Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer's disease: Evidence from the ADMET 2 study.

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire.HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms.

Heterogeneity of Response to Methylphenidate in Apathetic Patients in the ADMET 2 Trial.

OBJECTIVE: The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) found that methylphenidate was effective in treating apathy with a small-to-medium effect size but showed heterogeneity in response. We assessed clinical predictors of response to help determine individual likelihood of treatment benefit from methylphenidate. DESIGN: Univariate and multivariate analyses of 22 clinical predictors of response chosen a priori. SETTING: Data from the ADMET 2 randomized, placebo controlled multi-center clinical trial. PARTICIPANTS: Alzheimer's disease patients with clinically significant apathy. MEASUREMENTS: Apathy assessed with the Neuropsychiatric Inventory apathy domain (NPI-A). RESULTS: In total, 177 participants (67% male, mean [SD] age 76.4 [7.9], mini-mental state examination 19.3 [4.8]) had 6-months follow up data. Six potential predictors met criteria for inclusion in multivariate modeling. Methylphenidate was more efficacious in participants without NPI anxiety (change in NPI-A -2.21, standard error [SE]:0.60) or agitation (-2.63, SE:0.68), prescribed cholinesterase inhibitors (ChEI) (-2.44, SE:0.62), between 52 and 72 years of age (-2.93, SE:1.05), had 73-80 mm Hg diastolic blood pressure (-2.43, SE: 1.03), and more functional impairment (-2.56, SE:1.16) as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living scale. CONCLUSION: Individuals who were not anxious or agitated, younger, prescribed a ChEI, with optimal (73-80 mm Hg) diastolic blood pressure, or having more impaired function were more likely to benefit from methylphenidate compared to placebo. Clinicians may preferentially consider methylphenidate for apathetic AD participants already prescribed a ChEI and without baseline anxiety or agitation.

Cost consequence analysis of Apathy in Dementia Methylphenidate Trial 2 (ADMET 2).

BACKGROUND: 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. METHODS: 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. RESULTS: 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). DISCUSSION: 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.

A 2023 update on the advancements in the treatment of agitation in Alzheimer's disease.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Alzheimer's Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is a common and distressing NPS, without safe and effective treatments. Nonpharmacological interventions are first line treatment, but not effective or appropriate for every patient. Current pharmacological treatments of agitation in AD include off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite prevalent use, efficacy and safety concerns remain. AREAS COVERED: Better understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. Comprehensive search of ClinicalTrials.gov was completed from January 2017 to February 2023 using the search terms "Alzheimer's Disease" and "Agitation". Subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin. EXPERT OPINION: Clinical trials utilize both novel and repurposed agents for agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel development of agitation in AD, use of enahanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we advance closer to safe and efficacious treatment options for agitation in AD.

Effect of online tDCS to left somatomotor cortex on neuropsychiatric symptoms among older adults at risk for dementia.

BACKGROUND: Neuropsychiatric symptoms (NPS) in mild cognitive impairment (MCI) cause distress to patients and caregivers, and accelerate progression to dementia. Transcranial direct current stimulation (tDCS) is a promising non-invasive treatment for NPS. OBJECTIVE/HYPOTHESIS: This pilot study assessed behavioral and neural effects of a 4-week anodal tDCS intervention targeting left sensorimotor cortex (LSMC: left precentral/postcentral gyri) during visual attention (compared to online sham tDCS), in 40 older adults (24 females, mean age = 71) with MCI. METHODS: A phase 0 double-blinded randomized control trial was conducted. NPS (patient-reported mood symptoms plus a caregiver-reported questionnaire) and fMRI were measured at baseline and immediately post-intervention. RESULTS: Generalized Estimating Equations found no significant group by time interactions for either NPS measure. However, there was evidence of decreased patient-reported NPS (Wald's χ2 = 3.80, p = .051), decreased LSMC activation during visual attention (Wald's χ2 = 2.93, p = .087), and increased LSMC-amygdala resting-state functional connectivity (rsFC; Wald's χ2 = 3.13, p = .077) in intervention group from pre-to post-intervention. Decrease in LSMC activation (Wald's χ2 = 9.20, p = .002) and increase in LSMC-amygdala rsFC (Wald's χ2 = 4.72, p = .030) related to decreased patient-reported NPS. Increased positive valence across sessions was significantly associated with intervention-related NPS improvement (Wald's χ2 = 22.92, p < .001). There were no findings for caregiver-reported NPS. Effects were stronger for left postcentral compared to left precentral gyrus. CONCLUSION: We found tentative evidence that tDCS applied to LSMC during visual attention in older adults with MCI improved NPS via changes in LSMC activation and LSMC-amygdala rsFC, suggesting improved emotion regulation. Patient-reported NPS was more sensitive to these changes than caregiver-reports, and effects were strongest for left postcentral gyrus. Follow-up studies should perform precise mechanistic investigation and efficacy testing.

Brain amyloid burden, sleep, and 24-hour rest/activity rhythms: screening findings from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration Studies.

STUDY OBJECTIVES: To examine in a subsample at the screening phase of a clinical trial of a ß-amyloid (Aß) antibody whether disturbed sleep and altered 24-hour rest/activity rhythms (RARs) may serve as markers of preclinical Alzheimer's disease (AD). METHODS: Overall, 26 Aß-positive (Aß+) and 33 Aß-negative (Aß-) cognitively unimpaired participants (mean age = 71.3 ± 4.6 years, 59% women) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies, respectively, wore actigraphs for 5.66 ± 0.88 24-hour periods. We computed standard sleep parameters, standard RAR metrics (mean estimating statistic of rhythm, amplitude, acrophase, interdaily stability, intradaily variability, relative amplitude), and performed a novel RAR analysis (function-on-scalar regression [FOSR]). RESULTS: We were unable to detect any differences between Aß+ and Aß- participants in standard sleep parameters or RAR metrics with our sample size. When we used novel FOSR methods, however, Aß+ participants had lower activity levels than Aß- participants in the late night through early morning (11:30 pm to 3:00 am), and higher levels in the early morning (4:30 am to 8:30 am) and from midday through late afternoon (12:30 pm to 5:30 pm; all p < .05). Aß+ participants also had higher variability in activity across days from 9:30 pm to 1:00 am and 4:30 am to 8:30 am, and lower variability from 2:30 am to 3:30 am (all p < .05). CONCLUSIONS: Although we found no association of preclinical AD with standard actigraphic sleep or RAR metrics, a novel data-driven analytic method identified temporally "local" RAR alterations in preclinical AD.

Effect of Methylphenidate on Apathy in Patients With Alzheimer Disease: The ADMET 2 Randomized Clinical Trial.

Importance: Apathy, characterized by diminished will or initiative and one of the most prevalent neuropsychiatric symptoms in individuals with Alzheimer disease, is associated with significant caregiver burden, excess disability, increased medical costs, and mortality. Objective: To measure whether methylphenidate compared with placebo decreases the severity of apathy in individuals with Alzheimer disease. Design, Setting, and participants: This multicenter randomized placebo-controlled clinical trial was conducted from August 2016 to July 2020 in 9 US clinics and 1 Canadian clinic specializing in dementia care. A total of 307 potential participants were screened. Of those, 52 did not pass screening and 55 were not eligible. Participants with Alzheimer disease, mild to moderate cognitive impairment, and frequent and/or severe apathy as measured by the Neuropsychiatric Inventory (NPI) were included. Interventions: Ten milligrams of methylphenidate, twice daily, vs matching placebo. Main Outcomes and Measures: The coprimary outcomes included (1) change from baseline to 6 months in the NPI apathy subscale or (2) improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change. Other outcomes include safety, change in cognition, and quality of life. Results: Of 200 participants, 99 were assigned to methylphenidate and 101 to placebo. The median (interquartile range) age of study participants was 76 (71-81) years; 68 (34%) were female and 131 (66%) were male. A larger decrease was found from baseline to 6 months in the NPI apathy score in those receiving methylphenidate compared with placebo (mean difference, -1.25; 95% CI, -2.03 to -0.47; P = .002). The largest decrease in the NPI apathy score was observed in the first 100 days, with a significant hazard ratio for the proportion of participants with no apathy symptoms receiving methylphenidate compared with placebo (hazard ratio, 2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio of having an improved rating on the Alzheimer's Disease Cooperative Study Clinical Global Impression of Change for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). The difference in mean change from baseline to 6 months estimated using a longitudinal model was 1.43 (95% CI, 1.00-2.04; P = .048). Cognitive measures and quality of life were not significantly different between groups. Of the 17 serious adverse events that occurred during the study, none were related to the study drug. No significant differences in the safety profile were noted between treatment groups. Conclusions and Relevance: This study found methylphenidate to be a safe and efficacious medication to use in the treatment of apathy in Alzheimer disease. Trial Registration: ClinicalTrials.gov Identifier: NCT02346201.

Neurobiologic Rationale for Treatment of Apathy in Alzheimer's Disease With Methylphenidate.

The public health burden of Alzheimer's disease (AD) is related not only to cognitive symptoms, but also to neuropsychiatric symptoms, including apathy. Apathy is defined as a quantitative reduction of goal-directed activity in comparison to a previous level of functioning and affects 30%-70% of persons with AD. Previous attempts to treat apathy in AD-both nonpharmacologically and pharmacologically-have been wanting. Catecholaminergic treatment with methylphenidate has shown encouraging results in initial trials of apathy in AD. Understanding the neuronal circuits underlying motivated behavior and their reliance on catecholamine actions helps provide a rationale for methylphenidate actions in the treatment of apathy in patients with AD. Anatomical, physiological, and behavioral studies have identified parallel, cortical-basal ganglia circuits that govern action, cognition, and emotion and play key roles in motivated behavior. Understanding the distinct contributions to motivated behavior of subregions of the prefrontal cortex-dorsolateral, orbital-ventromedial, and dorsomedial-helps to explain why degeneration of these areas in AD results in apathetic behaviors. We propose that the degeneration of the prefrontal cortex in AD produces symptoms of apathy. We further propose that methylphenidate treatment may ameliorate those symptoms by boosting norepinephrine and dopamine actions in prefrontal-striatal-thalamocortical circuits.

Measuring Apathy in Alzheimer's Disease in the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): A Comparison of Instruments.

BACKGROUND: Diagnostic criteria for apathy have been published but have yet to be evaluated in the context of clinical trials. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) operationalized the diagnostic criteria for apathy (DCA) into a clinician-rated questionnaire informed by interviews with the patient and caregiver. OBJECTIVE: The goal of the present study was to compare the classification of apathy using the DCA with that using the Neuropsychiatric Inventory-apathy (NPI-apathy) subscale in ADMET 2. Comparisons between NPI-Apathy and Dementia Apathy Interview Rating (DAIR) scale, and DCA and DAIR were also explored. METHODS: ADMET 2 is a randomized, double-blind, placebo-controlled phase III trial examining the effects of 20 mg/day methylphenidate on symptoms of apathy over 6 months in patients with mild to moderate Alzheimer's disease (AD). Participants scoring at least 4 on the NPI-Apathy were recruited. This analysis focuses on cross-sectional correlations between baseline apathy scale scores using cross-tabulation. RESULTS: Of 180 participants, the median age was 76.5 years and they were predominantly white (92.8%) and male (66.1%). The mean (±standard deviation) scores were 7.7 ± 2.4 on the NPI-apathy, and 1.9 ± 0.5 on the DAIR. Of those with NPI-defined apathy, 169 (93.9%, 95% confidence interval [CI] 89.3%-96.9%) met DCA diagnostic criteria. The DCA and DAIR overlapped on apathy diagnosis for 169 participants (93.9%, 95% CI 89.3%-96.9%). CONCLUSION: The measurements used for the assessment of apathy in patients with AD had a high degree of overlap with the DCA. The NPI-apathy cut-off used to determine apathy in ADMET 2 selects those likely to meet DCA criteria.

APOE ε4/ε4 homozygotes with early Alzheimer's disease show accelerated hippocampal atrophy and cortical thinning that correlates with cognitive decline.

INTRODUCTION: Hippocampal volume (HV) and cortical thickness are commonly used imaging biomarkers in Alzheimer's disease (AD) trials, and may have utility as selection criteria for enrichment strategies. Atrophy rates of these measures, in the high-risk apolipoprotein E (APOE) ε4/ε4 homozygous AD subjects are unknown. METHODS: Data from Alzheimer's Disease Neuroimaging Initiative (ADNI-1) and a tramiprosate trial were analyzed in APOE ε4/ε4 and APOE ε3/ε3 subjects with mild cognitive impairment (MCI) or mild AD. Magnetic resonance imaging (MRI) data were centrally processed using FreeSurfer; total HV and composite average cortical thickness were derived and adjusted for age, head size, and education. Volumetric changes from baseline were assessed using Boundary Shift Integral, and correlated with cognitive changes. RESULTS: APOE ε4/ε4 MCI subjects showed significantly higher % HV atrophy and cortical thinning at 12 months (4.4%, 3.1%, n = 29) compared to APOE ε3/ε3 subjects (2.8%, 1.8%, n = 93) and similarly in mild AD (7.4%, 4.7% n = 21 vs 5.4%, 3.3% n = 29). Differences were all significant at 24 months. Over 24 months, HV atrophy and cortical thinning correlated significantly with Alzheimer's Disease Assessment Scale-Cognitive subscale worsening in APOE ε4/ε4 MCI subjects, but not in mild AD. DISCUSSION: Correlation of volumetric measures to cognitive change in APOE ε4/ε4 subjects with early AD supports their role as efficacy biomarkers. If confirmed in a Phase 3 trial with ALZ-801 (pro-drug of tramiprosate) in APOE ε4/ε4 early AD subjects, it may allow their use as surrogate outcomes in future treatment or prevention trials in AD.

Escitalopram for agitation in Alzheimer's disease (S-CitAD): Methods and design of an investigator-initiated, randomized, controlled, multicenter clinical trial.

INTRODUCTION: Alzheimer's disease (AD) is a disabling, common cause of dementia, and agitation is one of the most common and distressing symptoms for patients with AD. Escitalopram for agitation in Alzheimer's disease (S-CitAD) tests a novel, clinically derived therapeutic approach to treat agitation in patients with AD. METHODS: S-CitAD is a NIH-funded, investigator-initiated, randomized, multicenter clinical trial. Participants receive a structured psychosocial intervention (PSI) as standard of care. Participants without sufficient response to PSI are randomized to receive 15 mg escitalopram/day or a matching placebo in addition to PSI. Primary outcome is the Modified Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change (mADCS-CGIC). DISCUSSION: S-CitAD will provide information about a practical, immediately available approach to treating agitation in patients with AD. S-CitAD may become a model of how to evaluate and predict treatment response in patients with AD and agitation as a neuropsychiatric symptom (ClinicalTrials.gov Identifier: NCT03108846).

Identify a shared neural circuit linking multiple neuropsychiatric symptoms with Alzheimer's pathology.

Neuropsychiatric symptoms (NPS) are common in Alzheimer's disease (AD)-associated neurodegeneration. However, NPS lack a consistent relationship with AD pathology. It is unknown whether any common neural circuits can link these clinically disparate while mechanistically similar features with AD pathology. Here, we explored the neural circuits of NPS in AD-associated neurodegeneration using multivariate pattern analysis (MVPA) of resting-state functional MRI data. Data from 98 subjects (70 amnestic mild cognitive impairment and 28 AD subjects) were obtained. The top 10 regions differentiating symptom presence across NPS were identified, which were mostly the fronto-limbic regions (medial prefrontal cortex, caudate, etc.). These 10 regions' functional connectivity classified symptomatic subjects across individual NPS at 69.46-81.27%, and predicted multiple NPS (indexed by Neuropsychiatric Symptom Questionnaire-Inventory) and AD pathology (indexed by baseline and change of beta-amyloid/pTau ratio) all above 70%. Our findings suggest a fronto-limbic dominated neural circuit that links multiple NPS and AD pathology. With further examination of the structural and pathological changes within the circuit, the circuit may shed light on linking behavioral disturbances with AD-associated neurodegeneration.

Efficacy and mechanisms of combined aerobic exercise and cognitive training in mild cognitive impairment: study protocol of the ACT trial.

BACKGROUND: Developing non-pharmacological interventions with strong potential to prevent or delay the onset of Alzheimer's disease (AD) in high-risk populations is critical. Aerobic exercise and cognitive training are two promising interventions. Aerobic exercise increases aerobic fitness, which in turn improves brain structure and function, while cognitive training improves selective brain function intensively. Hence, combined aerobic exercise and cognitive training may have a synergistic effect on cognition by complementary strengthening of different neural functions. Few studies have tested the effects of such a combined intervention, and the findings have been discrepant, largely due to varying doses and formats of the interventions. METHODS/DESIGN: The purpose of this single-blinded, 2 × 2 factorial phase II randomized controlled trial is to test the efficacy and synergistic effects of a 6-month combined cycling and speed of processing training intervention on cognition and relevant mechanisms (aerobic fitness, cortical thickness, and functional connectivity in the default mode network) in older adults with amnestic mild cognitive impairment. This trial will randomize 128 participants equally to four arms: cycling and speed of processing, cycling only, speed of processing only, or attention control for 6 months, and then follow them for another 12 months. Cognition and aerobic fitness will be assessed at baseline and at 3, 6, 12, and 18 months; cortical thickness and functional connectivity at baseline and at 6, 12, and 18 months; Alzheimer's disease (AD) conversion at 6, 12, and 18 months. The specific aims are to (1) determine the efficacy and synergistic effects of the combined intervention on cognition over 6 months, (2) examine the underlying mechanisms of the combined intervention, and (3) calculate the long-term effect sizes of the combined intervention on cognition and AD conversion. The analysis will use intention-to-treat and linear mixed-effects modeling. DISCUSSION: This trial will be among the first to test the synergistic effects on cognition and mechanisms (relevant to Alzheimer's-associated neurodegeneration) of a uniquely conceptualized and rigorously designed aerobic exercise and cognitive training intervention in older adults with mild cognitive impairment. It will advance Alzheimer's prevention research by providing precise effect-size estimates of the combined intervention. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03313895 . Registered on 18 October 2017.

Temporospatial components of brain ERPs as biomarkers for Alzheimer's disease.

INTRODUCTION: Developing biomarkers that distinguish individuals with Alzheimer's disease (AD) from those with normal cognition remains a crucial goal for improving the health of older adults. We investigated adding brain spatial information to temporal event-related potentials (ERPs) to increase AD identification accuracy over temporal ERPs alone. METHODS: With two-step principal components analysis, we applied multivariate analyses that incorporated temporal and spatial ERP information from a cognitive task. Discriminant analysis used temporospatial ERP scores to classify participants as belonging to either the AD or healthy control group. RESULTS: Temporospatial ERPs produced a cross-validated area under the curve of 0.84. Adding spatial information through a formal procedure significantly improves classification accuracy. DISCUSSION: A weighted combination of temporospatial ERP markers performs well in detecting AD. Because ERPs are noninvasive and inexpensive, they may be promising biomarkers for AD that can add functional information to other biomarker systems while providing the individual's probability of correct classification.

Attributable Cost of Dementia: Demonstrating Pitfalls of Ignoring Multiple Health Care System Utilization.

OBJECTIVES: To determine dementia prevalence and costs attributable to dementia using Veterans Health Administration (VHA) data with and without Medicare data. DATA SOURCES: VHA inpatient, outpatient, purchased care and other data and Medicare enrollment, claims, and assessments in fiscal year (FY) 2013. STUDY DESIGN: Analyses were conducted with VHA data alone and with combined VHA and Medicare data. Dementia was identified from a VHA sanctioned list of ICD-9 diagnoses. Attributable cost of dementia was estimated using recycled predictions. DATA COLLECTION: Veterans age 65 and older who used VHA and were enrolled in Traditional Medicare in FY 2013 (1.9 million). PRINCIPAL FINDINGS: VHA records indicated the prevalence of dementia in FY 2013 was 4.8 percent while combined VHA and Medicare data indicated the prevalence was 7.4 percent. Attributable cost of dementia to VHA was, on average, $10,950 per veteran per year (pvpy) using VHA alone and $6,662 pvpy using combined VHA and Medicare data. Combined VHA and Medicare attributable cost of dementia was $11,285 pvpy. Utilization attributed to dementia using VHA data alone was lower for long-term institutionalization and higher for supportive care services than indicated in combined VHA and Medicare data. CONCLUSIONS: Better planning for clinical and cost-efficient care requires VHA and Medicare to share data for veterans with dementia and likely more generally.

Sex Differences in the Neuropsychiatric Symptoms of Patients With Alzheimer's Disease.

The aim of this study was to describe sex differences in neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD). Baseline scores on the Cohen-Mansfield Agitation Inventory, Neurobehavioral Rating Scale-Agitation subscale, and the Neuropsychiatric Inventory from patients with AD enrolled in a multicenter trial of citalopram for the treatment of agitation were analyzed. We found not only that patients with AD having agitation were likely to exhibit many other NPSs but also that the women in this study were more likely to exhibit a broader range of NPS than were the men. These results suggest greater heterogeneity in the clinical presentation of women compared to men, and thus in the potential targets for treatment in these patients. Further characterization of sex differences in NPS can inform future efforts aimed at establishing subtypes of patients for whom various treatment approaches will be most appropriate.

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer's Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study.

BACKGROUND: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease dementia (apolipoprotein (APOE) ɛ4 carriers and noncarriers) is summarized. OBJECTIVES: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. METHODS: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. RESULTS: A total of 1,462 (688 were APOEɛ4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. CONCLUSIONS: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.

An update on the advancements in the treatment of agitation in Alzheimer's disease.

INTRODUCTION: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks safe and effective long term interventions. Nonpharmacological interventions are suggested as first-line treatment, but aren't effective for every patient, resulting in pharmacological interventions for some patients, consisting of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine, and antidepressants; where efficacy doesn't necessarily outweigh associated risks. Areas covered: Gains in understanding neurobiological mechanisms underlying agitation have fueled several recent clinical trials. This article updates our review published in 2014. Comprehensive literature search for published articles from January 2014 to December 2016 evaluating pharmacologic interventions for agitation in AD was done. A review of several clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, citalopram, escitalopram, pimavanserin, ITI-007, ORM-12741 show promise in treating agitation. Expert opinion: Neurobiological findings, innovative trials designs, statistical approaches, and preliminary paths for regulatory agency acceptance have re-ignited the area of pharmacological treatment of NPS. Though further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to find effective treatments for neuropsychiatric symptoms such as agitation in patients with dementia is well underway.