Agitation In Alzheimer's Disease Research Articles

An overview of the pathophysiology of agitation in Alzheimer's dementia with a focus on neurotransmitters and circuits.

Alzheimer's dementia (AD) is a progressive, neurodegenerative disease often accompanied by neuropsychiatric symptoms that profoundly impact both patients and caregivers. Agitation is among the most prevalent and distressing of these symptoms and often requires treatment. Appropriate therapeutic interventions depend on understanding the biological basis of agitation and how it may be affected by treatment. This narrative review discusses a proposed pathophysiology of agitation in Alzheimer's dementia based on convergent evidence across research approaches. Available data indicate that agitation in Alzheimer's dementia is associated with an imbalance of activity between key prefrontal and subcortical brain regions. The monoamine neurotransmitter systems serve as key modulators of activity within these brain regions and circuits and are rendered abnormal in AD. Patients with AD who exhibited agitation symptoms during life have alterations in neurotransmitter nuclei and related systems when the brain is examined at autopsy. The authors present a model of agitation in Alzheimer's dementia in which noradrenergic hyperactivity along with serotonergic deficits and dysregulated striatal dopamine release contribute to agitated and aggressive behaviors.

Brexpiprazole treatment for agitation in Alzheimer's dementia: A randomized study.

We evaluated the efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's dementia (AAD) in Japanese patients. This was a phase 2/3 multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Patients with AAD were randomized to receive brexpiprazole 1 mg/day or 2mg/day, or placebo (3:4:4) for 10weeks. For the primary endpoint (change in Cohen-Mansfield Agitation Inventory [CMAI] total score from baseline to Week 10), both brexpiprazole 1 mg and 2mg groups demonstrated statistically significant improvement versus placebo (2mg: least squares [LS] mean difference -7.2 [95% confidence interval (CI): -10.0 to -4.3], p-value<0.0001, 1mg: LS mean difference -3.7 [95% CI: -6.8 to -0.7], p-value=0.0175). The incidences of treatment-emergent adverse events reported in the brexpiprazole 1mg, 2mg, and placebo groups were 76.8%, 84.6%, and 73.8%, respectively. Brexpiprazole 1mg/day and 2mg/day for 10weeks was efficacious and well tolerated. Brexpiprazole treatment for 10weeks improved agitation in Alzheimer's dementia. The efficacy of brexpiprazole 1mg/day has been confirmed for the first time. The incidence of adverse events was higher compared to the previous studies. Both brexpiprazole 1mg/day and 2mg/day were generally well tolerated.

Interprofessional insights in Agitation in Alzheimer's disease: An interview with the experts from Emory Integrated Memory Care

Agitation in Alzheimer's disease (AAD) is a troubling condition experienced by many of the 6.9 million people living with Alzheimer's disease in the United States. The Gerontological Society of America (GSA) initially published an evidence-based care pathway to treat this condition, Agitation in Alzheimer's Disease: A Decision Tree for Healthcare Providers, in 2022 and updated this resource in 2023 with the International Psychogeriatric Association (IPA) consensus definition of agitation. A new, research-informed screening tool launched in November 2023, the Agitation in Alzheimer's Screener for Caregivers (AASCTM), supports care teams in identifying individuals with AAD who can benefit from the evidence-based care outlined in the decision tree. This column features an interview with interprofessional dementia care experts from Emory Integrated Memory Care who share their insights into AAD, the significance of the condition, and how care teams can use the AASCTM and other strategies to detect AAD. By detecting AAD and implementing person-centered care to address the condition, care teams can improve quality of life for the individual with the condition and their caregiver.

Brexpiprazole for Agitation Associated With Dementia Due to Alzheimer's Disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by progressive cognitive and functional decline. Nearly all patients with AD develop neuropsychiatric symptoms (NPSs). Agitation is one of the most distressing and challenging NPS. Brexpiprazole is an oral antipsychotic and is the first approved pharmacologic agent in the United States for the treatment of agitation associated with dementia due to AD. Its effect is thought to be from its partial serotonin 5-HT1A and dopamine D2 receptor agonist activity and serotonin 5-HT2A receptor antagonism. Brexpiprazole is a maintenance medication, and it should not be used “as needed” or as a “PRN” treatment for breakthrough agitation. Brexpiprazole is a major substrate of CYP2D6 and CYP3A4. Dose adjustments may be required for drug interactions or impaired renal or hepatic function. Clinical trials found brexpiprazole 2 to 3 mg/d demonstrated significant improvements in agitation, with brexpiprazole showing an approximate 5-point greater reduction on change in the Cohen-Mansfield Agitation Inventory total score at week 12 from baseline compared with placebo. Brexpiprazole is generally well tolerated and safe, and common adverse reactions when used for this indication include dizziness, headaches, insomnia, nasopharyngitis, somnolence, and urinary tract infections. Like other antipsychotics used for agitation in AD, brexpiprazole is associated with higher mortality rates compared with placebo. In a long-term care setting, there are several considerations for its use. Benefits include an oral agent that is well tolerated and clinical data showing statistically significant effects on agitation. However, brexpiprazole has not been studied in head-to-head clinical trials against other antipsychotics, and there are differing opinions if the agitation score reductions translate to a clinically meaningful difference. The approval of brexpiprazole signals favorably for upcoming agents for this indication, including escitalopram and dextromethorphan-bupropion. Both escitalopram and dextromethorphan-bupropion are currently undergoing clinical trials.

Neurobiological alteration in agitation in Alzheimer's disease and possible interventions.

Neurobiological alteration in agitation in Alzheimer's disease and possible interventions.

Brexpiprazole: A new option in treating agitation in Alzheimer's dementia-Insights from transgenic mouse models.

Brexpiprazole is the first FDA-approved treatment for agitation associated with dementia due to Alzheimer's disease. Agitation in Alzheimer's dementia (AAD) occurs in high prevalence and is a great burden for patients and caregivers. Efficacy, safety, and tolerability of brexpiprazole were demonstrated in the AAD clinical trials. To demonstrate the agitation-ameliorating effect of brexpiprazole in animals, we evaluated brexpiprazole in two AAD mouse models. The resident-intruder test was conducted in 5- to 6-month-old Tg2576 mice, given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally 1 h before the test. Locomotor activity was measured in 6-month-old APPSL-Tg mice given vehicle or brexpiprazole (0.01 or 0.03 mg/kg) orally the evening before the start of locomotor measurement for 3 days. In the resident-intruder test, Tg2576 mice showed significantly higher attack number and shorter latency to first attack compared to non-Tg mice. In the Tg mice, brexpiprazole treatment (0.03 mg/kg) significantly delayed the latency to first attack and showed a trend toward a decrease in attack number. APPSL-Tg mice (≧6 months old) showed significantly higher locomotion during dark period Phase II (Zeitgeber time [ZT] 16-20) and Phase III (ZT20-24) compared to non-Tg mice, correlating with the clinical observations of late afternoon agitation in Alzheimer's disease. Brexpiprazole treatment (0.01 and 0.03 mg/kg) significantly decreased hyperlocomotion during the Phase III in APPSL-Tg mice. The suppression of attack behavior and the reduction of nocturnal hyperlocomotion in these Tg mice may be indicative of the therapeutic effect of brexpiprazole on AAD, as demonstrated in the clinical trials.

Efficacy and safety of brexpiprazole for the treatment of agitation in Alzheimer's disease: a meta-analysis of randomized controlled trials.

Recent randomized controlled trials (RCTs) have shown a benefit of brexpiprazole in managing agitation in patients with Alzheimer's disease (AD). However, its efficacy and safety remain unclear. We systematically searched PubMed, Embase, and Cochrane Library for RCTs comparing brexpiprazole with placebo in patients with agitation and AD. Three studies comprising 1,048 patients were included. In patients with agitation and AD, brexpiprazole significantly improved the Cohen-Mansfield Agitation Inventory total score (CMAI) at any dose (MD -3.05; 95% CI -5.12, -0.98; p < 0.01; I2 = 19%) and at 2mg (MD -4.36; 95% CI -7.02, -1.70; p < 0.01; I2 = 0%) over 12weeks. Brexpiprazole at any dose and 2mg also showed benefit in the Clinical Global Impression - Severity of illness (CGI-S) score as related to agitation over 12weeks (MD -0.20; 95% CI -0.36, -0.05; p < 0.01; I2 = 35%). There is no significant difference between the groups in the incidence of at least one treatment-emergent adverse events (TEAEs; RR 1.14; 95% CI 0.95, 1.37; p = 0.16; I2 = 45%) and all-cause mortality (RR 1.99; 95% CI 0.37, 10.84; p = 0.42; I2 = 0%). Brexpiprazole at any dose significantly increased the Simpson-Angus Scale (SAS; MD 0.47; 95% CI 0.28, 0.66; p < 0.01). Our results suggest that brexpiprazole is more efficacious than placebo in the treatment of agitation in AD patients. Further studies are still necessary to confirm long-term effects of brexpiprazole.Prospero registry: CRD42023486694.

Alzheimer’s and Parkinson’s disease drugs side effects

IntroductionAlzheimer’s and Parkinson’s disease are neurodegenerative disorders with life limiting conditions. The symptomatic pharmacological therapeutic strategies unfortunately are also related to undesirable side effects. Acetylcholinesterase inhibitors administered to Alzheimer’s disease patients increase cholinergic transmission in cortex and hippocampus.Antiparkinsonian drugs increase dopaminergic system activity, to compensate for dopaminergic neurons’ degeneration in corpus striatum, therefore supplying the imbalance of these neurotransmitters in these degenerative areas.But undesirable the increase of these neurotransmitters in other cerebral and peripheral areas brings us important side effectsObjectivesTo study Alzheimer’s cholinergic drugs and Parkinson’s dopaminergic drugs’ side effectsMethods This retrospective study included 107 geriatric patients enrolled in a private long-term care institution. 79 patients with Alzheimer’s disease had mean age of 88.11 ± 5,78 years old, mean weight of 61.62 ± 13.10 kg. 28 patients with Parkinson’s disease had mean age of 84.93 ± 5.71 years old, weight mean 66.36 ± 2.83 kg.ResultsAlzheimer’s disease patients 41.77% (33) received. Acetylcholinesterase inhibitors (Donepezil, galantamine and rivastigmine) Psychomotor agitation and aggressive behavior 63.666% and nausea (15%) were observed in the patients treated with these drugs. The association of L-DOPA and DOPA decarboxylase inhibitors (benserazide) were administered to 53%(15) of the Parkinson’s disease patients in doses between 2.0-19.0 mg/kg/day. L-DOPA associated to catechol-O-methyltransferase inhibitor (entacapone) 3 mg/kg/day were given to 7.14% (2) patients. Bromocriptine 0.04 mg/kg/day was given to 3.57% (1) patients. Mental confusion and hallucination side effects were observed in 53.33% (8) patients treated with L-DOPA associated with the DOPA decarboxylase inhibitor (benserazide).ConclusionsThe increase of cholinergic activity due to the acetylcholinesterase inhibitors in the Nigro- striatal pathway could be related to psychomotor agitation in Alzheimer’s disease patients in a similar way to akathisia induced by neuroleptics. The increase of dopamine levels due to the administration of L-DOPA, in corpus striatum improved Parkinson’s disease symptoms although the increase of dopaminergic activity at mesocortical pathways may be related to confusion and hallucination observed in these patients. Adjustments in dosage of these drugs could provide improvement in these patients’ daily life conditions.Disclosure of InterestNone Declared

Caring for Behavioral Symptoms of Dementia (CBD): A New Investigation into Cannabidiol for the Treatment of Anxiety and Agitation in Alzheimer's Dementia

Caring for Behavioral Symptoms of Dementia (CBD): A New Investigation into Cannabidiol for the Treatment of Anxiety and Agitation in Alzheimer's Dementia

Care partner evaluation of the behaviors in the Cohen-Mansfield Agitation Inventory.

Agitation is a common symptom in patients with Alzheimer's dementia. But agitation can be a heterogeneous symptom, encompassing a diverse array of behaviors exhibited by patients. The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item scale that is used to systematically assess the frequency and severity of agitation in older adults as rated by a primary caregiver. The CMAI was originally designed for use by professional care givers in institutional care settings. Alzheimer's dementia, however, is associated with a significant burden on family members, who provide the majority of care, and other informal care partners. Our qualitative study aimed to assess the accuracy and applicability of the CMAI according to the needs and perceptions of non-professional care partners. Specifically, we wanted to determine if the behaviors included in the instrument reflect: (a) the care partner's experience with agitation in Alzheimer's dementia patients, (b) how the behaviors and their frequency are related to the perception of agitation severity, and (c) what changes in agitation behaviors are meaningful to care partners. We interviewed 30 care partners for patients with Alzheimer's dementia in the United States. The care partners confirmed all behaviors listed in the CMAI as relevant. The behaviors reflect a spectrum of severity, with aggressive behaviors considered more severe than non-aggressive behaviors and physical behaviors generally considered more severe than verbal behaviors. Any reduction or increase in the frequency of a behavior was meaningful to care partners. Generally, a change from physical to verbal behaviors and aggressive to non-aggressive was considered a meaningful improvement while a change from verbal to physical and non-aggressive to aggressive was considered a meaningful worsening. The CMAI appropriately captures relevant behaviors of agitation in Alzheimer's dementia and provides insight into the relative improvement or worsening of agitation symptoms.

Short Report: Measuring the Behavioral Disturbance of Autism Spectrum Disorder by Cohen-Mansfield Agitation Inventory

Introduction: Cohen-Mansfield Agitation Inventory (CMAI) has originally been developed for the evaluation of agitation in Alzheimer’s disease. Reliable tools for measuring behavioral symptoms in autism spectrum disorder (ASD) are missing. Methods: The reproducibility of the CMAI was evaluated in 26 patients. The CMAI-questionnaire was filled for each participant by three different nurses. The measurement was repeated by the primary caregiver for 15 patients. Agreement between nurses was measured using Cohen’s weighed kappa, intraclass correlation coefficient (ICC) was used to evaluate intra-rater reliability and Cronbach’s alphas to quantify internal consistency. Results: The inter-rater reliability was found to be substantial for all items ICC 0.64 (95%CI 0.43-0.80). Cronbach’s alpha was good for the whole CMAI score (α=0.87 with 95% CI 0.82-0.91). No statistically significant differences were seen in the CMAI-scores between repeated measurements. Conclusions: The CMAI may be a reasonably reliable tool to follow-up changes in behavioral symptoms of ASD.

A real-world assessment of healthcare costs associated with agitation in Alzheimer’s dementia

Aims To describe and compare clinical characteristics, healthcare costs, and institutionalization/mortality outcomes among patients with and without agitation associated with Alzheimer’s dementia (AAD). Methods Data from the Reliant Medical Group database (01/01/2016-03/31/2020) were used, including claims, electronic medical records, and clinical information/physician notes abstracted from medical charts. Patients aged ≥55 years with Alzheimer’s dementia (AD) were observed during a randomly selected 12-month study period after AD diagnosis. Using information recorded in medical charts, patients were classified into cohorts based on experiencing (agitation cohort) and not experiencing (no agitation cohort) agitated behaviours during the study period. Entropy balancing was used to create reweighted cohorts with similar characteristics. Study outcomes (patient demographic and clinical characteristics, treatments received, healthcare costs, institutionalization and death events) were compared between cohorts; agitation characteristics were described for the agitation cohort only. Results Among 711 patients included in the study, 240 were classified in the agitation cohort and 471 in the no agitation cohort. After reweighting, several comorbidities were more frequently observed in the agitation versus no agitation cohort, including infection, depression, and altered mental status. Use of antidepressants, anticonvulsants, antipsychotics, and antianxiety medications was more common in the agitation versus no agitation cohort. Common agitated behaviours included hitting (20.8%), pacing/aimless wandering (17.5%), and cursing/verbal aggression (15.0%). Total all-cause healthcare costs were $4287 per-patient-per-year higher in the agitation cohort versus no agitation cohort (p = 0.04), driven by higher inpatient costs. Death was more common and time to death and institutionalization were shorter in the agitation versus no agitation cohort. Limitations Results may not be generalizable to the US population with AD. Conclusions Among patients with AD, agitation was associated with shorter time to death/institutionalization and increased comorbidities, medication use, and healthcare costs, highlighting the additional clinical and economic burden that agitation poses to patients and the healthcare system.

ONE MINUTE TO RECOGNITION: THE AGITATION IN ALZHEIMER’S SCREENER FOR CAREGIVERS (AASC™)

Abstract Agitation is a common neuropsychiatric symptom of Alzheimer’s dementia (AD) and both a complex and burdensome aspect of patient care. Caregivers are often first to encounter agitation-associated behaviors and play a pivotal role in communicating these symptoms to healthcare providers (HCPs). However, most caregivers do not identify the breadth of signs/symptoms of agitation and are hesitant to discuss these behaviors with HCPs. There is, therefore, an unmet need for an easy, pragmatic screener to facilitate caregiver recognition of agitation associated with AD (AAD) and HCP discussions. Here, we report on the development of the Agitation in Alzheimer’s Screener for Caregivers (AASC™), a brief screening tool based on the International Psychogeriatric Association (IPA) consensus definition for agitation in cognitive disorders, designed to assist caregivers in recognizing agitation-associated behaviors in patients with AD. Initial draft development involved identification of specific behaviors that were discriminative for AD with/without agitation and representative of the full range of IPA-defined agitation behaviors (i.e., excessive motor activity, verbal aggression, physical aggression) based on current literature and input from 6 opinion leaders. An initial draft was then refined across 2 rounds of cognitive debriefing with caregivers (n=12; mean age=62 years) who described the screening tool as comprehensive yet easy to complete, and perceived it to be valuable, relevant, and easily understood. The AASC™ is a brief, easy-to-use tool supporting the identification and assessment of impact of agitation-associated behaviors. The screener can be completed by a caregiver in &amp;lt; 1 minute at home or in an HCP’s office setting.

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.

P170: Safety and Tolerability of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: Pooled Results From Three Phase III Trials

Objective:Agitation in Alzheimer’s dementia (AAD) is prevalent, distressing, and burdensome. Medications for agitation are commonly prescribed off-label, although use is hindered by safety and tolerability concerns. This pooled analysis evaluates the safety and tolerability of brexpiprazole in patients with AAD.Methods:Data were pooled from three Phase 3, 12-week, placebo-controlled trials (NCT01862640, NCT01922258, NCT03548584) (overall, and by brexpiprazole dose). The primary objective of each trial was to assess the efficacy of brexpiprazole on agitation. Safety was a secondary objective.Results:658 patients were randomized to brexpiprazole (0.5–3 mg/day, depending on the trial; n=655 treated), and 389 patients were randomized to placebo (n=388 treated). Mean baseline age was 73.5–74.2 years, and mean time since diagnosis of Alzheimer’s disease was 28.2–35.6 months. The pooled incidence of treatment-emergent adverse events (TEAEs) was 51.1% with brexpiprazole, with no notable differences between doses, and 45.9% with placebo. The incidence of serious TEAEs was 6.4% (brexpiprazole) versus 4.1% (placebo), and the incidence of TEAEs leading to discontinuation was 6.3% versus 3.4%, respectively. TEAEs that occurred in ≥2% of patients receiving brexpiprazole and more than in placebo-treated patients were insomnia (3.7% versus 2.8%), somnolence (3.4% versus 1.8%), nasopharyngitis (2.7% versus 2.6%), and urinary tract infection (2.6% versus 1.5%). Other TEAEs of interest included falls (1.7% versus 2.6%) and sedation (0.3% versus 0.0%). TEAE categories of interest included extrapyramidal symptom (EPS)-related TEAEs (5.3% versus 3.1%), cardiovascular TEAEs (3.7% versus 2.3%), and cerebrovascular TEAEs (0.5% versus 0.3%). The mean change from baseline to last visit in Mini–Mental State Examination score was 0.21 (brexpiprazole) and 0.14 (placebo). Six patients receiving brexpiprazole (0.9%) and one patient receiving placebo (0.3%) died; none of the deaths was considered related to brexpiprazole.Conclusion:Based on pooled data, brexpiprazole was well tolerated in patients with AAD, and had a clinical safety profile consistent with that of brexpiprazole in other indications. Patients receiving brexpiprazole had a similar incidence of sedation, EPS events, falls, cardiovascular events, and cerebrovascular events compared with placebo, and no worsening of cognition. The incidence of death was low, and no deaths were considered related to study treatment.

P96: Efficacy of Brexpiprazole for the Treatment of Agitation in Alzheimer’s Dementia: Post Hoc Line Item Analysis of the Cohen-Mansfield Agitation Inventory

Objective:Agitation is a common neuropsychiatric symptom in Alzheimer’s dementia. The Cohen-Mansfield Agitation Inventory (CMAI) assesses the frequency of 29 agitation behaviors in elderly persons. The frequency of each behavior is rated from 1–7 (1=never, 2=less than once a week, 3=once or twice a week, 4=several times a week, 5=once or twice a day, 6=several times a day, 7=several times an hour), typically reported as a single total score. This post hoc analysis explored the efficacy of brexpiprazole on the frequency of individual agitation behaviors.Methods:Post hoc analyses were conducted for two 12-week, randomized, double- blind, placebo-controlled, parallel-arm, fixed-dose trials of brexpiprazole in patients with agitation in Alzheimer’s dementia (NCT01862640, NCT03548584). Data are reported using descriptive statistics for brexpiprazole (2 or 3 mg/day) and placebo, for patients who completed 12 weeks of treatment.Results:In the first fixed-dose trial (brexpiprazole 2 mg/day, n=120; placebo, n=118), baseline behavior frequency was similar between groups (range 1.12 to 4.92). At baseline, the most frequently observed behavior was “general restlessness” (brexpiprazole, 4.92; placebo, 4.82; approximately “once or twice a day”), and the least frequently observed behaviors were “biting” (brexpiprazole, 1.12) and “making physical sexual advances” (placebo, 1.14). At Week 12, the average reduction in mean frequency was -0.73 (brexpiprazole) and -0.60 (placebo), with a greater numerical reduction for 21/29 behaviors with brexpiprazole versus placebo. In the second fixed-dose trial (brexpiprazole 2 or 3 mg/day, n=192; placebo, n=103), baseline behavior frequency was similar between groups (range 1.12 to 5.22), and higher than in the first trial due to study inclusion criteria. At baseline, the most frequently observed behavior was “general restlessness” (brexpiprazole, 5.22; placebo, 5.09; approximately “once or twice a day”), and the least frequently observed behaviors were “making physical sexual advances” (brexpiprazole, 1.13) and “intentional falling” (placebo, 1.12). At Week 12, the average reduction in mean frequency was -0.78 (brexpiprazole) and -0.54 (placebo), with a greater numerical reduction for 26/29 behaviors with brexpiprazole versus placebo.Conclusion:In this post hoc analysis, brexpiprazole was associated with numerically greater reduction in the frequency of most individual agitation behaviors versus placebo.

P62: Agitation in Alzheimer’s Disease (AAD): A Decision Tree for Healthcare Providers

Developed by THE GERONTOLOGIC SOCIETY OF AMERICASupported by an unrestricted educational grant from AvanirThe prevalence of agitation in Alzheimer’s Disease (AAD) approaches 80%. Patients with AAD have more severe behavioral,depressive, and frontal lobe symptoms and are at increased risk for hospitalization and nursing home placement.Early agitation is a robust predictor of accelerated progression and mortality and is distressing and dangerous for patients and care partners.This presentation was recently developed by the Gerontologic Society of America (GSA) which convened an expert AD Working Group to develop a “Decision Tree” for healthcare providers relative to the assessment of AAD and the employment of Non-Pharmacologic and Pharmacologic treatment options

P137: Cost Considerations of Untreated Agitation: Direct, Indirect, and Intangible

OBJECTIVE:In the past decade, researchers and advocates have taken important steps toward understanding the full costs of Alzheimer’s disease and related dementias. However, our current approach to framing these costs does not fully consider the behavioral symptoms of dementia, notably agitation. Agitation in Alzheimer’s disease contributes to negative social and financial outcomes for people with the condition, their care partners, and health systems. When left untreated, the negative impact of these outcomes is exacerbated, yet the full scale of this impact is unknown. “Cost Considerations of Untreated Agitation” seeks to propose a framework to help in evaluating the variables that impact these costs.METHODS:We created a model that investigates each stage of Alzheimer’s disease with agitation. This model assesses direct, indirect, and intangible costs of the disease. Direct costs include professional caregiving, non-pharmacological intervention, nursing home costs, healthcare professional consultations, and hospitalizations. Indirect costs included loss of income and value of unpaid caregiving. Intangible costs include the mental health impact of agitation on individuals living with Alzheimer’s and their care partners. Additionally, we used quality-adjusted life years to measure disease burden and health outcomes. Finally, we leveraged qualitative research to overlay the experience of care partners and individuals with lived experience to bring their voice to this work.RESULTS:Results are a tentative framework and describe what additional research and input is necessary in order to create a version with which one can assess the comprehensive costs of untreated agitation in Alzheimer’s. This framework will include perspectives and feedback from individuals with lived experience, care partners, and key opinion leaders in Alzheimer’s research from across the world.CONCLUSION:Agitation has severe consequences on individuals, families, and health systems. Oftentimes one of the first symptoms of Alzheimer’s or dementia, agitation can increase the caregiving responsibilities, trigger placement into nursing homes, and cause severe emotional and physical toll on care partners. We cannot understand the full costs of dementia or AD until we account for untreated agitation vis-à-vis a multi-symptom assessment, therefore an accepted framework is necessary in order to fully consider the costs of untreated agitation.

Heart rate variability and risk of agitation in Alzheimer's disease: the Atherosclerosis Risk in Communities Study.

Agitation in Alzheimer's disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer's disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer's disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1-5 heart rate variability measures were the log-transformed root mean square of successive differences in R-R intervals and standard deviation of normal-to-normal R-R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer's disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants' cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer's disease and to explore underlying mechanisms as targets for treatment development.

Examining the Effects of Music Therapy on Decreasing Agitation in Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a crippling epidemic that is predicted to affect over 15 million people worldwide by the year 2050. Symptoms such as refusal to cooperate, impaired communication and cognition, and agitation and anxiety can play a large part in the difficulties that surround caring for an AD patient. There are medications that are marketed to treat AD symptoms, but many have harmful side effects. Holistic methods, such as music therapy, are gaining attention for their ease of implementation and limited side effects. Aim: The purpose of this project was to implement a music therapy intervention for people with AD in hospice and evaluate the levels of agitation experienced by the patient. Method: The study was conducted over a period of eight weeks. Music therapy was administered nightly for 20 minutes by caregivers and the Pittsburgh Agitation Scale was completed at the beginning of the study, at four weeks into the study, and at the completion of the study. Results: The intervention was found to be significant in reducing aberrant vocalization, motor agitation, aggressiveness, and resisting care. Conclusion: Based on the findings, music therapy may be useful as a holistic intervention for decreasing agitation in individuals with AD.