Agitation In Dementia Research Articles

COVID-19 and Its Influence on Prevalence of Dementia and Agitation in Australian Residential Aged Care: A Comparative Study

Agitation is one of the most common and persistent behavioral and psychological symptoms among persons with dementia (PWD) in residential aged care facilities (RACFs). While most studies have explored the general impact of COVID-19 on the mental health and well-being of aged care residents, there has been limited research on the pandemic’s impact on agitation in dementia within RACFs. This knowledge is crucial to ensuring that RACFs are better equipped to handle future public health emergencies. Therefore, this retrospective cohort study investigates the impact of the pandemic on agitation incidents within 40 Australian RACFs. Using Python, we extracted agitation symptoms from nursing notes and compared the frequency and percentage of symptom occurrence pre-pandemic versus during-pandemic. Chi-square tests examined any significant change in the prevalence of dementia and agitation in dementia between the comparative groups and periods. Dementia prevalence dropped significantly during the second year of the pandemic, with a concurrent increase in early-onset dementia cases. Overall, agitation symptoms decreased by 20.1%, but six symptoms significantly increased: resisting (28.98%), wandering (11.78%), restlessness (3.19%), complaining (10.1%), arguing (2.36%), and outbursts (1.74%). Conversely, pacing decreased by 15.88% and speaking loudly decreased by 10.9%. Over half of the care recipients with dementia experienced agitation symptoms 2–5 times each year, increasing from 50.56% in 2019 to 58.28% in 2021. Despite the co-occurrence of symptoms such as falls, confusion, and weakness, there was no evidence to suggest that these comorbidities were specific to COVID-19; rather, they appeared to be prevalent even before the pandemic. Persons with agitation in dementia had a significantly higher death rate during the COVID-19 pandemic than otherwise.

Dexmedetomidine for agitation in dementia: Current data and future direction.

The incidence and prevalence of dementia, and thus dementia-related behavioral and psychological symptoms, are increasing significantly. Currently, there are limited safe and efficacious options for treating these symptoms. Dexmedetomidine has been used for agitation related to delirium and showed significant benefit in prior studies. This raises the question whether dexmedetomidine could also provide a safe and effective treatment for BPSD, including agitation related to dementia. Our team searched PubMed, Cochrane Database, and Ovid with the terms dexmedetomidine and dementia. Only studies published in English language journals, or with official English language translations, and human studies were included. All reports of dexmedetomidine for dementia were included regardless of study type. No completed studies on dexmedetomidine for agitation in dementia were identified. The TRANQUILITY study is in progress, although results are yet to be published. Dexmedetomidine has shown benefit for hospital delirium and for agitation in schizophrenia and bipolar disorder. However, there are no completed studies published on dexmedetomidine for agitation in dementia. Controlled studies with larger sample sizes are needed to assess the efficacy, safety, and the best route of administration for this drug in managing BPSD including agitation.

Electroconvulsive therapy for the acute management of severe agitation in dementia (ECT-AD): A modified study protocol

Electroconvulsive therapy for the acute management of severe agitation in dementia (ECT-AD): A modified study protocol

Physiological Profiling of Agitation in Dementia: Insights From Wearable Sensor Data.

The number of people with dementia is expected to triple to 152 million in 2050, with 90% having accompanying behavioral and psychological symptoms (BPSD). Agitation is among the most critical BPSD and can lead to decreased quality of life for people with dementia and their caregivers. This study aims to explore objective quantification of agitation in people with dementia by analyzing the relationships between physiological and movement data from wearables and observational measures of agitation. The data presented here is from 30 people with dementia, each included for 1 week, collected following our previously published multimodal data collection protocol. This observational protocol has a cross-sectional repeated measures design, encompassing data from both wearable and fixed sensors. Generalized linear mixed models were used to quantify the relationship between data from different wearable sensor modalities and agitation, as well as motor and verbal agitation specifically. Several features from wearable data are significantly associated with agitation, at least the p < .05 level (absolute β: 0.224-0.753). Additionally, different features are informative depending on the agitation type or the patient the data were collected from. Adding context with key confounding variables (time of day, movement, and temperature) allows for a clearer interpretation of feature differences when a person with dementia is agitated. The features shown to be significantly different, across the study population, suggest possible autonomic nervous system activation when agitated. Differences when splitting the data by agitation type point toward a need for future detection models to tailor to the primary type of agitation expressed. Finally, patient-specific differences in features indicate a need for patient- or group-level model personalization. The findings reported in this study both reinforce and add to the fundamental understanding of and can be used to drive the objective quantification of agitation.

“From Stigma to Solution” – Using THC Edibles for the Palliative Treatment of Aggression and Agitation in Dementia

“From Stigma to Solution” – Using THC Edibles for the Palliative Treatment of Aggression and Agitation in Dementia

Neuromodulation in Behavioral and Psychological Symptoms of Dementia (BPSD)

Behavioral and psychological symptoms of dementia (BPSD) affect up to 90% of people living with dementia and include agitation, hallucinations, delusions, sleep or mood changes. BPSD are challenging to treat and there are limited safe and effective pharmacologic treatments. Electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), Deep Brain Stimulation (DBS), Vagal nerve stimulation (VNS), ketamine, and cannabinoids are interventions that have proven effectiveness for other psychiatric conditions including depression and psychosis. More recently, many of these have also been investigated for the treatment of BPSD.This presentation will review the current evidence for using ECT, TMS, ketamine, DBS, VNS, and cannabinoids for the treatment of BPSD. Out of these techniques, ECT has been the most studied and shows some benefit for the treatment of BPSD. TMS has also been studied in over 10 trials and most of these studies show an improvement in BPSD. The effect of TMS on apathy in dementia has been examined in multiple studies, the majority of which have shown benefit. DBS has shown some benefit for improving hallucinations in Parkinson disease dementia in one small RCT of six patients, and the procedure was well tolerated. VNS for BPSD has not been studied. Ketamine, in evidence from heterogeneous case reports, has shown to target three distinct behavioral disturbances, agitation, catatonia and depression, in dementia.Cannabinoids, particularly dronabinol and nabilone, have also been investigated in a number of RCTs and show mixed results for treating agitation in dementia. Sedation was the most common side effect reported but often did not result in discontinuation of therapy.In conclusion, neuromodulation has increasing evidence for the treatment of BPSD and most studies show good safety profiles. Larger and more rigorous trials are needed to further investigate the effectiveness, safety, and practicality of these interventions in this population. This presentation will summarize the effects of these various interventions, their side effects, doses used, and durations of treatment.

Wrist-worn actigraphy in agitated late-stage dementia patients: A feasibility study on digital inclusion.

Wrist-worn actigraphy can be an objective tool to assess sleep and other behavioral and psychological symptoms in dementia (BPSD). We investigated the feasibility of using wearable actigraphy in agitated late-stage dementia patients. Agitated, late-stage Alzheimer's dementia care home residents in Greater London area (n=29; 14 females, mean age±SD: 80.8±8.2; 93.1% White) were recruited to wear an actigraphy watch for 4weeks. Wearing time was extracted to evaluate compliance, and factors influencing compliance were explored. A high watch-acceptance (96.6%) and compliance rate (88.0%) was noted. Non-compliance was not associated with age or BPSD symptomatology. However, participants with "better" cognitive function (R=0.42, p=0.022) and during nightshift (F1.240, 33.475=8.075, p=0.005) were less compliant. Female participants were also marginally less compliant (F1, 26=3.790, p=0.062). Wrist-worn actigraphy appears acceptable and feasible in late-stage agitated dementia patients. Accommodating the needs of both the patients and their carers may further improve compliance.

Extracting Symptoms of Agitation in Dementia from Free-Text Nursing Notes Using Advanced Natural Language Processing.

Nursing staff record observations about older people under their care in free-text nursing notes. These notes contain older people's care needs, disease symptoms, frequency of symptom occurrence, nursing actions, etc. Therefore, it is vital to develop a technique to uncover important data from these notes. This study developed and evaluated a deep learning and transfer learning-based named entity recognition (NER) model for extracting symptoms of agitation in dementia from the nursing notes. We employed a Clinical BioBERT model for word embedding. Then we applied bidirectional long-short-term memory (BiLSTM) and conditional random field (CRF) models for NER on nursing notes from Australian residential aged care facilities. The proposed NER model achieves satisfactory performance in extracting symptoms of agitation in dementia with a 75% F1 score and 78% accuracy. We will further develop machine learning models to recommend the optimal nursing actions to manage agitation.

Structural brain network degeneration associated with agitation in dementia

AbstractBackgroundAgitation is a behavioral syndrome involving increased motor activity, restlessness, aggressiveness and emotional distress. Its has a 30% prevalence across multiple types of dementia and is associated with negative outcomes, including reduced quality of life, caregiver distress, and mortality. Pharmacological treatment risks serious side effects, including mortality. Understanding brain network topology could provide insights into novel treatment methods.MethodParticipants comprised 600 subjects from 3 existing databases: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD) and the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University. Participants were clinically diagnosed with either behavioral variant frontotemporal dementia (bvFTD), mild cognitive impairment (MCI), dementia of the Alzeheimer type (DAT) or cognitively normal (CN). The Neuropsychiatric Inventory Questionnaire (NPI‐Q) caregiver rating was used to determine whether individuals were agitated or not. Morphometric similarity networks (MSNs) were generated from Freesurfer statistics calculated from T1‐weighted MRIs. 7 surface‐based cortical metrics (e.g. gray matter volume, surface area) were calculated for each of 360 parcels. Pairwise inter‐parcel Pearson correlations of feature vectors were calculated to produce a morphometric similarity matrix for each individual. We calculated sub‐matrices for salience (SN) cognitive control (CCN) and default mode networks (DMN). Brain Connectivity Toolbox calculated transitivity and global efficiency of each network. Metrics were calculated at different thresholds to ensure the results were not threshold‐dependent. We calculated 2 (Agitation present/absent) x 4 (Diagnosis) repeated measures ANCOVAS for transitivity and global efficiency for each network. Covariates were age, sex, race, database, education, ICV, CDR‐SB and days MRI‐NPI‐Q.ResultFor the SN, people with Agitation had significantly lower global efficiency than people without Agitation (Figure 1). There were no significant effects of diagnosis or interaction. For the CCN, people with agitation had significantly lower transitivity than people without Agitation (Figure 2). There were no significant effect of diagnosis or interaction.ConclusionAcross different forms of dementia, Agitation is associated with reduced integration (global efficiency) of the salience network, and reduced segregation (transitivity) of the cognitive control network. Interventions that alter these topological network features may be effective in reducing agitation in dementia, regardless of clinical diagnosis.

Structural brain network degeneration associated with agitation in dementia

AbstractBackgroundAgitation is a behavioral syndrome involving increased motor activity, restlessness, aggressiveness and emotional distress. Its has a 30% prevalence across multiple types of dementia and is associated with negative outcomes, including reduced quality of life, caregiver distress, and mortality. Pharmacological treatment risks serious side effects, including mortality. Understanding brain network topology could provide insights into novel treatment methods.MethodParticipants comprised 600 subjects from 3 existing databases: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD) and the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University.Participants were clinically diagnosed with either behavioral variant frontotemporal dementia (bvFTD), mild cognitive impairment (MCI), dementia of the Alzeheimer type (DAT) or cognitively normal (CN). The Neuropsychiatric Inventory Questionnaire (NPI‐Q) caregiver rating was used to determine whether individuals were agitated or not.Morphometric similarity networks (MSNs) were generated from Freesurfer statistics calculated from T1‐weighted MRIs. 7 surface‐based cortical metrics (e.g. gray matter volume, surface area) were calculated for each of 360 parcels. Pairwise inter‐parcel Pearson correlations of feature vectors were calculated to produce a morphometric similarity matrix for each individual. We calculated sub‐matrices for salience (SN) cognitive control (CCN) and default mode networks (DMN). Brain Connectivity Toolbox calculated transitivity and global efficiency of each network. Metrics were calculated at different thresholds to ensure the results were not threshold‐dependent.We calculated 2 (Agitation present/absent) x 4 (Diagnosis) repeated measures ANCOVAS for transitivity and global efficiency for each network. Covariates were age, sex, race, database, education, ICV, CDR‐SB and days MRI‐NPI‐Q.ResultFor the SN, people with Agitation had significantly lower global efficiency than people without Agitation (Figure 1). There were no significant effects of diagnosis or interaction.For the CCN, people with agitation had significantly lower transitivity than people without Agitation (Figure 2). There were no significant effect of diagnosis or interaction.ConclusionAcross different forms of dementia, Agitation is associated with reduced integration (global efficiency) of the salience network, and reduced segregation (transitivity) of the cognitive control network. Interventions that alter these topological network features may be effective in reducing agitation in dementia, regardless of clinical diagnosis.

S7: Updates on Electroconvulsive Therapy practice and research

Electroconvulsive Therapy (ECT) has evolved into a highly safe, effective, and well tolerated treatment for several severe psychiatric conditions and has become a necessary tool in the armamentarium of modern psychiatry. In this symposium we will review current state of the art clinical practices in Electroconvulsive Therapy (ECT) and new data on research.More specifically Dr. Charles Kellner will review the elements of optimal patient selection/preparation in the ECT consultation and review clinical decision-making during a course of ECT (including electrode placement, stimulus dosing and other technical procedural details.)Dr Raphael Braga will review the evidence for the use of ECT as an augmentation to antipsychotic medications strategy for the treatment of patients with schizophrenia who are resistant to medications, including clozapine.Dr. Brent Forester will discuss the rationale and evidence base for the safety and efficacy of ECT for the treatment of Agitation in Dementia. Agitation is the most common neuropsychiatric symptom of dementia, accounts for about 12% of the total health and social care costs (approximately $31billion/year). It is implicated in a vicious cycle of negative events including deterioration of family and professional relationships, increased risk of death, and increased caregiver burden, which is a significant predictor for institutionalization or death of patients with dementia. His presentation will highlight the existing evidence base and method of ECT delivery to target symptoms of severe agitation, and review an ongoing multi-site NIA funded clinical trial of ECT for severe agitation in dementia.Dr Søren Dinesen Østergaard will discuss the suicide risk in patients receiving ECT which, despite the well-established anti-suicidal effect of ECT, remains high due to the severity of their underlying illness. He will present data quantifying and identifying risk factors for suicide among patients receiving ECT using data from nationwide Danish registers on 11,780 patients.Dr. Georgios Petrides is the organizer and will moderate this symposium

Lessons from Covid‐19: A narrative and reflective practice review of non‐pharmacological treatments for agitation in Alzheimer’s dementia, in a time of social distancing

AbstractBackgroundAgitation as a behavioural and psychological symptom of dementia is common and distressing for patients and their carers. There are several non‐pharmacological approaches to managing agitation in Alzheimer’s Dementia (AD). Many of these require close interactions with the patient. However, social distancing during the coronavirus pandemic has made many of these interventions impractical. As busy clinicians working on a psychiatric unit managing AD patients with agitation, we wished to explore what we could offer in a time of social distancing. Our study sought to review the literature looking at the non‐pharmacological management of agitation in dementia and reflect on this as clinicians working amid a pandemic. While the pandemic recedes, this review and reflection still offers guidance for the management of agitation in AD whilst reducing the risk of disease transmission. The review would help to keep our most vulnerable safe during future outbreaks of infectious disease.MethodWe conducted a systematic review of the literature to identify non‐pharmacological treatments for the management of agitation in Alzheimer’s disease related dementia. Specifically, we sought evidence related to treatment in inpatient and care facilities. We appraised the evidence about these treatments. We then went on to use practitioner reflection on this evidence to consider the practicalities of implementation during the social distancing restrictions of the Covid‐19 pandemic.ResultMyriad non‐pharmacological therapies exist to help treat agitation in individuals with AD. Of these the evidence suggests music therapies and caregiver education interventions reduced agitation most significantly. We found that the most effective methods tailor treatment to the individual’s preferences and needs and use active engagement in therapies. Non‐group activities and those which do not involve shared equipment are most easily implementable during Covid‐19.ConclusionInterventions which are individually tailored to the patient and involve an active element to them are most effective, however those with an active element are less easily used during a pandemic. Given the evidence base and practicalities of implementation, our review suggests music therapy for those with agitation in AD.

Feasibility of Using Wearable Actigraphy for Behavioural Monitoring in Care Home Residents Living with Moderate to Severe Alzheimer’s Disease and Agitation

AbstractBackgroundMeasuring and monitoring behaviour is difficult in people living with later stage Alzheimer’s disease and specific behavioural symptoms such as agitation and aggression (AA). Currently, subjective information given by these patients is highly susceptible to inaccurate recall, clinicians rely on answers provided by care givers, which can be biased and lack fine‐grain temporal detail. Although actigraphy watches have been useful tools for research, little is known about the feasibility of their use in agitated dementia participants and on the factors influencing watch compliance.MethodPeople diagnosed with Alzheimer’s disease and significant AA symptoms living in care homes were asked to wear an actigraphy watch (GENEactiv Original) for 4 consecutive weeks. Demographic data, Functional Assessment Staging Tool (FAST) score, behavioural symptom pattern and severity were recorded using the Neuropsychiatric Inventory Nursing Home Version (NPI‐NH). Watch‐recorded wearing time and activity data were used to evaluate adherence. Care home staff were interviewed to explore factors influencing watch wearing by participants and to develop solutions to improve compliance.ResultWe recruited 28 participants (14 female) and found wearing the watch feasible overall. No statistical compliance difference was found between different groups based on age, FAST score, agitation pattern or severity; however, a significant gender difference was found with male participants being more adherent (Table). Participants were more compliant in weeks 3‐4, and first week adherence predicted overall adherence (Figure). Factors influencing compliance include the design and appearance of the watch, previous watch wearing habit, and the perceived purpose of the study. Using documents easily readable to participants and care givers to facilitate understanding of the study and to communicate challenging clinical scenarios appeared to enhance adherence.ConclusionWearing an actigraphy watch for behavioural monitoring was feasible for moderate to severe Alzheimer’s disease patients with AA symptoms in care home settings. Gender‐specific design and appearance should be considered when selecting the actigraphy watch. For dementia studies planning to use an actigraphy watch, compliance can be improved by incorporating a short lead‐in phase to establish a watch wearing routine and by providing reader‐friendly documents about the watch purpose to communicate with participants and care givers.

34 Specific Agitation Behaviors in Dementia Differentially Contribute to Caregiver Burden

Objective:Agitation is a common neuropsychiatric symptom within the dementia spectrum, experienced by 70 percent of individuals with cognitive decline. Prior literature demonstrates a strong association between care recipient agitation and burden in caregivers of individuals with dementia, as these symptoms are often difficult to manage and predict. Understanding how agitation symptoms in the person with dementia may influence caregiver burden is imperative given these strong associations; however, both agitation and burden are complex, multidimensional constructs. Agitation in dementia involves a range of behaviors including increased motor activity, emotional distress, and aggressive behaviors. Caregiver burden is also multi-faceted and often incorporates dimensions of social/relationship, emotional, and physical health strain. The current study sought to determine whether specific presentations of agitation differentially relate to distinct patterns of caregiver burden.Participants and Methods:Medical record data from an outpatient memory clinic were extracted for 609 persons with dementia and their caregivers. Caregivers completed the Zarit Burden Interview (ZBI) to assess caregiver burden and the Cohen-Mansfield Agitation Inventory (CMAI) to assess care recipient agitation behaviors. At their initial outpatient appointment, care recipients were also administered a measure of global cognitive functioning (either the Montreal Cognitive Assessment or the Mini-Mental State Examination). Demographic information was extracted from medical records. Exploratory factor analysis was used to determine ZBI and CMAI factor structures. Hierarchical multiple regression analyses then examined whether factors of the CMAI differentially predicted ZBI factors, controlling for dementia severity and demographic variables.Results:Exploratory factor analysis yielded three domains of agitation on the CMAI ("Physically Aggressive," "Physically NonAggressive," "Verbally Agitated") and four domains of burden on the ZBI ("Impact on Life," "Guilt/Uncertainty," "Embarrassed/Frustrated," and "Overwhelm"). Regression analyses demonstrated all domains of agitation positively predicted overall burden. Regarding specific aspects of burden, Physically Aggressive behaviors predicted only Embarrassment/Frustration (B=.41, SE=.10, ß=.16, p&lt;.001). Non-Aggressive behaviors predicted Impact on Life (B=.14, SE=.05, ß=.13, p&lt;.01) and Guilt/Uncertainty (B=.05, SE=.02, ß=.10, p&lt;.05). Verbally Agitated behaviors predicted all burden dimensions: Impact on Life (B=.35, SE=.06, ß=.32, p&lt;.001), Guilt/Uncertainty (B=.12, SE=.03, ß=.22, p&lt;.001), Embarrassment/Frustration (B=.17, SE=.02, ß=.38, p&lt;.001), and Overwhelm (B=.16, SE=.02, ß=.40, p&lt;.001).Conclusions:Findings enhance understanding of the relationships between specific agitation symptoms and distinctive aspects of caregiver burden, suggesting that targeted interventions for aspects of caregiver burden based on agitation symptoms may be useful in alleviating burden. Interventions focused on caregivers' feelings of guilt, personal health decline, lack of time for themselves, and fear and uncertainty about the future may be effective when care recipients present with physically nonaggressive behaviors (e.g., pacing, restlessness, inappropriate dress or disrobing). When a care recipient presents with physically aggressive behaviors, helping the caregiver cope with embarrassment or anger may be of benefit. When a care recipient presents with verbally agitated behaviors, interventions targeting burden globally may be most useful. Future work should seek to replicate the current findings and explore such interventions.

Characteristics of Music Therapy With Beneficial Impacts on Agitation in Dementia

Several reviews in recent years have reported evidence of the effect of music on the serious problem of agitation in dementia. Some reviews draw different conclusions, however, which actualizes the need for studies that examine characteristics of music therapy with beneficial impacts on agitation. In an instrumental case study, documented through qualitative interviews, recordings of group meetings, and patient record excerpts, we examine how music was used intensively in interaction with a man in his 70s at a unit for persons with dementia. Music therapy was often able to ease his agitation and was especially valuable in a period when he needed to be isolated due to a suspected coronavirus infection. However, the interventions did not work every time, and his responses differed considerably. The case illustrates that music therapy can address agitation in dementia for some clients, but the claim must be qualified. Potential characteristics of music therapy with such an ability might be i) situated use of the most favored music, ii) careful adjustment to signs of pain and discomfort, iii) sustained effort to build trustful relationships, iv) transferable interaction patterns of health musicking, and v) sufficient access to attention and support for the client(s) during the musical interventions.

Clinical Trial Studies of Antipsychotics during Symptomatic Presentations of Agitation and/or Psychosis in Alzheimer’s Dementia: A Systematic Review

Aggressive behaviors of people with dementia pose a significant challenge to employees in nursing homes and aged care facilities. Aggressive behavior is a result of psychomotor agitation in dementia (BPSD). Globally, psychotropic interventions are the preferred treatment for BPSD. However, it is still unclear which psychotropic should be prescribed. The purpose of this systematic review is to compare pharmacological interventions for psychomotor agitation and psychosis symptoms. Method: The studies were extracted from databases, such as PubMed, OVID, and Cochrane, with a date restriction from 2000 to present, and in English. PRISMA steps were used to refine the extracted data. The RCTs extracted for this systematic review compared active ingredient medications to one another or to a placebo. Results: PRISMA was used to assess all selected trials comprehensively. Four trials are being conducted on quetiapine, two on haloperidol, one on olanzapine, three on risperidone, one on brexpiprazole, one on pimavanserin, and two on aripiprazole. Compared to typical antipsychotics, quetiapine showed tolerable adverse effects and did not worsen parkinsonism. Psychosis symptoms and behavioral improvements can be improved with haloperidol. Among elderly patients with psychosis, risperidone reduces angriness, paranoia, and aggression, as well as improves global functioning. As compared with other antipsychotics, aripiprazole provides a lower risk of adverse effects and demonstrated improvement in agitation, anxiety, and depression associated with psychosis. While olanzapine improves hostile suspiciousness, hallucinations, aggression, mistrust, and uncooperativeness, it worsens depression symptoms. Psychosis was treated effectively with pimavanserin without adverse effects on motor functions. Psychosis symptoms are well tolerated by brexpiprazole, but insomnia, headache, and urinary tract infections are common side effects. Conclusions: In this systematic review, we provide an overview of how to choose the correct antipsychotics and dosages for the management of BPSD and emphasize the importance of safe and conservative use of these drugs.

Sativex® for the treatment of Agitation &amp; Aggression in Alzheimer’s Dementia in UK nursing homes (STAND): Protocol for a feasibility randomised controlled trial

Background: People living with dementia often experience a myriad of behavioural and psychological symptoms of dementia (BPSD). Agitation is highly common within BPSD, negatively impacting their health, accelerating dementia progression, and is distressing both to patients and those caring for them. It also costs society a great deal, with increased hospitalisations, cost of care and earlier institutionalisation. Unfortunately, current treatments for these symptoms do not work very well and have a lot of unwanted side-effects. Recently, cannabinoid-based medicines have emerged as potentially safer alternative candidates for agitation in dementia. However, there is little systematic and robust evidence to support these encouraging early reports. Therefore, we specifically hope to investigate Sativex®, administered as an oral-spray, containing 50% delta-9-tetrahydrocannabinol (THC) and 50% cannabidiol (CBD) for agitation in dementia. Methods: STAND is a mixed-methods, randomised, double-blind, parallel group, placebo-controlled feasibility clinical trial, recruiting 60 people living with Alzheimer’s disease displaying behavioural symptoms from UK nursing homes. Conclusions: We aim to assess the safety, feasibility and acceptability of Sativex® within a nursing home context, and estimate its efficacy for agitation in Alzheimer’s disease. Findings will be used to inform a potential larger phase III confirmatory effectiveness trial. ISRCTN registry: 97163562.

Neuropathological correlates of neuropsychiatric symptoms in dementia

AbstractBackgroundNeuropsychiatric symptoms (NPS) are very common in Lewy body dementias (LBD), but their aetiology is poorly understood. In a post‐mortem study we aimed to characterise the contribution of neuropathological substrates to some of the most common NPS in dementia.MethodParticipants who passed away between 2004 and 2021 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies. Neuropathological data was collected for Lewy body neuropathology (LBD Braak score), neurofibrillary tangles (NFT Braak score), amyloid‐β burden (CERAD‐NP), TDP‐43, lacunar infarcts, cerebral amyloid angiopathy and hyaline atherosclerosis. Post‐mortem interviews were used to collect information regarding neuropsychiatric and cognitive status using the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR). A total of 948 cases were classified according to neuropathological assessment: (1) No pathology (NP) (n = 678); (2) Alzheimer’s Disease (AD) (n = 183); (3) LBD (n = 57); (4) AD+LBD (n = 30).ResultMultinomial logistic regression models comparing LBD, AD and AD+LBD to NP, adjusted for age, ethnicity, sex, and education level, showed significantly higher odds of hallucination and delusions across all groups compared to NP with the relative risk of hallucinations most elevated in AD+LBD cases (RRR = 19.3,[95%CI = 8.00‐46.3], p&lt;0.001). All groups had increased risk of higher NPI scores relative to NP, but the greatest increase was for AD+LBD (RRR = 1.04, [95%CI = 1.02‐1.06], p&lt;0.001). There were significantly greater risk of agitation and apathy in AD and AD+LBD groups relative to NP. (Table 1) Additionally, hallucinations were associated with higher Lewy body Braak scores (OR = 1.30, 95%CI = 1.13‐1.49, p&lt;0.001). Higher NFT Braak scores were associated with depression (OR = 1.28, 95%CI = 1.09‐1.50, p&lt;0.001), agitation (OR = 1.30, 95% CI = 1.07‐1.57, p = 0.009) and overall NPI score (IRR = 1.15, 95%CI = 1.05‐1.27, p = 0.004). Lacunar infarcts were associated with delusions (OR = 4.68, 95%CI = 1.12‐19.5, p = 0.03). More frequent neuritic plaques was inversely associated with apathy (OR = 0.70, 95%CI = 0.52‐0.93, p = 0.01). Cerebral amyloid angiopathy, hyaline atherosclerosis, and TDP‐43 did not associate with any of the neuropsychiatric symptoms in the multivariable logistic models. (Table 2)ConclusionLewy body pathology was the most significant contributor to the aetiology of hallucinations, while NFT were important contributors to depression and agitation in dementia. Supporting the dual importance of these pathologies, subjects with AD and LBD co‐pathology showed the greatest burden of NPS.

Progress in Investigational Agents Targeting Serotonin-6 Receptors for the Treatment of Brain Disorders.

Serotonin (5-HT) plays an important role in the regulation of several basic functions of the central and peripheral nervous system. Among the 5-HT receptors, serotonin-6 (5-HT6) receptor has been an area of substantial research. 5-HT6 receptor is a G-protein-coupled receptor mediating its effects through diverse signaling pathways. Exceptional features of the receptors fueling drug discovery efforts include unique localization and specific distribution in the brain regions having a role in learning, memory, mood, and behavior, and the affinity of several clinically used psychotropic agents. Although non-clinical data suggest that both agonist and antagonist may have similar behavioral effects, most of the agents that entered clinical evaluation were antagonists. Schizophrenia was the initial target; more recently, cognitive deficits associated with Alzheimer's disease (AD) or other neurological disorders has been the target for clinically evaluated 5-HT6 receptor antagonists. Several 5-HT6 receptor antagonists (idalopirdine, intepirdine and latrepirdine) showed efficacy in alleviating cognitive deficits associated with AD in the proof-of-concept clinical studies; however, the outcomes of the subsequent phase 3 studies were largely disappointing. The observations from both non-clinical and clinical studies suggest that 5-HT6 receptor antagonists may have a role in the management of neuropsychiatric symptoms in dementia. Masupirdine, a selective 5-HT6 receptor antagonist, reduced agitation/aggression-like behaviors in animal models, and a post hoc analysis of a phase 2 trial suggested potential beneficial effects on agitation/aggression and psychosis in AD. This agent will be assessed in additional trials, and the outcome of the trials will inform the use of 5-HT6 receptor antagonists in the treatment of agitation in dementia of the Alzheimer's type.

Challenges of Agitation in Dementia: A Plea for Early Discussion.

Behavioral and psychological symptoms of dementia (BPSD) occur frequently among people with dementia and are known precipitants for placement in care facilities. Despite the social, financial, and psychological impact on dementia care, education and discussions on BPSD have not been routinely included in advance care planning (ACP). As a result, families can face great challenges in making complex medical decisions when their loved ones are admitted to the geriatric psychiatric inpatient unit with refractory BPSD. We present the case of an 83-year-old gentleman with BPSD to illustrate universal struggles in dementia care experienced by many families, which could have been alleviated by education and discussions around BPSD earlier in the patient's dementia course. A literature search did not yield any articles that mention discussions of BPSD in ACP. The lack of literature referencing BPSD in ACP supports our clinical experiences with the case and highlights the need for improvement in current dementia care. We propose a guideline for providers to facilitate conversations around BPSD as an integral part of ACP, including discussions of four key points related to the progressive nature of dementia, the commonality of BPSD, the lack of FDA-approved treatment for BPSD, and the difficulty in balancing agitation and sedation to allow safe placement. We firmly believe it is important to start discussion on BPSD as part of ACP as early as possible. Early education and discussion will help to facilitate meaningful care decisions as patients and families navigate the challenges associated with this progressive disease.