Wenyaw Chan

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.

Validation of the new interpretive guidelines for the clinical dementia rating scale sum of boxes score in the national Alzheimer's coordinating center database.

BACKGROUNDnIt was recently demonstrated that the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) score can be used to accurately stage severity of Alzheimer dementia and mild cognitive impairment (MCI). However, to our knowledge, the utility of those interpretive guidelines has not been cross-validated or applied to a heterogeneous sample of dementia cases.nnnOBJECTIVEnTo cross-validate the staging guidelines proposed in a previous study using the National Alzheimers Coordinating Center (NACC) database.nnnDESIGNnThe previously published cut scores were applied to the NACC sample and diagnostic accuracy estimates obtained. Next, analyses were restricted to NACC participants with a CDR global score (CDR-GS) of 0.5 and receiver operating characteristic curves generated to determine optimal CDR-SB cut scores for distinguishing MCI from very early dementia.nnnSETTINGnThe 2008 NACC uniform data set.nnnPARTICIPANTSnThere were 12 462 participants (5115 controls; 2551 patients with MCI; 4796 patients with dementia, all etiologies) in the NACC data set used for the current analysis. Main Outcome Measure Accurate prediction of diagnoses (MCI or dementia) using the CDR-SB score.nnnRESULTSnThe previously proposed CDR-SB ranges successfully classified the vast majority of patients across all impairment ranges with a kappa of 0.91 and 94% overall correct classification rate. Additionally, the CDR-SB score discriminated between patients diagnosed with MCI and dementia when CDR-GS was restricted to 0.5 (overall area under the curve = 0.83).nnnCONCLUSIONSnThese findings cross-validate the previously published CDR-SB interpretative guidelines for staging dementia severity and extend those findings to a large heterogeneous sample of patients with dementia. Additionally, the CDR-SB scores distinguished MCI from dementia in patients with reasonable accuracy when CDR-GS was restricted to 0.5.

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.

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.

Changing Patient Characteristics and Survival Experience in an Alzheimer’s Center Patient Cohort

Background:Large and diverse dementia patient cohorts can further a variety of research programs aimed at improving diagnosis, treatment, and meaningful survival in AD. Method: We recruited 1,502 dementia patients between 1989 and 2002, subclassified using standardized criteria and laboratory procedures, and treated according to established guidelines. Baseline clinical and psychometric measures were repeated annually, in person or by use of a multi-modal telephone follow-up program that included many of the measures obtained at in-person visits. We tracked vital status of all subjects at 6-month intervals and offered autopsies to all participants. We assessed for cohort effects in baseline characteristics by 2-year intervals, examined the characteristics and outcomes for those who remained active compared to those who were eventually lost to follow-up, examined survival times for demographic or diagnostic subgroups, and assessed the accuracy of clinical diagnoses versus neuropathology. Results: The average age at entry, average educational level, and baseline MMSE scores for subjects are increasing over time, and probable AD diagnoses are also increasing. Most (80.6%) subjects have remained active in our Center; those who did not were more likely to have a non-AD diagnosis. Survival averages 5.2 years (CI 4.98–5.37) and is influenced by age and gender, but not by diagnosis of probable versus possible AD. Our diagnostic accuracy is 89.6%, with high sensitivity to the presence of AD (96%). Conclusions: In a large and representative clinical cohort, the demographics of AD are changing over time. Careful analyses of those who continue and those who drop out from follow-up suggest that atypical diagnosis, rather than severity or demographic issues accounts for most of the attrition. Clinicians are likely to encounter increasingly older patients with milder disease, and these trends have implications for the design of clinical trials. Survival from the onset of first symptoms, similar for probable and possible AD cases, may be increasing over time.

Influence of Premorbid IQ and Education on Progression of Alzheimer’s Disease

Background: Lower education is associated with a higher risk of developing Alzheimer’s disease (AD). Years of education and measures of general intellectual function (IQ) are highly correlated. It is important to determine whether there is a relationship between education and AD outcomes that is independent of IQ. Objective: To test the hypothesis that premorbid IQ is a stronger predictor of cognitive decline, global progression, and overall survival, than education in patients with AD. Methods: The study included 478 probable AD patients (322 women and 156 men, mean age 74.5 years) followed in a large AD referral center for a mean of 3.2 years. Eligible participants had a baseline estimate of premorbid IQ using the American version of the Nelson Adult Reading Test (AMNART) and at least one follow-up visit with complete neuropsychological assessment. We used random effects linear regression analysis, and Cox proportional hazards analysis to determine whether or not education and/or premorbid IQ were independently associated with cognitive decline, global progression of AD, and survival. Results: When the baseline AMNART score was included in regression models along with education and other demographic variables, AMNART score, but not education, was associated with a higher baseline score and slower rate of decline in MMSE and ADAS-Cog scores, and the Clinical Dementia Rating sum of boxes score. Neither higher premorbid IQ nor higher education was associated with longer survival. Conclusions: We conclude that a baseline AMNART score is a better predictor of cognitive change in AD than education, but neither variable is associated with survival after diagnosis.

Pre-Morbid Body Mass Index and Mortality After Incident Heart Failure: The ARIC Study

BACKGROUNDnAlthough obesity is an independent risk factor for heart failure (HF), once HF is established, obesity is associated with lower mortality. It is unclear if the weight loss due to advanced HF leads to this paradoxical finding.nnnOBJECTIVESnThis study sought to evaluate the prognostic impact of pre-morbid obesity in patients with HF.nnnMETHODSnIn the ARIC (Atherosclerosis Risk In Communities) study, we used body mass index (BMI) measured ≥6 months before incident HF (pre-morbid BMI) to evaluate the association of overweight (BMI 25 to <30 kg/m(2)) and obesity (BMI ≥30 kg/m(2)) compared with normal BMI (18.5 to <25 kg/m(2)) with mortality after incident HF.nnnRESULTSnAmong 1,487 patients with incident HF, 35% were overweight and 47% were obese by pre-morbid BMI measured 4.3 ± 3.1 years before HF diagnosis. Over 10-year follow-up after incident HF, 43% of patients died. After adjustment for demographics and comorbidities, being pre-morbidly overweight (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.58 to 0.90; p = 0.004) or obese (HR: 0.70; 95% CI: 0.56 to 0.87; p = 0.001) had a protective association with survival compared with normal BMI. The protective effect of overweight and obesity was consistent across subgroups on the basis of a history of cancer, smoking, and diabetes.nnnCONCLUSIONSnOur results, for the first time, demonstrate that patients who were overweight or obese before HF development have lower mortality after HF diagnosis compared with normal BMI patients. Thus, weight loss due to advanced HF may not completely explain the protective effect of higher BMI in HF patients.

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.

Apolipoprotein E Polymorphism and Age at Onset of Alzheimer’s Disease in a Quadriethnic Sample

Background: The relationship between the apolipoprotein E (ApoE) genotype and the risk for developing Alzheimer’s disease (AD) or age at onset of AD is relatively well established in Caucasians, but less established in other ethnicities. We examined the association between the ApoE genotype and age at onset of AD in a quadriethnic group of community-dwelling AD patients. Methods: AD patients were evaluated at 2 university-based outpatient memory disorder clinics. The ethnic distribution was as follows: Caucasians (n = 1,083), Hispanics (n = 55), African Americans (n = 84) and Koreans (n = 87). All were diagnosed with probable AD according to NINCDS-ADRDA diagnostic criteria. Results: After adjusting for ethnicity, the Ε4 allele was significantly associated with earlier age at onset (p < 0.0001) for the combined group. Within ethnic groups, the effect of Apo Ε4 on age at onset was significant in Caucasians (p < 0.0001) and African Americans (p < 0.05), but nonsignificant in Koreans (p = 0.43) and in the smaller Hispanic (p = 0.07) group. Conclusions: The association between Apo Ε4 and younger age at onset was significant in Caucasians and African Americans, where the Ε4 allele was also most frequent. This study suggests that the impact of ApoE polymorphism on age at onset of AD may be different among distinct ethnic groups.

Correction: Predicting progression of Alzheimer's disease

It has been brought to our attention that Figure 7 in our recently published paper [1] contains a labeling error. The group marked slow should be labeled fast and the group marked fast should be labeled slow. The corrected figure 7 is given here as Figure u200bFigure11. n n n nFigure 1 n nKaplan-Meier Survival curves by pre-progression group adjusted for age and sex. HR for slow vs. fast = 0.62 (P = 0.024).