Susceptibility to acute cognitive dysfunction in aged mice is underpinned by reduced white matter integrity and microgliosis.

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.

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.

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.

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.

Measuring the success of programmes of care for people living with dementia: a protocol for consensus building with consumers to develop a set of Core Outcome Measures for Improving Care (COM-IC).

INTRODUCTION: The Core Outcome Measures for Improving Care (COM-IC) project aims to deliver practical recommendations on the selection and implementation of a suite of core outcomes to measure the effectiveness of interventions for dementia care. METHODS AND ANALYSIS: COM-IC embeds a participatory action approach to using the Alignment-Harmonisation-Results framework for measuring dementia care in Australia. Using this framework, suitable core outcome measures will be identified, analysed, implemented and audited. The methods for analysing each stage will be codesigned with stakeholders, through the conduit of a Stakeholder Reference Group including people living with dementia, formal and informal carers, aged care industry representatives, researchers, clinicians and policy actors. The codesigned evaluation methods consider two key factors: feasibility and acceptability. These considerations will be tested during a 6-month feasibility study embedded in aged care industry partner organisations. ETHICS AND DISSEMINATION: COM-IC has received ethical approval from The University of Queensland (HREC 2021/HE001932). Results will be disseminated through networks established over the project, and in accordance with both the publication schedule and requests from the Stakeholder Reference Group. Full access to publications and reports will be made available through UQ eSpace (https://espace.library.uq.edu.au/), an open access repository hosted by The University of Queensland.

EEG microstate quantifiers and state space descriptors during anaesthesia in patients with postoperative delirium: a descriptive analysis.

Postoperative delirium is a serious sequela of surgery and surgery-related anaesthesia. One recommended method to prevent postoperative delirium is using bi-frontal EEG recording. The single, processed index of depth of anaesthesia allows the anaesthetist to avoid episodes of suppression EEG and excessively deep anaesthesia. The study data presented here were based on multichannel (19 channels) EEG recordings during anaesthesia. This enabled the analysis of various parameters of global electrical brain activity. These parameters were used to compare microstate topographies under anaesthesia with those in healthy volunteers and to analyse changes in microstate quantifiers and EEG global state space descriptors with increasing exposure to anaesthesia. Seventy-three patients from the Surgery Depth of Anaesthesia and Cognitive Outcome study (SRCTN 36437985) received intraoperative multichannel EEG recordings. Altogether, 720 min of artefact-free EEG data, including 210 min (29.2%) of suppression EEG, were analysed. EEG microstate topographies, microstate quantifiers (duration, frequency of occurrence and global field power) and the state space descriptors sigma (overall EEG power), phi (generalized frequency) and omega (number of uncorrelated brain processes) were evaluated as a function of duration of exposure to anaesthesia, suppression EEG and subsequent development of postoperative delirium. The major analyses involved covariate-adjusted linear mixed-effects models. The older (71 ± 7 years), predominantly male (60%) patients received a median exposure of 210 (range: 75-675) min of anaesthesia. During seven postoperative days, 21 patients (29%) developed postoperative delirium. Microstate topographies under anaesthesia resembled topographies from healthy and much younger awake persons. With increasing duration of exposure to anaesthesia, single microstate quantifiers progressed differently in suppression or non-suppression EEG and in patients with or without subsequent postoperative delirium. The most pronounced changes occurred during enduring suppression EEG in patients with subsequent postoperative delirium: duration and frequency of occurrence of microstates C and D progressed in opposite directions, and the state space descriptors showed a pattern of declining uncorrelated brain processes (omega) combined with increasing EEG variance (sigma). With increasing exposure to general anaesthesia, multiple changes in the dynamics of microstates and global EEG parameters occurred. These changes varied partly between suppression and non-suppression EEG and between patients with or without subsequent postoperative delirium. Ongoing suppression EEG in patients with subsequent postoperative delirium was associated with reduced network complexity in combination with increased overall EEG power. Additionally, marked changes in quantifiers in microstate C and in microstate D occurred. These putatively adverse intraoperative trajectories in global electrical brain activity may be seen as preceding and ultimately predicting postoperative delirium.

Hyperthermia elevates brain temperature and improves behavioural signs in animal models of autism spectrum disorder.

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.

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.

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.

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.

Microglia states and nomenclature: A field at its crossroads.

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions. To address these issues, we assembled a group of multidisciplinary experts to discuss our current understanding of microglial states as a dynamic concept and the importance of addressing microglial function. Here, we provide a conceptual framework and recommendations on the use of microglial nomenclature for researchers, reviewers, and editors, which will serve as the foundations for a future white paper.

The effect of baseline cognition and delirium on long-term cognitive impairment and mortality: a prospective population-based study.

Background: There is an unmet public health need to understand better the relationship between baseline cognitive function, the occurrence and severity of delirium, and subsequent cognitive decline. Our aim was to quantify the relationship between baseline cognition and delirium and follow-up cognitive impairment. Methods: We did a prospective longitudinal study in a stable representative community sample of adults aged 70 years or older who were registered with a Camden-based general practitioner in the London Borough of Camden (London, UK). Participants were recruited by invitation letters from general practice lists or by direct recruitment of patients from memory clinics or patients recently discharged from secondary care. We quantified baseline cognitive function with the modified Telephone Interview for Cognitive Status. In patients who were admitted to hospital, we undertook daily assessments of delirium using the Memorial Delirium Assessment Scale (MDAS). We estimated the association of pre-admission baseline cognitive function with delirium prevalence, severity, and duration. We assessed subsequent cognitive function 2 years after baseline recruitment using the Telephone Interview for Cognitive Status. Regression models were adjusted by age, sex, education, illness severity, and frailty. Findings: We recruited 1510 participants (median age 77 [IQR 73-82], 57% women) between March, 2017, and October, 2018. 209 participants were admitted to hospital across 371 episodes (1999 person-days of assessment). Better baseline cognition was associated with a lower risk of delirium (odds ratio 0·63, 95% CI 0·45 to 0·89) and with less severe delirium (-1·6 MDAS point, 95% CI -2·6 to -0·7). Individuals with high baseline cognition (baseline Z score +2·0 SD) had demonstrable decline even without delirium (follow-up Z score +1·2 SD). However, those with a high delirium burden had an even larger absolute decline of 2·2 SD in Z score (follow-up Z score -0·2). Once individuals had more than 2 days of moderate delirium, the rates of death over 2 years were similar regardless of baseline cognition; a better baseline cognition no longer conferred any mortality benefit. Interpretation: A higher baseline cognitive function is associated with a good prognosis with regard to likelihood and severity of delirium. However, those with a high baseline cognition and with delirium had the highest degree of cognitive decline, a change similar to the decline observed in individuals with a high amyloid burden in other cohorts. Older people with a healthy baseline cognitive function who develop delirium stand to lose the most after delirium. This group could benefit from targeted cognitive rehabilitation interventions after delirium.

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.

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.

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.

Specialist residential dementia care for people with severe and persistent behaviours: A ten-year retrospective review.

Very severe behavioural and psychological symptoms of dementia (BPSD) have low prevalence but disproportionately poor outcomes for persons with dementia, others and systems of care, including inappropriate use of medication, tenuous accommodation, poor quality of life and increased costs. The Australian Government has established new Special Dementia Care Programmes (SDCPs) to provide interim care for up to 12 months for those with severe and persistent BPSD unsuitable for mainstream aged care. This 10-year retrospective review describes environmental design, governance, clinical processes, characteristics and outcomes for 80 residents of a similar-aged care mental health partnership SDCP. A key finding was that average length of stay was slightly over 12 months. All surviving residents except one were able to be transferred to mainstream aged care services. Doses of regular and PRN antipsychotic and anxiolytic medications were significantly reduced. SDCPs may have the potential to improve care and outcomes for this group of vulnerable older people.

Evaluating the Clinical Impact of National Dementia Behaviour Support Programs on Neuropsychiatric Outcomes in Australia.

Background/Objective: People living with dementia (PLWD) in residential aged care homes (RACHs) are frequently prescribed psychotropic medications due to the high prevalence of neuropsychiatric symptoms, also known as behaviours and psychological symptoms of dementia (BPSD). However, the gold standard to support BPSD is using psychosocial/non-pharmacological therapies. This study aims to describe and evaluate services and neuropsychiatric outcomes associated with the provision of psychosocial person-centred care interventions delivered by national multidisciplinary dementia-specific behaviour support programs. Methods: A 2-year retrospective pre-post study with a single-arm analysis was conducted on BPSD referrals received from Australian RACHs to the two Dementia Support Australia (DSA) programs, the Dementia Behaviour Management Advisory Service (DBMAS) and the Severe Behaviour Response Teams (SBRT). Neuropsychiatric outcomes were measured using the Neuropsychiatric Inventory (NPI) total scores and total distress scores. The questionnaire version "NPI-Q" was administered for DBMAS referrals whereas the nursing home version "NPI-NH" was administered for SBRT referrals. Linear mixed effects models were used for analysis, with time, baseline score, age, sex, and case length as predictors. Clinical significance was measured using Cohen's effect size (d; ≥0.3), the mean change score (MCS; 3 points for the NPI-Q and 4 points for the NPI-NH) and the mean percent change (MPC; ≥30%) in NPI parameters. Results: A total of 5,914 referrals (55.9% female, age 82.3 ± 8.6 y) from 1,996 RACHs were eligible for analysis. The most common types of dementia were Alzheimer's disease (37.4%) and vascular dementia (11.7%). The average case length in DSA programs was 57.2 ± 26.3 days. The NPI scores were significantly reduced as a result of DSA programs, independent of covariates. There were significant reductions in total NPI scores as a result of the DBMAS (61.4%) and SBRT (74.3%) programs. For NPI distress scores, there were 66.5% and 69.1% reductions from baseline for the DBMAS and SBRT programs, respectively. All metrics (d, MCS, MPC) were above the threshold set for determining a clinically significant effect. Conclusions: Multimodal psychosocial interventions delivered by DSA programs are clinically effective as demonstrated by positive referral outcomes, such as improved BPSD and related caregiver distress.