- Email: [email protected]
S3-01-04
S46
Symposia S3-02: Disease Mechanisms (APOE)
clinical process of conversion from pure amnesia to dementia, over and above the changes that take place in stable MCI patients over time. Acknowledgments: G. Chetelat, B. Desgranges, F. Eustache. S3-01-02
DETECTING CHANGE IN ALZHEIMER’S DISEASE BRAINS
Nick Fox, Institute of Neurology, University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Progressive cerebral atrophy is a characteristic feature of Alzheimer disease (AD). MRI-based measures of atrophy may help in early diagnosis and have been suggested as an objective measure of progression. The insidious onset of cognitive decline in AD makes clinical diagnosis difficult. Definitive diagnosis is only possible with histopathological examination of brain tissue. For these reasons there is interest in biomarkers to improve diagnosis. One potential marker is cerebral atrophy. Methods: Using rigid and fluid registration of serial brain MRI we have measured rates and patterns of atrophy in AD and related disorders. These methods have also been applied to trials of potential disease-modifying therapy. Conclusions: Rates of brain atrophy measured from serial MRI increase gradually from first symptoms through mild cognitive impairment (MCI) to established AD. Rates of global atrophy in AD are four times greater than in healthy aging (2.2⫾1.2 vs. 0.5⫾0.5%/year) with MCI having intermediate values in those who will progress to AD. Non-linear (fluid) registration shows early sites of atrophy including entorhinal cortex, hippocampus, amygdala and posterior cingulate. APOE genotype appears to modify clinical and MRI phenotype in AD: ApoE4 is associated with medial temporal lobe atrophy presentations but not with posterior cortical/biparietal atrophy presentations. Serial MRI to track atrophy progression is an objective and powerful measure. However a number of technical hurdles occur in its use in multi-centre trials. Furthermore as with all biomarkers there are issues of interpretation. A recent trial of immunotherapy showed that an antibody response to A was associated with increased cerebral volume loss relative to placebo. Despite this significant (titre-related) difference the antibody-responder group had better performance on a neuropsychometric battery. Further analyses of these datasets will be presented analysing location of change with evidence for cortical and medial temporal lobe grey matter losses and relative preservation of brain stem and cerebellum. Key questions remain about the use and limitation of biomarkers, such as atrophy, in trials. Combination of markers and the use of multiple time points may aid the use and interpretation of biomarker changes in future studies. S3-01-03
MCI and AD patients was conducted within each center. The significance threshold was set at ␣ ⫽ 0.01, corrected for false discovery rate (FDR). In a second step, the resulting statistical maps were combined in a metaanalytical approach, using a homemade script written in Matlab6.5. Results: Prominent changes were observed primarily within the frontal cortex, postcentral and superior-temporal gyri and the hippocampal region. No significant increase in grey matter in AD at any voxel in the entire brain was detected. Overlap in findings between centers varied depending upon the brain region examined, with highest consistency between centers in the middle frontal gyrus, postcentral gyrus, and precuneus (⬎ 77% overlap). Conclusions: Regional cerebral volume loss in AD can be detected in a variety of cortical areas by a multicenter voxel-based analysis using a meta-analytical approach. Future studies need to confirm that those brain regions that exhibited volumetric group differences across centers may define a useful set of volumetric measures to improve diagnostics of AD. (1) Ewers M, Teipel SJ, Dietrich O, Schoenberg SO, Jessen F, Heun R, Scheltens P, Pol LA, Freymann NR, Moeller HJ, Hampel H. Multicenter assessment of reliability of cranial MRI. Neurobiol Aging. 2005;[Epub ahead of print]. S3-01-04
Abstract not available. S3-01-05
Background: MRI-based volumetry provides a promising tool for diagnostics in Alzheimer’s disease (AD). The German Competence Network on Dementia (KND) is a national initiative to examine and validate potential tools to improve diagnosis and prediction of AD. Within the KND, we have previously assessed the between-center variability of voxel-signal intensity assessed by MRI(1). Objective(s): To develop a multicenter voxel-based analysis in a large sample of mild cognitive impairment (MCI) and AD patients. Methods: A total of 150 MCI and 125 AD patients were recruited at 9 centers of the KND. The mean MMSE was 27.21 (SD ⫽ 2.12, N ⫽ 132) for the MCI patients and 23.96 (SD ⫽ 3.09, N ⫽ 98) for the AD patients. Scans were spatially normalized towards the standard template implemented in the software program SPM2. As a first step of the statistical analysis, a voxel-based group comparison of grey matter volume between
MONITORING DRUG STUDIES IN DEMENTIA WITH IMAGING
Jeremie Pariente, INSERM, Unknown, France. Contact e-mail: [email protected] Abstract not available. S3-01-06
TRACERS FOR MONITORING CEREBRAL AMYLOID
Bengt Langstrom, Uppsala University, Uppsala, Sweden. Contact e-mail: [email protected] Abstract not available. TUESDAY, JULY 18, 2006 SYMPOSIA S3-02 DISEASE MECHANISMS (APOE)
MULTI CENTER MR IMAGING OF DEMENTIA
Michael Ewers1, Stefan J. Teipel1, Christine Born2, Hans-Juergen Mo¨ller3, Harald Hampel1, 1Alzheimer Memorial Center, University of Munich, Munich, Germany; 2Department of Clinical Radiology, University Hospital of Munich, Ludwig-Maximilian University, Munich, Germany; 3Dementia and Neuroimaging Research Section, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. Contact e-mail: [email protected]
IMAGING COGNITIVE DYSFUNCTION
Marilyn Albert, Johns Hopkins, Baltimore, MD, USA. Contact e-mail: [email protected]
S3-02-01
A-PEPTIDES A40 AND A42 ARE PHYSIOLOGICAL REGULATORS OF CHOLESTEROL AND SPHINGOLIPID HOMEOSTASIS
Tobias Hartmann, University of Heidelberg, Heidelberg, Germany. Contact e-mail: [email protected] During the past decade multiple links between Alzheimer’s disease (AD), cholesterol and other lipids have been noticed. Two independent regulatory cycles that control cholesterol and sphingomyelin lipid homeostasis. Surprisingly, these feed-back cycles utilize as central enzymatic events APP processing and A release. The molecular pathways involved reveal a physiological function for A40 - which down regulates cholesterol de novo synthesis, and A42 - which activates sphingomyelin degrading enzymes (SMases). This biological function of APP processing ultimately results in keeping the molar ratio between the typical raft lipids cholesterol and sphingomyelin constant during steady state conditions. At the same time the molecular independency of these cycles sets a necessary condition to allow adjustments at a subcellular level, e.g. during neuronal differentiation or synaptic plasticity. Similar changes are observed in case of FAD-presenilin mutations. These mutations induce a shift in the ratio of
Symposia S3-02: Disease Mechanisms (APOE)
clinical process of conversion from pure amnesia to dementia, over and above the changes that take place in stable MCI patients over time. Acknowledgments: G. Chetelat, B. Desgranges, F. Eustache. S3-01-02
DETECTING CHANGE IN ALZHEIMER’S DISEASE BRAINS
Nick Fox, Institute of Neurology, University College London, London, United Kingdom. Contact e-mail: [email protected] Background: Progressive cerebral atrophy is a characteristic feature of Alzheimer disease (AD). MRI-based measures of atrophy may help in early diagnosis and have been suggested as an objective measure of progression. The insidious onset of cognitive decline in AD makes clinical diagnosis difficult. Definitive diagnosis is only possible with histopathological examination of brain tissue. For these reasons there is interest in biomarkers to improve diagnosis. One potential marker is cerebral atrophy. Methods: Using rigid and fluid registration of serial brain MRI we have measured rates and patterns of atrophy in AD and related disorders. These methods have also been applied to trials of potential disease-modifying therapy. Conclusions: Rates of brain atrophy measured from serial MRI increase gradually from first symptoms through mild cognitive impairment (MCI) to established AD. Rates of global atrophy in AD are four times greater than in healthy aging (2.2⫾1.2 vs. 0.5⫾0.5%/year) with MCI having intermediate values in those who will progress to AD. Non-linear (fluid) registration shows early sites of atrophy including entorhinal cortex, hippocampus, amygdala and posterior cingulate. APOE genotype appears to modify clinical and MRI phenotype in AD: ApoE4 is associated with medial temporal lobe atrophy presentations but not with posterior cortical/biparietal atrophy presentations. Serial MRI to track atrophy progression is an objective and powerful measure. However a number of technical hurdles occur in its use in multi-centre trials. Furthermore as with all biomarkers there are issues of interpretation. A recent trial of immunotherapy showed that an antibody response to A was associated with increased cerebral volume loss relative to placebo. Despite this significant (titre-related) difference the antibody-responder group had better performance on a neuropsychometric battery. Further analyses of these datasets will be presented analysing location of change with evidence for cortical and medial temporal lobe grey matter losses and relative preservation of brain stem and cerebellum. Key questions remain about the use and limitation of biomarkers, such as atrophy, in trials. Combination of markers and the use of multiple time points may aid the use and interpretation of biomarker changes in future studies. S3-01-03
MCI and AD patients was conducted within each center. The significance threshold was set at ␣ ⫽ 0.01, corrected for false discovery rate (FDR). In a second step, the resulting statistical maps were combined in a metaanalytical approach, using a homemade script written in Matlab6.5. Results: Prominent changes were observed primarily within the frontal cortex, postcentral and superior-temporal gyri and the hippocampal region. No significant increase in grey matter in AD at any voxel in the entire brain was detected. Overlap in findings between centers varied depending upon the brain region examined, with highest consistency between centers in the middle frontal gyrus, postcentral gyrus, and precuneus (⬎ 77% overlap). Conclusions: Regional cerebral volume loss in AD can be detected in a variety of cortical areas by a multicenter voxel-based analysis using a meta-analytical approach. Future studies need to confirm that those brain regions that exhibited volumetric group differences across centers may define a useful set of volumetric measures to improve diagnostics of AD. (1) Ewers M, Teipel SJ, Dietrich O, Schoenberg SO, Jessen F, Heun R, Scheltens P, Pol LA, Freymann NR, Moeller HJ, Hampel H. Multicenter assessment of reliability of cranial MRI. Neurobiol Aging. 2005;[Epub ahead of print]. S3-01-04
Abstract not available. S3-01-05
Background: MRI-based volumetry provides a promising tool for diagnostics in Alzheimer’s disease (AD). The German Competence Network on Dementia (KND) is a national initiative to examine and validate potential tools to improve diagnosis and prediction of AD. Within the KND, we have previously assessed the between-center variability of voxel-signal intensity assessed by MRI(1). Objective(s): To develop a multicenter voxel-based analysis in a large sample of mild cognitive impairment (MCI) and AD patients. Methods: A total of 150 MCI and 125 AD patients were recruited at 9 centers of the KND. The mean MMSE was 27.21 (SD ⫽ 2.12, N ⫽ 132) for the MCI patients and 23.96 (SD ⫽ 3.09, N ⫽ 98) for the AD patients. Scans were spatially normalized towards the standard template implemented in the software program SPM2. As a first step of the statistical analysis, a voxel-based group comparison of grey matter volume between
MONITORING DRUG STUDIES IN DEMENTIA WITH IMAGING
Jeremie Pariente, INSERM, Unknown, France. Contact e-mail: [email protected] Abstract not available. S3-01-06
TRACERS FOR MONITORING CEREBRAL AMYLOID
Bengt Langstrom, Uppsala University, Uppsala, Sweden. Contact e-mail: [email protected] Abstract not available. TUESDAY, JULY 18, 2006 SYMPOSIA S3-02 DISEASE MECHANISMS (APOE)
MULTI CENTER MR IMAGING OF DEMENTIA
Michael Ewers1, Stefan J. Teipel1, Christine Born2, Hans-Juergen Mo¨ller3, Harald Hampel1, 1Alzheimer Memorial Center, University of Munich, Munich, Germany; 2Department of Clinical Radiology, University Hospital of Munich, Ludwig-Maximilian University, Munich, Germany; 3Dementia and Neuroimaging Research Section, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany. Contact e-mail: [email protected]
IMAGING COGNITIVE DYSFUNCTION
Marilyn Albert, Johns Hopkins, Baltimore, MD, USA. Contact e-mail: [email protected]
S3-02-01
A-PEPTIDES A40 AND A42 ARE PHYSIOLOGICAL REGULATORS OF CHOLESTEROL AND SPHINGOLIPID HOMEOSTASIS
Tobias Hartmann, University of Heidelberg, Heidelberg, Germany. Contact e-mail: [email protected] During the past decade multiple links between Alzheimer’s disease (AD), cholesterol and other lipids have been noticed. Two independent regulatory cycles that control cholesterol and sphingomyelin lipid homeostasis. Surprisingly, these feed-back cycles utilize as central enzymatic events APP processing and A release. The molecular pathways involved reveal a physiological function for A40 - which down regulates cholesterol de novo synthesis, and A42 - which activates sphingomyelin degrading enzymes (SMases). This biological function of APP processing ultimately results in keeping the molar ratio between the typical raft lipids cholesterol and sphingomyelin constant during steady state conditions. At the same time the molecular independency of these cycles sets a necessary condition to allow adjustments at a subcellular level, e.g. during neuronal differentiation or synaptic plasticity. Similar changes are observed in case of FAD-presenilin mutations. These mutations induce a shift in the ratio of