of multicomponent strategies aimed to reduce the surgical stress response. Although some putative precipitating risk factors are not modifiable (length of surgery, surgical site), others (such as depth of anaesthesia, appropriate analgesia and haemodynamic stability) are under the control of the anaesthesiologists. Multicomponent preoperative, intra-operative and postoperative preventive measures showed potential to reduce the incidence and duration of POD, confirming the pivotal role of a comprehensive and team-based approach to improve patients' clinical and functional status.

Advancing specificity in delirium: The delirium subtyping initiative.

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Gamma-patterned sensory stimulation reverses synaptic plasticity deficits in rat models of early Alzheimer's disease.

Non-invasive sensory stimulation in the range of the brain's gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Here, we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily treatment with 40 Hz sensory stimulation for 2 weeks fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals, which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD.

Preclinical and translational models for delirium: Recommendations for future research from the NIDUS delirium network.

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.

Macrophages in the cochlea; an immunological link between risk factors and progressive hearing loss.

Macrophages are abundant in the cochlea; however, their role in hearing loss is not well understood. Insults to the cochlea, such as noise or insertion of a cochlear implant, cause an inflammatory response, which includes activation of tissue-resident macrophages. Activation is characterized by changes in macrophage morphology, mediator expression, and distribution. Evidence from other organs shows activated macrophages can become primed, whereby subsequent insults cause an elevated inflammatory response. Primed macrophages in brain pathologies respond to circulating inflammatory mediators by disproportionate synthesis of inflammatory mediators. This signaling occurs behind an intact blood-brain barrier, similar to the blood-labyrinth barrier in the cochlea. Local tissue damage can occur as the result of mediator release by activated macrophages. Damage is typically localized; however, if it is to structures with limited ability to repair, such as neurons or hair cells within the cochlea, it is feasible that this contributes to the progressive loss of function seen in hearing loss. We propose that macrophages in the cochlea link risk factors and hearing loss. Injury to the cochlea causes local macrophage activation that typically resolves. However, in susceptible individuals, some macrophages enter a primed state. Once primed, these macrophages can be further activated, as a consequence of circulating inflammatory molecules associated with common co-morbidities. Hypothetically, this would lead to further cochlear damage and loss of hearing. We review the evidence for the role of tissue-resident macrophages in the cochlea and propose that cochlear macrophages contribute to the trajectory of hearing loss and warrant further study.

Priming Microglia for Innate Immune Memory in the Brain.

Microglia, the resident macrophages of the brain, are highly plastic and well known to be pre-activated or 'primed' by active inflammatory processes, resulting in amplified responses to a second inflammatory insult. Furthermore, the capacity of microglia to develop 'innate immune memory' (IIM), that is, long-lasting molecular reprogramming, has recently been demonstrated. Depending on the initial stimulus, IIM can either enhance or suppress microglial responses to a delayed, secondary insult. Moreover, both priming and IIM can affect pathological hallmarks of neurological disease in mouse models, which may be consistent with certain clinical observations in patients. Here, we discuss the remarkable capacity of microglia to process inflammatory signals over short and long timeframes and propose new integrated nomenclature for these processes. We also highlight future research avenues, with implications for human brain disease.

Clinico-demographics of people with younger-onset dementia and neuropsychiatric symptoms referred to an Australian dementia support service: A comparison study with older-onset dementia.

OBJECTIVE: Younger-onset dementia accounts for about 5-10% of all dementias in Australia. Little data is available on neuropsychiatric symptoms in people with younger-onset dementia compared to those with older-onset dementia. This study aims to compare the types of neuropsychiatric symptoms and their clinico-demographic characteristics of people with younger-onset dementia and older-onset dementia who are referred to a specific dementia support service. METHODS: A 2-year retrospective observational cross-sectional analysis was undertaken on referrals with neuropsychiatric symptoms from Dementia Support Australia programmes. Neuropsychiatric symptoms were measured using the Neuropsychiatric Inventory total severity scores and distress scores. Contributing factors to neuropsychiatric symptoms for dementia groups were examined. Logistic regression was used to examine the relationship between individual neuropsychiatric symptoms and having older-onset dementia vs younger-onset dementia. RESULTS: Of the 15,952 referrals, about 5% (n = 729, mean age: 60.7 years, standard deviation = 5.4) were individuals with younger-onset dementia. Referrals with older-onset dementia were more likely to be female (56%), whereas referrals with younger-onset dementia were more likely to be male (54%). There was a four times greater rate of frontotemporal dementia for those with younger-onset dementia (16.0%, n = 117) compared to those with older-onset dementia (2.8%, n = 427), χ2 (1) = 366.2, p < 0.001. Referrals with younger-onset dementia were more likely to be referred from community settings and those with older-onset dementia were more likely to be from residential aged care. Overall, there was no difference in the severity and distress of neuropsychiatric symptoms between the two groups. Contributing factors to neuropsychiatric symptoms were different between the groups, with pain being more frequently endorsed for individuals with older-onset dementia whereas communication difficulties were more commonly identified for those with younger-onset dementia. CONCLUSION: Clinico-demographics of referrals with younger-onset dementia differ from those with older-onset dementia. There were some differences in the characteristics of neuropsychiatric symptoms between younger-onset dementia and older-onset dementia. Our findings have implications for service provision and support for people with dementia at different ages.

Acute Inflammation Alters Brain Energy Metabolism in Mice and Humans: Role in Suppressed Spontaneous Activity, Impaired Cognition, and Delirium.

Systemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, which while adaptive, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here, we used bacterial lipopolysaccharide (LPS) in female C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 µg/kg) induced hypoglycemia, which was mimicked by interleukin (IL)-1ß (25 µg/kg) but not prevented in IL-1RI-/- mice, nor by IL-1 receptor antagonist (IL-1RA; 10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentrations, was mitigated by exogenous glucose (2 g/kg), and was exacerbated by 2-deoxyglucose (2-DG) glycolytic inhibition, despite preventing IL-1ß synthesis. Using the ME7 model of chronic neurodegeneration in female mice, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 µg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition selectively in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in CSF in humans during inflammatory trauma-induced delirium. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with acutely altered brain energy metabolism. Collectively, the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.SIGNIFICANCE STATEMENT Acute systemic inflammation alters behavior and produces disproportionate effects, such as delirium, in vulnerable individuals. Delirium has serious short and long-term sequelae but mechanisms remain unclear. Here, we show that both LPS and interleukin (IL)-1ß trigger hypoglycemia, reduce CSF glucose, and suppress spontaneous activity. Exogenous glucose mitigates these outcomes. Equivalent hypoglycemia, induced by lipopolysaccharide (LPS) or insulin, was sufficient to trigger cognitive impairment selectively in animals with existing neurodegeneration and glucose also mitigated those impairments. Patient CSF from inflammatory trauma-induced delirium also shows altered brain carbohydrate metabolism. The data suggest that the degenerating brain is exquisitely sensitive to acute behavioral and cognitive consequences of disrupted energy metabolism. Thus "bioenergetic stress" drives systemic inflammation-induced dysfunction. Elucidating this may offer routes to mitigating delirium.

Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice.

Locus coeruleus (LC)-derived noradrenaline is important in cognition and decreases with age, but the impact of prior noradrenaline deficiency on vulnerability to inflammation-induced acute cognitive dysfunction is unclear. Here we assessed whether noradrenergic depletion, in female mice, impacted upon inflammation, locomotor activity and working memory directly after acute systemic immune challenge with bacterial lipopolysaccharide (LPS), a paradigm we have previously used to capture delirium-like acute cognitive deficits. Mice received 2 doses of the LC-selective noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) and were challenged, 2 weeks later, with LPS (100 µg/kg i.p.). DSP-4 dramatically reduced noradrenaline concentrations and tyrosine hydroxylase-positive afferents in the frontal cortex and hippocampus. This did not significantly alter numbers of Pu.1-positive microglia, Iba1-positive microglial morphology or mRNA expression of microglia-associated gene transcripts (Tyrobp, Sall1, Cd68, Sra2, Clec7a) in the hippocampus or frontal cortex and produced modest reductions in Cx3cr1 and P2ry12. LPS induced blood and brain cytokine levels, cFOS activation and locomotor responses that were highly similar in DSP-4- and vehicle-treated mice, although LPS-induced plasma TNF-α was significantly reduced in those treated with DSP-4. Importantly, prior noradrenergic depletion did not predispose to LPS-induced T-maze working memory deficits. The data demonstrate that significant depletion of noradrenaline in the hippocampus and frontal cortex does not prompt acutely exaggerated neuroinflammation or leave the brain vulnerable to acute, transient working memory deficits upon low dose LPS challenge. These findings have implications for our understanding of the impact of systemic inflammation on the aging and vulnerable brain during septic encephalopathy and delirium.

Double stranded RNA drives anti-viral innate immune responses, sickness behavior and cognitive dysfunction dependent on dsRNA length, IFNAR1 expression and age.

Double stranded RNA is generated during viral replication. The synthetic analogue poly I:C is frequently used to mimic anti-viral innate immune responses in models of psychiatric and neurodegenerative disorders including schizophrenia, autism, Parkinson's disease and Alzheimer's disease. Many studies perform limited analysis of innate immunity despite these responses potentially differing as a function of dsRNA molecular weight and age. Therefore fundamental questions relevant to impacts of systemic viral infection on brain function and integrity remain. Here, we studied innate immune-inducing properties of poly I:C preparations of different lengths and responses in adult and aged mice. High molecular weight (HMW) poly I:C (1-6 kb, 12 mg/kg) produced more robust sickness behavior and more robust IL-6, IFN-I and TNF-α responses than poly I:C of < 500 bases (low MW) preparations. This was partly overcome with higher doses of LMW (up to 80 mg/kg), but neither circulating IFNß nor brain transcription of Irf7 were significantly induced by LMW poly I:C, despite brain Ifnb transcription, suggesting that brain IFN-dependent gene expression is predominantly triggered by circulating IFNß binding of IFNAR1. In aged animals, poly I:C induced exaggerated IL-6, IL-1ß and IFN-I in the plasma and similar exaggerated brain cytokine responses. This was associated with acute working memory deficits selectively in aged mice. Thus, we demonstrate dsRNA length-, IFNAR1- and age-dependent effects on anti-viral inflammation and cognitive function. The data have implications for CNS symptoms of acute systemic viral infection such as those with SARS-CoV-2 and for models of maternal immune activation.

Effect of COVID-19 on BPSD severity and caregiver distress: Trend data from national dementia-specific behavior support programs in Australia.

BACKGROUND: Globally, Coronavirus disease 2019 (COVID-19) caused a significant disruption to the physical and mental well-being of all individuals, including those living with dementia. Social restrictions and lockdown measures due to COVID-19 have worsened the feelings of loneliness and behaviours and psychological symptoms of dementia (BPSD). National BPSD support programs in Australia are offered by Dementia Support Australia (DSA) through the Dementia Behavior Management Advisory Service (DBMAS) and the Severe Behavior Response Teams (SBRT). This study aims to investigate the impact of COVID-19 on BPSD severity and related caregiver distress among referrals to DSA programs. METHODS: A retrospective comparative analysis was conducted on the intake data of referrals to DSA between two periods: Pre-COVID-19 Period (January 2018-Decmeber 2019) and COVID-19 Period (January 2020-July 2021). Referrals were compared on demographic characteristics (e.g., age), and BPSD severity (i.e., neuropsychiatric symptoms such as agitation) and caregiver distress as measured by the Neuropsychiatric Inventory (NPI). NPI scores were compared on a month-to-month basis between the specified periods. RESULTS: Across the two periods, there were a total of 23,180 referrals eligible for the analysis. While no differences were noted in age, sex, or dementia subtype, there were elevated levels of NPI severity and caregiver distress scores during COVID-19 Period compared to the Pre-COVID-19 Period. The month-to-month trends of these differences (Figure 1, Figure 2) reflect the timing of outbreaks across Australia. Specifically, there were no significant differences at the start of 2020 prior to the declaration of the pandemic, with an initial rise in NPI severity and distress through April after initial measures were implemented nationally in March 2020. These levels of severity and distress continued to rise through the remainder of 2020, alongside outbreaks in specific regions within Australia, such as Victoria (June-October), and New South Wales (December/January). NPI severity and caregiver distress then began to return to Pre-COVID levels from February-May before elevating again with the outbreak of the Delta variant in Australia. CONCLUSIONS: COVID-19 has a significant impact on the severity levels of BPSD and related caregiver distress.

Feasibility and evaluation of the Dementia Engagement Modelling Program (DEMP): a novel model of aged care during COVID-19.

BACKGROUND: The COVID-19 pandemic has a significant impact on the quality of life of aged care residents living with dementia (RLWD). Lockdown measures necessary to protect RLWD and caring staff from COVID-19 have resulted in increased social isolation, loneliness, and behaviors and psychological symptoms of dementia (BPSD). In response, the Australian Government funded a pilot program, the Dementia Engagement Modelling Program (DEMP) as part of the Aged Care COVID-19 Grief and Trauma support package for RLWD, their families and aged care staff. Operated by the Dementia Centre of HammondCare, the DEMP provides first-line multimodal external support for RLWD at a greater risk of developing BPSD due to COVID-19 restrictions. This study aims to describe the DEMP and evaluate its feasibility and outcomes for Australian RLWD. METHODS: A team of 10 trained DEMP consultants was involved in delivering a consultancy service that modelled best practice and person-centred activities of engagement to support staff in providing residents with meaningful purpose, comfort, and reassurance. Consultants also provided coaching and development opportunities for staff to enhance their knowledge regarding communication and engagement. Outcome measures included the regular administration of the Engagement in Preferred ActivitieS Scale (EPASS; ≥4-9 moderate-to-high engagement). A phone evaluation survey for supported residential aged care homes (RACHs) was conducted to determine the feasibility of DEMP. RESULTS: A total of 60 residents (86.0 ± 7.8 y; 68% female) across 10 RACHs from three Australian states (VIC, NSW, QLD) was supported by DEMP between May and July 2021. More than half of the residents had Alzheimer's disease (n = 24, 40%) and vascular dementia (n = 7, 12%). Completed EPASS assessments (n = 389) demonstrated that the vast majority (64%-72%) of residents scored moderate-to-high engagement. All supported RACHs highly recommended the DEMP to other colleagues and rated the program highly for implementation feasibility including the recommended engagement activities/brokered items. CONCLUSIONS: The DEMP is a novel, feasible and effective dementia-specific engagement modelling program for Australian RLWD in the era of COVID-19 pandemic.

Acute systemic inflammation exacerbates neuroinflammation in Alzheimer's disease: IL-1ß drives amplified responses in primed astrocytes and neuronal network dysfunction.

Neuroinflammation contributes to Alzheimer's disease (AD) progression. Secondary inflammatory insults trigger delirium and can accelerate cognitive decline. Individual cellular contributors to this vulnerability require elucidation. Using APP/PS1 mice and AD brain, we studied secondary inflammatory insults to investigate hypersensitive responses in microglia, astrocytes, neurons, and human brain tissue. The NLRP3 inflammasome was assembled surrounding amyloid beta, and microglia were primed, facilitating exaggerated interleukin-1ß (IL-1ß) responses to subsequent LPS stimulation. Astrocytes were primed to produce exaggerated chemokine responses to intrahippocampal IL-1ß. Systemic LPS triggered microglial IL-1ß, astrocytic chemokines, IL-6, and acute cognitive dysfunction, whereas IL-1ß disrupted hippocampal gamma rhythm, all selectively in APP/PS1 mice. Brains from AD patients with infection showed elevated IL-1ß and IL-6 levels. Therefore, amyloid leaves the brain vulnerable to secondary inflammation at microglial, astrocytic, neuronal, and cognitive levels, and infection amplifies neuroinflammatory cytokine synthesis in humans. Exacerbation of neuroinflammation to produce deleterious outcomes like delirium and accelerated disease progression merits careful investigation in humans.

Limiting antipsychotic drugs in dementia.

Most patients with dementia have behavioural and psychological symptoms. The first-line treatments for these symptoms are not drugs, but behavioural and psychological interventions Antipsychotic drugs are widely prescribed for people living with dementia. This is despite a high adverse effect burden and limited evidence of efficacy Most behavioural and psychological symptoms will subside spontaneously within six months. Trials of deprescribing are therefore recommended Behaviours should be seen as symptoms that have an underlying cause. Treatment should target these causes, rather than the resultant behaviours.

Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Systemic inflammation can impair cognition with relevance to dementia, delirium and post-operative cognitive dysfunction. Episodes of delirium also contribute to rates of long-term cognitive decline, implying that these acute events induce injury. Whether systemic inflammation-induced acute dysfunction and acute brain injury occur by overlapping or discrete mechanisms remains unexplored. Here we show that systemic inflammation, induced by bacterial LPS, produces both working-memory deficits and acute brain injury in the degenerating brain and that these occur by dissociable IL-1-dependent processes. In normal C57BL/6 mice, LPS (100 µg/kg) did not affect working memory but impaired long-term memory consolidation. However prior hippocampal synaptic loss left mice selectively vulnerable to LPS-induced working memory deficits. Systemically administered IL-1 receptor antagonist (IL-1RA) was protective against, and systemic IL-1ß replicated, these working memory deficits. Dexamethasone abolished systemic cytokine synthesis and was protective against working memory deficits, without blocking brain IL-1ß synthesis. Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion. The data suggest that LPS induces working memory dysfunction via circulating IL-1ß but direct hippocampal action of IL-1ß causes neuronal dysfunction and may drive neuronal death. The data suggest that acute systemic inflammation produces both reversible cognitive deficits, resembling delirium, and acute brain injury contributing to long-term cognitive impairment but that these events are mechanistically dissociable. These data have significant implications for management of cognitive dysfunction during acute illness.

Correction: Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms.

Following publication of this article, the authors noticed an error in the abstract, where they incorrectly stated that: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-/--dependent fashion". This has now been corrected to: "Direct application of IL-1ß to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion". The authors would like to apologise for this error. This has been corrected in both the PDF and HTML versions of the article.

A roadmap to advance delirium research: Recommendations from the NIDUS Scientific Think Tank.

Delirium is an acute disorder of attention and cognition. It occurs across the life span, yet it is particularly common among older adults, and is closely linked with underlying neurocognitive disorders. Evidence is mounting that intervening on delirium may represent an important opportunity for delaying the onset or progression of dementia. To accelerate the current understanding of delirium, the Network for Investigation of Delirium: Unifying Scientists (NIDUS) held a conference "Advancing Delirium Research: A Scientific Think Tank" in June 2019. This White Paper encompasses the major knowledge and research gaps identified at the conference: advancing delirium definition and measurement, understanding delirium pathophysiology, and prevention and treatment of delirium. A roadmap of research priorities is proposed to advance the field in a systematic, interdisciplinary, and coordinated fashion. A call is made for an international consortium and biobank targeted to delirium, as well as a public health campaign to advance the field.