Christopher Leibman

Long-Term Follow-Up of Patients Immunized with AN1792: Reduced Functional Decline in Antibody Responders

Background: Immunization of patients with Alzheimer’s disease (AD) with synthetic amyloid-β peptide (Aβ42) (AN1792) was previously studied in a randomized, double-blind, placebo-controlled phase 2a clinical trial, Study AN1792(QS-21)-201. Treatment was discontinued following reports of encephalitis. One year follow-up revealed that AN1792 antibody responders showed improvements in cognitive measures as assessed by the neuropsychological test battery (NTB) and a decrease in brain volume compared with placebo. Methods: A follow-up study, Study AN1792(QS-21)-251, was conducted to assess the long-term functional, psychometric, neuroimaging, and safety outcomes of patients from the phase 2a study 4.6 years after immunization with AN1792. The results were analyzed by comparing patients originally identified as antibody responders in the AN1792 phase 2a study with placebo-treated patients. Results: One hundred and fifty-nine patients/caregivers (30 placebo; 129 AN1792) participated in this follow-up study. Of the 129 AN1792-treated patients, 25 were classified in the phase 2a study as antibody responders (anti-AN1792 titers ≥1:2,200 at any time after the first injection). Low but detectable, sustained anti-AN1792 titers were found in 17 of 19 samples obtained from patients classified as antibody responders in the phase 2a study. No detectable anti-AN1792 antibodies were found in patients not classified as antibody responders in the phase 2a study. Significantly less decline was observed on the Disability Assessment for Dementia scale among antibody responders than placebo-treated patients (p=0.015) after 4.6 years. Significant differences in favor of responders were also observed on the Dependence Scale (p=0.033). Of the small number of patients who underwent a follow-up MRI, antibody responders showed similar brain volume loss during the follow-up period subsequent to the AN1792 phase 2a study compared with placebo-treated patients. Conclusions: Approximately 4.6 years after immunization with AN1792, patients defined as responders in the phase 2a study maintained low but detectable, sustained anti-AN1792 antibody titers and demonstrated significantly reduced functional decline compared with placebo-treated patients. Brain volume loss in antibody responders was not significantly different from placebo-treated patients approximately 3.6 years from the end of the original study. No further cases of encephalitis were noted. These data support the hypothesis that Aβ immunotherapy may have long-term functional benefits.

Patient Dependence and Longitudinal Changes in Costs of Care in Alzheimer's Disease

Background/Aims: To examine the incremental effect of patients’ dependence on others, on cost of medical and nonmedical care, and on informal caregiving hours over time. Methods: Data are obtained from 172 patients from the Predictors Study, a large, multicenter cohort of patients with probable Alzheimer disease (AD) followed annually for 4 years in 3 University-based AD centers in the USA. Enrollment required a modified Mini-Mental State Examination score ≧30. We examined the effects of patient dependence (measured by the Dependence Scale, DS) and function (measured by the Blessed Dementia Rating Scale, BDRS) on medical care cost, nonmedical care cost, and informal caregiving time using random effects regression models. Results: A one-point increase in DS score was associated with a 5.7% increase in medical cost, a 10.5% increase in nonmedical cost, and a 4.1% increase in caregiving time. A one-point increase in BDRS score was associated with a 7.6% increase in medical cost, a 3.9% increase in nonmedical cost and an 8.7% increase in caregiving time. Conclusions: Both functional impairment and patient dependence were associated with higher costs of care and caregiving time. Measures of functional impairment and patient dependence provide unique and incremental information on the overall impact of AD on patients and their caregivers.

Dependence as a Unifying Construct in Defining Alzheimer's Disease Severity

This article reviews measures of Alzheimers disease (AD) progression in relation to patient dependence and offers a unifying conceptual framework for dependence in AD. Clinicians typically characterize AD by symptomatic impairments in three domains: cognition, function, and behavior. From a patients perspective, changes in these domains, individually and in concert, ultimately lead to increased dependence and loss of autonomy. Examples of dependence in AD range from a need for reminders (early AD) to requiring safety supervision and assistance with basic functions (late AD). Published literature has focused on the clinical domains as somewhat separate constructs and has given limited attention to the concept of patient dependence as a descriptor of AD progression. This article presents the concept of dependence on others for care needs as a potential method for translating the effect of changes in cognition, function, and behavior into a more holistic, transparent description of AD progression.

Risk of recurrent emergency department visits or hospitalizations in children with asthma receiving nebulized budesonide inhalation suspension compared with other asthma medications.

ABSTRACT Objective: To examine whether nebulized budesonide inhalation suspension treatment reduces asthma-related emergency department visit/hospitalization recurrence risk in children compared with other asthma medications, particularly non-nebulized inhaled corticosteroids. Research design and methods: Longitudinal, retrospective claims analysis of data from a managed care organization database in the United States (July 1, 2000–June 30, 2002). Participants were children aged ≤ 8 years with an asthma diagnosis and asthma-related emergency department visit or hospitalization (index event). Asthma medication use, evaluated by asthma-related prescriptions ≤ 30 days after the index event, determined treatment groups. Main outcome measure: Emergency department visit/hospitalization recurrence risk from post-index day 31–180 across treatment groups. Results: Of 10 176 patients with an index event, 13% experienced a post-index recurrence. For patients receiving asthma prescriptions ≤ 30 days after the index event, those receiving budesonide inhalation suspension showed a significant reduction in emergency department visit/hospitalization recurrence risk compared with those not prescribed this treatment (adjusted hazard ratio, 0.71; 95% confidence interval, 0.57–0.89). For patients receiving asthma controller medication in the post-index period, those receiving budesonide inhalation suspension had a significantly lower recurrence risk than patients receiving prescriptions for other controller medications (hazard ratio, 0.71; 95% confidence interval, 0.52–0.97). Recurrence risk was significantly reduced (53%) in patients receiving budesonide inhalation suspension prescriptions compared with non-nebulized inhaled corticosteroid prescriptions (hazard ratio, 0.47; 95% confidence interval, 0.28–0.78). Conclusion: For children aged ≤ 8 years, budesonide inhalation suspension treatment after an asthma-related emergency department visit/hospitalization was associated with a significantly reduced risk of recurrence compared with other asthma medications and with non-nebulized inhaled corticosteroids. Because this was an observational study, results should be interpreted cautiously. However, this study allowed evaluation of treatment in real-world practice settings not often included in clinical trials.

Association between illness progression measures and total cost in Alzheimer’s disease

ObjectiveTo compare the associations between dependence and clinical measures of cognition, function and behaviour and total care cost using data from a longitudinal study in Alzheimer’s disease (AD).DesignLongitudinal, observational study.SettingCommunity-dwelling subjects.ParticipantsMale and female subjects between 50 and 85 years of age with mild to moderate AD.InterventionNone.MeasurementsSubject dependence was assessed using the Dependence Scale (DS), cognition (ADAS-Cog, MMSE), function (DAD), behaviour (NPI) and resource utilization with the Resource Utilization in Dementia Questionnaire.ResultsThe repeated measures models confirmed a significant association between the DS and total care cost indicating an increase in cost with increasing dependence. A 1-unit increase in DS score was associated with a 28.60% increase in total care cost. Model 2 indicated that a one point change in MMSE, DAD and NPI is associated with 5.29%, 2.32% and 1.71% increase in total cost, respectively. Model 3 indicated that a one point change in ADAS-Cog, DAD and NPI is associated with a 1.74%, 2.42%and 1.62% increase in total cost, respectively.ConclusionStrategies which prevent deterioration in clinical measures or delay dependence should result in total cost savings. The quantitative relationships observed should assist in the economic assessment of interventions which effect cognition, function, behaviour and dependence.

Prevalence and Impact of Dementia-related Functional Limitations in the United States, 2001 to 2005

These analyses examined the relationship between dementia and comorbid conditions with respect to degree of functional impairment and emotional impact. Analyses were conducted using National Health Interview Survey (2001 through 2005) data from a subset of individuals aged ≥60 years with activity limitations attributed to dementia, senility, or Alzheimer disease compared with those whose limitations were attributed to other conditions. The mean number of limited activities was 6.84 (95% confidence interval: 6.48-7.20) for persons with dementia-related limitations and 4.87 (95% confidence interval: 4.81-4.93) for those with limitations not dementia related. Both groups reported similar prevalence of diabetes, acute myocardial infarction, heart disease, prostate cancer, breast cancer, angina, and emphysema; respondents with dementia-related functional limitations were more likely to report diabetes, depression or anxiety, and vision problems as being related to functional limitations. Persons with dementia-related functional limitations were also more likely than persons with non-dementia-related functional limitations to report feeling sad, hopeless, worthless, nervous, and that “everything is an effort.” Improving or maintaining functional independence in patients with dementia will likely require a multifaceted approach across disease states. Additional research will help define the impact of dementia on the development and progression of functional limitations related to comorbidities.

Psychometric Properties of the Dependence Scale in Large Randomized Clinical Trials of Patients With Mild and Moderate Alzheimer’s Disease

Objective: The need for assistance from others is a hallmark concern in Alzheimer’s disease (AD). The psychometric properties of the Dependence Scale (DS) for measuring treatment benefit were investigated in large randomized clinical trials of patients with mild to moderate AD. Methods: Reliability, validity, and responsiveness of the DS were examined. Path models appraised relationships and distinctiveness of key AD measures. The responder definition was empirically derived. Results: Generally acceptable reliability (α ≥ .65), significant (P < .001) known-groups tests, and moderate to strong correlations (r ≥ .31) confirmed the DS psychometric properties. Path models supported relationships and distinctiveness of key AD measures. A DS change of ≤1 point for patients with limited home care and ≤2 points for patients with assisted living care best described stability of the level of dependence on caregivers. Conclusion: The DS is a psychometrically robust measure in mild to moderate AD. The empirically derived responder definition aids in the interpretation of DS change.

Estimating health-related quality of life for unique dependence levels in patients with Alzheimer's disease

Background: Cognitive aging is associated to changes in cognition, in particular, in memory abilities. It is plausible that older adults with memory deficits may complain about memory more frequently. Methods: 67 older adults (ages between 60-75 years) were recruited at the Centro de Referência da Cidadania do Idoso CRECI. They were divided into 3 groups according to education: group 1, 1 to 4 years of education (n1⁄423), group 2, 4 to 8 years (n1⁄420), and group 3, 9 years of education or more (n1⁄4 24). Participants completed a socio-demographic questionnaire, Brief Cognitive Battery (which includes Verbal Fluency and the Clock Drawing Test), a questionnaire about frequency of forgetting, the Memory Complaint Questionnaire MAC-Q, the Beck Anxiety Inventory, the Geriatric Depression Scale, and the Mini Mental State Examination. Results: Significant differences were found among the 3 groups for the MMSE, VF, the CDT, and picture recognition. Conclusions: For memory complaints no differences were found among the groups, and there was no association between complaints, cognitive performance and depressive symptoms. Complaints were associated with anxiety.

Use of informant-reported web-based data collection to assess dementia symptoms: Validation in relation to the dependence scale

Of 250 profilees, most care partners were women (203; 81%), 208 (83%) were less than 65 years old, usually with adult children (125; 50%) or spouses (71; 28%). Most caregivers lived in the same household (115; 46%) or saw the person with dementia at least 5 days a week (46; 18%) although 18 (7%) saw the person less than weekly. Most site users came from the United States (113; 45%) Canada (82; 33%) or the United Kingdom (22; 9%). The mean age of the patients was 77.1 years (SD = 11.1) and 133 (53%) were women. Most (198; 79%) were community dwelling, with the remaining (52; 21%) in assisted living or nursing home care. DS scores ranged from 0 to 14, with a mode of 8. With respect to patient residence (community versus institution) none of the 33 people profiled at the lowest levels of dependence (DS 12) 13 (52%) were resident in a long term care facility (χ²=27.9, P 10.

O1-02-03: Associated conditions impacting limitations among the US population with limitations due to Alzheimer’s disease

Objective: To investigate regional and gender differences in the doubling of Alzheimer’s disease age specific incidence rates. Methods: We identified all studies in the peer review literature that reported age specific incidence rates for Alzheimer’s disease. We modeled the logarithm of the incidence rate as a polynomial in age. We used both fixed effects models and random effects models to account for inter-study variation. Results: Alzheimer’s disease incidence rates exponentially increase with increasing age. The overall estimate of the doubling time was 5.7 years (95% confidence interval 4.2 to 9.0.) The doubling times from studies performed in North America, Europe, and other parts of the world were 6.0, 5.8, and 5.0 respectively, and were not significantly different (p .3). No significant differences were detected by gender (6.7 years for males; 5.3 for females, p 0.12). Conclusion: Doubling times of Alzheimer’s disease incidence rates are remarkably similar among populations throughout the world. The variation in absolute incidence rates could be due to methodological and diagnostic differences among studies or indicate different underlying, risk factors.