Verbal Fluency Predicts Mortality in Alzheimer Disease

OBJECTIVES: To assess the predictive value of neuropsychologic profiles, at diagnosis, for mortality in incident Alzheimer disease (AD). BACKGROUND: Rate of AD progression varies significantly across individuals for reasons that are not well understood. Several studies have linked rapid decline with disproportionately impaired executive functioning, presumably reflecting greater impairment of frontal networks. To the extent that differential neuropsychologic profiles reflect various neuropathologic presentations of AD, such profiles may inform survival estimates early in the disease. METHODS: Five neuropsychologic indices were used to characterize performance in 161 individuals at diagnosis of AD during a 15-year, longitudinal, primarily community-based study. RESULTS: Fifty-two percent of participants reached the mortality end point with a median survival of 5.52 years (95% confidence interval, 4.41-6.63). Cox proportional hazards analyses indicated that older age at diagnosis was associated with higher risk of mortality (risk ratios, 1.08; 95% confidence interval, 1.04-1.12) whereas Hispanic ethnicity predicted lower mortality [0.22 (0.09-0.55)]. Controlling for these 2 demographic variables, higher verbal fluency scores at diagnosis predicted lower mortality [0.69 (0.49-0.96)]. CONCLUSIONS: Disproportionate impairment of both category and letter fluency at the earliest stages of AD predicts mortality. The prognostic value of these tests may derive from their general psychometric properties, or may reflect the measures' sensitivity to an early or critical level of compromise to frontal networks

Extrapyramidal Signs Before and After Diagnosis of Incident Alzheimer Disease in a Prospective Population Study

Background: Extrapyramidal signs (EPSs) are commonly accepted as a feature of Alzheimer disease (AD) and may influence both the profile of impairment and prognosis. Objective: To examine rates of occurrence and risk factors for all types of EPSs and to describe the impact of EPSs over time on the clinical course of AD. Design: Longitudinal study. Setting: The Washington Heights Hamilton Heights Inwood Columbia Aging Project. Patients: A total of 388 patients with incident AD (mean age, 79 years; 71.4% female). Outcome Measures: Extrapyramidal signs rated by means of a standardized portion of the Unified Parkinson's Disease Rating Scale; prevalence and incidence rates and cumulative risk for non–drug-induced EPSs; and rates of change in EPSs over time, taking into account potential covariates. Results: Extrapyramidal signs were detected in 12.3% of patients at first evaluation and 22.6% at last evaluation. In a multivariate-adjusted generalized estimating equation model of change, total EPS score increased at an annual rate of 1.3%. Women (relative risk [RR], 1.57; P = .03), older patients (RR, 1.03; P = .02), and those with EPSs at baseline (RR, 2.07; P = .001) had greater rates of cognitive decline. Conclusions: Extrapyramidal signs occur frequently and progress significantly in AD. Patients with incident AD and concomitant EPSs have a greater rate of cognitive decline than do patients with incident AD but without EPSs

Leisure Activity and Cognitive Decline in Incident Alzheimer Disease

Background: High rates of leisure activity have been associated with reduced risk of Alzheimer disease (AD). Objective: To determine whether prediagnosis leisure activity modifies the rate of cognitive decline in patients with AD. Design: Inception cohort followed up longitudinally for a mean of 5.3 years (up to 13.9 years). Setting: Urban community. Participants: A total of 283 patients with incident AD (mean age, 79 years; 56.2% Hispanic and 31.1% African American). Main Outcome Measures: Change in a composite cognitive score from diagnosis on and during the entire study follow-up. Results: In multivariate-adjusted generalized estimating equation models of postdiagnosis change (n = 133), each leisure activity was associated with an additional yearly decline of 0.005 of a z-score unit in cognitive score (P = .17). In models expanded to include cognitive change during study follow-up, including evaluations before and after diagnosis (n = 283), each activity was associated with an additional yearly decline of 0.005 of a z-score unit in cognitive score (P = .03). The association was strongest for intellectual activities. Conclusions: Greater participation in prediagnosis leisure activities, especially intellectual activities, was associated with faster cognitive decline, supporting the hypothesis that the disease course in AD may vary as a function of cognitive reserve

Longitudinal Relationships between Alzheimer Disease Progression and Psychosis, Depressed Mood, and Agitation/Aggression

OBJECTIVES: Behavioral and psychological symptoms of dementia (BPSD) are prevalent in Alzheimer disease (AD) and are related to poor outcomes such as nursing home placement. No study has examined the impact of individual BPSD on dependence, a clinically important feature that reflects changing patient needs and their effect on caregivers. The current study characterized independent cross-sectional and longitudinal relationships between three BPSD (psychosis, depressed mood, and agitation/aggression), cognition, and dependence to better understand the interplay between these symptoms over time. DESIGN: The Predictors Study measured changes in BPSD, cognition, and dependence every 6 months in patients with AD. Cross-sectional and longitudinal relationships between individual BPSD, cognition, and dependence over 6 years were characterized by using multivariate latent growth curve modeling. This approach characterizes independent changes in multiple outcome measures over time. SETTING: Four memory clinics in the United States and Europe. PARTICIPANTS: A total of 517 patients with probable AD. MEASUREMENTS: Columbia University Scale for Psychopathology, modified Mini-Mental State Examination, and Dependence Scale. RESULTS: Both psychosis and depressed mood at study entry were associated with worse subsequent cognitive decline. Independent of cognitive decline, initial psychosis was associated with worse subsequent increases in dependence. Rates of increase in agitation/aggression separately correlated with rates of declines in both cognition and independence. CONCLUSIONS: Although purely observational, our findings support the poor prognosis associated with psychosis and depression in AD. Results also show that agitation/aggression tracks declines in cognition and independence independently over time. Targeted intervention for individual BPSD, particularly psychosis, could have broad effects not only on patient well-being but also on care costs and family burden

Survival in Alzheimer Disease: A Multiethnic, Population-Based Study of Incident Cases

OBJECTIVE: To describe factors associated with survival in Alzheimer disease (AD) in a multiethnic, population-based longitudinal study. METHODS: AD cases were identified in the Washington Heights Inwood Columbia Aging Project, a longitudinal, community-based study of cognitive aging in Northern Manhattan. The sample comprised 323 participants who were initially dementia-free but developed AD during study follow-up (incident cases). Participants were followed for an average of 4.1 (up to 12.6) years. Possible factors associated with shorter lifespan were assessed using Cox proportional hazards models with attained age as the time to event (time from birth to death or last follow-up). In subanalyses, median postdiagnosis survival durations were estimated using postdiagnosis study follow-up as the timescale. RESULTS: The mortality rate was 10.7 per 100 person-years. Mortality rates were higher among those diagnosed at older ages, and among Hispanics compared to non-Hispanic whites. The median lifespan of the entire sample was 92.2 years (95% CI: 90.3, 94.1). In a multivariable-adjusted Cox model, history of diabetes and history of hypertension were independently associated with a shorter lifespan. No differences in lifespan were seen by race/ethnicity after multivariable adjustment. The median postdiagnosis survival duration was 3.7 years among non-Hispanic whites, 4.8 years among African Americans, and 7.6 years among Hispanics. CONCLUSION: Factors influencing survival in Alzheimer disease include race/ethnicity and comorbid diabetes and hypertension

Use and Cost of Hospitalization in Dementia: Longitudinal Results from a Community-Based Study

OBJECTIVES: The aim of this study is to examine the relative contribution of functional impairment and cognitive deficits on risk of hospitalization and costs. METHODS: A prospective cohort of Medicare beneficiaries aged 65 and older who participated in the Washington Heights-Inwood Columbia Aging Project (WHICAP) were followed approximately every 18 months for over 10 years (1805 never diagnosed with dementia during study period, 221 diagnosed with dementia at enrollment). Hospitalization and Medicare expenditures data (1999-2010) were obtained from Medicare claims. Multivariate analyses were conducted to examine (1) risk of all-cause hospitalizations, (2) hospitalizations from ambulatory care sensitive (ACSs) conditions, (3) hospital length of stay (LOS), and (4) Medicare expenditures. Propensity score matching methods were used to reduce observed differences between demented and non-demented groups at study enrollment. Analyses took into account repeated observations within each individual. RESULTS: Compared to propensity-matched individuals without dementia, individuals with dementia had significantly higher risk for all-cause hospitalization, longer LOS, and higher Medicare expenditures. Functional and cognitive deficits were significantly associated with higher risks for hospitalizations, hospital LOS, and Medicare expenditures. Functional and cognitive deficits were associated with higher risks of for some ACS but not all admissions. CONCLUSIONS: These results allow us to differentiate the impact of functional and cognitive deficits on hospitalizations. To develop strategies to reduce hospitalizations and expenditures, better understanding of which types of hospitalizations and which disease characteristics impact these outcomes will be critical

Change in Body Mass Index before and after Alzheimer's Disease Onset

OBJECTIVES: A high body mass index (BMI) in middle-age or a decrease in BMI at late-age has been considered a predictor for the development of Alzheimer's disease (AD). However, little is known about the BMI change close to or after AD onset. METHODS: BMI of participants from three cohorts, the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based), and National Alzheimer's Coordinating Center (NACC; clinic-based) were analyzed longitudinally. We used generalized estimating equations to test whether there were significant changes of BMI over time, adjusting for age, sex, education, race, and research center. Stratification analyses were run to determine whether BMI changes depended on baseline BMI status. RESULTS: BMI declined over time up to AD clinical onset, with an annual decrease of 0.21 (p=0.02) in WHICAP and 0.18 (p=0.04) kg/m2 in NACC. After clinical onset of AD, there was no significant decrease of BMI. BMI even increased (b=0.11, p=0.004) among prevalent AD participants in NACC. During the prodromal period, BMI decreased over time in overweight (BMI>/=25 and /=30) NACC participants. After AD onset, BMI tended to increase in underweight/normal weight (BMI<25) patients and decrease in obese patients in all three cohorts, although the results were significant in NACC study only. CONCLUSIONS: Our study suggests that while BMI declines before the clinical AD onset, it levels off after clinical AD onset, and might even increase in prevalent AD. The pattern of BMI change may also depend on the initial BMI

Physical Activity, Diet, and Risk of Alzheimer Disease

CONTEXT: Both higher adherence to a Mediterranean-type diet and more physical activity have been independently associated with lower Alzheimer disease (AD) risk but their combined association has not been investigated. OBJECTIVE: To investigate the combined association of diet and physical activity with AD risk. DESIGN, SETTING, AND PATIENTS: Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York, with both diet and physical activity information available. Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006. Adherence to a Mediterranean-type diet (scale of 0-9; trichotomized into low, middle, or high; and dichotomized into low or high) and physical activity (sum of weekly participation in various physical activities, weighted by the type of physical activity [light, moderate, vigorous]; trichotomized into no physical activity, some, or much; and dichotomized into low or high), separately and combined, were the main predictors in Cox models. Models were adjusted for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, body mass index, smoking status, depression, leisure activities, a comorbidity index, and baseline Clinical Dementia Rating score. MAIN OUTCOME MEASURE: Time to incident AD. RESULTS: A total of 282 incident AD cases occurred during a mean (SD) of 5.4 (3.3) years of follow-up. When considered simultaneously, both Mediterranean-type diet adherence (compared with low diet score, hazard ratio [HR] for middle diet score was 0.98 [95% confidence interval {CI}, 0.72-1.33]; the HR for high diet score was 0.60 [95% CI, 0.42-0.87]; P = .008 for trend) and physical activity (compared with no physical activity, the HR for some physical activity was 0.75 [95% CI, 0.54-1.04]; the HR for much physical activity was 0.67 [95% CI, 0.47-0.95]; P = .03 for trend) were associated with lower AD risk. Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; HR, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). CONCLUSION: In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD

Contribution of Vascular Risk Factors to the Progression in Alzheimer Disease

Background: Vascular factors including medical history (heart disease, stroke, diabetes, and hypertension), smoking, and prediagnosis blood lipid measurements (cholesterol: total, high-density lipoprotein, low-density lipoprotein [LDL-C], and triglyceride concentrations) may be predictors for progression of Alzheimer disease (AD). Objective: To determine whether prediagnosis vascular risk factors are associated with progression of AD. Design: Inception cohort followed up longitudinally for a mean of 3.5 (up to 10.2) years. Setting: Washington Heights/Inwood Columbia Aging Project, New York, New York. Patients: One hundred fifty-six patients with incident AD (mean age at diagnosis, 83 years). Main Outcome Measure: Change in a composite score of cognitive ability from diagnosis onward. Results: In generalized estimating equation models (adjusted for age, race/ethnicity, and years of education), higher cholesterol (total cholesterol and LDL-C) concentrations and history of diabetes were associated with faster cognitive decline. Each 10-U increase in cholesterol and LDL-C was associated with a 0.10-SD decrease in cognitive score per year of follow-up (P < .001 for total cholesterol; P = .001 for LDL-C). High-density lipoprotein cholesterol and triglyceride concentrations were not associated with rate of decline. A history of diabetes was associated with an additional 0.05-SD decrease in cognitive score per year (P = .05). History of heart disease and stroke were associated with cognitive decline only in carriers of the apolipoprotein E ε4 (APOE-ε4) gene. In a final generalized estimating equation model that included high-density lipoprotein cholesterol and LDL-C concentrations and history of diabetes, only higher LDL-C was independently associated with faster cognitive decline. Conclusion: Higher prediagnosis total cholesterol and LDL-C concentrations and history of diabetes were associated with faster cognitive decline in patients with incident AD, which provides further evidence for the role of vascular risk factors in the course of AD

Mild motor impairment as prodromal state in amyotrophic lateral sclerosis:A new diagnostic entity

Amyotrophic lateral sclerosis, when viewed as a biological entity rather than a clinical syndrome, probably evolves along a continuum, with the initial clinically silent phase eventually evolving into clinically manifest amyotrophic lateral sclerosis. Since motor neuron degeneration is incremental and cumulative over time, it stands to reason that the clinical syndrome of amyotrophic lateral sclerosis is probably preceded by a prodromal state characterized by minor motor abnormalities that are initially insufficient to permit a diagnosis of amyotrophic lateral sclerosis. This prodromal period, however, is usually missed, given the invariably long delays between symptom onset and diagnostic evaluation. The Pre-Symptomatic Familial ALS Study, a cohort study of pre-symptomatic gene mutation carriers, offers a unique opportunity to observe what is typically unseen. Here we describe the clinical characterization of 20 pre-symptomatic mutation carriers (in SOD1, FUS and C9orf72) whose phenoconversion to clinically manifest disease has been prospectively studied. In so doing, we observed a prodromal phase of mild motor impairment in 11 of 20 phenoconverters. Among the n = 12 SOD1 A4V mutation carriers, phenoconversion was characterized by abrupt onset of weakness, with a short (1–3.5 months) prodromal period observable in a small minority (n = 3); the observable prodrome invariably involved the lower motor neuron axis. By contrast, in all n = 3 SOD1 I113T mutation carriers, diffuse lower motor neuron and upper motor neuron signs evolved insidiously during a prodromal period that extended over a period of many years; prodromal manifestations eventually coalesced into a clinical syndrome that is recognizable as amyotrophic lateral sclerosis. Similarly, in all n = 3 C9orf72 hexanucleotide repeat expansion mutation carriers, focal or multifocal manifestations of disease evolved gradually over a prodromal period of 1–2 years. Clinically manifest ALS also emerged following a prodromal period of mild motor impairment, lasting >4 years and ∼9 months, respectively, in n = 2 with other gene mutations (SOD1 L106V and FUS c.521del6). On the basis of this empirical evidence, we conclude that mild motor impairment is an observable state that precedes clinically manifest disease in three of the most common genetic forms of amyotrophic lateral sclerosis (SOD1, FUS, C9orf72), and perhaps in all genetic amyotrophic lateral sclerosis; we also propose that this might be true of non-genetic amyotrophic lateral sclerosis. As a diagnostic label, mild motor impairment provides the language to describe the indeterminate (and sometimes intermediate) transition between the unaffected state and clinically manifest amyotrophic lateral sclerosis. Recognizing mild motor impairment as a distinct clinical entity should generate fresh urgency for developing biomarkers reflecting the earliest events in the degenerative cascade, with potential to reduce the diagnostic delay and to permit earlier therapeutic intervention