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1.  Validation of a cognitive assessment battery administered by telephone 
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.
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.
Academic medical center
110 non-demented women between the ages of 65 and 90 years.
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.
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.
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.
PMCID: PMC3448122  PMID: 22985137
cognition; assessment; telephone; validation; tests
2.  Neuroanatomical target theory as a predictive model for radiation-induced cognitive decline 
Neurology  2013;80(8):747-753.
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.
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.
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.
Modeling of radiation-induced cognitive decline using neuroanatomical target theory appears to be feasible. A prospective trial is necessary to validate these data.
PMCID: PMC3589296  PMID: 23390169
3.  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.
PMCID: PMC3881440  PMID: 24454359
4.  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.
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.
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.
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.
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.
PMCID: PMC3832189  PMID: 21229597
clinical trial design; cognitive interventions; eligibility criteria
5.  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.
PMCID: PMC3826736  PMID: 24250789
6.  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.
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.
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.
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).
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.
PMCID: PMC3752650  PMID: 22700031
ginkgo biloba; radiation; cognitive function; quality of life; brain tumors
7.  The Relationship Between Cognitive Function and Physical Performance in Older Women: Results From the Women’s Health Initiative Memory Study 
Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear.
In the Women’s Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change.
Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS—gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p ≤ .01 both). Changes in 3MS and PPM were associated, particularly with chair stands and grip strength (p < .003 both). Baseline PPMs were not associated with subsequent 3MS change.
Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline.
PMCID: PMC2822281  PMID: 19789197
Cognitive function; Physical performance; Cognition; Physical function
8.  Relative Effects of Tamoxifen, Raloxifene, and Conjugated Equine Estrogens on Cognition 
Journal of Women's Health  2010;19(3):371-379.
To compare the relative effects of conjugated equine estrogens (CEE), raloxifene, and tamoxifen therapies on cognition among women aged ≥65 years.
Annual Modified Mini-Mental State (3MS) examinations were used to assess global cognitive function in the two randomized placebo-controlled clinical trials of CEE therapies of the Women's Health Initiative Memory Study (WHIMS) and the Cognition in the Study of Tamoxifen and Raloxifene (CoSTAR). Analyses were limited to women who had 3MS testing at baseline and the first 3 years of follow-up and, because of potential ethnic-related differences between studies, to Caucasian women (WHIMS n = 6211, CoSTAR n = 250). Covariate adjustment was used to compare the postrandomization mean 3MS scores among the three active therapies with placebo therapy while controlling for differences between groups with respect to dementia risk factors.
At baseline, the average (SD) 3MS scores by group were 95.24 (4.28) for placebo, 95.19 (4.33) for CEE, 94.60 (4.76) for raloxifene, and 95.02 (4.03) for tamoxifen. Compared with placebo, each active therapy was associated with a small mean relative deficit in 3MS scores of ≤0.5 units, which was fairly consistent between women with and without prior hysterectomy. Relative deficits were slightly greater for tamoxifen (p = 0.001) and less marked for raloxifene (p = 0.06) and CEE (p = 0.02) therapies. Relative deficits appeared to be greater among women with lower baseline 3MS scores: p = 0.009 (tamoxifen), p = 0.08 (raloxifene), and p = 0.03 (CEE).
Although unmeasured differences between trials may have confounded analyses, these findings raise the possibility that both tamoxifen and raloxifene adversely affect cognitive function in older women; however, the magnitude of the effect is small, and the long-term consequences are unknown.
PMCID: PMC2867626  PMID: 20136553
9.  Ginkgo biloba for Preventing Cognitive Decline in Older Adults 
The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.
To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.
Design, Setting, and Participants
The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.
Twice-daily dose of 120-mg extract of G biloba (n=1545) or identical-appearing placebo (n=1524).
Main Outcome Measures
Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.
Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P=.71; for ADAS-Cog, P=.97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P>.05).
Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.
Trial Registration Identifier: NCT00010803
PMCID: PMC2832285  PMID: 20040554
10.  Psychiatric Disorders and Cognitive Dysfunction Among Older, Postmenopausal Women: Results From the Women’s Health Initiative Memory Study 
To estimate the frequency of depressive symptoms and selected psychiatric disorders in the Women’s Health Initiative Memory Study (WHIMS) cohort and related them to cognitive syndromes.
WHIMS was a randomized, double-blinded, placebo-controlled prevention clinical trial examining whether opposed and unopposed hormone therapy reduced the risk of dementia in healthy postmenopausal women. Participants scoring below a designated cutpoint on a cognitive screener received a comprehensive neuropsychiatric workup and adjudicated outcome of no cognitive impairment, mild cognitive impairment, or probable dementia.
Seven thousand four hundred seventy-nine WHIMS participants between age 65 and 79 years and free of dementia at the time of enrollment in WHIMS. Five hundred twenty-one unique participants contributed complete data required for these analyses.
Depressive symptoms were measured with the 15-item Geriatric Depression Scale and the presence of selected psychiatric disorders (major depression, generalized anxiety, and panic and alcohol abuse) was made using the PRIME-MD.
The 18% of women had at least one psychiatric disorder with depression being the most common (16%) followed by general anxiety or panic (6%) and alcohol abuse (1%). Depression and the presence of a psychiatric disorder were associated with impaired cognitive status. Participants having a psychiatric disorder were more than twice as likely to be diagnosed with cognitive impairment as those with no psychiatric disorder (odds ratio = 2.06, 95% confidence interval = 1.17–3.60). Older age, white race, and diabetes were also associated with cognitive impairment.
The frequency of a psychiatric disorder is associated with poorer cognitive functioning among older women enrolled in WHIMS. That approximately one in five women had a probable psychiatric disorder, most typically depression, highlights the need for greater detection and treatment efforts in this population.
PMCID: PMC2939041  PMID: 20104074
Psychiatric disorders; cognition; MCI; risk of dementia; comorbidity
Aging & mental health  2009;13(2):171-182.
To identify, characterize and compare the frequency of Mild Cognitive Impairment (MCI) subtypes at baseline in a large, late-life cohort (N=3,063) recruited into a dementia prevention trial.
A retrospective, data-algorithmic approach was used to classify participants as cognitively normal or MCI with corresponding subtype (e.g., amnestic vs. non-amnestic, single domain vs. multiple domain) based on a comprehensive battery of neuropsychological test scores, with and without Clinical Dementia Rating (CDR) global score included in the algorithm.
Overall, 15.7% of cases (n=480) were classified as MCI. Amnestic MCI was characterized as unilateral memory impairment (i.e., only verbal or only visual memory impaired) or bilateral memory impairment (i.e., both verbal and visual memory impaired). All forms of amnestic MCI were almost twice as frequent as non-amnestic MCI (10.0% vs. 5.7%). Removing the CDR = 0.5 (“questionable dementia”) criterion resulted in a near doubling of the overall MCI frequency to 28.1%.
Combining CDR and cognitive test data to classify participants as MCI resulted in overall MCI and amnestic MCI frequencies consistent with other large community-based studies, most of which relied on the “gold standard” of individual case review and diagnostic consensus. The present data-driven approach may prove to be an effective alternative for use in future large-scale dementia prevention trials.
PMCID: PMC2767255  PMID: 19347684
MCI; Neuropsychology; Dementia Prevention Trials

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