Eveleen Darby

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.

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 Alzheimers 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 Alzheimers 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), Alzheimers 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

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.

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.

Total Cholesterol and Neuropsychiatric Symptoms in Alzheimer's Disease: The Impact of Total Cholesterol Level and Gender

Background: Neuropsychiatric symptoms (NPS) in Alzheimers disease (AD) are a major factor in nursing home placement and a primary cause of stress for caregivers. Elevated cholesterol has been linked to psychiatric disorders and has been shown to be a risk factor for AD and to impact disease progression. The present study investigated the relationship between cholesterol and NPS in AD. Methods: Data on cholesterol and NPS from 220 individuals (144 females, 76 males) with mild-to-moderate AD from the Texas Alzheimers Research and Care Consortium (TARCC) cohort were analyzed. The total number of NPS and symptoms of hyperactivity, psychosis, affect and apathy were evaluated. Groups based on total cholesterol (TC; ≥200 vs. <200 mg/dl) were compared with regard to NPS. The impact of gender was also assessed. Results: Individuals with high TC had lower MMSE scores as well as significantly more NPS and more symptoms of psychosis. When stratified by gender, males with high TC had significantly more NPS than females with high TC or than males or females with low TC. Conclusion: The role of elevated cholesterol in the occurrence of NPS in AD appears to be gender and symptom specific. A cross-validation of these findings will have implications for possible treatment interventions, especially for males with high TC.

Odorant Item Specific Olfactory Identification Deficit May Differentiate Alzheimer Disease From Aging

OBJECTIVES To explore whether the ability to recognize specific odorant items is differentially affected in aging versus Alzheimer disease (AD); to refine olfactory identification deficit (OID) as a biomarker of prodromal and early AD. DESIGN Prospective multicenter cross-sectional study with a longitudinal arm. SETTING Outpatient memory diagnostic clinics in New York and Texas. PARTICIPANTS Adults aged 65 and older with amnestic mild cognitive impairment (aMCI) and AD and healthy aging (HA) subjects in the comparison group. MEASUREMENTS Participants completed the University of Pennsylvania Smell Identification Test (UPSIT) and neuropsychological testing. AD-associated odorants (AD-10) were selected based on a model of ordinal logistic regression. Age-associated odorants (Age-10) were identified using a linear model. RESULTS For the 841 participants (234 HA, 192 aMCI, 415 AD), AD-10 was superior to Age-10 in separating HA and AD. AD-10 was associated with a more widespread cognitive deficit across multiple domains, in contrast to Age-10. The disease- and age-associated odorants clustered separately in age and AD. AD-10 predicted conversion from aMCI to AD. CONCLUSIONS Nonoverlapping UPSIT items were identified that were individually associated with age and disease. Despite a modest predictive value of the AD-specific items for conversion to AD, the AD-specific items may be useful in enriching samples to better identify those at risk for AD. Further studies are needed with monomolecular and unilateral stimulation and orthogonal biomarker validation to further refine disease- and age-associated signals.

TWENTY-YEAR TRENDS IN PROPORTIONAL MORTALITY IN A PROBABLE AD COHORT

impairment. Many of these contain neurotoxic and carcinogenic properties known to cause cancer, reproductive problems, and central nervous system impairments that have been linked to Alzheimer’s disease. Nail salon technicians are continuously exposed to them, and this exposure may occur at greater frequency and at higher levels than in other occupational settings. This research aims to examine the association of neurotoxin-exposure with mild cognitive impairment among Vietnamese female nail technicians aged 50 or above in the Northern California areas. Methods: Quasi-experimental interviews were conducted with 45 Vietnamese female nail technicians to assess the association between mild cognitive impairment and early dementia (e.g. MOCA) with occupational exposure (e.g. years of employment, work hours per week), demographics (e.g. education, age), depression (e.g. CESD scale) and acculturation level (e.g. US citizenship). Results: Multiple regression analysis revealed that among Vietnamese female nail technicians, level of education (b 1⁄4 1.36, p 1⁄4 0.010) and depression (b 1⁄4 -4.22, p 1⁄4 0.007) significantly predict mild cognitive impairment. Work hours per week (b 1⁄4 2.53, p 1⁄4 0.065) and having US citizenship (b 1⁄4 -3.79, p 1⁄4 0.63) are also marginally significant. Conclusions: Preliminary results from Year 1 show that Vietnamese female nail technicians may be at risk for mild cognitive impairment. Explanations for why working more hours are positively associated with higher MOCA score will be discussed. Research is funded by the Alzheimer’s Association.