Susan Rountree

Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease

IntroductionThere are no empiric data to support guidelines for duration of therapy with antidementia drugs. This study examined whether persistent use of antidementia drugs slows clinical progression of Alzheimer disease (AD) assessed by repeated measures on serial tests of cognition and function.MethodsSix hundred forty-one probable AD patients were followed prospectively at an academic center over 20 years. Cumulative drug exposure was expressed as a persistency index (PI) reflecting total years of drug use divided by total years of disease symptoms. Baseline and annual testing consisted of Mini-Mental State Examination (MMSE), Alzheimers Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Baylor Profound Mental Status Examination (BPMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), Physical Self-Maintenance Scale (PSMS), and Instrumental Activities of Daily Living (IADL). Annual change in slope of neuropsychological and functional tests as predicted by follow-up time, PI, and the interaction of these two variables was evaluated.ResultsPI was associated with significantly slower rates of decline (with, without adjustment for covariates) on MMSE (P < 0.0001), PSMS (P < 0.05), IADL (P < 0.0001), and CDR-SB (P < 0.001). There was an insignificant trend (P = 0.053) for the PI to be associated with slower rate of decline on BPMSE. The association of PI with ADAS-Cog followed a quadratic trend (P < 0.01). Analysis including both linear and quadratic terms suggests that PI slowed ADAS-Cog decline temporarily. The magnitude of the favorable effect of a rate change in PI was: MMSE 1 point per year, PSMS 0.4 points per year, IADL 1.4 points per year, and CDR-SB 0.6 points per year. The change in mean test scores is additive over the follow-up period (3 ± 1.94 years).ConclusionsPersistent drug treatment had a positive impact on AD progression assessed by multiple cognitive, functional, and global outcome measures. The magnitude of the treatment effect was clinically significant. Positive treatment effects were even found in those with advanced disease.

Predicting progression of Alzheimer's disease

IntroductionClinicians need to predict prognosis of Alzheimers disease (AD), and researchers need models of progression to develop biomarkers and clinical trials designs. We tested a calculated initial progression rate to see whether it predicted performance on cognition, function and behavior over time, and to see whether it predicted survival.MethodsWe used standardized approaches to assess baseline characteristics and to estimate disease duration, and calculated the initial (pre-progression) rate in 597 AD patients followed for up to 15 years. We designated slow, intermediate and rapidly progressing groups. Using mixed effects regression analysis, we examined the predictive value of a pre-progression group for longitudinal performance on standardized measures. We used Cox survival analysis to compare survival time by progression group.ResultsPatients in the slow and intermediate groups maintained better performance on the cognitive (ADAScog and VSAT), global (CDR-SB) and complex activities of daily living measures (IADL) (P values < 0.001 slow versus fast; P values < 0.003 to 0.03 intermediate versus fast). Interaction terms indicated that slopes of ADAScog and PSMS change for the slow group were smaller than for the fast group, and that rates of change on the ADAScog were also slower for the intermediate group, but that CDR-SB rates increased in this group relative to the fast group. Slow progressors survived longer than fast progressors (P = 0.024).ConclusionsA simple, calculated progression rate at the initial visit gives reliable information regarding performance over time on cognition, global performance and activities of daily living. The slowest progression group also survives longer. This baseline measure should be considered in the design of long duration Alzheimers disease clinical trials.

Alzheimer's disease and mild cognitive impairment deteriorate fine movement control

Sensory-motor dysfunctions are often associated with Alzheimers disease (AD) or mild cognitive impairment (MCI). This study suggests that deterioration in fine motor control and coordination characterizes sensory-motor deficiencies of AD and MCI. Nine patients with a clinical diagnosis of probable AD, 9 amnestic MCI subjects and 10 cognitively normal controls performed four types of handwriting movement on a digitizer. Movement time and smoothness were analyzed between the groups and across the movement patterns. Kinematic profiles were also compared among the groups. AD and MCI patients demonstrated slower, less smooth, less coordinated, and less consistent handwriting movements than their healthy counterparts. The theoretical relevance and practical implications of fine motor tasks, such as these movements involved in handwriting, are discussed relative to the deteriorated sensory-motor system of AD and MCI patients.

Importance of subtle amnestic and nonamnestic deficits in mild cognitive impairment : Prognosis and conversion to dementia

Background/Aims: To evaluate baseline characteristics and conversion to dementia in mild cognitive impairment (MCI) subtypes. Methods: We prospectively evaluated conversion to dementia in 106 patients with amnestic MCI (A-MCI) as defined by Petersen’s operationalized criteria on a paragraph recall task, amnestic-subthreshold MCI (AS-MCI) as defined by impairment on the ADAS-cog delayed word list recall with normal paragraph recall, nonamnestic MCI (NA-MCI) defined by a nonmemory domain, and in 27 patients with subjective memory loss who had no deficit on formal neuropsychological testing. Results: For all MCI subtypes, the 4-year conversion to dementia was 56% (14% annually) and to AD was 46% (11% annually). Conversion to AD in the A-MCI (56%) was similar to the rate in AS-MCI (50%). Conversion to AD in the A-MCI and AS-MCI combined was 56% (14% annually). Conversion to dementia in the NA-MCI was 52% (13% annually) and the majority converted to AD (62%). Conclusions: All MCI subtypes are at risk of converting to AD if the groups are carefully defined by an abnormal psychometric domain. All subtypes except subjective memory loss converted to AD at higher than expected rates. Both the A-MCI and AS-MCI subtypes had a similarly high rate of conversion to AD. The deficit on a word list recall task may develop before an abnormality on delayed paragraph recall is evident, at least in some subjects.

Effectiveness of antidementia drugs in delaying Alzheimer's disease progression

Randomized controlled trials (RCTs) provide safety and efficacy data for regulatory approval of antidementia drugs, but offer limited data regarding real‐world effectiveness. Long‐term observational controlled studies (LTOCs) extend our understanding by providing longitudinal data across multiple stages of Alzheimers disease (AD).

Factors that influence survival in a probable Alzheimer disease cohort

IntroductionThis longitudinal study examined multiple factors that influence survival in a cohort of Alzheimer patients followed over two decades.MethodsTime to death after symptom onset was determined in 641 probable AD patients who were evaluated annually until death or loss to follow-up, and information was entered into a longitudinal database. Date of death was available for everyone including those eventually lost. Baseline variables included age, sex, race, disease severity, a calculated index of rate of initial cognitive decline from symptom onset to cohort entry (pre-progression rate or PPR), years of education, and medical comorbidities (diabetes, hypertension, hyperlipidemia, coronary disease, cerebrovascular disease). Multivariable Cox proportional hazard regression analysis was used to analyze the baseline and/or time dependent association in Mini-mental Status Exam (MMSE) severity, Physical Self Maintenance Scale (PSMS), Persistency Index (PI) of exposure to antipsychotic and antidementia drugs, and psychotic symptoms (hallucinations, delusions) with mortality.ResultsBaseline covariates significantly associated with increased survival were younger age (p = .0016), female sex (p = .0001), and a slower PPR (p < .0001). Overall disease severity at baseline, medical comorbidities, and education did not influence time to death. Time-dependent changes in antipsychotic drug use, development of psychotic symptoms, antidementia drug use, and observed MMSE change were not predictive. In the final model the only time-dependent covariate that significantly decreased survival was worsening of functional ability on the PSMS (hazard ratio = 1.10; CI: 1.07-1.11).ConclusionsIn this large AD cohort survival is influenced by age, sex, and the development of functional disability during follow-up. The most important predictor of mortality was a faster rate of cognitive decline at the initial patient visit (PPR). The currently available antidementia drugs do not prolong survival in Alzheimer patients.

Vitamin E use is associated with improved survival in an Alzheimer's disease cohort.

Background: Vitamin E at a dose of 2,000 IU per day has been shown to delay Alzheimer’s disease (AD) progression, but recent studies have questioned the safety of this dose level and the overall efficacy of vitamin E in AD treatment. Methods: We analyzed the survival history of 847 probable or mixed AD patients followed in a research center between 1990 and the censoring date of December 31, 2004. Standard practice during this period was to recommend vitamin E at 1,000 IU twice daily to all patients. We used Cox proportional hazards modeling to assess the association of vitamin E alone, or in combination with a cholinesterase inhibitor (ChEI), with all-cause mortality, adjusting for important covariates. Approximately two thirds of the patients took vitamin E with a ChEI, 10% took vitamin E alone, and 15% took no antidementia drug. Results: The adjusted hazard ratio (HR) associated with vitamin E (with or without a ChEI) was 0.71 (95% CI: 0.57–0.89; p = 0.003). Compared to the no drug treatment group, the HR for vitamin E alone or with another drug was 0.77 (95% CI: 0.60–1.0); the HR for ChEI use alone was 1.2 (95% CI: 0.87–1.60). Conclusion: The results do not support a concern over increased mortality with high-dose vitamin E supplementation.

Is Functional Decline Necessary for a Diagnosis of Alzheimer’s Disease?

Background: The purpose of this study is to examine baseline differences and annualized cognitive and functional change scores in mild Alzheimer’s disease (AD) patients with and without impaired activities of daily living (ADL). Methods: We recruited 267 mild probable AD patients with at least 1 year of follow-up (NINCDS-ADRDA criteria, MMSE ≧20). Based on initial ADL scores, they were divided into 2 groups: unimpaired (n = 40) and impaired (n = 227). We compared the differences in annualized change scores on MMSE, Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), ADL and Clinical Dementia Rating sum of box score (CDR-SB) for patients with and without functional impairment at baseline. Results: The group with unimpaired ADL at baseline had a significantly shorter symptom duration (p = 0.01) and better neuropsychological test scores at baseline (p < 0.001) than those with impaired ADL. The annualized cognitive and functional change of each group from baseline to 1-year follow-up was not significantly different on the MMSE, ADAS-cog, CDR-SB, Physical Self-Maintenance Scale and Instrumental Activities of Daily Living. After 1 year, 56% of the initially unimpaired group and 6% of the initially impaired group reported no ADL impairment. Conclusions: Our study suggests that functional decline should not be required for the diagnosis of mild AD.

Validity, Significance, Strengths, Limitations, and Evidentiary Value of Real-World Clinical Data for Combination Therapy in Alzheimer's Disease: Comparison of Efficacy and Effectiveness Studies

Background: Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer’s disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. Objective: To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs). Methods: Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs. Results: RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization. Conclusions: Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.

Weight change in Parkinson and Alzheimer patients taking atypical antipsychotic drugs.

Atypical antipsychotics (AA) are generally associated with weight gain. We determined body mass index (BMI) change in Parkinsons disease (PD) before and after taking AA and compared against PD controls and Alzheimers disease (AD) patients on AA. In 66 consecutive PD subjects started on AA who had accurate weights for more than 6 months before and after initiation of AA, we compared weight change before and after AA use, against a control group of sixty-one sex-matched PD subjects, and against twenty-eight AD subjects taking AA. A linear regression model was created to compare weight changes. Fifty-nine PD subjects had complete data, quetiapine (n=53) and clozapine (n=6). The mean BMI change in the period before starting AA was 0.00 kg/m(2)/month over 1.95+/-1.41 years. After starting AA, subjects lost 0.03 kg/m(2)/month (95% CI 0.62-1.21, P<0.0001), comparing PD before AA to the same PD patients after AA. In 61 PD controls, the mean BMI loss was 0.01 kg/m(2)/month (95% CI 0.15-0.94, P=0.007) comparing PD on AA vs. PD controls. The BMI for 28 AD subjects on AA increased 0.01 kg/m(2)/month (95% CI 0.26-0.83, P<0.0001), comparing PD on AA vs. AD on AA. The weight loss seen in the PD/AA group, compared to AD, suggest uniquely altered weight homeostasis in PD.