Factors Associated with Supportive Care Service Use Among California Alzheimer's Disease Patients and Their Caregivers.

BACKGROUND: Existing literature on factors associated with supportive care service (SCS) use is limited. A better understanding of these factors could help tailor SCS to the needs of frequent users, as well as facilitate targeted outreach to populations that underutilize available services. OBJECTIVE: To investigate the prevalence of SCS use and to identify factors associated with, and barriers to, service use. METHODS: California Alzheimer's Disease Center patients with AD (n = 220) participated in the study from 2006-2009. Patients and their caregivers completed assessments to determine SCS use. Cognitive, functional, and behavioral status of the patients were also assessed. A two-part hurdle analysis identified 1) factors associated with any service use and 2) service use frequency among users. RESULTS: Forty percent of participants reported using at least one SCS. Patients with more impaired cognition and activities of daily living and more of the following: total number of medications, comorbid medical conditions, and years of education were more likely to use any SCS (p < 0.05). Factors associated with more frequent SCS use included younger age, more years of education, older age of AD onset, female gender, and having a spouse or relative for a caregiver (p < 0.05). Caregivers frequently indicated insufficient time as a reason for not receiving enough services. CONCLUSION: Factors associated with any SCS use mostly differed from those associated with SCS frequency, suggesting different characteristics between those who initiate versus those who continue SCS use. Our findings highlight the importance of targeted education on services and identifying barriers to long-term SCS use.

Donepezil treatment in ethnically diverse patients with Alzheimer disease.

OBJECTIVE: To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil. METHODS: Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity. RESULTS: The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data. CONCLUSION: Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

Memantine is associated with longer survival than donepezil in a Veterans Affairs prescription database, 1997 to 2008.

Alzheimer's disease (AD) shortens life-expectancy, but the effects of pharmacological treatments for this disorder on mortality have not been studied. We compared two commonly prescribed medications, donepezil and memantine, with respect to the length of survival of veterans presumed to have AD. The Computerized Medical Records System at the Veterans Affairs Palo Alto Health Care System (VAPAHCS) was used to identify all patients prescribed these medications between 1997 and 2008. The VAPAHCS approved donepezil in 1997 and memantine in 2004. Kaplan-Meier and Cox regression analyses were used to test for chronological and drug-related associations with survival in 2,083 male veterans aged 55 years and older receiving prescriptions for donepezil, memantine, or both. Overall patient mortality decreased in the 2004 to 2008 era, compared with the 1997 to 2003 era, pre-memantine (HR: 0.75; 95% CI: 0.63, 0.89; p = 0.001). In analyses confined to the 2004 to 2008 era, patients prescribed memantine alone survived significantly longer than those prescribed donepezil alone (HR: 2.24; 95% CI: 1.53, 3.28; p < 0.001) or both donepezil and memantine (HR: 1.83; 95% CI: 1.14, 2.94; p = 0.012). While this study has several limitations, these findings suggest that memantine treatment is associated with an increased life-expectancy relative to donepezil treatment. Additional research is needed to replicate these unexpected findings and identify potential mechanisms to explain this apparent association, to establish if the relationship applies to other cholinesterase inhibitors, and to discover whether the findings generalize to women and patient populations with characteristics different from those of the veterans in this study.

Circadian clock gene polymorphisms and sleep-wake disturbance in Alzheimer disease.

OBJECTIVES: One of the hypothesized causes of the breakdown in sleep-wake consolidation often occurring in individuals with Alzheimer disease (AD) is the dysfunction of the circadian clock. The goal of this study is to report indices of sleep-wake function collected from individuals with AD in relation to relevant polymorphisms in circadian clock-related genes. DESIGN: One week of ad libitum ambulatory sleep data collection. SETTING: At-home collection of sleep data and in-laboratory questionnaire. PARTICIPANTS: Two cohorts of AD participants. Cohort 1 (N = 124): individuals with probable AD recruited from the Stanford/Veterans Affairs, National Institute on Aging Alzheimer's Disease Core Center (N = 81), and the Memory Disorders Clinic at the University of Nice School of Medicine (N = 43). Cohort 2 (N = 176): individuals with probable AD derived from the Alzheimer's Disease Neuroimaging Initiative data set. MEASUREMENTS: Determination of sleep-wake state was obtained by wrist actigraphy data for 7 days in Cohort 1 and by the Neuropsychiatric Inventory questionnaire for Cohort 2. Both cohorts were genotyped by using an Illumina Beadstation (Illumina, San Diego, CA), and 122 circadian-related single-nucleotide polymorphisms (SNPs) were examined. In Cohort 1, an additional polymorphism (variable-number tandem repeat in per3) was also determined. RESULTS: Adjusting for multiple tests, none of the candidate gene SNPs were significantly associated with the amount of wake time after sleep onset (WASO), a marker of sleep consolidation. Although the study was powered sufficiently to identify moderate-sized correlations, we found no relationships likely to be of clinical relevance. CONCLUSIONS: It is unlikely that a relationship with a clinically meaningful correlation exists between the circadian rhythm-associated SNPs and WASO in individuals with AD.

Donepezil treatment and Alzheimer disease: can the results of randomized clinical trials be applied to Alzheimer disease patients in clinical practice?

OBJECTIVE: To determine if results from randomized clinical trials of donepezil in Alzheimer disease (AD) patients can be applied to AD patients in clinical practice by comparing the findings from a Nordic one-year randomized AD donepezil trial with data from a one-year prospective, observational study of AD patients. METHODS: AD patients from a consortium of California sites were systematically followed for at least one year. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. RESULTS: The 148 California patients treated with donepezil had a one-year decline of 1.3 (3.5 SD) points on the Mini-Mental State Exam compared to a decline of 3.3 (4.4 SD) in the 158 AD patients who received no anti-Alzheimer drugs. The Mini-Mental State Exam decline in Nordic sample was approximately 0.25 points for the 91 patients receiving donepezil and approximately 2.2 for the 98 placebo patients. The overall effect sizes were estimated at about 0.49 in both studies. The California data were further analyzed using propensity methods; after taking into account differences that could bias prescribing decisions, benefits associated with taking donepezil remained. CONCLUSION: A comparison of a randomized clinical trial of donepezil in AD patients and this observational study indicates that if appropriate methodological and statistical precautions are undertaken, then results from randomized clinical trials can be predictive with AD patients in clinical practice. This California study supports the modest effectiveness of donepezil in AD patients having clinical characteristics similar to those of the Nordic study.

Factors in choosing atypical antipsychotics: toward understanding the bases of physicians' prescribing decisions.

OBJECTIVE: Off-label prescribing of medications, polypharmacy, and other questionable prescribing practices have led investigators to examine a large VA pharmacy database to determine if physician prescribing decisions appear reasonable. METHOD: The current study addresses the question of physician prescribing of atypical antipsychotics in 34,925 veterans with schizophrenia, using a series of signal detection analyses. RESULTS: These results suggest that only three factors (hospital size, age, and secondary diagnosis) allow classification of patients prescribed atypicals into three groups with frequencies of use of atypicals ranging from 43% to 79%, and that these results are consistent with reasonable clinical practice. CONCLUSIONS: Results of two-stage signal detection analyses are readily interpretable by clinicians and administrators who are faced with the task of evaluating how physicians prescribe medications in clinical practice. Physicians' decisions to prescribe atypical antipsychotics are based on both patient and fiscal considerations. This likely reflects a combination of clinical judgment and institutional guidelines.

Factors associated with use of medications with potential to impair cognition or cholinesterase inhibitors among Alzheimer's disease patients.

BACKGROUND: The aim of this study was to use a signal detection method to examine the prevalence of, and patient characteristics associated with, medication with potential to impair cognition and cholinesterase inhibitor use in patients with Alzheimer's disease. METHODS: A cross-sectional study was conducted of 1,954 patients with a diagnosis of probable or possible Alzheimer's disease. Concurrent medications were measured, specifically: (1) a medication with potential to impair cognition or (2) a cholinesterase inhibitor. Predictor variables included age, gender, ethnic group, education, age of symptom onset, number of prescriptions, number of medical diagnoses, Mini-Mental State Examination (MMSE), Blessed-Roth Dementia Rating Scale (BRDRS), probable versus possible AD diagnosis. RESULTS: Fifteen percent of the Alzheimer's disease patients were on a medication with potential to impair cognition, and 44% were on a cholinesterase inhibitor. Patient characteristics associated with the prescription of a medication with potential to impair cognition included total number of prescription medications, low education, low MMSE, older age, reported lack of vitamin use, and more medical diagnoses. Patient characteristics associated with the prescription of a cholinesterase inhibitor included reported use of vitamins, the total number of prescription medications, fewer medical diagnoses, lower age of symptom onset, and higher education. CONCLUSIONS: Determining the patient characteristics associated with the prescription of a medication with potential to impair cognition can help clinicians identify patients who are at risk for drug-related morbidity. Patient characteristics unassociated with dementia appear to influence the prescription of cholinesterase inhibitors. Signal detection analysis is well suited to this type of research.

Tolerability and effectiveness of lamotrigine in complex elderly patients.

There is paucity of medical literature on the use of lamotrigine in elderly patients who have behavior problems and diverse psychiatric syndromes. This article is a retrospective case series summarizing the authors' experience with this medication. In a 20-patient case series from an institutional review board-approved retrospective chart review, the tolerability and efficacy of lamotrigine was evaluated for the management of agitated and aggressive behaviors in nursing home patients with a range of psychiatric and medical diagnoses. Nineteen of the elderly nursing home patients tolerated lamotrigine treatment, and 18 showed modest clinical improvement. These results support the authors' belief that controlled clinical investigations of this medication should be performed.

Validation of a 26-point telephone version of the Mini-Mental State Examination.

The objective of this study was to assess the convergent validity of a 26-point Telephone Mini-Mental State Examination (MMSE) in a longitudinal cohort of 46 Alzheimer's disease (AD) patients. Paired in-person and telephone MMSE observations were collected within 35 days of each other. The setting was the Stanford/VA Alzheimer's Center in Palo Alto, California, and patients' residences. The 30-point Folstein MMSE was administered in-person, and a 26-point telephone version of the MMSE, adapted from the Adult Lifestyles and Function Interview (ALFI)-MMSE. Total scores for the in-person and telephone MMSE versions correlated strongly (Pearson's r =.88, P <.001). Hearing impairment and education level did not significantly affect telephone-based performance. The Telephone MMSE can be used to validly estimate in-person MMSE scores of patients with AD. Use of this practical measure can enhance reassessment if returning to the clinic is difficult or if a change in the patient's medical condition merits a check of mental status by telephone.

Sleep/wake disruption in Alzheimer's disease: APOE status and longitudinal course.

Disturbed sleep is a major clinical problem in Alzheimer's disease (AD). Apolipoprotein epsilon4 (APOE epsilon4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE epsilon4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-epsilon4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the epsilon4 allele.

Age and disease severity predict choice of atypical neuroleptic: a signal detection approach to physicians' prescribing decisions.

OBJECTIVE: We used a novel application of a signal detection technique, receiver operator characteristics (ROC), to describe factors entering a physician's decision to switch a patient from a typical high potency neuroleptic to a particular atypical, olanzapine (OLA) or risperidone (RIS). METHODS: ROC analyses were performed on pharmacy records of 476 VA patients who had been treated on a high potency neuroleptic then changed to either OLA or RIS. RESULTS: Overall 68% patients switched to OLA and 32% to RIS. The best predictor of neuroleptic choice was age at switch, with 78% of patients aged less than 55 years receiving OLA and 51% of those aged greater than or equal to 55 years receiving OLA (chi(2)=38.2, P<0.001). Further analysis of the former group indicated that adding the predictor of one or more inpatient days to age increased the likelihood of an OLA switch from 78% to 85% (chi(2)=7.3, P<0.01) while further analysis of the latter group indicated that adding the predictor of less than 10 inpatients days to age decreased the likelihood of an OLA switch from 51% to 45% (chi(2)=7.0, P<0.01). CONCLUSIONS: ROC analyses have the advantage over other analyses, such as regression techniques, insofar as their "cut-points" are readily interpretable, their sequential use forms an intuitive "decision tree" and allows the potential identification of clinically relevant "subgroups". The software used in this analysis is in the public domain (http://mirecc.stanford.edu).

On disentangling states versus traits: demonstration of a new technique using the Alzheimer's disease assessment scale.

Part of the challenge in research on degenerative neurologic disease relates to distinguishing those measurements that essentially describe patient characteristics stable across the course of illness (traits) from those that vary systematically within subjects (states), particularly those specifically related to stage or duration of illness. A components-of-variance approach was used to examine the state versus trait aspects of the Alzheimer's Disease Assessment Scale (ADAS) Cognitive and Noncognitive subscales, a clinical instrument frequently used in research on Alzheimer disease. Subjects were 190 patients with probable AD followed longitudinally. Stage of illness was indexed by mental status scores. Analysis of variance was used to partition total variance into that associated with subjects (trait), stages (state: stage), subjects x stages (state: other), and error. ADAS Cognitive scores were strongly related to stage of illness (83% of true variance). ADAS Noncognitive scores were modestly related to stage (approximately 21% of true variance) and moderately related to state: other (47%). We discuss how state-trait analyses can be helpful in focusing attention on those areas of assessment most likely to accomplish specific objectives.

Which Alzheimer patients are at risk for rapid cognitive decline?

In the current study of 1062 Alzheimer's disease (AD) patients, we employed receiver operating characteristic curve analysis to identify characteristics of patients at increased risk for rapid cognitive decline. The patients are participants at one of the nine Alzheimer's Disease Research Centers of California. Rapid decline was defined as a 3-point or greater loss on the Mini-Mental State Examination (MMSE) per year, post visit. The independent variables were age at clinic visit, age at symptom onset of AD, MMSE at patient visit, years of education, gender, ethnicity, living arrangement, presence of aphasia, delusions, hallucinations, and extrapyramidal signs. Receiver operating characteristic curve analysis indicated that AD patients presenting with moderate to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater than 7 were at increased risk for rapid cognitive decline. This information could help clinicians target these patients for pharmacologic interventions, facilitate long-term care planning, and potentially create savings by delaying or stabilizing the course of the disease.

Sleep/wake cycle disturbance in Alzheimer's disease: how much is due to an inherent trait?

Major advances in understanding the physiology and genetics of circadian rhythm in the past decade challenge the researcher of sleep/wake disorders in Alzheimer's disease (AD) to distinguish patient characteristics stable across the course of illness ("traits") from characteristics that vary with stage of illness ("states"). A components-of-variance approach with a repeated measures model was used to examine the between-subjects variance over time ("trait") vs. within-subjects ("state") variance in 42 patients with probable AD followed, on average, over 2 years on actigraphic sleep/wake measures. Mental status scores indexed stage of illness. Actigraphic measures of sleep efficiency and circadian rhythmicity appeared predominantly "trait," with between-individual differences accounting for over 55% of variance compared to the less than 5% of variance related to stage of cognitive impairment. We discuss how "state-trait" analyses can be helpful in identifying areas of assessment most likely to be fruitful objectives of physiologic and genetic research on sleep/wake disturbance in AD.

Patterns of behavior in adolescent rape.

A study of 67 rapes by 63 California adolescents has yielded a highly representative composite picture of the typical rape episode by a juvenile assailant. Previously unexplored behavior patterns have emerged, including prior drug use, impulsivity, and lack of victim provocation. These findings have practical implications for clinicians treating rape victims and for the rehabilitation of adolescent rapists.