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This paper used data from the Apathy in Dementia Methylphenidate Trial 2 (NCT02346201) to conduct a planned cost consequence analysis to investigate whether treatment of apathy with methylphenidate is economically attractive.
A total of 167 patients with clinically significant apathy randomized to either methylphenidate or placebo were included. The Resource Utilization in Dementia Lite instrument assessed resource utilization for the past 30 days and the EuroQol five dimension five level questionnaire assessed health utility at baseline, 3 months, and 6 months. Resources were converted to costs using standard sources and reported in 2021 USD. A repeated measures analysis of variance compared change in costs and utility over time between the treatment and placebo groups. A binary logistic regression was used to assess cost predictors.
Costs were not significantly different between groups whether the cost of methylphenidate was excluded (F(2,330) = 0.626, ηp2 = 0.004, p = 0.535) or included (F(2,330) = 0.629, ηp2 = 0.004, p = 0.534). Utility improved with methylphenidate treatment as there was a group by time interaction (F(2,330) = 7.525, ηp2 = 0.044, p < 0.001).
Results from this study indicated that there was no evidence for a difference in resource utilization costs between methylphenidate and placebo treatment. However, utility improved significantly over the 6-month follow-up period. These results can aid in decision-making to improve quality of life in patients with Alzheimer’s disease while considering the burden on the healthcare system.
The 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.
This 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.
We 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.
The 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.
To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA)
Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion
IPA Agitation Workgroup
IPA panel of international experts on agitation
Integration of available information into a comprehensive algorithm
The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues—home, nursing home, emergency department, hospice—and adjustments to the therapeutic approach are presented.
The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.
Agitation is a common complication of Alzheimer’s dementia (Agit-AD) associated with substantial morbidity, high healthcare service utilization, and adverse emotional and physical impact on care partners. There are currently no FDA-approved pharmacological treatments for Agit-AD. We present the study design and baseline data for an ongoing multisite, three-week, double-blind, placebo-controlled, randomized clinical trial of dronabinol (synthetic tetrahydrocannabinol [THC]), titrated to a dose of 10 mg daily, in 80 participants to examine the safety and efficacy of dronabinol as an adjunctive treatment for Agit-AD. Preliminary findings for 44 participants enrolled thus far show a predominately female, white sample with advanced cognitive impairment (Mini Mental Status Examination mean 7.8) and agitation (Neuropsychiatric Inventory-Clinician Agitation subscale mean 14.1). Adjustments to study design in light of the COVID-19 pandemic are described. Findings from this study will provide guidance for the clinical utility of dronabinol for Agit-AD. ClinicalTrials.gov Identifier: NCT02792257.
To examine the interaction between structural brain volume measures derived from a clinical magnetic resonance imaging (MRI) and occurrence of neuropsychiatric symptoms (NPS) in outpatient memory clinic patients.
Clinical and neuroimaging data were collected from the medical records of outpatient memory clinic patients who were seen by neurologists, geriatric neuropsychiatrists, and geriatricians. MRI scan acquisition was carried out on a 3 T Siemens Verio scanner at Johns Hopkins Bayview Medical Center. Image analyses used an automated multi-label atlas fusion method with a geriatric atlas inventory to generate 193 anatomical regions from which volumes were measured. Regions of interest were generated a priori based on previous literature review of NPS in dementia. Regional volumes for agitation, apathy, and delusions were carried forward in a linear regression analysis.
Seventy-two patients had clinical and usable neuroimaging data that were analyzed and grouped by Mini-Mental State Exam (MMSE). Neuropsychiatric Inventory Questionnaire (NPI-Q) agitation was inversely associated with rostral anterior cingulate cortex (ACC) bilaterally and left subcallosal ACC volumes in the moderate severity group. Delusions were positively associated with left ACC volumes in both severe and mild groups but inversely associated with the right dorsolateral prefrontal cortex (DLPFC) in the moderate subgroup.
Agitation, apathy, and delusions are associated with volumes of a priori selected brain regions using clinical data and clinically acquired MRI scans. The ACC is an anatomic region common to these symptoms, particularly agitation and delusions, which closely mirror the findings of research-quality studies and suggest its importance as a behavioral hub.
There is increasing evidence of an association between depressive symptoms and mild cognitive impairment (MCI) in cross-sectional studies, but the longitudinal association between depressive symptoms and risk of MCI onset is less clear. The authors investigated whether baseline symptom severity of depression was predictive of time to onset of symptoms of MCI.
These analyses included 300 participants from the BIOCARD study, a cohort of individuals who were cognitively normal at baseline (mean age = 57.4 years) and followed for up to 20 years (mean follow-up = 2.5 years). Depression symptom severity was measured using the Hamilton Depression Scale (HAM-D). The authors assessed the association between dichotomous and continuous HAM-D and time to onset of MCI within 7 years versus after 7 years from baseline (reflecting the mean time from baseline to onset of clinical symptoms in the cohort) using Cox regression models adjusted for gender, age, and education.
At baseline, subjects had a mean HAM-D score of 2.2 (SD = 2.8). Higher baseline HAM-D scores were associated with an increased risk of progression from normal cognition to clinical symptom onset ≤ 7 years from baseline (p = 0.043), but not with progression > 7 years from baseline (p = 0.194). These findings remained significant after adjustment for baseline cognition.
These results suggest that low levels of depressive symptoms may be predictive of clinical symptom onset within approximately 7 years among cognitively normal individuals and may be useful in identifying persons at risk for MCI due to Alzheimer’s disease.
Alzheimer's disease has become an important public health burden for older adults. Clinicians face a challenging task to efficiently evaluate cognition in dementia in clinical settings. We sought to assess the validity and inter-correlations of brief cognitive assessments in a cohort of severely demented patients.
In total, 49 individual patients (N = 49) ranging in age from 62 to 97 years old were included in this performance improvement project. Over the course of two–three sessions, five cognitive instruments were administered to each patient: Severe Impairment Battery (SIB), Severe Impairment Battery-8 (SIB-8), Mini Mental State Examination (MMSE), Severe Mini Mental State Examination (sMMSE) and Brief Interview of Mental Status (BIMS). We sought to assess patient factors that might have been barriers to optimal performance on cognitive/functional tests. Researchers assessed her impression of the participants’ difficulty comprehending instructions, distractibility, apparent fatigue, and frustration, which were the four barriers rated.
Data were analyzed for 49 patients from the inpatient dementia unit with a total of 51 samples. All of the inter-correlations between the five cognitive instruments had Spearman coefficients of (rs) > 0.7 and were statistically significant with p < 0.001. The SIB-8 and sMMSE were positively correlated with the SIB. The perceived barrier scores ranged from 0- no issue to 1-mild issue on all five cognitive instruments.
Brief cognitive tests designed for severe dementia such as the SIB-8 and sMMSE have been evaluated in this project to be shorter in administration duration and highly correlated with gold standard instruments: the SIB and MMSE.
There are relatively small but observable changes in functional ability in those without Mild cognitive impairment (MCI) or dementia. The present study seeks to understand whether these individuals go on to develop MCI or dementia by assessing the association between baseline Functional Activities Questionnaire (FAQ) and conversion independent and after adjustment for cognitive tests.
The NACC database was used to conduct the analysis of which 7,625 participants were initially identified as having more than one visit and who were cognitively normal at their first visit. Cox proportional hazards were used to fit three models that controlled for executive and non-executive cognitive domains. A similar model was used to assess the effect of FAQ subcategories on conversion.
Of these individuals, 1,328 converted to either MCI or dementia by visit 10. Converters had a total visit 1 FAQ score significantly higher than non-converters indicating more functional impairment at baseline. After adjustment for cognitive tests, the association between visit 1 FAQ and subsequent conversion was not attenuated. Doing taxes, remembering dates, and traveling were individually identified as significant predictors of conversion.
The FAQ can be used as an indirect measure of functional ability and is associated with conversion to MCI or dementia. There is a selective and significant association between changes in financial ability and conversion that is in accordance with other research of financial capacity.
Placebo responses raise significant challenges for the design of clinical trials. We report changes in agitation outcomes in the placebo arm of a recent trial of citalopram for agitation in Alzheimer's disease (CitAD).
In the CitAD study, all participants and caregivers received a psychosocial intervention and 92 were assigned to placebo for nine weeks. Outcomes included Neurobehavioral Rating Scale agitation subscale (NBRS-A), modified AD Cooperative Study-Clinical Global Impression of Change (CGIC), Cohen-Mansfield Agitation Inventory (CMAI), the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (NPI A/A) and Total (NPI-Total) and ADLs. Continuous outcomes were analyzed with mixed-effects modeling and dichotomous outcomes with logistic regression.
Agitation outcomes improved over nine weeks: NBRS-A mean (SD) decreased from 7.8 (3.0) at baseline to 5.4 (3.2), CMAI from 28.7 (6.7) to 26.7 (7.4), NPI A/A from 8.0 (2.4) to 4.9 (3.8), and NPI-Total from 37.3 (17.7) to 28.4 (22.1). The proportion of CGI-C agitation responders ranged from 21 to 29% and was significantly different from zero. MMSE improved from 14.4 (6.9) to 15.7 (7.2) and ADLs similarly improved. Most of the improvement was observed by three weeks and was sustained through nine weeks. The major predictor of improvement in each agitation measure was a higher baseline score in that measure.
We observed significant placebo response which may be due to regression to the mean, response to a psychosocial intervention, natural course of symptoms, or nonspecific benefits of participation in a trial.
The management of disruptive neuropsychiatric symptom (NPS) such as agitation and aggression (A/A) is a major priority in caring for people with Alzheimer's disease (AD). Few effective pharmacological or non-pharmacological options are available. Results of randomized clinical trials (RCTs) of drugs for A/A have been disappointing. This may result from the absence of biological efficacy for medications tested in treating A/A. It may also be related to methodological issues such as the choice of outcomes. The aim of this review was to highlight key methodological issues pertaining to RCTs of current and emerging medications for the treatment of A/A in AD.
We searched PubMed/Medline, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for RCTs comparing medications with either placebo or other drugs in the treatment of A/A in AD, between January 2008 and December 2013.
We identified a total of 18 RCTs; of these, 11 were completed and 7 ongoing. Of the ongoing RCTs, only one is in Phase III. Seven of 10 completed RCTs with reported results did not report greater benefit from drug than placebo. Each of the completed RCTs used a different definition of “clinically significant A/A.” There was considerable heterogeneity in study design. The primary endpoints were largely proxy-based but a variety of scales were used. The definition of caregiver and scales used to assess caregiver outcomes were similarly heterogeneous. Placebo response was notable in all trials.
This review highlights a great heterogeneity in RCTs design of drugs for A/A in AD and some key methodological issues such as definition of A/A, choice of outcome measures and caregiver participation that could be addressed by an expert consensus to optimize future trials design.
Little is known about the effect of methylphenidate (MPH) on attention in Alzheimer's disease (AD). MPH has shown to improve apathy in AD, and both apathy and attention have been related to dopaminergic function. The goal was to investigate MPH effects on attention in AD and assess the relationship between attention and apathy responses.
MPH (10 mg PO twice daily) or placebo was administered for six weeks in a randomized, double-blind trial in mild-to-moderate AD outpatients with apathy (Neuropsychiatric Inventory (NPI) Apathy ≥ 4). Attention was measured with the Wechsler Adult Intelligence Scale – Digit Span (DS) subtest (DS forward, selective attention) and apathy with the Apathy Evaluation Scale (AES). A mixed effects linear regression estimated the difference in change from baseline between treatment groups, defined as δ (MPH (DS week 6–DS baseline)) – (placebo (DS week 6–DS baseline)).
In 60 patients (37 females, age = 76 ± 8, Mini-Mental State Examination (MMSE) = 20 ± 5, NPI Apathy = 7 ± 2), the change in DS forward (δ = 0.87 (95% CI: 0.06–1.68), p = 0.03) and DS total (δ = 1.01 (95% CI: 0.09–1.93), p = 0.03) favored MPH over placebo. Of 57 completers, 17 patients had improved apathy (≥3.3 points on the AES from baseline to end point) and 40 did not. There were no significant associations between AES and NPI Apathy with DS change scores in the MPH, placebo, AES responder, or non-responder groups. DS scores did not predict apathy response to MPH treatment.
These results suggest MPH can improve attention and apathy in AD; however, the effects appear independent in this population.
Some countries have introduced mandatory folic acid fortification, whereas others support periconceptional supplementation of women in childbearing age. Several European countries are considering whether to adopt a fortification policy. Projections of the possible beneficial effects of increased folic acid intake assume that the measure will result in a considerable reduction in neural-tube defects (NTD) in the target population. Therefore, the objective of the present study is to evaluate the beneficial effects of different levels of folic acid administration on the prevalence of NTD. Countries with mandatory fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTD. This was also true for supplementation trials. However, the prevalence of NTD at birth declined to approximately five cases at birth per 10 000 births and seven to eight cases at birth or abortion per 10 000 births. This decline was independent of the amount of folic acid administered and apparently reveals a ‘floor effect’ for folic acid-preventable NTD. This clearly shows that not all cases of NTD are preventable by increasing the folate intake. The relative decline depends on the initial NTD rate. Countries with NTD prevalence close to the observed floor may have much smaller reductions in NTD rates with folic acid fortification. Additionally, potential adverse effects of fortification on other vulnerable population groups have to be seriously considered. Policy decisions concerning national mandatory fortification programmes must take into account realistically projected benefits as well as the evidence of risks to all vulnerable groups.
There is increasing evidence for the role of activated microglia in the neurotoxic pathways of Alzheimer's disease (AD). Amyloid-β1-42 is a potent activator of microglia (Benveniste et al., 2001), causing them to release pro-inflammatory cytokines including IL-6, IL-1β, TNF-α among others. A peripheral blood marker reflecting CNS inflammatory processes would be useful for treatment development, but the search for such an in vivo marker has been elusive. Peripheral blood and CSF levels of pro-inflammatory cytokines do not consistently differ in AD and controls (reviewed in Rosenberg, 2005). Both microglia and peripheral blood mononuclear cells (PBMCs) release pro-inflammatory cytokines when exposed to immunologic stimuli including lipopolysaccharide (LPS) and phytohemagglutinin (PHA). There are recent data suggesting that PBMCs from AD patients release more cytokines in this paradigm than normal controls (Reale et al., 2004).