Different Cognitive Profiles Are Associated with Progression Rate and Age at Death in Probable Alzheimer's Disease.

BACKGROUND: Cognitive profiles characterized by primarily language or visuospatial deficits have been documented in individuals meeting diagnostic criteria for probable Alzheimer's disease (AD), but their association with progression rate or overall survival is not well described. OBJECTIVE: To compare time from diagnosis to severe disease stage and death in probable AD patients classified into three groups based on neuropsychological test performance: marked verbal impairment (Verb-PI) with relatively preserved visuospatial function, marked visuospatial impairment with preserved verbal function (Vis-PI), and balanced verbal and visuospatial impairments (Bal-PI). METHODS: This prospective cohort study included 540 probable AD patients attending an academic memory clinic who were enrolled from 1995-2013 and followed annually. Eligible individuals had a Mini-Mental State Exam (MMSE) score ≥10 at baseline, and at least one annual follow up visit. We used Cox proportional hazards modeling to analyze the association of cognitive profiles with time to decline in MMSE and CDR Global Score. RESULTS: Sixty-one (11.3%) individuals had a Verb-PI profile, 86 (16%) had a Vis-PI profile, and 393 (72.8%) a Bal-PI profile. MMSE decline to <10 was faster in Verb-PI than Vis-PI (HR 2.004, 95%CI, 1.062-3.780; p = 0.032). Progression to CDR-GS = 3 was faster in Verb-PI individuals compared to Bal-PI (HR 1.604, 95%CI, 1.022-2.515; p = 0.040) or Vis-PI (HR 2.388, 95%CI, 1.330-4.288; p = 0.004) individuals. Baseline cognitive profile did not affect mortality. CONCLUSION: A recognition of different AD profiles may help to personalize care by providing a better understanding of pathogenesis and expected progression.

Cohort Effects in Progression Rate on Cognitive and Functional Measures in an Alzheimer's Disease Clinical Cohort.

BACKGROUND: Accurate prediction of Alzheimer's disease (AD) cognitive and functional outcomes in clinical research requires consistent underlying rates of change over time. OBJECTIVE: To examine cohort effects in AD progression rate over five years of follow-up using a clinical database of probable AD patients. METHODS: Baseline characteristics of three cohorts enrolled from 1995-1999, 2000-2004, and 2005-2009 were compared using ANOVA and chi-square tests. Differences in 5-year decline on the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), the Lawton and Brody Physical Self-maintenance Scale (PSMS), and Activities of Daily Living Scale (ADL) were assessed using longitudinal mixed effects regression, adjusting for age, sex, education, and other relevant clinical characteristics. RESULTS: Cohorts 1 (n = 287), 2 (n = 257), and 3 (n = 374) did not differ on age, race, APOE genotype, or cognitive and functional measures. Educational attainment increased over time (13.4, 14.1, and 14.5 years, respectively, p < 0.001). Anti-dementia drug use at baseline was less common in Cohort 1 (32.2% versus 65.0%, and 66.8%, p < 0.001). The rate of decline in MMSE and CDR-SB did not differ across cohorts. ADAS-Cog scores for Cohort 2 declined more slowly than Cohort 3 (Btime ×cohort2 = -0.91 ± 0.35, p = 0.009), whereas Cohort 1 did not differ from cohort 3 (reference). Cohorts 1 and 2 differed from Cohort 3 in progression rate on the PSMS, but not the IADL. CONCLUSIONS: There were no consistent temporal trends in progression rates over time. Longitudinal data over 15-20 years may be confidently pooled for outcomes analysis, but unexplained variability in rate of decline on some measures may occur.

Factors that influence survival in a probable Alzheimer disease cohort.

INTRODUCTION: This longitudinal study examined multiple factors that influence survival in a cohort of Alzheimer patients followed over two decades. METHODS: Time 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. RESULTS: Baseline 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). CONCLUSIONS: In 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.

Plasma sphingomyelins are associated with cognitive progression in Alzheimer's disease.

Plasma sphingolipids have been shown to predict cognitive impairment and hippocampal volume loss, but there is little research in patients with Alzheimer's disease (AD). In this study we sought to determine whether plasma ceramides, dihydroceramides (DHCer), sphingomyelins (SM), or dihydrosphingomyelin (DHSM) levels and ratios of SM/ceramide or DHSM/DHCer were predictive of progression in AD. Probable AD patients (n = 120) were enrolled in the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine. Plasma sphingolipids were assessed using ESI/MS/MS. Linear mixed effects models were used to examine the relation between baseline plasma sphingolipid levels and cross-sectional and longitudinal performance on the Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating-Sum of Boxes (CDR-Sum). Participants were followed a mean of 4.2 visits and 2.3 years. There were no cross-sectional associations. In longitudinal analyses, high levels of DHCer and ceramide were associated with greater progression, but findings did not reach significance (p > 0.05). In contrast, higher plasma levels of SM, DHSM, SM/ceramide, and DHSM/DHCer ratios were associated with less progression on the MMSE and ADAS-Cog; the ratios were the strongest predictors of clinical progression. Compared to the lowest tertiles, the highest tertiles of DHSM/DHCer and SM/ceramide ratios declined 1.35 points (p = 0.001) and 1.19 (p = 0.004) points less per year on the MMSE and increased 3.18 (p = 0.001) and 2.42 (p = 0.016) points less per year on the ADAS-Cog. These results suggest that increased SM/ceramide and DHSM/DHCer ratios dose-dependently predict slower progression among AD patients and may be sensitive blood-based biomarkers for clinical progression.

Predicting progression of Alzheimer's disease.

INTRODUCTION: Clinicians need to predict prognosis of Alzheimer's 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. METHODS: We 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. RESULTS: Patients 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). CONCLUSIONS: A 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 Alzheimer's disease clinical trials.

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.

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

INTRODUCTION: There 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. METHODS: Six 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), Alzheimer's 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. RESULTS: PI 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). CONCLUSIONS: Persistent 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.

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>or=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.