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1.  Cognition in Older Women: The Importance of Daytime Movement 
To determine whether an objective measure of daytime movement is associated with better cognitive function in women in their 80s.
Cross-sectional study of 2,736 older women without evidence of dementia participating in a study of health and aging.
Daytime movement was assessed with actigraphy—a watch-like device that objectively quantifies accelerometer motion—over a mean of 3.0 ± 0.8 days. Cognitive function was measured by the Trail-Making Test, Part B (Trails B) and the Mini-Mental State Examination (MMSE). Cognitive impairment was defined as performing > 1.5 standard deviations (SD) worse than the mean on a given test.
Women had a mean age of 83 ± 4 years; 10% were African American. After adjustment for age, race and education, women in the highest versus lowest movement quartiles had better mean cognitive test scores (20 seconds [0.3 SD] faster on Trails B and 0.3 [0.2 SD] points higher on MMSE, both p<0.001) and were less likely to be cognitively impaired (Odds Ratio [95% Confidence Interval]: 0.61 [0.41 to 0.92] for Trails B and 0.68 [0.44 to 1.07] for MMSE). Associations were similar in different subgroups and were independent of self-reported walking, medical comorbidities, physical function and other healthy behaviors.
Daytime movement as measured objectively using actigraphy was associated with better cognitive function and lower odds of cognitive impairment in women in their 80s. Additional studies are needed to clarify the direction of the association and to explore potential mechanisms.
PMCID: PMC2680379  PMID: 18662201
movement; exercise; activity; cognition; risk factor
2.  Mid-life versus late-life depressive symptoms and risk of dementia: Differential effects for Alzheimer’s disease and vascular dementia 
Archives of general psychiatry  2012;69(5):493-498.
Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia.
Objective, Design, Setting and Participants
To clarify the timing and etiology of the association, we examined depressive symptoms assessed in mid-life (1964–1973) and late-life (1994–2000) and the risks of dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) (2003–2009) in a retrospective cohort study of 13,535 long-term Kaiser Permanente members. Depressive symptoms were categorized as none, mid-life only, late-life only or both. Cox proportional hazards models (age as time-scale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD or VaD.
Main Outcome Measure
Any medical record diagnosis of dementia; Neurology clinic diagnosis of AD or VaD.
Subjects had a mean (standard deviation) age of 81 (5) years in 2003; 58% were women and 25% were non-white. Depressive symptoms were present in 14.1% of subjects in mid-life only, 9.2% late-life only, and 4.2% both. Over 6 years, 23.1% were diagnosed with dementia (5.5% AD, 2.3% VaD). The adjusted hazard of dementia was increased by approximately 20% for mid-life depressive symptoms only (Hazard Ratio [95% confidence interval]: 1.19 [1.07, 1.32]), 70% for late-life symptoms only (1.72 [1.54, 1.92]), and 80% for both (1.77 [1.52, 2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a two-fold increase in AD risk (2.06 [1.67, 2.55]) whereas subjects with both mid-life and late-life symptoms had more than a three-fold increase in VaD risk (3.51 [2.44, 5.05]).
Depressive symptoms in mid-life or late-life are associated with an increased risk of developing dementia. Depression that begins in late-life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.
PMCID: PMC3704214  PMID: 22566581
3.  Traumatic brain injury and risk of dementia in older veterans 
Neurology  2014;83(4):312-319.
Traumatic brain injury (TBI) is common in military personnel, and there is growing concern about the long-term effects of TBI on the brain; however, few studies have examined the association between TBI and risk of dementia in veterans.
We performed a retrospective cohort study of 188,764 US veterans aged 55 years or older who had at least one inpatient or outpatient visit during both the baseline (2000–2003) and follow-up (2003–2012) periods and did not have a dementia diagnosis at baseline. TBI and dementia diagnoses were determined using ICD-9 codes in electronic medical records. Fine-Gray proportional hazards models were used to determine whether TBI was associated with greater risk of incident dementia, accounting for the competing risk of death and adjusting for demographics, medical comorbidities, and psychiatric disorders.
Veterans were a mean age of 68 years at baseline. During the 9-year follow-up period, 16% of those with TBI developed dementia compared with 10% of those without TBI (adjusted hazard ratio, 1.57; 95% confidence interval: 1.35–1.83). There was evidence of an additive association between TBI and other conditions on risk of dementia.
TBI in older veterans was associated with a 60% increase in the risk of developing dementia over 9 years after accounting for competing risks and potential confounders. Our results suggest that TBI in older veterans may predispose toward development of symptomatic dementia and raise concern about the potential long-term consequences of TBI in younger veterans and civilians.
PMCID: PMC4115602  PMID: 24966406
5.  Secondhand Smoke, Vascular Disease, and Dementia Incidence: Findings From the Cardiovascular Health Cognition Study 
American Journal of Epidemiology  2010;171(3):292-302.
Recent studies have found that smoking is associated with an increased risk of dementia, but the effects of secondhand smoke (SHS) on dementia risk are not known to have previously been studied. The authors used Cox proportional hazards marginal structural models to examine the association between self-reported lifetime household SHS exposure and risk of incident dementia over 6 years among 970 US participants in the Cardiovascular Health Cognition Study (performed from 1991 to 1999) who were never smokers and were free of clinical cardiovascular disease (CVD), dementia, and mild cognitive impairment at baseline. In addition, because prior studies have found that SHS is associated with increased risk of CVD and that CVD is associated with increased risk of dementia, the authors tested for interactions between SHS and measures of clinical and subclinical CVD on dementia risk. Moderate (16–25 years) and high (>25 years) SHS exposure levels were not independently associated with dementia risk; however, subjects with >25 years of SHS exposure and >25% carotid artery stenosis had a 3-fold increase (hazard ratio = 3.00, 95% confidence interval: 1.03, 9.72) in dementia risk compared with subjects with no/low (0–15 years) SHS exposure and ≤25% carotid artery stenosis. High lifetime SHS exposure may increase the risk of dementia in elderly with undiagnosed CVD.
PMCID: PMC2878108  PMID: 20051462
aged; dementia; longitudinal studies; models, statistical; tobacco smoke pollution
6.  Computer-Based Cognitive Training for Mild Cognitive Impairment: Results from a Pilot Randomized, Controlled Trial 
We performed a pilot randomized, controlled trial of intensive, computer-based cognitive training in 47 subjects with mild cognitive impairment (MCI). The intervention group performed exercises specifically designed to improve auditory processing speed and accuracy for 100 minutes/day, 5 days/week for 6 weeks; the control group performed more passive computer activities (reading, listening, visuospatial game) for similar amounts of time. Subjects had a mean age of 74 years and 60% were men; 77% successfully completed training. On our primary outcome, Repeatable Battery for Assessment of Neuropsychological Status (RBANS) total scores improved 0.36 standard deviations (SD) in the intervention group (p=0.097) compared to 0.03 SD in the control group (p=0.88) for a non-significant difference between the groups of 0.33 SD (p=0.26). On 12 secondary outcome measures, most differences between the groups were not statistically significant. However, we observed a pattern in which effect sizes for verbal learning and memory measures tended to favor the intervention group while effect sizes for language and visuospatial function measures tended to favor the control group, which raises the possibility that these training programs may have domain-specific effects. We conclude that intensive, computer-based mental activity is feasible in subjects with MCI and that larger trials are warranted.
PMCID: PMC2760033  PMID: 19812460
human; aged; cognition; cognitive rehabilitation; memory; neuropsychological tests; randomized controlled trial; mild cognitive impairment
7.  A Novel Website to Prepare Diverse Older Adults for Decision Making and Advance Care Planning: A Pilot Study 
We have reconceptualized advance care planning (ACP) as a multi-step process focused on preparing patients with skills needed for communication and in-the-moment decision making.
To operationalize this paradigm, we created an easy-to-use ACP website ( based on a theoretical framework of behavior change and pilot-tested its efficacy to engage older adults in ACP.
At baseline and one week after viewing the PREPARE website, we assessed behavior change in ACP using a validated survey that includes Process Measures (knowledge, contemplation, self-efficacy, and readiness, 5-point Likert scales) and Action Measures (yes/no whether an ACP behavior was completed). We also assigned participants into behavior change stages (i.e., precontemplation, contemplation, preparation, action, maintenance) and determined the percentage of participants who moved from precontemplation at baseline to higher stages at one week. We also assessed PREPARE ease-of-use (10-point scale, 10 being the easiest). Changes were assessed with paired t-tests and McNemar’s tests.
Participants’ mean age was 68.4 years (SD 6.6) and 65% were non-white. Process Measures average Likert scores increased from 3.1 (0.9) to 3.7 (0.7), P <0.001. Action Measures did not change significantly. However, precontemplation significantly decreased for most actions, (e.g., talking to doctor about desired medical care, 61% to 35%, P<0.003), with a mean decrease of 21% (range, 16%-33%). PREPARE was rated a 9 out of 10 (±1.9) for ease-of-use.
A new, patient-centered ACP website that focuses on preparing patients for communication and decision making significantly improves engagement in the process of ACP and behavior change. A clinical trial of PREPARE is currently underway.
PMCID: PMC4111443  PMID: 23972574
Advance care planning; medical decision making; aging; technology
8.  Effect of Exercise and Cognitive Activity on Self-Reported Sleep Quality in Community-Dwelling Older Adults with Cognitive Complaints: A Randomized Controlled Trial 
To compare the effects of different types of physical and mental activity on self-reported sleep quality over 12 weeks in older adults with cognitive and sleep complaints.
Randomized controlled trial.
General community.
Seventy-two inactive community-dwelling older adults with self-reported sleep and cognitive problems (mean age 73.3±6.1; 60% women).
Random allocation to four arms using a two-by-two factorial design: aerobic+cognitive training, aerobic+educational DVD, stretching+cognitive training, and stretching+educational DVD arms (60 min/d, 3 d/wk for physical and mental activity for 12 weeks).
Change in sleep quality using seven questions from the Sleep Disorders Questionnaire on the 2005–06 National Health and Nutrition Examination Survey (range 0–28, with higher scores reflecting worse sleep quality). Analyses used intention-to-treat methods.
Sleep quality scores did not differ at baseline, but there was a significant difference between the study arms in change in sleep quality over time (p<.005). Mean sleep quality scores improved significantly more in the stretching+educational DVD arm (5.1 points) than in the stretching+cognitive training (1.2 points), aerobic+educational DVD (1.1 points), or aerobic+cognitive training (0.25 points) arm (all p<.05, corrected for multiple comparisons). Differences between arms were strongest for waking at night (p=.02) and taking sleep medications (p=.004).
Self-reported sleep quality improved significantly more with low-intensity physical and mental activities than with moderate- or high-intensity activities in older adults with self-reported cognitive and sleep difficulties. Future longer-term studies with objective sleep measures are needed to corroborate these results.
PMCID: PMC4356237  PMID: 25516028
physical activity; cognition; sleep; aging; intervention
9.  Preventing Loss of Independence through Exercise (PLIÉ): A Pilot Clinical Trial in Older Adults with Dementia 
PLoS ONE  2015;10(2):e0113367.
Current dementia medications have small effect sizes, many adverse effects and do not change the disease course. Therefore, it is critically important to study alternative treatment strategies. The goal of this study was to pilot-test a novel, integrative group exercise program for individuals with mild-to-moderate dementia called Preventing Loss of Independence through Exercise (PLIÉ), which focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection.
We performed a 36-week cross-over pilot clinical trial to compare PLIÉ with usual care (UC) at an adult day program for individuals with dementia in San Francisco, CA. Assessments of physical performance, cognitive function, physical function, dementia-related behaviors, quality of life and caregiver burden were performed by blinded assessors at baseline, 18 weeks (cross-over) and 36 weeks. Our primary outcomes were effect sizes based on between-group comparisons of change from baseline to 18 weeks; secondary outcomes were within-group comparisons of change before and after cross-over.
Twelve individuals enrolled (7 PLIÉ, 5 UC) and 2 withdrew (1 PLIÉ, 18 weeks; 1 UC, 36 weeks). Participants were 82% women (mean age, 84 ± 4 years); caregivers were 82% daughters (mean age, 56 ± 13 years). Effect sizes were not statistically significant but suggested potentially clinically meaningful (≥0.25 SDs) improvement with PLIÉ versus UC for physical performance (Cohen’s D: 0.34 SDs), cognitive function (0.76 SDs) and quality of life (0.83 SDs) as well as for caregiver measures of participant’s quality of life (0.33 SDs) and caregiver burden (0.49 SDs). Results were similar when within-group comparisons were made before and after cross-over.
PLIÉ is a novel, integrative exercise program that shows promise for improving physical function, cognitive function, quality of life and caregiver burden in individuals with mild-to-moderate dementia. Larger randomized, controlled trials are warranted.
Trial Registration NCT01371214
PMCID: PMC4324943  PMID: 25671576
10.  A Clinical Index to Predict Progression from Mild Cognitive Impairment to Dementia Due to Alzheimer's Disease 
PLoS ONE  2014;9(12):e113535.
Mild cognitive impairment is often a precursor to dementia due to Alzheimer's disease, but many patients with mild cognitive impairment never develop dementia. New diagnostic criteria may lead to more patients receiving a diagnosis of mild cognitive impairment.
To develop a prediction index for the 3-year risk of progression from mild cognitive impairment to dementia relying only on information that can be readily obtained in most clinical settings.
Design and Participants
382 participants diagnosed with amnestic mild cognitive impairment enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI), a multi-site, longitudinal, observational study.
Main Predictors Measures
Demographics, comorbid conditions, caregiver report of participant symptoms and function, and participant performance on individual items from basic neuropsychological scales.
Main Outcome Measure
Progression to probable Alzheimer's disease.
Key Results
Subjects had a mean (SD) age of 75 (7) years and 43% progressed to probable Alzheimer's disease within 3 years. Important independent predictors of progression included being female, resisting help, becoming upset when separated from caregiver, difficulty shopping alone, forgetting appointments, number of words recalled from a 10-word list, orientation and difficulty drawing a clock. The final point score could range from 0 to 16 (mean [SD]: 4.2 [2.9]). The optimism-corrected Harrell's c-statistic was 0.71(95% CI: 0.68–0.75). Fourteen percent of subjects with low risk scores (0–2 points, n = 124) converted to probable Alzheimer's disease over 3 years, compared to 51% of those with moderate risk scores (3–8 points, n = 223) and 91% of those with high risk scores (9–16 points, n = 35).
An index using factors that can be obtained in most clinical settings can predict progression from amnestic mild cognitive impairment to probable Alzheimer's disease and may help clinicians differentiate between mild cognitive impairment patients at low vs. high risk of progression.
PMCID: PMC4259326  PMID: 25486250
11.  Recovery, Dependence or Death After Discharge 
PMCID: PMC3579963  PMID: 23435831
Archives of internal medicine  2011;171(14):1251-1257.
Studies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on subjective self-reports of physical activity, which only moderately correlate to objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment.
We calculated AEE as 90% of total energy expenditure (assessed over two weeks using doubly-labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998–2000). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination (3MS). Cognitive impairment was defined as a decline of >1.0 SD (9 points) between baseline and follow-up.
After adjustment for baseline 3MS, demographics, fat free mass, sleep duration, self-reported health, and diabetes, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (OR, 95% CI 0.09, 0.01–0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (p-for-trend over tertiles=0.05).
These findings indicate that greater activity energy expenditure may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined.
PMCID: PMC3923462  PMID: 21771893
13.  Prediction of Recovery, Dependence or Death in Elders Who Become Disabled During Hospitalization 
Many older adults become dependent in one or more activities of daily living (ADLs: dressing, bathing, transferring, eating, toileting) when hospitalized, and their prognosis after discharge is unclear.
To develop a prognostic index to estimate one-year probabilities of recovery, dependence or death in older hospitalized patients who are discharged with incident ADL dependence.
Retrospective cohort study.
449 adults aged ≥ 70 years hospitalized for acute illness and discharged with incident ADL dependence.
Potential predictors included demographics (age, sex, race, education, marital status), functional measures (ADL dependencies, instrumental activities of daily living [IADL] dependencies, walking ability), chronic conditions (e.g., congestive heart failure, dementia, cancer), reason for admission (e.g., neurologic, cardiovascular), and laboratory values (creatinine, albumin, hematocrit). Multinomial logistic regression was used to develop a prognostic index for estimating the probabilities of recovery, disability or death over 1 year. Discrimination of the index was assessed for each outcome based on the c statistic.
During the year following hospitalization, 36 % of patients recovered, 27 % remained dependent and 37 % died. Key predictors of recovery, dependence or death were age, sex, number of IADL dependencies 2 weeks prior to admission, number of ADL dependencies at discharge, dementia, cancer, number of other chronic conditions, reason for admission, and creatinine levels. The final prognostic index had good to excellent discrimination for all three outcomes based on the c statistic (recovery: 0.81, dependence: 0.72, death: 0.78).
This index accurately estimated the probabilities of recovery, dependence or death in adults aged 70 years or older who were discharged with incident disability following hospitalization. This tool may be useful in clinical settings to guide care discussions and inform decision-making related to post-hospitalization care.
PMCID: PMC3614138  PMID: 23054919
functional status; disability; mortality; hospitalization; prognosis
14.  Acute Care For Elders Units Produced Shorter Hospital Stays At Lower Cost While Maintaining Patients’ Functional Status 
Health affairs (Project Hope)  2012;31(6):10.1377/hlthaff.2012.0142.
Acute Care for Elders Units offer enhanced care for older adults in specially designed hospital units. The care is delivered by interdisciplinary teams, which can include geriatricians, advanced practice nurses, social workers, pharmacists, and physical therapists. In a randomized controlled trial of 1,632 elderly patients, length-of-stay was significantly shorter—6.7 days per patient versus 7.3 days per patient—among those receiving care in the Acute Care for Elders Unit compared to usual care. This difference produced lower total inpatient costs—$9,477 per patient versus $10,451 per patient—while maintaining patients’ functional abilities and not increasing hospital readmission rates. The practices of Acute Care for Elders Units, and the principles they embody, can provide hospitals with effective strategies for lowering costs while preserving quality of care for hospitalized elders.
PMCID: PMC3870859  PMID: 22665834
15.  Development and Validation of a Questionnaire to Detect Behavior Change in Multiple Advance Care Planning Behaviors 
PLoS ONE  2013;8(9):e72465.
Advance directives have traditionally been considered the gold standard for advance care planning. However, recent evidence suggests that advance care planning involves a series of multiple discrete behaviors for which people are in varying stages of behavior change. The goal of our study was to develop and validate a survey to measure the full advance care planning process.
The Advance Care Planning Engagement Survey assesses “Process Measures” of factors known from Behavior Change Theory to affect behavior (knowledge, contemplation, self-efficacy, and readiness, using 5-point Likert scales) and “Action Measures” (yes/no) of multiple behaviors related to surrogate decision makers, values and quality of life, flexibility for surrogate decision making, and informed decision making. We administered surveys at baseline and 1 week later to 50 diverse, older adults from San Francisco hospitals. Internal consistency reliability of Process Measures was assessed using Cronbach's alpha (only continuous variables) and test-retest reliability of Process and Action Measures was examined using intraclass correlations. For discriminant validity, we compared Process and Action Measure scores between this cohort and 20 healthy college students (mean age 23.2 years, SD 2.7).
Mean age was 69.3 (SD 10.5) and 42% were non-White. The survey took a mean of 21.4 minutes (±6.2) to administer. The survey had good internal consistency (Process Measures Cronbach's alpha, 0.94) and test-retest reliability (Process Measures intraclass correlation, 0.70; Action Measures, 0.87). Both Process and Action Measure scores were higher in the older than younger group, p<.001.
A new Advance Care Planning Engagement Survey that measures behavior change (knowledge, contemplation, self-efficacy, and readiness) and multiple advance care planning actions demonstrates good reliability and validity. Further research is needed to assess whether survey scores improve in response to advance care planning interventions and whether scores are associated with receipt of care consistent with one's wishes.
PMCID: PMC3764010  PMID: 24039772
16.  Dysthymia and Depression Increase Risk of Dementia and Mortality among Older Veterans 
To determine if less severe depression spectrum diagnoses such as dysthymia, as well as depression, are associated with risk of developing dementia and mortality in a “real world” setting.
Retrospective cohort study conducted using the Department of Veterans Affairs (VA) National Patient Care Database (1997-2007).
VA medical centers in the United States.
A total of 281,540 veterans 55 years and older without dementia at study baseline (1997-2000).
Depression status and incident dementia were ascertained from ICD-9 codes during study baseline (1997-2000) and follow-up (2001-2007), respectively. Mortality was ascertained by time of death dates in the VA Vital Status File.
Ten percent of veterans had baseline diagnosis of depression and nearly 1% had dysthymia. The unadjusted incidence of dementia was 11.2% in veterans with depression, 10.2% with dysthymia and 6.4% with neither. After adjusting for demographics and comorbidities, patients diagnosed with dysthymia or depression were twice as likely to develop incident dementia compared to those with no dysthymia/depression (adjusted dysthymia hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.71-2.25; and depression HR: 2.18, 95% CI: 2.08-2.28). Dysthymia and depression also were associated with increased risk of death (31.6% dysthymia and 32.9% depression vs 28.5% neither; adjusted dysthymia HR: 1.41, 95% CI: 1.31-1.53; and depression HR: 1.47, 95% CI: 1.43-1.51).
Findings suggest that older adults with dysthymia or depression need to be monitored closely for adverse outcomes. Future studies should determine whether treatment of depression spectrum disorders may reduce risk of these outcomes.
PMCID: PMC3229643  PMID: 21597358
Dysthymia; Depression; Dementia; Mortality
17.  Physical Activity Over the Life Course and its Association with Cognitive Performance and Impairment in Old Age 
To determine how physical activity at various ages over the life course is associated with cognitive impairment in late life.
Cross-sectional study
Four US sites.
We administered a modified Mini-Mental State Examination (mMMSE) to 9344 women ≥65 years (mean 71.6 years) who self-reported teenage, age 30, age 50, and late life physical activity.
We used logistic regressions to determine the association between physical activity status at each age and likelihood of cognitive impairment (mMMSE score >1.5SD below the mean, mMMSE≤22). Models were adjusted for age, education, marital status, diabetes, hypertension, depressive symptoms, smoking, and body mass index.
Women who reported being physically active had lower prevalence of cognitive impairment in late life compared to women who were inactive at each time (teenage: 8.5% vs. 16.7%; adjusted Odds Ratio (95% Confidence Interval): 0.65 (0.53–0.80); age 30: 8.9% vs. 12.0%; 0.80 (0.67–0.96); age 50: 8.5% vs. 13.1%; 0.71 (0.59–0.85); old age: 8.2% vs. 15.9%; 0.74 (0.61–0.91)). When the four times were analyzed together, teenage physical activity was most strongly associated with lower odds of late-life cognitive impairment (OR=0.73 (0.58–0.92)). However, women who were physically inactive at teenage and became active in later life had lower risk than those who remained inactive.
Women who reported being physically active at any point over the life course, and especially at teenage, have lower likelihood of cognitive impairment in late life. Interventions should promote physical activity early in life and throughout the life course.
PMCID: PMC3662219  PMID: 20609030
Physical Activity; Exercise; Cognition; Cognitive Impairment; Life Course
18.  Predicting Alzheimer's risk: why and how? 
Because the pathologic processes that underlie Alzheimer's disease (AD) appear to start 10 to 20 years before symptoms develop, there is currently intense interest in developing techniques to accurately predict which individuals are most likely to become symptomatic. Several AD risk prediction strategies - including identification of biomarkers and neuroimaging techniques and development of risk indices that combine traditional and non-traditional risk factors - are being explored. Most AD risk prediction strategies developed to date have had moderate prognostic accuracy but are limited by two key issues. First, they do not explicitly model mortality along with AD risk and, therefore, do not differentiate individuals who are likely to develop symptomatic AD prior to death from those who are likely to die of other causes. This is critically important so that any preventive treatments can be targeted to maximize the potential benefit and minimize the potential harm. Second, AD risk prediction strategies developed to date have not explored the full range of predictive variables (biomarkers, imaging, and traditional and non-traditional risk factors) over the full preclinical period (10 to 20 years). Sophisticated modeling techniques such as hidden Markov models may enable the development of a more comprehensive AD risk prediction algorithm by combining data from multiple cohorts. As the field moves forward, it will be critically important to develop techniques that simultaneously model the risk of mortality as well as the risk of AD over the full preclinical spectrum and to consider the potential harm as well as the benefit of identifying and treating high-risk older patients.
PMCID: PMC3308022  PMID: 22126363
19.  Neuropsychiatric Symptoms in Mild Cognitive Impairment: Differences by Subtype and Progression to Dementia 
Neuropsychiatric symptoms (NPS) are common in patients with mild cognitive impairment (MCI). Little is known, however, about how NPS vary by MCI subtype (i.e., amnestic, single domain non-memory, and multiple domain). In addition, it is unclear whether NPS increase risk of progression to dementia. We investigated the distribution of NPS across MCI subtypes and determined whether NPS increase risk of progression to dementia.
Participants were 521 patients diagnosed with MCI at the Alzheimer's Research Centers of California between 1988 and 1999. At baseline, patients were classified into MCI subtypes and were assessed for NPS.
The mean number of NPS was 2.3 (range 0-9.6; 74% had ≥ 1 NPS). Patients with ≥ 4 NPS had more medical comorbidities and greater functional impairment (p ≤ 0.0001 for both). Patients with ≥ 4 NPS were more likely than patients with 0-3 NPS to have amnestic MCI (81% vs. 71%, respectively, p = 0.03), and patients with amnestic MCI were more likely than those with other subtypes to exhibit depressive symptoms. Patients with ≥ 4 NPS had nearly 2.5 times the odds of developing dementia at follow-up than patients with 0-3 NPS (adjusted OR = 2.44, 95% CI 1.07, 5.55).
NPS are common in MCI patients. Those with an elevated number of NPS may be more likely to have the amnestic subtype of MCI, and depression may be more common in amnestic MCI than in other subtypes. An elevated number of NPS may increase risk of progression to dementia for patients with MCI.
PMCID: PMC2735341  PMID: 19140134
Mild cognitive impairment; neuropsychiatric symptoms; dementia
20.  Predicting dementia: role of dementia risk indices 
Future neurology  2009;4(5):555-560.
There are currently more than 5 million people in the USA living with Alzheimer’s disease and other forms of dementia, and prevalence is expected to triple over the next 40 years. As new strategies for prevention and treatment are developed, it will be critically important to be able to identify older adults who do not currently have dementia but have a high risk of developing symptoms within a few years so that they can be targeted for monitoring, prevention and early treatment. In other fields, prognostic models and risk indices are often used to identify high-risk individuals (e.g., Framingham Heart Index and Breast Cancer Risk Assessment Tool). The objective of this paper is to describe the development of Dementia Risk Indices and to discuss the potential for these tools to be incorporated into clinical and research settings for the identification of individuals with a high risk of dementia.
PMCID: PMC2805956  PMID: 20161571
dementia; prevention; risk assessment; risk factors
21.  An Advance Directive Redesigned to Meet the Literacy Level of Most Adults: A Randomized Trial 
Patient education and counseling  2007;69(1-3):165-195.
To determine whether an advance directive redesigned to meet most adults’ literacy needs (5th grade reading level with graphics) was more useful for advance care planning than a standard form (>12th grade level).
We enrolled 205 English and Spanish-speaking patients, aged ≥ 50 years from an urban, general medicine clinic. We randomized participants to review either form. Main outcomes included acceptability and usefulness in advance care planning. Participants then reviewed the alternate form; we assessed form preference and six-month completion rates.
40% of enrolled participants had limited literacy. Compared to the standard form, the redesigned form was rated higher for acceptability and usefulness in care planning, P≤0.03, particularly for limited literacy participants (P for interaction ≤ 0.07). The redesigned form was preferred by 73% of participants. More participants randomized to the redesigned form completed an advance directive at six months (19% vs. 8%, P=0.03); of these, 95% completed the redesigned form.
The redesigned advance directive was rated more acceptable and useful for advance care planning and was preferred over a standard form. It also resulted in higher six month completion rates.
Practice Implications
An advance directive redesigned to meet most adults’ literacy needs may better enable patients to engage in advance care planning.
PMCID: PMC2257986  PMID: 17942272
advance directive; health literacy; communication; decision-making; ethics; health disparities
22.  Use of a Modified Informed Consent Process among Vulnerable Patients: A Descriptive Study 
Little is known about patient characteristics associated with comprehension of consent information, and whether modifications to the consent process can promote understanding.
To describe a modified research consent process, and determine whether literacy and demographic characteristics are associated with understanding consent information.
Descriptive study of a modified consent process: consent form (written at a sixth-grade level) read to participants, combined with 7 comprehension questions and targeted education, repeated until comprehension achieved (teach-to-goal).
Two hundred and four ethnically diverse subjects, aged ≥50, consenting for a trial to improve the forms used for advance directives.
Number of passes through the consent process required to achieve complete comprehension. Literacy assessed in English and Spanish with the Short Form Test of Functional Health Literacy in Adults (scores 0 to 36).
Participants had a mean age of 61 years and 40% had limited literacy (s-TOHFLA<23). Only 28% of subjects answered all comprehension questions correctly on the first pass. After adjustment, lower literacy (P=.04) and being black (P=.03) were associated with requiring more passes through the consent process. Not speaking English as a primary language was associated with requiring more passes through the consent process in bivariate analyses (P<.01), but not in multivariable analyses (P>.05). After the second pass, most subjects (80%) answered all questions correctly. With a teach-to-goal strategy, 98% of participants who engaged in the consent process achieved complete comprehension.
Lower literacy and minority status are important determinants of understanding consent information. Using a modified consent process, little additional education was required to achieve complete comprehension, regardless of literacy or language barriers.
PMCID: PMC1831581  PMID: 16881949
informed consent; health literacy; communication; vulnerable populations; ethics
23.  Gene-Targeted Mice Lacking the Trex1 (DNase III) 3′→5′ DNA Exonuclease Develop Inflammatory Myocarditis 
Molecular and Cellular Biology  2004;24(15):6719-6727.
TREX1, originally designated DNase III, was isolated as a major nuclear DNA-specific 3′→5′ exonuclease that is widely distributed in both proliferating and nonproliferating mammalian tissues. The cognate cDNA shows homology to the editing subunit of the Escherichia coli replicative DNA polymerase III holoenzyme and encodes an exonuclease which was able to serve a DNA-editing function in vitro, promoting rejoining of a 3′ mismatched residue in a reconstituted DNA base excision repair system. Here we report the generation of gene-targeted Trex1−/− mice. The null mice are viable and do not show the increase in spontaneous mutation frequency or cancer incidence that would be predicted if Trex1 served an obligatory role of editing mismatched 3′ termini generated during DNA repair or DNA replication in vivo. Unexpectedly, Trex1−/− mice exhibit a dramatically reduced survival and develop inflammatory myocarditis leading to progressive, often dilated, cardiomyopathy and circulatory failure.
PMCID: PMC444847  PMID: 15254239

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