Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may... more Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may increase the risk for Alzheimer’s disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer’s disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer’s disease associated with exposure. Participants included older females (n = 998; aged 73–87) enrolled in both the Women’s Health Initiative Study of Cognitive Aging and the Women’s Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999–2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1–3; List B) and delayed free ...
International Journal of Geriatric Psychiatry, 2019
ObjectiveWhile a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's... more ObjectiveWhile a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS).MethodsWe analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non‐Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model.ResultsOne SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with t...
The journals of gerontology. Series A, Biological sciences and medical sciences, Jan 9, 2016
Midlife obesity has been linked to age-related brain atrophy and risk of dementia, but the relati... more Midlife obesity has been linked to age-related brain atrophy and risk of dementia, but the relationships are less clear for older individuals. These associations may be explained by changes in appetite or metabolism in the dementia prodrome; thus, prospective studies with adequate follow-up are needed. We examined the associations that obesity (body mass index, BMI) and change in BMI over an average of 6.6 (1.0-9.1) years have with global and regional brain and white matter lesion volumes in a sample of 1,366 women aged 65-80. Least square means for regional brain volumes and white matter lesion loads for women grouped by BMI and changes in BMI were generated from multivariable linear models with and without adjustment for demographic and health covariates. Both global obesity and increase in BMI were associated with lower cerebrospinal fluid and higher specific brain volumes (ps < .05), after controlling for diabetes and other cerebrovascular disease risk factors. Obesity, but n...
The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an... more The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an opportunity to evaluate how menopausal hormone therapy (HT) affects the structure of older women's brains. Our earlier work based on region of interest (ROI) analysis demonstrated potential structural changes underlying adverse effects of HT on cognition. However, the ROI-based analysis is limited in statistical power and precision, and cannot provide fine-grained mapping of whole-brain changes. We aimed to identify local structural differences between HT and placebo groups from WHIMS-MRI in a whole-brain refined level, by using a novel method, named Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a recently proposed imaging pattern analysis approach for group comparisons utilizing a spatially adaptive analysis scheme to accurately locate areas of group differences, thereby providing superior sensitivity and specificity to detect the structural brain changes over con...
Journal of the American Geriatrics Society, Jul 4, 2018
Background/Objectives-To examine whether trajectories of global cognitive function over time in s... more Background/Objectives-To examine whether trajectories of global cognitive function over time in studies that change assessment protocols may be modeled based on an individual's performance relative to others in the study cohort. Design-The Women's Health Initiative Memory Study switched from an in-person interview with the Modified MiniMental State Exam (3MSE) to a telephone-based interview with the Telephone Interview for Cognitive Status (TICSm) for assessing global cognitive function during long term follow-up. Annual cognitive assessments from participants, ranked according to ageand race/ethnicity-adjusted performance levels, were used to identify distinct trajectories. Participants assigned to the resulting trajectories were compared for selected risk factor profiles. Setting-Extended follow-up of a cohort originally enrolled in a clinical trial of postmenopausal hormone therapy Participants-Women (N=2,561) aged 75 to 92 years Results-Our approach grouped participants into five trajectories according to relative cognitive performance over time. These groups differed significantly according to three known risk factors for cognitive decline-education level, APOE-ε4 genotype, and type 2 diabetes-and a biomarker based on brain structure that has been linked to increased cognitive decline and Alzheimer's disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles. Conclusion-Longitudinal measures of an individual's relative performance across different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors.
International Journal of Biomedical Data Mining, 2011
In this work we introduce the use of penalized logistic regression (PLR) to the problem of classi... more In this work we introduce the use of penalized logistic regression (PLR) to the problem of classification of MRI images and automatic detection of Alzheimer's disease. Classification of sMRI is approached as a large scale regularization problem which uses voxels as input features. We evaluate how differences in sMRI preprocessing steps such as smoothing, normalization, and template selection affect the performance of highdimensional classification methods. In addition, we compared the relative performance of PLR to a different approach based on support vector machines. To study these questions we used data from the Alzheimer Disease Neuroimaging Initiative (ADNI). The ADNI project follows a protocol consisting of acquisition of two images in each session, image correction steps and further evaluation by experts to obtain the optimized images. We evaluated here the impact of this optimization process on the performance of high-dimensional machine learning techniques.
In this work we use a large scale regularization approach based on penalized logistic regression ... more In this work we use a large scale regularization approach based on penalized logistic regression to automatically classify structural MRI images (sMRI) according to cognitive status. Its performance is illustrated using sMRI data from the Alzheimer Disease ...
Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in wom... more Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L 1 penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers.
Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may... more Evidence suggests exposure to particulate matter with aerodynamic diameter <2.5 μm (PM2.5) may increase the risk for Alzheimer’s disease and related dementias. Whether PM2.5 alters brain structure and accelerates the preclinical neuropsychological processes remains unknown. Early decline of episodic memory is detectable in preclinical Alzheimer’s disease. Therefore, we conducted a longitudinal study to examine whether PM2.5 affects the episodic memory decline, and also explored the potential mediating role of increased neuroanatomic risk of Alzheimer’s disease associated with exposure. Participants included older females (n = 998; aged 73–87) enrolled in both the Women’s Health Initiative Study of Cognitive Aging and the Women’s Health Initiative Memory Study of Magnetic Resonance Imaging, with annual (1999–2010) episodic memory assessment by the California Verbal Learning Test, including measures of immediate free recall/new learning (List A Trials 1–3; List B) and delayed free ...
International Journal of Geriatric Psychiatry, 2019
ObjectiveWhile a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's... more ObjectiveWhile a number of single nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) or cognitive impairment have been identified, independent replications remain the only way to validate proposed signals. We investigated SNPs in candidate genes associated with either cognitive impairment or AD pathogenesis and their relationships with probable dementia (PD) in the Women's Health Initiative Memory Study (WHIMS).MethodsWe analyzed 96 SNPs across five genes (APOE/TOMM40, BDNF, COMT, SORL1, and KIBRA) in 2857 women (ages ≥65) from the WHIMS randomized trials of hormone therapy using a custom Illumina GoldenGate assay; 19% of the sample were MCI (N = 165) or PD (N = 387), and the remaining 81% were free of cognitive impairment. SNP associations were evaluated for PD in non‐Hispanic whites adjusting for age and HT using logistic regression under an additive genetic model.ResultsOne SNP (rs157582), located in the TOMM40 gene nearby APOE, was associated with t...
The journals of gerontology. Series A, Biological sciences and medical sciences, Jan 9, 2016
Midlife obesity has been linked to age-related brain atrophy and risk of dementia, but the relati... more Midlife obesity has been linked to age-related brain atrophy and risk of dementia, but the relationships are less clear for older individuals. These associations may be explained by changes in appetite or metabolism in the dementia prodrome; thus, prospective studies with adequate follow-up are needed. We examined the associations that obesity (body mass index, BMI) and change in BMI over an average of 6.6 (1.0-9.1) years have with global and regional brain and white matter lesion volumes in a sample of 1,366 women aged 65-80. Least square means for regional brain volumes and white matter lesion loads for women grouped by BMI and changes in BMI were generated from multivariable linear models with and without adjustment for demographic and health covariates. Both global obesity and increase in BMI were associated with lower cerebrospinal fluid and higher specific brain volumes (ps < .05), after controlling for diabetes and other cerebrovascular disease risk factors. Obesity, but n...
The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an... more The Women's Health Initiative Memory Study Magnetic Resonance Imaging (WHIMS-MRI) provides an opportunity to evaluate how menopausal hormone therapy (HT) affects the structure of older women's brains. Our earlier work based on region of interest (ROI) analysis demonstrated potential structural changes underlying adverse effects of HT on cognition. However, the ROI-based analysis is limited in statistical power and precision, and cannot provide fine-grained mapping of whole-brain changes. We aimed to identify local structural differences between HT and placebo groups from WHIMS-MRI in a whole-brain refined level, by using a novel method, named Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a recently proposed imaging pattern analysis approach for group comparisons utilizing a spatially adaptive analysis scheme to accurately locate areas of group differences, thereby providing superior sensitivity and specificity to detect the structural brain changes over con...
Journal of the American Geriatrics Society, Jul 4, 2018
Background/Objectives-To examine whether trajectories of global cognitive function over time in s... more Background/Objectives-To examine whether trajectories of global cognitive function over time in studies that change assessment protocols may be modeled based on an individual's performance relative to others in the study cohort. Design-The Women's Health Initiative Memory Study switched from an in-person interview with the Modified MiniMental State Exam (3MSE) to a telephone-based interview with the Telephone Interview for Cognitive Status (TICSm) for assessing global cognitive function during long term follow-up. Annual cognitive assessments from participants, ranked according to ageand race/ethnicity-adjusted performance levels, were used to identify distinct trajectories. Participants assigned to the resulting trajectories were compared for selected risk factor profiles. Setting-Extended follow-up of a cohort originally enrolled in a clinical trial of postmenopausal hormone therapy Participants-Women (N=2,561) aged 75 to 92 years Results-Our approach grouped participants into five trajectories according to relative cognitive performance over time. These groups differed significantly according to three known risk factors for cognitive decline-education level, APOE-ε4 genotype, and type 2 diabetes-and a biomarker based on brain structure that has been linked to increased cognitive decline and Alzheimer's disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles. Conclusion-Longitudinal measures of an individual's relative performance across different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors.
International Journal of Biomedical Data Mining, 2011
In this work we introduce the use of penalized logistic regression (PLR) to the problem of classi... more In this work we introduce the use of penalized logistic regression (PLR) to the problem of classification of MRI images and automatic detection of Alzheimer's disease. Classification of sMRI is approached as a large scale regularization problem which uses voxels as input features. We evaluate how differences in sMRI preprocessing steps such as smoothing, normalization, and template selection affect the performance of highdimensional classification methods. In addition, we compared the relative performance of PLR to a different approach based on support vector machines. To study these questions we used data from the Alzheimer Disease Neuroimaging Initiative (ADNI). The ADNI project follows a protocol consisting of acquisition of two images in each session, image correction steps and further evaluation by experts to obtain the optimized images. We evaluated here the impact of this optimization process on the performance of high-dimensional machine learning techniques.
In this work we use a large scale regularization approach based on penalized logistic regression ... more In this work we use a large scale regularization approach based on penalized logistic regression to automatically classify structural MRI images (sMRI) according to cognitive status. Its performance is illustrated using sMRI data from the Alzheimer Disease ...
Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in wom... more Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L 1 penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers.
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Papers by Ramon Casanova