Papers by Michael C Donohue
Contemporary clinical trials, Jan 10, 2015
Advances in information technology and near ubiquity of the Internet have spawned novel modes of ... more Advances in information technology and near ubiquity of the Internet have spawned novel modes of communication and unprecedented insights into human behavior via the digital footprint. Health behavior randomized controlled trials (RCTs), especially technology-based, can leverage these advances to improve the overall clinical trials management process and benefit from improvements at every stage, from recruitment and enrollment to engagement and retention. In this paper, we report the results for recruitment and retention of participants in the SMART study and introduce a new model for clinical trials management that is a result of interdisciplinary team science. The MARKIT model brings together best practices from information technology, marketing, and clinical research into a single framework to maximize efforts for recruitment, enrollment, engagement, and retention of participants into a RCT. These practices may have contributed to the study's on-time recruitment that was with...
Background: As many as 40% of older people are prescribed medications with anticholinergic activi... more Background: As many as 40% of older people are prescribed medications with anticholinergic activity. Studies have suggested the significant effect of anticholinergic medication on cognition but there is controversy. Objective: Analysis of 15908 patients impact of anticholinergic drugs on cognition. Methods: The anticholinergic burden scale (ABS) coded drugs 0 (none), 1 (mild), 2 (moderate), or 3 (severe). Scores were summed for each participant to give a total Anticholinergic Cognitive Burden (ACB) score. Study 1 MRC CFAS with 11,994 participants and cross sectional coding part of a 19 year longitudinal; Study 2 LASER-AD -Dementia Specific 18 month longitudinal with 224 participants. Study 3 SAP REDS USA 1 year follow up with 3690 participants. Study 1 MRC-CFAS -A statistically significant dose-response relation was observed between increasing ACB score and decreasing MMSE, e.g. those with an ACB score of 5 or greater were associated with making 21% (95%CI 8%-35%) more errors on the MMSE. The relationship with cognitive impairment was only seen for ACB conferred by Central Nervous System medications, in particular antipsychotics. Study 2 LASER AD -Anti-cholinergic burden had no significant effect on cognitive decline at 18 months as assessed by the ADAS-cog. The ADAS-cog decreased by a mean of 4.63 in the cohort of patients with an ACB of 0, compared with a mean decrease of 7.4 in patients with an ACB of > 0 (mean difference ¼ 2.83; t ¼ 1.107; df ¼ 100; p ¼ 0.271; CI-2.24-7.9). Study 3 SAP REDS -Anticholinergic burden for 60 days was associated with a significant effect on cognitive decline as measured by the Community Screening Interview for Dementia odds ratio 1.55p < 0.05 (CI-1.05-2.29) with a possible burden dose response effect. Conclusion: An inverse relation existed between the anticholinergic burden of current medication use and cognition in study 1 and study 3; in study 1 the association was driven by the ACB of CNS medications. However, in study 2 no association was detected. Thus the abandonment of use of medication with anticholinergic effects may not be warranted. Further research is required to determine the clinical relevance.
JAMA neurology, 2014
The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of... more The effect of β-amyloid (Aβ) accumulation on regional structural brain changes in early stages of Alzheimer disease (AD) is not well understood. To test the hypothesis that the development of Aβ pathology is related to increased regional atrophy in the brains of cognitively normal (CN) persons. Longitudinal clinicobiomarker cohort study involving 47 CN control subjects and 15 patients with AD dementia. All participants underwent repeated cerebrospinal fluid Aβ42 and structural magnetic resonance imaging measurements for up to 4 years. Cognitively normal controls were classified using the longitudinal cerebrospinal fluid Aβ42 data and included 13 stable Aβ negative (normal baseline Aβ42 levels, with less than the median reduction over time), 13 declining Aβ negative (normal baseline Aβ42 levels, with greater than the median reduction over time), and 21 Aβ positive (pathologic baseline Aβ42 levels). All 15 patients with AD dementia were Aβ positive. Group effects on regional gray matt...
Gastrointestinal Endoscopy, 2007
This report describes the baseline experience of the multicenter, Home-Based Assessment study, de... more This report describes the baseline experience of the multicenter, Home-Based Assessment study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Nondemented individuals of 75 years of age or more were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: (1) mail-in questionnaire/live telephone interviews [mail-in/phone (MIP)];
Alzheimer's & dementia : the journal of the Alzheimer's Association, 2011
Background-Low cerebrospinal fluid (CSF) amyloid-β 1-42 concentration and high total-tau/ Aβ 1-42... more Background-Low cerebrospinal fluid (CSF) amyloid-β 1-42 concentration and high total-tau/ Aβ 1-42 ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials.
Brain : a journal of neurology, Jan 24, 2014
Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission ... more Reduced cerebrospinal fluid amyloid-β42 and increased retention of florbetapir positron emission tomography are biomarkers reflecting cortical amyloid load in Alzheimer's disease. However, these measurements do not always agree and may represent partly different aspects of the underlying Alzheimer's disease pathology. The goal of this study was therefore to test if cerebrospinal fluid and positron emission tomography amyloid-β biomarkers are independently related to other Alzheimer's disease markers, and to examine individuals who are discordantly classified by these two biomarker modalities. Cerebrospinal fluid and positron emission tomography amyloid-β were measured at baseline in 769 persons [161 healthy controls, 68 subjective memory complaints, 419 mild cognitive impairment and 121 Alzheimer's disease dementia, mean age 72 years (standard deviation 7 years), 47% females] and used to predict diagnosis, APOE ε4 carriage status, cerebral blood flow, cerebrospinal f...
Annals of clinical and translational neurology, 2014
Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission ... more Reduced cerebrospinal fluid (CSF) β-amyloid42 (Aβ42) and increased florbetapir positron emission tomography (PET) uptake reflects brain Aβ accumulation. These biomarkers are correlated with each other and altered in Alzheimer's disease (AD), but no study has directly compared their diagnostic performance. We examined healthy controls (CN, N = 169) versus AD dementia patients (N = 118), and stable (sMCI; no dementia, followed up for at least 2 years, N = 165) versus progressive MCI (pMCI; conversion to AD dementia, N = 59). All subjects had florbetapir PET (global and regional; temporal, frontal, parietal, and cingulate) and CSF Aβ42 measurements at baseline. We compared area under the curve (AUC), sensitivity, and specificity (testing a priori and optimized cutoffs). Clinical diagnosis was the reference standard. CSF Aβ42 and (global or regional) PET florbetapir did not differ in AUC (CN vs. AD, CSF 84.4%; global PET 86.9%; difference [95% confidence interval] -6.7 to 1.5). CSF ...
Journal of Hepatology, 2012
Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor. Alt... more Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor. Although modest alcohol consumption may reduce the risk for cardiovascular mortality, whether patients with NAFLD should be allowed modest alcohol consumption remains an important unaddressed issue. We aimed to evaluate the association between modest alcohol drinking and non-alcoholic steatohepatitis (NASH), among subjects with NAFLD. Methods: In a cross-sectional analysis of adult participants in the NIH NASH Clinical Research Network, only modest or non-drinkers were included: participants identified as (1) drinking >20 g/day, (2) binge drinkers, or (3) non-drinkers with previous alcohol consumption were excluded. The odds of having a histological diagnosis of NASH and other histological features of NAFLD were analyzed using multiple ordinal logistic regression. Results: The analysis included 251 lifetime non-drinkers and 331 modest drinkers. Modest drinkers compared to non-drinkers had lower odds of having a diagnosis of NASH (summary odds ratio 0.56, 95% CI 0.39-0.84, p = 0.002). The odds of NASH decreased as the frequency of alcohol consumption increased within the range of modest consumption. Modest drinkers also had significantly lower odds for fibrosis (OR 0.56 95% CI 0.41-0.77) and ballooning hepatocellular injury (OR 0.66 95% CI 0.48-0.92) than lifetime non-drinkers. Conclusions: In a large, well-characterized population with biopsy-proven NAFLD, modest alcohol consumption was associated with lesser degree of severity as determined by lower odds of the key features that comprise a diagnosis of steatohepatitis, as well as fibrosis. These findings demonstrate the need for prospective studies and a coordinated consensus on alcohol consumption recommendations in NAFLD. Ó (J.B. Schwimmer). For the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN): NASH CRN Roster in Acknowledgements section.
Alzheimer's & Dementia, 2012
Neurology, 2011
Background: A large number of promising candidate disease-modifying treatments for Alzheimer dise... more Background: A large number of promising candidate disease-modifying treatments for Alzheimer disease (AD) continue to advance into phase II and phase III testing. However, most completed trials have failed to demonstrate efficacy, and there is growing concern that methodologic difficulties may contribute to these clinical trial failures. The optimal time to intervene with such treatments is probably in the years prior to the onset of dementia, before the neuropathology has progressed to the advanced stage corresponding to clinical dementia. Method: An international task force of individuals from academia, industry, nonprofit foundations, and regulatory agencies was convened to discuss optimal trial design in early (predementia) AD.
NeuroImage, 2010
Neurodegeneration precedes the onset of dementias such as Alzheimer's by several years. Recent ad... more Neurodegeneration precedes the onset of dementias such as Alzheimer's by several years. Recent advances in volumetric imaging allow quantification of subtle neuroanatomical change over time periods as short as six months. This study investigates whether neuroanatomical change in medial temporal lobe subregions is associated with later memory decline in elderly controls. Using highresolution, T1-weighted magnetic resonance images acquired at baseline and six months follow-up, change in cortical thickness and subcortical volumes was measured in 142 healthy elderly subjects (aged 59 -90 years) from the ADNI cohort. Regression analysis was used to identify whether change in fourteen subregions, selected a priori, was associated with declining performance on memory tests from baseline to two years follow-up. Percent thickness change in the right fusiform and inferior temporal cortices and expansion of the right inferior lateral ventricle were found to be significant predictors of subsequent decline on memory-specific neuropsychological measures. These results demonstrate that six-month regional neurodegeneration can be quantified in the healthy elderly and might help identify those at risk for subsequent cognitive decline.
JAMA neurology, Jan 16, 2015
Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation witho... more Alzheimer disease has a long preclinical stage characterized by β-amyloid (Aβ) accumulation without symptoms. Several trials focus on this stage and use biomarkers to include Aβ-positive participants, but an even earlier prevention of Aβ accumulation may be an effective treatment strategy. To determine whether people who appear to be Aβ negative but are at high risk for Aβ positivity within the near future can be identified. Longitudinal biomarker cohort study involving 35 cognitively healthy individuals who underwent cerebrospinal fluid (CSF) sampling for up to 3 years during the study (October 24, 2005, to September 1, 2014). All participants had normal CSF Aβ42 levels at baseline. Predictors of future Aβ positivity (levels of CSF Aβ42 declining below a previously validated cutoff level of 192 ng/L) tested by random forest models. Tested predictors included levels of protein in the CSF, hippocampal volume, genetics, demographics, and cognitive scores. The CSF Aβ42 levels declined ...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 9, 2014
Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated wi... more Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) associated with brain atrophy and cognitive decline. The functional form to model the association between Aβ and regional brain atrophy has not been well defined. To determine the relationship between Aβ and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Aβ to identify subjects as Aβ+ and Aβ- with a trilinear spline model of CSF Aβ. One hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Aβ and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF Aβ and regional atrophy and to identify points of acceleration of atrophy with respect to Aβ. Several parameterizations of CSF Aβ were c...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2014
Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer'... more Little is known about the utility of plasma amyloid beta (Aβ) in clinical trials of Alzheimer's disease (AD). We analyzed longitudinal plasma samples from two large multicenter clinical trials: (1) donezepil and vitamin E in mild cognitive impairment (n = 405, 24 months) and (2) simvastatin in mild to moderate AD (n = 225, 18 months). Baseline plasma Aβ was not related to cognitive or clinical progression. We observed a decrease in plasma Aβ40 and 42 among apolipoprotein E epsilon 4 (APOE ε4) carriers relative to noncarriers in the mild cognitive impairment trial. Patients treated with simvastatin showed a significant increase in Aβ compared with placebo. We found significant storage time effects and considerable plate-to-plate variation. We found no support for the utility of plasma Aβ as a prognostic factor or correlate of cognitive change. Analysis of stored specimens requires careful standardization and experimental design, but plasma Aβ may prove useful in pharmacodynamic s...
PEDIATRICS, 2007
In this study we aimed to explore parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more In this study we aimed to explore parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; weight perceptions of their children and of unrelated children. Parents of children &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; or = 18 years of age who were attending pediatric clinics throughout San Diego County, California, were surveyed concerning their children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s weight status and the weight status of unrelated children in various age groups. Height and weight were measured, and weight status was determined for both the parent and child. The influence of various demographic variables on parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; weight perceptions and the relationship between parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; perceptions of weight of their children and parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; perceptions of weight of unrelated children were evaluated. Multivariate regression modeling was applied to identify predictors of parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; perceptions of weight of their own children. Of 1098 parents surveyed, 87% were women, 74% were white, and 46% reported Hispanic ethnicity. Seventy percent of the parents surveyed were overweight or obese, and 39% of their children were at risk for overweight or overweight. Sixty-one percent of parents correctly identified their children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s weight status, and parents were able to correctly identify the weight status of unrelated children in 58% of reviewed photographs. Parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; weight perceptions of their children were not related to their ability to determine the weight status of unrelated children or to their ideal weight selections among unrelated children. In a multivariate logistic regression analysis, parental ability to correctly assess their child&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s weight status was associated with their child&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s age and weight status. Parents&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; perceptions of their own children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s weight status are influenced by their children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s characteristics and do not seem to correspond with their weight perceptions of unrelated children. Parental recognition of weight issues in their offspring may be impeded by their inability to apply criteria used to ascertain the weight status of unrelated children to their own children.
Alzheimer's & Dementia, 2008
none of them were evaluated in Mexican patients. Therefore we conducted this study to determine t... more none of them were evaluated in Mexican patients. Therefore we conducted this study to determine the clinimetrical properties (construct validity and reliability) of the NPI Q and NPI D in a group of Mexican demented patients. Methods: We conducted a transversal, analytical and validation essay. We selected 100 dyads, with dementia diagnosis (of any type). The dyads were interviewed with neuropsychological tools (Mini Mental State Examination, Geriatric Depression Scale, Screening Caregiver Burden, Sleep Disorders Inventory NPI Q, NPI D), sociodemographic questionnaire (age, sex, caregiver relationship, work status, scholarship, etc), a thorough record of comorbidities, medications, and an exploration to complete the Mini Nutritional Assessment. NPI QЈs total score was correlated with MMSE, GDS, NPI D and SCB; and individual domains were also evaluated (depression, psychotic symptoms, nutrition and sleep). The NPI DЈs total score was correlated with SCB and NPI Q. Six patients were selected for a test-retest, to evaluate reliability. SpearmanЈs one tailed correlation, intraclass correlation coefficient (ICC) and CronbachЈs alpha, were performed for statistical analysis. Results: Eighty-seven dyads were interviewed, general characteristics are shown in . The NPI-Q had a significant correlation with MMSE of 0,190 (pϭ0.001), NPI-D of rϭ0,887 (p Ͻ0,001), with GDS of rϭ0,385 (pϭ0.0001). The NPI-Q with a testretest of rϭ0,829 (p ϭ0.021), ICC 0.824 and internal consistency of ␣ϭ0.778, the individual domain results are shown in . The NPI D had a significant correlation of rϭ0.555 with the SCB; test-retest rϭ 0.986, ICC 0.857 and ␣ϭ0.779. Conclusions: Our NPI-Q and NPI-D versions are valid in the evaluation of Mexican patients with dementia. Our results are similar to those reported previously, but add the significant evaluation in the individual domains of sleep and oral intake.
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Papers by Michael C Donohue