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Abstract Today, half of the patients suffering from Alzheimer's disease (AD) will use hospice care in the last days of their life. Most of them will present with moderate to severe agitation. In the absence of evidence-based guidelines, Hospice care eligible patients with Agitation and Alzheimer's disease (AD) or other types of Dementia (HAD) are treated with a combination of antipsychotics, benzodiazepines, and opiates, which generate a variety of side effects. Two cannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD), appear to be promising therapies for agitation in HAD with minimal side effects. Specifically, we suggest that a combination of THC and CBD oils have enhanced synergistic effects while maintaining a low side effect profile that the combination may provide. The evidence for this hypothesis will be discussed during the symposium.

In a study of patients with Alzheimer's disease and associated psychosis or agitation that had responded to risperidone, the risk of relapse was greater among patients randomly assigned to switch to placebo than among those who continued to receive risperidone. Symptoms of psychosis or agitation are common in Alzheimer's disease. 1 , 2 These symptoms are associated with distress on the part of the patient, an increased burden on caregivers, more rapid cognitive decline, an increased likelihood of institutionalization, and increased health care costs. 3 Nonpharmacologic behavioral treatment approaches may help, 4 – 9 but large, controlled trials are needed to confirm the effectiveness of these strategies. Among psychotropic medications, only antipsychotic agents show superiority over placebo for the treatment of psychosis and agitation–aggression in patients with dementia, although they are associated with only low-to-moderate efficacy. 10 – 12 Side effects of antipsychotic drugs include sedation, extrapyramidal . . .

ABSTRACTBackgroundThe International Psychogeriatric Association (IPA) published a provisional consensus definition of agitation in cognitive disorders in 2015. As proposed by the original work group, we summarize the use and validation of criteria in order to remove “provisional” from the definition. MethodsThis report summarizes information from the academic literature, research resources, clinical guidelines, expert surveys, and patient and family advocates on the experience of use of the IPA definition. The information was reviewed by a working group of topic experts to create a finalized definition. ResultsWe present a final definition which closely resembles the provisional definition with modifications to address special circumstances. We also summarize the development of tools for diagnosis and assessment of agitation and propose strategies for dissemination and integration into precision diagnosis and agitation interventions. ConclusionThe IPA definition of agitation captures a common and important entity that is recognized by many stakeholders. Dissemination of the definition will permit broader detection and can advance research and best practices for care of patients with agitation.

ABSTRACTBackgroundAgitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs. MethodsThe ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process. ResultsAgitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as “strongly agree” or “somewhat agree” (68–88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications. ConclusionsA provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment.

Depression is common in Alzheimer disease (AD), and antidepressants are commonly used for its treatment, however, evidence for antidepressant efficacy in this population is lacking. The authors conducted a multicenter, randomized, placebo-controlled trial titled “Depression in Alzheimer's Disease-2” to assess the efficacy and tolerability of sertraline for depression in AD. One hundred thirty-one participants from five U.S. medical centers with mild-to-moderate AD (Mini-Mental State Examination scores 10-26) and depression of AD were randomized to double-blinded treatment with sertraline (N = 67) or placebo (N = 64), with a target dosage of 100 mg daily. Efficacy was assessed using logistic regressions and mixed effects models in an intention-to-treat analysis with imputation of missing data. Principal outcome measures were modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC), change in Cornell Scale for Depression in Dementia (CSDD) scores, and remission defined by both mADCS-CGIC score ≤2 and CSDD score ≤6. mADCS-CGIC ratings (odd ratio [OR = 1.01], 95% confidence interval [CI]: 0.52-1.97, p = 0.98), CSDD scores (median difference at 12 weeks 1.2, 95% CI: 1.65-4.05, p = 0.41), and remission at 12 weeks of follow-up (OR = 2.06, 95% CI: 0.84-5.04, p = 0.11) did not differ between sertraline (N = 67) and placebo (N = 64). Sertraline-treated patients experienced more adverse events, most notably gastrointestinal and respiratory, than placebo-treated patients. Sertraline did not demonstrate efficacy for the treatment depression symptoms in patients with AD. In addition, its use was associated with an increased incidence of adverse events. Thus, selective serotonin reuptake inhibitors may be of limited value for treating depression in patients with AD.

This article is largely based on the recommendations of the AARP's Global Council on Brain Health (GCBH) and aims to provide an overview of evidence from current literature and expert opinion on key elements known to be relevant in preserving brain health as people age. Although we realize that there may be other lifestyle choices of importance to brain health, the GCBH has decided to initially focus on the issues below based on the preferences and concerns of its members. The areas to be discussed are: mental well-being, exercise, cognitively stimulating activities, sleep, nutrition, and social connectedness. Our review concluded that each of these areas offer opportunities for aging individuals to make lifestyle adjustments to positively impact brain health.

Depression and antidepressant use are common in Alzheimer disease (AD), but the effect of antidepressant treatment for depression on longer term outcomes is unknown. The authors report the Week-24 outcomes of patients who participated in a 12-week efficacy study of sertraline for depression of AD. One hundred thirty-one participants (sertraline = 67, placebo = 64) with mild-moderate AD and depression participated in the study. Patients who showed improvement on the modified Alzheimer's Disease Cooperative Study Clinical Global Impression-Change (mADCS-CGIC) after 12 weeks of randomized treatment with sertraline or placebo continued double-blinded treatment for an additional 12 weeks. Depression response and remission at 24 weeks were based on mADCS-CGIC score and change in Cornell Scale for Depression in Dementia (CSDD) score. Secondary outcome measures included time to remission, nonmood neuropsychiatric symptoms, global cognition, function, and quality of life. One hundred seventeen (89.3%) participants completed all study assessments and 74 (56.5%; sertraline = 38, placebo = 36) completed all 24 weeks on randomized treatment. By 24 weeks, there were no between-group differences in depression response (sertraline = 44.8%, placebo = 35.9%; odds ratio [95% CI] = 1.23 [0.64–2.35]), change in CSDD score (median difference = 0.6 [95% CI: −2.26 to 3.46], χ2 [df = 2] = 1.03), remission rates (sertraline = 32.8%, placebo = 21.8%; odds ratio [95% CI] = 1.61 [0.70–3.68]), or secondary outcomes. Common selective serotonin reuptake inhibitor-associated adverse events, specifically diarrhea, dizziness, and dry mouth, and pulmonary serious adverse events were more frequent in sertraline-randomized patients than in placebo subjects. Sertraline treatment is not associated with delayed improvement between 12 and 24 weeks of treatment and may not be indicated for the treatment of depression of AD.

Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. In 2015 IPA convened a transparent process to build a consensus definition of agitation and agreement on what elements should be included in the syndrome that resulted in publication of provisional guidelines. (Cummings et al, 2015) In the 2020-2021 year, the two co-chairs of this symposium have led a new workgroup to make the provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies and guide treatment final. Co-Chairs will discuss methods used in updating and findings and compare changes made to the provisional guidelines. Dr. Sano will present new findings on the biological basis of agitation in dementia and Dr. Mintzer will present on application of guidelines in the special circumstances of persons in palliative and hospice care. Dr. Rosenberg will discuss the special circumstance of agitation care in hospital emergency departments. Mr. Splaine will present findings about the utilization of the 2015 guidelines in the peer reviewed literature, professional and government dementia care guidance, and clinical trials. Cummings, J., Mintzer, J., Brodaty, H., Sano, M., Banerjee, S., Devanand, D., … Zhong, K. (2015). Agitation in cognitive disorders: International Psychogeriatric Association provisional consensus clinical and research definition. International Psychogeriatrics, 27(1), 7-17. doi:10.1017/S1041610214001963

A Food and Drug Administration (FDA) safety communication in August 2011 warned that citalopram was associated with a dose dependent risk of QT prolongation and recommended dose restriction in patients over the age of 60 but did not provide data for this age group. CitAD was a randomized, double-masked, placebo-controlled, multicenter clinical trial for agitation in Alzheimer's disease (AD). Participants were assigned to citalopram (target dose of 30 mg/day) or placebo in a 1 ∶ 1 ratio. 186 people, 181 of whom were over the age of 60, having probable AD with clinically significant agitation were recruited from September 2009 to January 2013. After the FDA safety communication about citalopram, ECG was added to the required study procedures before enrollment and repeated at week 3 to monitor change in QTc interval. Forty-eight participants were enrolled after enhanced monitoring began. Citalopram treatment was associated with a larger increase in QTc interval than placebo (difference in week 3 QTc adjusting for baseline QTc: 18.1 ms [95% CI: 6.1, 30.1]; p = 0.004). More participants in the citalopram group had an increase ≥ 30 ms from baseline to week 3 (7 in citalopram versus 1 in placebo; Fisher's exact p = 0.046), but only slightly more in the citalopram group met a gender-specific threshold for prolonged QTc (450 ms for males; 470 ms for females) at any point during follow-up (3 in citalopram versus 1 in placebo, Fisher's exact p = 0.611). One of the citalopram participants who developed prolonged QTc also displayed ventricular bigeminy. No participants in either group had a cardiovascular-related death. Citalopram at 30 mg/day was associated with improvement in agitation in patients with AD but was also associated with QT prolongation. ClinicalTrials.gov NCT00898807.

Introduction Language impairment is frequently observed in patients with Alzheimer’s disease (AD): in this study, we investigated the extent and distribution of brain atrophy in subjects with conversion from mild cognitive impairment (MCI) to AD with and without naming difficulties. Methods This study was approved by the institutional review board and was HIPAA compliant. All subjects or their legal representatives gave informed consent for participation. Ninety-one subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with ( N  = 51) and without ( N  = 40) naming impairment as per the Boston Naming Test (BNT), underwent brain magnetic resonance (MR) imaging 12 months before, at AD diagnosis, and 12 months after. Structural MR images were processed using voxel-based morphometry. Cross-sectional comparisons and mixed ANOVA models for assessing regional gray matter (GM) volume differences were performed. Results As from 12 months prior to AD diagnosis, patients with naming difficulties showed distinct areas of greater GM loss in the left fusiform gyrus (Brodmann area 20) than patients without naming difficulties. Differences in the GM atrophy extended to the left hemisphere in the subsequent 12 months. Conclusion This study provided evidence of distinct patterns and dynamics of brain atrophy in AD patients with naming difficulties when compared to those with intact language, as early as 12 months prior to AD diagnosis and in the subsequent 12 months.