- Email: [email protected]
LEFT LATERALIZED CEREBRAL GLUCOSE METABOLISM DECLINES IN AMYLOID-β– POSITIVE SUBJECTS WITH MILD COGNITIVE IMPAIRMENT
P152
Poster Presentations: Saturday, July 15, 2017
measurements acquired at two times over an observed time interval (DTo). While this approach may be suitable for RCT in which the proposed treatment time interval (DTt) is equal to DTo, its use need some cautions when a) DTt is longer or shorter than DTo or b) there are substantial individual variations in DTo. Methods: We considered the case in which each individual j had two observed serial measurements, xj1 and xj2, before and after time interval DToj for total of N subjects in an existing data set. The subtraction method multiplies the annualized subject group’s mean change P m¼(1/N)( (xj1 - xj2)/DToj) and its standard deviation s by DTt to form DTt3m and DTt3s and use them to estimate the number of subjects needed to detect a particular treatment effect with a predefined statistical power and type-I error. As is known, the sample size estimate would then depend entirely on the std/mean ratio, with no additional consideration of the impact of longer or shorter DTt rather than serving as a common multiplier. Results: 1), Using the simple subtraction method, sample size estimates would be the same regardless of RCT duration due to the common std/mean ratio and without additional models or assumptions. 2, The reason for this limitation is the misuse of the linear assumption (common multiplier) and the overlook of the measurement errors in forming the subtraction. 3, The simple subtraction approach works if one of several conditions holds. For example, a) the measurement error is ignorable or linearly related to trial duration; b) the P proposed RCT duration DTt and the individualized DToj satisfy Nj¼1(1/DToj2)¼ N/DTt2; or c) if the between-subject variability of the annualized change is low, the std/mean ratio will be proportional to 1/DTt and the corresponding sample size decreases for longer DTt duration. Conclusions: The subtraction procedure should be used with caution. Importantly, this approach would require assumptions about the impact of treatment interval or use of an alternative (e.g., mixed model) approach.
IC-P-210
LEFT LATERALIZED CEREBRAL GLUCOSE METABOLISM DECLINES IN AMYLOID-b– POSITIVE SUBJECTS WITH MILD COGNITIVE IMPAIRMENT
Christopher M. Weise1, Kewei Chen2,3,4,5, Xiaoying Kuang2,5, Cary Savage2, Eric M. Reiman2,3,4,6, 1University of Leipzig, Leipzig, Germany; 2Banner Alzheimer’s Institute, Phoenix, AZ, USA; 3University of Arizona, Tucson, AZ, USA; 4Arizona State University, Tempe, AZ, USA; 5 Arizona Alzheimer’s Consortium, Phoenix, AZ, USA; 6Translational Genomics Research Institute, Phoenix, AZ, USA. Contact e-mail: kewei. [email protected] Background: It has been suggested that Alzheimer’s Disease (AD)
related neurodegeneration and cortical atrophy may develop in asymmetric patterns, with accentuation in the left hemisphere (e.g. Thompson et al., 2003). Flourodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate of glucose (rCMRgl) provide an indicator of AD progression. Longitudinal FDG PET images from the AD Neuroimaging Initiative (ADNI) were used to explore the possibility of lateralized (i.e., left>right rCMRgl progression in the clinical stages of AD. Methods: An automated brain mapping algorithm (SPM8) was used to characterize and compare 24-mo rCMRgl declines in 167 7666 yo subjects, including 51 amyloid-b+ (Ab+) subjects with AD dementia, 76 Ab+ subjects with mild cognitive impairment (MCI), and 40 amyloid-b negative (Ab-) normal con-
trols. Lateralization of rCMRgl declines was assessed by calculating an overall weighted bootstrapped lateralization index (LI) as implemented within the LI-toolbox (Wilke and Lidzba, 2007). Based on the calculated weighted means (LIwm), lateralization was classified as either absent (LIwm -0.25 to 0.25), weak (LIwm -0.25 to -0.50 and 0.25 to 0.50) or strong (LIwm <-0.50 and >0.50). Results: Compared to NC, MCI patients showed strong left hemispheric lateralization (LIwm -0.78) with rCMRgl declines predominantly located within the left lateral temporal cortex and the precuneus. Subjects with AD exhibited widespread bilateral declines of rCMRgl, predominatly within the bilateral temporal cortices (lateral>medial), the parietal lobes (i.e. bilateral inferior parietal lobule), bilateral precuneus and the posterior cingulate with signs of weak right hemispheric lateralization (LIwm 0.33). Within group analyses yielded similar patterns of lateralization for MCI and AD patients, however in MCI left hemispheric lateralization was weaker as when compared to NC (MCI: LIwm 0.46; AD: LIwm -0.44). Additional exploratory analyses yielded significant correlations between left hemispheric rCMRgl declines with worsening of cognitive function in subjects with MCI (DMMSE: rho¼0.32 p¼0.005; DADAS-Cog: rho¼-0.37, p<0.001). Conclusions: These data suggest that AD may be characterized by an asymmetric pattern of left lateralized rCMRgl declines in the MCI but not dementia stages of AD.
IC-P-211
A COMPUTATIONAL MONTE CARLO SIMULATION STRATEGY TO COMPARE THE ONSET OF DIFFERENT BIOMARKER AND COGNITIVE CHANGES
Kewei Chen1,2,3,4, Yinghua Chen1,4, Chengjie Xiong5,6, Eric M. Reiman1,2,3,4,7, 1Banner Alzheimer’s Institute, Phoenix, AZ, USA; 2 University of Arizona, Tucson, AZ, USA; 3Arizona State University, Tempe, AZ, USA; 4Arizona Alzheimer’s Consortium, Phoenix, AZ, USA; 5Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA; 6Washington University in St. Louis School of Medicine, St. Louis, MO, USA; 7 Translational Genomics Research Institute, Phoenix, AZ, USA. Contact e-mail: [email protected] Background: Longitudinal data can be used to clarify the temporal sequence of biomarker and cognitive changes associated with Alzheimer’s disease (AD). Here, we capitalizing on longitudinal data from the AD Neuroimaging Initiative (ADNI) and mixed effect modeling to introduce the use of a Computational Monte-Carlo Simulation (CMCS) method to compare the onset of different AD-related biomarker and cognitive changes. Methods: We sought to characterize and compare the onset of progressive hippocampus volume (VHC) and Mini-Mental State Examination (MMSE) declines in 129 persons with mild cognitive impairment (MCI) who progressed to probable AD dementia and 253 persons with MCI who remained stage during the same time frame. The CMCS method was used in the following way to test the hypothesis that the onset of VHC decline is x-years earlier than MMSE decline in subsequent progressors versus non-progressors: It 1) simulated each person’s longitudinal data with mixed effect model using the perspective fixed effect parameters, characterized random effect parameters and residual error, and accounted for a variance as high as 200%; 2) fitted the mixed effect model to simulated data to characterize respective ages at onset of progressive VHC and MMSE decline in the progressors; 3) computed the difference between these ages of onset; 4) repeated the process N times; and 5)
Poster Presentations: Saturday, July 15, 2017
measurements acquired at two times over an observed time interval (DTo). While this approach may be suitable for RCT in which the proposed treatment time interval (DTt) is equal to DTo, its use need some cautions when a) DTt is longer or shorter than DTo or b) there are substantial individual variations in DTo. Methods: We considered the case in which each individual j had two observed serial measurements, xj1 and xj2, before and after time interval DToj for total of N subjects in an existing data set. The subtraction method multiplies the annualized subject group’s mean change P m¼(1/N)( (xj1 - xj2)/DToj) and its standard deviation s by DTt to form DTt3m and DTt3s and use them to estimate the number of subjects needed to detect a particular treatment effect with a predefined statistical power and type-I error. As is known, the sample size estimate would then depend entirely on the std/mean ratio, with no additional consideration of the impact of longer or shorter DTt rather than serving as a common multiplier. Results: 1), Using the simple subtraction method, sample size estimates would be the same regardless of RCT duration due to the common std/mean ratio and without additional models or assumptions. 2, The reason for this limitation is the misuse of the linear assumption (common multiplier) and the overlook of the measurement errors in forming the subtraction. 3, The simple subtraction approach works if one of several conditions holds. For example, a) the measurement error is ignorable or linearly related to trial duration; b) the P proposed RCT duration DTt and the individualized DToj satisfy Nj¼1(1/DToj2)¼ N/DTt2; or c) if the between-subject variability of the annualized change is low, the std/mean ratio will be proportional to 1/DTt and the corresponding sample size decreases for longer DTt duration. Conclusions: The subtraction procedure should be used with caution. Importantly, this approach would require assumptions about the impact of treatment interval or use of an alternative (e.g., mixed model) approach.
IC-P-210
LEFT LATERALIZED CEREBRAL GLUCOSE METABOLISM DECLINES IN AMYLOID-b– POSITIVE SUBJECTS WITH MILD COGNITIVE IMPAIRMENT
Christopher M. Weise1, Kewei Chen2,3,4,5, Xiaoying Kuang2,5, Cary Savage2, Eric M. Reiman2,3,4,6, 1University of Leipzig, Leipzig, Germany; 2Banner Alzheimer’s Institute, Phoenix, AZ, USA; 3University of Arizona, Tucson, AZ, USA; 4Arizona State University, Tempe, AZ, USA; 5 Arizona Alzheimer’s Consortium, Phoenix, AZ, USA; 6Translational Genomics Research Institute, Phoenix, AZ, USA. Contact e-mail: kewei. [email protected] Background: It has been suggested that Alzheimer’s Disease (AD)
related neurodegeneration and cortical atrophy may develop in asymmetric patterns, with accentuation in the left hemisphere (e.g. Thompson et al., 2003). Flourodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate of glucose (rCMRgl) provide an indicator of AD progression. Longitudinal FDG PET images from the AD Neuroimaging Initiative (ADNI) were used to explore the possibility of lateralized (i.e., left>right rCMRgl progression in the clinical stages of AD. Methods: An automated brain mapping algorithm (SPM8) was used to characterize and compare 24-mo rCMRgl declines in 167 7666 yo subjects, including 51 amyloid-b+ (Ab+) subjects with AD dementia, 76 Ab+ subjects with mild cognitive impairment (MCI), and 40 amyloid-b negative (Ab-) normal con-
trols. Lateralization of rCMRgl declines was assessed by calculating an overall weighted bootstrapped lateralization index (LI) as implemented within the LI-toolbox (Wilke and Lidzba, 2007). Based on the calculated weighted means (LIwm), lateralization was classified as either absent (LIwm -0.25 to 0.25), weak (LIwm -0.25 to -0.50 and 0.25 to 0.50) or strong (LIwm <-0.50 and >0.50). Results: Compared to NC, MCI patients showed strong left hemispheric lateralization (LIwm -0.78) with rCMRgl declines predominantly located within the left lateral temporal cortex and the precuneus. Subjects with AD exhibited widespread bilateral declines of rCMRgl, predominatly within the bilateral temporal cortices (lateral>medial), the parietal lobes (i.e. bilateral inferior parietal lobule), bilateral precuneus and the posterior cingulate with signs of weak right hemispheric lateralization (LIwm 0.33). Within group analyses yielded similar patterns of lateralization for MCI and AD patients, however in MCI left hemispheric lateralization was weaker as when compared to NC (MCI: LIwm 0.46; AD: LIwm -0.44). Additional exploratory analyses yielded significant correlations between left hemispheric rCMRgl declines with worsening of cognitive function in subjects with MCI (DMMSE: rho¼0.32 p¼0.005; DADAS-Cog: rho¼-0.37, p<0.001). Conclusions: These data suggest that AD may be characterized by an asymmetric pattern of left lateralized rCMRgl declines in the MCI but not dementia stages of AD.
IC-P-211
A COMPUTATIONAL MONTE CARLO SIMULATION STRATEGY TO COMPARE THE ONSET OF DIFFERENT BIOMARKER AND COGNITIVE CHANGES
Kewei Chen1,2,3,4, Yinghua Chen1,4, Chengjie Xiong5,6, Eric M. Reiman1,2,3,4,7, 1Banner Alzheimer’s Institute, Phoenix, AZ, USA; 2 University of Arizona, Tucson, AZ, USA; 3Arizona State University, Tempe, AZ, USA; 4Arizona Alzheimer’s Consortium, Phoenix, AZ, USA; 5Knight Alzheimer’s Disease Research Center, St. Louis, MO, USA; 6Washington University in St. Louis School of Medicine, St. Louis, MO, USA; 7 Translational Genomics Research Institute, Phoenix, AZ, USA. Contact e-mail: [email protected] Background: Longitudinal data can be used to clarify the temporal sequence of biomarker and cognitive changes associated with Alzheimer’s disease (AD). Here, we capitalizing on longitudinal data from the AD Neuroimaging Initiative (ADNI) and mixed effect modeling to introduce the use of a Computational Monte-Carlo Simulation (CMCS) method to compare the onset of different AD-related biomarker and cognitive changes. Methods: We sought to characterize and compare the onset of progressive hippocampus volume (VHC) and Mini-Mental State Examination (MMSE) declines in 129 persons with mild cognitive impairment (MCI) who progressed to probable AD dementia and 253 persons with MCI who remained stage during the same time frame. The CMCS method was used in the following way to test the hypothesis that the onset of VHC decline is x-years earlier than MMSE decline in subsequent progressors versus non-progressors: It 1) simulated each person’s longitudinal data with mixed effect model using the perspective fixed effect parameters, characterized random effect parameters and residual error, and accounted for a variance as high as 200%; 2) fitted the mixed effect model to simulated data to characterize respective ages at onset of progressive VHC and MMSE decline in the progressors; 3) computed the difference between these ages of onset; 4) repeated the process N times; and 5)