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1.  Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial 
Journal of Clinical Oncology  2015;33(15):1653-1659.
Purpose
Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive function.
Patients and Methods
A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated.
Results
Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment.
Conclusion
Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.
doi:10.1200/JCO.2014.58.4508
PMCID: PMC4429174  PMID: 25897156
2.  Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue 
Neuro-Oncology  2015;17(10):1393-1401.
Background
Common acute-term side effects of brain radiotherapy (RT) include fatigue, drowsiness, decreased physical functioning, and decreased quality of life (QOL). We hypothesized that armodafinil (a wakefulness-promoting drug known to reduce fatigue and increase cognitive function in breast cancer patients receiving chemotherapy) would result in reduced fatigue and sleepiness for patients receiving brain RT.
Methods
A phase II, multi-institutional, placebo-controlled randomized trial assessed feasibility of armodafinil 150 mg/day in participants receiving brain RT, from whom we obtained estimates of variability for fatigue, sleepiness, QOL, cognitive function, and treatment effect.
Results
From September 20, 2010, to October 20, 2012, 54 participants enrolled with 80% retention and 94% self-reported compliance. There were no grade 4–5 toxicities, and the incidence of grade 2–3 toxicities was similar between treatment arms, the most common of which were anxiety and nausea (15%), headaches (19%), and insomnia (20%). There were no statistically significant differences in end-RT or 4 week post-RT outcomes between armodafinil and placebo in any outcomes (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, Brief Fatigue Inventory, Epworth Sleepiness Scale, FACT-Brain, and FACIT-cognitive function). However, in participants with more baseline fatigue, those treated with armodafinil did better than those who received the placebo on the end-RT assessments for several outcomes.
Conclusion
Armodafinil 150 mg/day was well tolerated in primary brain tumor patients undergoing RT with good compliance. While there was no overall significant effect on fatigue, those with greater baseline fatigue experienced improved QOL and reduced fatigue when using armodafinil. These data suggest that a prospective, phase III randomized trial is warranted for patients with greater baseline fatigue.
doi:10.1093/neuonc/nov084
PMCID: PMC4578583  PMID: 25972454
armodafinil; cognitive function; fatigue; primary brain tumors; radiotherapy
3.  Factors Associated with Nursing Home Admission after Stroke in Older Women 
Objective
We examined the social and economic factors associated with nursing home (NH) admission in older women, overall and post-stroke.
Methods
The Women’s Health Initiative (WHI) included women aged 50–79 years at enrollment (1993–1998). In the WHI Extension Study (2005–2010), participants annually reported any NH admission in the preceding year. Separate multivariate logistic regression models analyzed social and economic factors associated with long-term NH admission, defined as an admission on two or more questionnaires, overall and post-stroke.
Results
Of 103,237 participants, 8,904 (8.6%) reported NH admission (2005–2010); 534 of 2,225 (24.0%) women with incident stroke reported post-stroke NH admission. Decreased likelihoods of NH admission overall were demonstrated for Asian, Black and Hispanic women (versus whites, aORs=0.35–0.44, p<.001) and women with higher income (aOR= 0.75, 95%CI=0.63–0.90); while increased likelihoods of NH admission overall were seen for women with lower social support (aOR=1.34, 95%CI=1.16–1.54) and with incident stroke (aOR=2.59, 95%CI=2.15–3.12). Increased odds of NH admission after stroke were demonstrated for women with moderate disability after stroke (aOR=2.76, 95%CI=1.73–4.42). Further adjustment for stroke severity eliminated the association found for race/ethnicity, income and social support.
Conclusion
The level of care needed after a disabling stroke may overwhelm social and economic structures in place that might otherwise enable avoidance of nursing home admission. We need to identify ways to provide care consistent with patients’ preferences, even after a disabling stroke.
doi:10.1016/j.jstrokecerebrovasdis.2015.06.013
PMCID: PMC4592792  PMID: 26169547
disability; institutionalization; race; ethnicity; social support; long-term care
4.  Driving with Mild Cognitive Impairment or Dementia: Cognitive Test Performance and Proxy Report of Daily Life Function in Older Women 
OBJECTIVES
To investigate associations between proxy report of cognitive and functional limitations and cognitive performance and current or former driving status in older women with mild cognitive impairment (MCI) and all-cause dementia.
DESIGN
Cross-sectional data analysis of retrospectively identified older women with adjudicated MCI and all-cause dementia in the Women’s Health Initiative Memory Study—Epidemiology of Cognitive Health Outcomes (WHIMS-ECHO).
SETTING
Academic medical center.
PARTICIPANTS
Women (mean age ± standard deviation 83.7 ± 3.5) adjudicated with MCI or dementia during Year 1, 2, 3, or 4 of the WHIMS-ECHO follow-up period (N = 385).
MEASUREMENTS
The telephone-administered cognitive battery included tests of attention, verbal learning and memory, verbal fluency, executive function, working memory, and global cognitive function plus self-report measures of depressive symptomatology. The Dementia Questionnaire (DQ) was administered to a knowledgeable proxy (family member, friend).
RESULTS
Sixty percent of women with MCI and 40% of those with dementia are current drivers. Proxy reports of functional limitations in instrumental activities of daily living (IADLs) are associated with current driving status in women with MCI, whereas performance-based cognitive tests are not. In women with dementia, proxy reports of functional limitations in IADLs and performance-based cognitive tests are associated with current driving status, as expected.
CONCLUSION
These findings have clinical implications for the importance of evaluating driving concurrently with other instrumental functional abilities in MCI and dementia. Additional work is needed to determine whether proxy report of cognitive and functional impairments should help guide referrals for driving assessment and rehabilitation or counseling for driving transition.
doi:10.1111/jgs.13634
PMCID: PMC4841465  PMID: 26338449
aging; driving; instrumental activities of daily living; mild cognitive impairment; dementia
5.  Sociodemographic Correlates of Cognition in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Objectives
To describe the methodology utilized to evaluate cognitive function in the Multi-Ethnic Study of Atherosclerosis (MESA) and to present preliminary results by age, gender and race/ethnicity.
Design
Cross-sectional measurements of a prospective observational cohort.
Setting
Residents of 6 US communities free of cardiovascular disease at baseline (2000-02).
Participants
4,591 adults who completed the 5th MESA clinical examination in 2011-12, mean age 70.3 (SD 9.5) years, 53.1% women, and 40.7% Non-Hispanic White, 26.4% Non-Hispanic Black, 21.4% Hispanic, and 11.5% Chinese.
Measurements
The cognitive battery consisted of the Cognitive Abilities Screening Instrument (version 2) to evaluate global cognition, the Digit Symbol Code for processing speed and Digit Spans Forward and Backward to assess memory. Demographic, socioeconomic, and cultural covariates were also collected for descriptive statistics and multivariate modeling.
Results
Associations between socio-economic factors and cognition revealed that age, race/ethnicity, education, occupational status, household income, health insurance type, household size, place of birth, years and generation in U.S., and the presence of the APOE4 allele were significantly associated with performance on the cognitive tests although patterns varied by specific test, racial/ethnicity, and socio-cultural factors.
Conclusions
As many of the influencing cultural and socioeconomic factors measured here are complex, multifactorial, and may not be adequately quantified, caution has been recommended with regard to comparison and interpretation of racial/ethnic group performance differences from these cross-sectional models. These data provide a baseline for future exams and more comprehensive longitudinal analyses of the contributions of subclinical and clinical diseases to cognitive function and decline.
doi:10.1016/j.jagp.2015.01.003
PMCID: PMC4465027  PMID: 25704999
MESA; cognition; methods; multi-ethnic; race; socioeconomic; cultural
6.  Loneliness, Depression, and Inflammation: Evidence from the Multi-Ethnic Study of Atherosclerosis 
PLoS ONE  2016;11(7):e0158056.
Objective
Both objective and subjective aspects of social isolation have been associated with alterations in immune markers relevant to multiple chronic diseases among older adults. However, these associations may be confounded by health status, and it is unclear whether these social factors are associated with immune functioning among relatively healthy adults. The goal of this study was to examine the associations between perceived loneliness and circulating levels of inflammatory markers among a diverse sample of adults.
Methods
Data come from a subset of the Multi-Ethnic Study of Atherosclerosis (n = 441). Loneliness was measured by three items derived from the UCLA Loneliness Scale. The association between loneliness and C-reactive protein (CRP) and fibrinogen was assessed using multivariable linear regression analyses. Models were adjusted for demographic and health characteristics.
Results
Approximately 50% of participants reported that they hardly ever felt lonely and 17.2% felt highly lonely. Individuals who were unmarried/unpartnered or with higher depressive symptoms were more likely to report being highly lonely. There was no relationship between perceived loneliness and ln(CRP) (β = -0.051, p = 0.239) adjusting for demographic and health characteristics. Loneliness was inversely associated with ln(fibrinogen) (β = -0.091, p = 0.040), although the absolute magnitude of this relationship was small.
Conclusion
These results indicate that loneliness is not positively associated with fibrinogen or CRP among relatively healthy middle-aged adults.
doi:10.1371/journal.pone.0158056
PMCID: PMC4930171  PMID: 27367428
7.  Educational attainment, MRI changes and cognitive function in older postmenopausal women from the Women’s Health Initiative Memory Study 
The relationship between neuropathology and clinically manifested functional and cognitive deficits is complex. Clinical observations of individuals with greater neuropathology who function better than some individuals with less neuropathology are common and puzzling. Educational attainment, a proxy for ‘cognitive reserve’, may help to explain this apparent contradiction. The objective of this study is to determine if educational attainment is correlated with cognitive decline, brain lesion volume and total brain atrophy. One thousand three hundred ninety of the 7,479 community-dwelling women 65 years of age and older enrolled in the Women’s Health Initiative Memory Study, two parallel randomized, placebo-controlled clinical trials comparing unopposed and opposed post-menopausal hormone therapy with placebo, were studied. Study participants received annual assessments of global cognitive function with the Modified Mini Mental State exam. One thousand sixty-three participants also received a supplemental neurocognitive battery and neuroimaging studies. Magnetic resonance imaging was used to calculate total ischemic lesion and brain volumes. Incident cases of probable dementia and mild cognitive impairment were centrally adjudicated. After adjustment for total lesion and total brain volumes (atrophy), higher educational attainment predicted better cognitive performance (p<0.001). Following conversion to dementia/MCI, higher education predicted steeper declines in cognitive function (p<0.001). Thus, higher educational attainment was associated with a delay in diagnosis of dementia/MCI in the face of a growing neuropathological load.
PMCID: PMC4544866  PMID: 24552037
cognition; MRI; cognitive reserve; aging; women; WHIMS
8.  Concurrent and Longitudinal Relationships Between Cognitive Activity, Cognitive Performance, and Brain Volume in Older Adult Women 
Objectives.
We investigated (a) cross-sectional associations between cognitive activity, cognitive performance, and MRI measures and (b) longitudinal associations between cognitive activity and change in cognitive performance, using structural equation modeling (SEM).
Method.
Women’s Health Initiative Memory Study (WHIMS) Extension participants who continued annual neuropsychological assessments by telephone and completed a concurrent questionnaire of cognitive activities and MRI scans were included (mean age = 81.4 years; N = 393). Cognitive performance was measured by tests of attention, working memory, verbal fluency, executive function, and memory. Cognitive activity was measured by self-reported participation in a variety of cognitive activities (e.g., reading books, playing games, computer activities; N = 11 items) during the previous 12 months. MRI measures included gray and white matter normal and white matter lesion volumes.
Results.
SEM demonstrated a significant association between cognitive activity and baseline cognitive performance but not change over 2–3 years. Gray and white matter was associated with cognitive performance but not cognitive activity. All effects remained significant after modeling covariates (age, education, depressive symptoms, WHIMS intervention assignment, and intracranial volume).
Conclusions.
Cognitive activity benefits current cognitive performance but is not associated with change over 2–3 years. Cognitive activity and MRI volumes are independently associated with cognitive performance, suggesting distinct cognitive and brain reserve constructs.
doi:10.1093/geronb/gbu109
PMCID: PMC4296141  PMID: 25209372
Cognition; Cognitive activity; Longitudinal change; MRI; SEM.
9.  Long-term Impact of Behavioral Weight Loss Intervention on Cognitive Function 
Background.
It is unknown whether intentional weight loss provides long-term benefits for cognitive function.
Methods.
An ancillary study to a randomized controlled clinical trial was conducted in overweight and obese individuals (N = 978), aged 45–76 years at enrollment, with type 2 diabetes. An intensive behavioral intervention designed to promote and maintain weight loss through caloric restriction and increased physical activity was compared with diabetes support and education. Standardized assessments of cognitive function were collected an average of 8.1 years after trial enrollment.
Results.
Participants assigned to intensive lifestyle intervention lost a mean (SE) 11.1% (0.4%) and 7.2% (0.5%) of weight at Years 1 and 8, respectively, compared with 1.0% (0.2%) and 3.3% (0.5%) in the control group (p < .001). Covariate-adjusted mean composite cognitive function test scores were similar for the two groups (p = .69), and no significant differences were found for any individual cognitive test. There was some evidence of a differential effect (nominal interaction p = .008) for a prespecified comparison: Intensive lifestyle intervention was associated with a relative mean benefit for composite cognitive function of 0.276 (95% confidence interval: 0.033, 0.520) SDs among individuals with body mass index less than 30kg/m2 at baseline compared with a relative mean deficit of 0.086 (−0.021, 0.194) SDs among individuals with body mass more than or equal to 30kg/m2.
Conclusions.
Eight years of intensive lifestyle intervention did not alter cognitive function in obese adults with type 2 diabetes; however, there was evidence for benefit among overweight but not obese individuals. Changes in cognition were not assessed in this cross-sectional study.
doi:10.1093/gerona/glu031
PMCID: PMC4158413  PMID: 24619151
Cognition; Obesity; Diabetes; Clinical trials.
10.  Postmenopausal Hormone Therapy and Cognitive Outcomes: the Women's Health Initiative Memory Study (WHIMS) 
This review discusses major findings from the Women's Health Initiative Memory Study (WHIMS). WHIMS reported hormone therapy (HT) - conjugated equine estrogen (CEE) with or without medroxyprogesterone acetate (MPA) - increased the risk for dementia (HR 1.76 [95% CI, 1.19-2.60]; P=0.005) and global cognitive decline, with a mean decrement relative to placebo of 0.21 points on the Modified Mini Mental State Examination (3MS) (P=0.006) in women age 65 and older.
A subset of WHIMS participants joined the ancillary WHI Study of Cognitive Aging (WHISCA) trials, in which domain-specific cognitive tests and mood were measured annually. Compared with placebo, CEE+MPA had a negative impact on verbal memory over time (p=0.01); and CEE-Alone was associated with lower spatial rotational ability (p=<.01) at the initial assessment, but the difference diminished over time.
The ancillary WHIMS-MRI study measured subclinical cerebrovascular disease to possibly explain the negative cognitive findings reported by WHIMS and the increased clinical stroke in older women reported by the WHI. WHIMS-MRI reported that while CEE+MPA and CEE-Alone were not associated with increased ischemic brain lesion volume relative to placebo; both CEE+MPA and CEE-Alone were associated with lower mean brain volumes in the hippocampus (p=0.05); frontal lobe (p=0.004);and total brain (p=0.07). HT-associated reductions in hippocampal volumes were greatest in women with baseline 3MS scores ≤ 90.
doi:10.1016/j.jsbmb.2009.11.007
PMCID: PMC4547365  PMID: 19932751
hormone therapy; cognition; brain MRI; cerebrovascular disease
11.  Validation of a cognitive assessment battery administered by telephone 
Background
While the gold standard method of cognitive assessment is a face-to-face administration, telephone-based assessments offer several advantages if they demonstrate reliability and validity.
Design
Observational study; 110 participants randomly assigned to receive two administrations of the same cognitive test battery 6 months apart in one of four combinations (1st administration/2nd administration): telephone/telephone; telephone/face-to-face; face-to-face/telephone; or face-to-face/face-to-face.
Setting
Academic medical center
Participants
110 non-demented women between the ages of 65 and 90 years.
Measures
The battery included tests of attention, verbal learning and memory, verbal fluency, executive function, working memory and global cognitive functioning plus self-report measures of perceived memory problems, depressive symptoms, sleep disturbance and health-related quality of life. Test-retest reliability, concurrent validity, relative bias associated with telephone administration, and change scores were evaluated.
Results
There were no statistically significant differences in scores on any of the cognitive tests or questionnaires between randomly assigned modes of administration at baseline indicating equivalence across modes. There was no significant bias for tests or questionnaires administered by telephone (ps>0.01). Nor was there a difference in mean change scores between administration modes except for the Category Fluency (p = 0.01) and the California Verbal Learning Test long delay-free recall (p < 0.01). Mean test-retest coefficients for the battery were not significantly different across groups though individual test-retest correlation coefficients were generally higher within mode than across mode.
Conclusions
Telephone administration of cognitive tests and questionnaires to older women is both reliable and valid. Use of telephone batteries can substantially reduce the economic cost and burden of cognitive assessments and increase enrollment, retention and data completeness thereby improving study validity.
doi:10.1111/j.1532-5415.2012.04111.x
PMCID: PMC3448122  PMID: 22985137
cognition; assessment; telephone; validation; tests
12.  Ascertaining dementia-related outcomes for deceased or proxy-dependent participants: an overview of the Women’s Health Initiative Memory Study supplemental case ascertainment protocol† 
Objective
The aim of the study was to compare a two-staged clinic-based standardized protocol with a supplemental proxy-based protocol.
Methods
The Women’s Health Initiative Memory Study enrolled 7479 women, aged 65–79 years and free of dementia, in a clinical trial of postmenopausal hormone therapy who were followed for up to 13 years with annual two-staged clinic-based standardized protocols to identify incidence of probable dementia. A supplemental proxy-based protocol, involving telephone administration of the dementia questionnaire, was designed to assess the cognitive status of women who could no longer attend clinic visits because they died (n = 1058) or became dependent (n = 228). Chi-squared tests were used to compare characteristics of women eligible for proxy-based versus clinic-based assessment. Risk factor relationships were described using proportional hazards regression.
Results
Women who were eligible for proxy-based assessments tended to have worse cognitive impairment risk factor profiles and had higher rates of probable dementia (15.2% vs 3.5%) than clinic-assessed participants. Augmenting the clinic-based cases with those identified from proxy interviews reduced undercounting and materially altered observed relationships that years since menopause, smoking status, diabetes, and prior use of hormone therapy had with incidence of probable dementia.
Conclusions
Although proxy interviews were successful in reducing biases in estimated incidence rates and risk factor relationships, it is unlikely that they will fully eliminate many biases. Proxy-based assessments are necessary in longer term studies to reduce undercounting of dementia cases and to characterize risk factor relationships.
doi:10.1002/gps.2714
PMCID: PMC4381429  PMID: 21416508
attrition; cognitive impairment; dementia; women’s health; missing data
13.  Cynicism: Incident diabetes and worsening of metabolic syndrome in postmenopausal women 
Diabetes & metabolic syndrome  2010;4(4):187-189.
Objective
To determine if self-reported cynical hostility predicted incident diabetes or increase in number of symptoms associated with metabolic syndrome in postmenopausal women.
Design
Prospective study of a subsample of women (n = 3,658) participating in the Women's Health Initiative Clinical Trial.
Methods
Subjects: Postmenopausal women aged 50 to 79 years at baseline who were enrolled in the Women's Health Initiative Dietary Modification Trial, Hormone Trial or both. Measures: The Cynicism subscale of the Cook-Medley Hostility Questionnaire was used to assess cynical hostility at baseline. Incident diabetes was ascertained by self-report of treatment with insulin or oral hypoglycemic medication at one year. Metabolic syndrome was defined based on number of Adult Treatment Panel (ATP) III criteria met at one year. Statistical Analysis: The relationship between baseline cynical hostility and incident diabetes and worsening of metabolic syndrome was assessed from baseline to one year using multivariable Cox proportional hazards models and multivariable logistic regression models, respectively.
Results
Incident diabetes was 36% higher among women in the upper tertile for baseline cynical hostility compared to the lowest tertile (p-trend = 0.05). The odds of a worsening of metabolic syndrome was 27% greater in the highest cynical hostility tertile compared to the lowest tertile (p-trend = 0.04).
Conclusions
Cynical hostility may increase the risk for developing diabetes and worsening of the metabolic syndrome in postmenopausal women.
doi:10.1016/j.dsx.2010.09.006
PMCID: PMC4317350  PMID: 25663951
Diabetes; Metabolic syndrome; Mood; Cynicism; Cynical hostility; Postmenopausal women
14.  Cognitive factors associated with adherence to oral anti-estrogen therapy: Results from the Cognition in the Study of Tamoxifen and Raloxifene (Co-STAR) Study 
Little is known about the cognitive factors associated with adherence to anti-estrogen therapy. Our objective was to investigate the association between domain-specific cognitive function and adherence among women in a clinical prevention trial of oral anti-estrogen therapies. We performed a secondary analysis of Co-STAR, an ancillary study of the STAR breast cancer prevention trial in which postmenopausal women at increased breast cancer risk were randomized to tamoxifen or raloxifene. Co-STAR enrolled non-demented participants ≥65 years old to compare treatment effects on cognition. The cognitive battery assessed global cognitive function (Modified Mini-Mental State Exam), and specific cognitive domains of verbal knowledge, verbal fluency, figural memory, verbal memory, attention and working memory, spatial ability, and fine motor speed. Adherence was defined by a ratio of actual time taking therapy per protocol ≥80% of expected time. Logistic regression was used to evaluate the association between cognitive test scores and adherence to therapy. The mean age of the 1,331 Co-STAR participants was 67.2±4.3 years. Mean 3MS score was 95.1 (4.7) and 14% were non-adherent. In adjusted analyses, the odds of non-adherence were lower for those with better scores on verbal memory [OR (95% CI): 0.75 (0.62, 0.92)]. Larger relative deficits in verbal memory compared to verbal fluency were also associated with non-adherence [1.28 (1.08, 1.51)]. Among non-demented older women, subtle differences in memory performance were associated with medication adherence. Differential performance across cognitive domains may help identify persons at greater risk for poor adherence.
doi:10.1158/1940-6207.CAPR-13-0165
PMCID: PMC3924583  PMID: 24253314
adherence; cancer; cognition; elderly; tamoxifen; women
15.  PERFORMANCE OF A COMPUTER-BASED ASSESSMENT OF COGNITIVE FUNCTION MEASURES IN TWO COHORTS OF SENIORS 
International journal of geriatric psychiatry  2013;28(12):10.1002/gps.3949.
Background
Computer-administered assessment of cognitive function is being increasingly incorporated in clinical trials, however its performance in these settings has not been systematically evaluated.
Design
The Seniors Health and Activity Research Program (SHARP) pilot trial (N=73) developed a computer-based tool for assessing memory performance and executive functioning. The Lifestyle Interventions and Independence for Seniors (LIFE) investigators incorporated this battery in a full scale multicenter clinical trial (N=1635). We describe relationships that test scores have with those from interviewer-administered cognitive function tests and risk factors for cognitive deficits and describe performance measures (completeness, intra-class correlations).
Results
Computer-based assessments of cognitive function had consistent relationships across the pilot and full scale trial cohorts with interviewer-administered assessments of cognitive function, age, and a measure of physical function. In the LIFE cohort, their external validity was further demonstrated by associations with other risk factors for cognitive dysfunction: education, hypertension, diabetes, and physical function. Acceptable levels of data completeness (>83%) were achieved on all computer-based measures, however rates of missing data were higher among older participants (odds ratio=1.06 for each additional year; p<0.001) and those who reported no current computer use (odds ratio=2.71; p<0.001). Intra-class correlations among clinics were at least as low (ICC≤0.013) as for interviewer measures (ICC≤0.023), reflecting good standardization. All cognitive measures loaded onto the first principal component (global cognitive function), which accounted for 40% of the overall variance.
Conclusion
Our results support the use of computer-based tools for assessing cognitive function in multicenter clinical trials of older individuals.
doi:10.1002/gps.3949
PMCID: PMC3775886  PMID: 23589390
Cognitive function; Clinical trial; Performance measures
16.  Subtypes of Mild Cognitive Impairment in Older Postmenopausal Women: The Women’s Health Initiative Memory Study 
Mild cognitive impairment (MCI) is a transitional state between normal cognitive functioning and dementia. A proposed MCI typology1 classifies individuals by the type and extent of cognitive impairment, yet few studies have characterized or compared these subtypes. 447 women 65 years of age and older from the Women’s Health Initiative Memory Study2 were classified into the four MCI subgroups and a ‘no impairment’ group and compared on clinical, sociodemographic, and health variables.
82.1% of participants had a cognitive deficit in at least one domain with most (74.3%) having deficits in multiple cognitive domains. Only 4.3% had an isolated memory deficit, while 21.3% had an isolated non-memory deficit. Of the 112 women who met all MCI criteria examined, the most common subtype was amnestic multi-domain MCI (42.8%) followed by non-amnestic multiple domain MCI (26.7%), non-amnestic single domain (24.1%) and amnestic single domain MCI (6.3%). Subtypes were similar with respect to education, health status, smoking, depression and pre- and on-study use of hormone therapy.
Despite the attention it receives in the literature amnestic MCI is the least common type highlighting the importance of identifying and characterizing other non-amnestic and multi-domain subtypes. Further research is needed on the epidemiology of MCI subtypes, clinical and biological differences between them and rates for conversion to dementia.
doi:10.1097/WAD.0b013e3181d715d5
PMCID: PMC2929315  PMID: 20473134
MCI; women; WHIMS; postmenopausal; cognition; dementia; hormone therapy
17.  The LIFE Cognition Study: design and baseline characteristics 
Observational studies have shown beneficial relationships between exercise and cognitive function. Some clinical trials have also demonstrated improvements in cognitive function in response to moderate–high intensity aerobic exercise; however, these have been limited by relatively small sample sizes and short durations. The Lifestyle Interventions and Independence for Elders (LIFE) Study is the largest and longest randomized controlled clinical trial of physical activity with cognitive outcomes, in older sedentary adults at increased risk for incident mobility disability. One LIFE Study objective is to evaluate the effects of a structured physical activity program on changes in cognitive function and incident all-cause mild cognitive impairment or dementia. Here, we present the design and baseline cognitive data. At baseline, participants completed the modified Mini Mental Status Examination, Hopkins Verbal Learning Test, Digit Symbol Coding, Modified Rey–Osterrieth Complex Figure, and a computerized battery, selected to be sensitive to changes in speed of processing and executive functioning. During follow up, participants completed the same battery, along with the Category Fluency for Animals, Boston Naming, and Trail Making tests. The description of the mild cognitive impairment/dementia adjudication process is presented here. Participants with worse baseline Short Physical Performance Battery scores (prespecified at ≤7) had significantly lower median cognitive test scores compared with those having scores of 8 or 9 with modified Mini Mental Status Examination score of 91 versus (vs) 93, Hopkins Verbal Learning Test delayed recall score of 7.4 vs 7.9, and Digit Symbol Coding score of 45 vs 48, respectively (all P<0.001). The LIFE Study will contribute important information on the effects of a structured physical activity program on cognitive outcomes in sedentary older adults at particular risk for mobility impairment. In addition to its importance in the area of prevention of cognitive decline, the LIFE Study will also likely serve as a model for exercise and other behavioral intervention trials in older adults.
doi:10.2147/CIA.S65381
PMCID: PMC4154884  PMID: 25210447
exercise; physical activity; older adults; dementia
18.  Long Term Effects on Cognitive Function of Postmenopausal Hormone Therapy Prescribed to Women Aged 50–55 Years 
JAMA internal medicine  2013;173(15):10.1001/jamainternmed.2013.7727.
Background
Postmenopausal hormone therapy with conjugated equine estrogens (CEE) may adversely affect older women’s cognitive function. It is not known whether this extends to younger women.
Methods
1,326 postmenopausal women, who had begun treatment in two randomized placebo-controlled clinical trials of hormone therapy when aged 50–55 years, were assessed with an annual telephone-administered cognitive battery that included measures of global (primary outcome) and domain-specific cognitive functions (verbal memory, attention, executive function, verbal fluency, and working memory). The clinical trials in which they participated had compared 0.625 mg CEE with or without 2.5 mg medroxyprogesterone acetate (MPA) over an average of 7.0 years. Cognitive testing was conducted an average of 7.2 years following the end of the trials, when women had mean age 67.2 years, and repeated one year later.
Results
Global cognitive function scores from women who had been assigned to CEE-based therapies were similar to those from women assigned to placebo: mean [95% confidence interval] intervention effect of 0.02 [−0.08,0.12]standard deviation units (p=0.66). Similarly, no overall differences were found for any individual cognitive domain (all p>0.15). Pre-specified subgroup analyses found some evidence that CEE-based therapies may have adversely affected verbal fluency among women who had prior hysterectomy or prior use of hormone therapy: mean treatment effects of −0.17 [−0.33, −0.02] and −0.25 [−0.42, −0.08], respectively, however this may be a chance finding. We are not able to address whether initiating hormone therapy during the menopause and maintaining therapy until any symptoms are passed affects cognitive function, either in the short or longer term.
Conclusions
CEE-based therapies produced no overall sustained benefit or risk to cognitive function when administered to postmenopausal women aged 50–55 years.
doi:10.1001/jamainternmed.2013.7727
PMCID: PMC3844547  PMID: 23797469
19.  Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline 
Neurology  2013;80(8):747-753.
Objective:
In a retrospective review to assess neuroanatomical targets of radiation-induced cognitive decline, dose volume histogram (DVH) analyses of specific brain regions of interest (ROI) are correlated to neurocognitive performance in 57 primary brain tumor survivors.
Methods:
Neurocognitive assessment at baseline included Trail Making Tests A/B, a modified Rey-Osterreith Complex Figure, California or Hopkins Verbal Learning Test, Digit Span, and Controlled Oral Word Association. DVH analysis was performed for multiple neuroanatomical targets considered to be involved in cognition. The %v10 (percent of ROI receiving 10 Gy), %v40, and %v60 were calculated for each ROI. Factor analysis was used to estimate global cognition based on a summary of performance on individual cognitive tests. Stepwise regression was used to determine which dose volume predicted performance on global factors and individual neurocognitive tests for each ROI.
Results:
Regions that predicted global cognitive outcomes at doses <60 Gy included the corpus callosum, left frontal white matter, right temporal lobe, bilateral hippocampi, subventricular zone, and cerebellum. Regions of adult neurogenesis primarily predicted cognition at %v40 except for the right hippocampus which predicted at %v10. Regions that did not predict global cognitive outcomes at any dose include total brain volume, frontal pole, anterior cingulate, right frontal white matter, and the right precentral gyrus.
Conclusions:
Modeling of radiation-induced cognitive decline using neuroanatomical target theory appears to be feasible. A prospective trial is necessary to validate these data.
doi:10.1212/WNL.0b013e318283bb0a
PMCID: PMC3589296  PMID: 23390169
20.  Intraindividual Variability in Domain-Specific Cognition and Risk of Mild Cognitive Impairment and Dementia 
Intraindividual variability among cognitive domains may predict dementia independently of interindividual differences in cognition. A multidomain cognitive battery was administered to 2305 older adult women (mean age 74 years) enrolled in an ancillary study of the Women's Health Initiative. Women were evaluated annually for probable dementia and mild cognitive impairment (MCI) for an average of 5.3 years using a standardized protocol. Proportional hazards regression showed that lower baseline domain-specific cognitive scores significantly predicted MCI (N = 74), probable dementia (N = 45), and MCI or probable dementia combined (N = 101) and that verbal and figural memory predicted each outcome independently of all other cognitive domains. The baseline intraindividual standard deviation across test scores (IAV Cognitive Domains) significantly predicted probable dementia and this effect was attenuated by interindividual differences in verbal episodic memory. Slope increases in IAV Cognitive Domains across measurement occasions (IAV Time) explained additional risk for MCI and MCI or probable dementia, beyond that accounted for by interindividual differences in multiple cognitive measures, but risk for probable dementia was attenuated by mean decreases in verbal episodic memory slope. These findings demonstrate that within-person variability across cognitive domains both at baseline and longitudinally independently accounts for risk of cognitive impairment and dementia in support of the predictive utility of within-person variability.
doi:10.1155/2013/495793
PMCID: PMC3881440  PMID: 24454359
21.  Telephone interview for cognitive status (TICS) screening for clinical trials of physical activity and cognitive training: the seniors health and activity research program pilot (SHARP-P) study† 
International journal of geriatric psychiatry  2011;26(2):10.1002/gps.2503.
Objective:
To examine the performance of the Telephone Interview for Cognitive Status (TICS) for identifying participants appropriate for trials of physical activity and cognitive training interventions.
Methods:
Volunteers (N = 343), ages 70–85 years, who were being recruited for a pilot clinical trial on approaches to prevent cognitive decline, were administered TICS and required to score ≥31 prior to an invitation to attend clinic-based assessments. The frequencies of contraindications for physical activity and cognitive training interventions were tallied for individuals grouped by TICS scores. Relationships between TICS scores and other measures of cognitive function were described by scatterplots and correlation coefficients.
Results:
Eligibility criteria to identify candidates who were appropriate candidates for the trial interventions excluded 51.7% of the volunteers with TICS<31. TICS scores above this range were not strongly related to cognition or attendance at screening visits, however overall enrollment yields were approximately half for participants with TICS = 31 versus TICS = 41, and increased in a graded fashion throughout the range of scores.
Conclusions:
Use of TICS to define eligibility criteria in trials of physical activity and cognitive training interventions may not be worthwhile in that many individuals with low scores would already be eliminated by intervention-specific criteria and the relationship of TICS with clinic-based tests of cognitive function among appropriate candidates for these interventions may be weak. TICS may be most useful in these trials to identify candidates for oversampling in order to obtain a balanced cohort of participants at risk for cognitive decline.
doi:10.1002/gps.2503
PMCID: PMC3832189  PMID: 21229597
clinical trial design; cognitive interventions; eligibility criteria
22.  Alzheimer's Disease Risk Assessment Using Large-Scale Machine Learning Methods 
PLoS ONE  2013;8(11):e77949.
The goal of this work is to introduce new metrics to assess risk of Alzheimer's disease (AD) which we call AD Pattern Similarity (AD-PS) scores. These metrics are the conditional probabilities modeled by large-scale regularized logistic regression. The AD-PS scores derived from structural MRI and cognitive test data were tested across different situations using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The scores were computed across groups of participants stratified by cognitive status, age and functional status. Cox proportional hazards regression was used to evaluate associations with the distribution of conversion times from mild cognitive impairment to AD. The performances of classifiers developed using data from different types of brain tissue were systematically characterized across cognitive status groups. We also explored the performance of anatomical and cognitive-anatomical composite scores generated by combining the outputs of classifiers developed using different types of data. In addition, we provide the AD-PS scores performance relative to other metrics used in the field including the Spatial Pattern of Abnormalities for Recognition of Early AD (SPARE-AD) index and total hippocampal volume for the variables examined.
doi:10.1371/journal.pone.0077949
PMCID: PMC3826736  PMID: 24250789
23.  Phase II Study of Ginkgo Biloba in Irradiated Brain Tumor Patients: Effect on Cognitive Function, Quality of Life, and Mood 
Journal of neuro-oncology  2012;109(2):357-363.
Objective
Ginkgo biloba has been reported to improve cognitive function in older adults and patients with Alzheimer’s disease and multi-infarct dementia. We conducted an open-label phase II study of this botanical product in symptomatic irradiated brain tumor survivors.
Methods
Eligibility criteria included: life expectancy ≥ 30 weeks, partial or whole brain radiation ≥ 6 months before enrollment, no imaging evidence of tumor progression in previous 3 months, or stable or decreasing steroid dose, and no brain tumor treatment planned while on study. The ginkgo biloba dose was 120 mg/day (40 mg t.i.d.) for 24 weeks followed by a 6-week washout period. Assessments performed at baseline, 12, 24 (end of treatment), and 30 weeks (end of washout) included KPS, Functional Assessment of Cancer Therapy-Brain (FACT-Br), Profile of Mood States (POMS), Mini-Mental Status Exam (MMSE), Trail Making Test Parts A (TMT-A) and B (TMT-B), Digit Span Test (DST), Modified Rey Osterrieth Complex Figure (ROCF), California Verbal Learning Test Part II (CVLT-II), and the F-A-S Test.
Results
Of the 34 patients enrolled on study, 23 (68%) completed 12 weeks of treatment and 19 (56%) completed 24 weeks of treatment. There were significant improvements at 24 weeks in: executive function (TMT-B) (p=0.007), attention/concentration (TMT-A) (p=0.002), and non-verbal memory (ROCF – immediate/delayed recall) (p=0.001/0.002), mood (p=.002), FACT brain subscale (p=0.001), and the FACT physical subscale (p=.003).
Conclusions
Some improvement in quality of life and cognitive function were noted with ginkgo biloba. However, treatment with ginkgo biloba was associated with a high dropout rate.
doi:10.1007/s11060-012-0901-9
PMCID: PMC3752650  PMID: 22700031
ginkgo biloba; radiation; cognitive function; quality of life; brain tumors
24.  Is neighborhood racial/ethnic composition associated with depressive symptoms? The multi-ethnic study of atherosclerosis 
Social science & medicine (1982)  2010;71(3):541-550.
The racial/ethnic composition of a neighborhood may be related to residents’ depressive symptoms through differential levels of neighborhood social support and/or stressors. We used the Multi-Ethnic Study of Atherosclerosis to investigate cross-sectional associations of neighborhood racial/ethnic composition with the Center for Epidemiologic Studies-Depression (CES-D) scale in adults aged 45–84. The key exposure was a census-derived measure of the percentage of residents of the same racial/ethnic background in each participant’s census tract. Two-level multilevel models were used to estimate associations of neighborhood racial/ethnic composition with CES-D scores after controlling for age, income, marital status, education and nativity. We found that living in a neighborhood with a higher percentage of residents of the same race/ethnicity was associated with increased CES-D scores in African American men (p < 0.05), and decreased CES-D scores in Hispanic men and women and Chinese women, although these differences were not statistically significant. Models were further adjusted for neighborhood-level covariates (social cohesion, safety, problems, aesthetic quality and socioeconomic factors) derived from survey responses and census data. Adjusting for other neighborhood characteristics strengthened protective associations amongst Hispanics, but did not change the significant associations in African American men. These results demonstrate heterogeneity in the associations of race/ethnic composition with mental health and the need for further exploration of which aspects of neighborhood environments may contribute to these associations.
doi:10.1016/j.socscimed.2010.04.014
PMCID: PMC2922985  PMID: 20541303
Neighborhoods; Depressive symptoms; Mental health; Race/ethnicity; Ethnic density effect; USA
25.  Long Term Effects of Conjugated Equine Estrogens Therapies on Domain-Specific Cognitive Function: Results from the Women's Health Initiative Study of Cognitive Aging (WHISCA) Extension 
Objectives
Conjugated equine estrogen (CEE) therapies when initiated among older women have been shown to produce small decrements in global cognitive function. We are interested whether these persist after cessation and extend to specific cognitive domains.
Design
Randomized controlled clinical trial
Setting
Fourteen clinical centers of the Women's Health Initiative
Participants
2,304 women aged 65-80 years and free of probable dementia at enrollment
Intervention
0.625 mg/day of CEE, with or without medroxyprogesterone acetate (MPA, 10 mg/day), and matching placebos
Measurements
Annual administrations of a battery of cognitive tests during and following the trial
Methods
General linear models were used to compare on-trial and post-trial mean standardized test scores between treatment groups, with adjustment for baseline risk factors for cognitive impairment.
Results
Assignment to CEE-based therapies was associated with small mean relative decrements in global and several domain-specific cognitive functions on-trial, which largely persisted through up to 4 years post-trial. The strongest statistical evidence was for global cognitive function: 0.07 standard deviation decrements both on-trial (p=0.007) and post-trial (p=0.01). Among domain specific scores, the mean relative decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy.
Conclusions
CEE-based therapies, when initiated after age 65 years, produce a small broad-based decrement in cognitive function that persists after their use is stopped. The differences in cognitive function however are small and would not be detectable or have clinical significance for an individual woman. Differences in effects among cognitive domains suggest that more than one mechanism may be involved.
doi:10.1111/j.1532-5415.2010.02953.x
PMCID: PMC2917208  PMID: 20649689
Postmenopausal hormone therapy; Cognitive function; Women's health

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