- Email: [email protected]
IM-07
Preconference - Imaging IM IM-05
MULTI-SITE MRI STUDIES: PROBLEMS AND PRINCIPLES
Derek L. Hill, IXICO, London, United Kingdom. Contact e-mail: [email protected] Background: Longitudinal structural MRI is highly sensitive to disease progression in Alzheimer’s disease. Image analysis methods can quantify the rate of brain atrophy from two or more scans, and is likely to be a valuable tool in assessment of new drugs. Objective(s): T1 weighted gradient echo volume scans are acquired. Even though these cans have been widely available since the early 1990s, it remains a challenge to standardize the acquisition across multiple centres. Methods: There are four key challenges to overcome. (1) Running equivalent imaging sequences on all scanners in the study. This is not just a matter of different scanner vendors, but also of the huge variety of different software and hardware configurations available. (2) MR scanners are not well calibrated measuring devices. MR scanners are designed to produce images for use in diagnosis - not for precise measurements. Images can contain considerable geometrical and intensity distortions. (3) Instability of scanners over time. MRI scanners change over time, both because the hardware drifts, and because the software might be upgraded. Also, if the same subject is positioned slightly differently, the geometrical and intensity distortions described in (2) above can lead to significant image differences. (4) Subject specific artefacts. Subject motion (eg: whole head motion, blood pulsating in vessels or eyeball movement) can result in substantial image degradation. Results: Image analysis methods that are sensitive to disease progression are also sensitive to the 4 problems described above. For multicentre trials, it is important to design imaging protocols as similar as possible between sites. It is also important to train the technologists, and carry out rigorous quality control to ensure protocol adherence. Image pre-processing can be used to partially correct the problems causing geometrical and intensity inhomogeneity, either on the scanners, or off-line using specialist software. Specialist phantoms can also quantify, and potentially correct, the instrument errors. Conclusions: Longitudinal structural MRI is an effective tool for quantifying disease progression in AD, but must be done carefully for it to be effective in multicentre trials. The ADNI project provides an example of good practice. IM-06
MULTICENTER PET IMAGING
Karl Herholz1,2, 1Wolfson Molecular Imaging Centre, University of Manchester, United Kingdom; 2Medical Faculty, University of Cologne, Germany. Contact e-mail: [email protected] Positron emission tomography (PET) provides the most sensitive and accurate tools for measuring local brain function (blood flow, metabolism, and receptor binding) in vivo. Some tracers, especially when labeled with the very short-lived isotope carbon-11, depend on local and costly tracer production by an on-site cyclotron, limiting their use to few research centers. In contrast, 18F-2-fluoro-2-deoxy-D-glucose (FDG) and some other tracers labeled by fluorine-18 (110 min half-life) are available more widely, often by commercial suppliers, and can be used easily in multicenter trials. Feasibility of multicenter FDG PET studies in Alzheimer’s Disease (AD) had been demonstrated in 1993 1, showing that with sufficiently homogeneous study conditions, scanning protocols, and procedures for data analysis controls and AD patients can be discriminated with better than 90% accuracy in typical PET study samples. More recent developments include larger samples (more than 1000 subjects in the European Network for Efficiency and Standardisation of Dementia Diagnosis NEST-DD), pooling of autopsy-confirmed cases, voxel-based image analysis, and multivariate methods for discrimination among dementia diseases2-5. FDG PET is sensitive to detect abnormalities in asymptomatic subjects at risk, has a high predictive value for development of dementia in mild cognitive impairment, and regional findings are closely related to neuropsychological deficits and their progression. It therefore has a huge potential for being used as an imaging biomarker for selecting non-demented patients at high risk for development of dementia, and as an outcome parameter. Amyloid
S93
imaging using the thioflavin analogue 11C-PIB has shown consistently 2-3 fold increased tracer retention in patients with AD in many laboratories across the world. Fluorine-18 tracers for easier use in a multicenter setting are currently being evaluated. Multicentre studies using these tracers will provide in-vivo demonstration of amyloid deposition in dementia patients, thus contributing to diagnostic specificity, and are also likely to be useful for monitoring of anti-amyloid therapies. The potential of other tracers targeting cholinergic and serotonergic transmitter pathways as well as microglial activation for multicenter studies is being evaluated within the European Network of Excellence on Diagnostic Molecular Imaging (www.dimi-net.org). IM-07
GENETIC MECHANISMS OF MEMORY
Daniel Weinberger, National Institutes of Health, Bethesda, MD, USA. Contact e-mail: [email protected] Abstract not available. IM-08
IMAGING AND GENES IN THE AGING BRAIN
Susan Bookheimer, Gary Small, Alison Burggren, University of California Los Angeles, Los Angeles, CA, USA. Contact e-mail: [email protected] Combining Imaging and Genetics for Aging Research Novel treatments of Alzheimer’s disease (AD) will likely target disease progression rather than symptom reversal. For this reason, a key focus in AD research is to identify brain changes early in the disease process and if possible, before clinical manifestations of cognitive change. Such efforts may be most beneficial when combined with known risk factors for AD including a family history of the disorder and presence of a known genetic risk marker. The APOE-4 allele is a well documented risk gene for AD which contributed to perhaps 50% of the genetic variance. A series of studies in our lab support the notion that combining genetic risk information with brain imaging reveals brain changes in at-risk individuals perhaps decades before the likely time of disease onset. Functional MRI activation studies indicate that APOE-4 carriers show compensatory increases in fMRI activation during challenging memory tasks but not during tasks relatively unaffected in AD, at a stage in which there is no measurable clinical decline. Structural MRI studies show a characteristic thinning of the cortical ribbon in APOE-4 in regions known to be affected by AD in a pattern of temporal progression consistent with the known pathology. PET measures of glucose metabolism, amyloid binding, and serotonin 1-a receptor binding all show abnormalities characteristic of AD in unaffected or MCI subjects. Together the data suggest that combining genetic risk information with imaging may identify individuals at higher risk for AD, and may be sensitive markers of disease progression. IM-09
ADVANTAGES OF MRI
Stefan J. Teipel1, Christine Born2, Harald Hampel1, 1Alzheimer Memorial Center, Ludwig-Maximilian University, Munich, Germany; 2 Department of Radiology, Ludwig-Maximilian University, Munich, Germany. Contact e-mail: [email protected] Background: The development of new treatment strategies aiming at secondary prevention of Alzheimer’s disease (AD) requires accurate detection of the early stages of the disease and mapping of disease modifying treatment effects. Structural MRI can help to improve diagnosis and to differentiate disease modifying from symptomatic treatment effects. Objective(s): To describe how MRI can be used to determine treatment effects and improve early diagnosis, and how MRI contributes to our understanding of disease pathogenesis. Methods: Methods have been developed to extract MRI features that are useful for early diagnosis and mapping of morphological disease progression, ranging from manual volumetry of vulnerable brain regions, such as the hippocampus, to automated extraction of cortical folding pattern, cortical thickness and volumes, and
MULTI-SITE MRI STUDIES: PROBLEMS AND PRINCIPLES
Derek L. Hill, IXICO, London, United Kingdom. Contact e-mail: [email protected] Background: Longitudinal structural MRI is highly sensitive to disease progression in Alzheimer’s disease. Image analysis methods can quantify the rate of brain atrophy from two or more scans, and is likely to be a valuable tool in assessment of new drugs. Objective(s): T1 weighted gradient echo volume scans are acquired. Even though these cans have been widely available since the early 1990s, it remains a challenge to standardize the acquisition across multiple centres. Methods: There are four key challenges to overcome. (1) Running equivalent imaging sequences on all scanners in the study. This is not just a matter of different scanner vendors, but also of the huge variety of different software and hardware configurations available. (2) MR scanners are not well calibrated measuring devices. MR scanners are designed to produce images for use in diagnosis - not for precise measurements. Images can contain considerable geometrical and intensity distortions. (3) Instability of scanners over time. MRI scanners change over time, both because the hardware drifts, and because the software might be upgraded. Also, if the same subject is positioned slightly differently, the geometrical and intensity distortions described in (2) above can lead to significant image differences. (4) Subject specific artefacts. Subject motion (eg: whole head motion, blood pulsating in vessels or eyeball movement) can result in substantial image degradation. Results: Image analysis methods that are sensitive to disease progression are also sensitive to the 4 problems described above. For multicentre trials, it is important to design imaging protocols as similar as possible between sites. It is also important to train the technologists, and carry out rigorous quality control to ensure protocol adherence. Image pre-processing can be used to partially correct the problems causing geometrical and intensity inhomogeneity, either on the scanners, or off-line using specialist software. Specialist phantoms can also quantify, and potentially correct, the instrument errors. Conclusions: Longitudinal structural MRI is an effective tool for quantifying disease progression in AD, but must be done carefully for it to be effective in multicentre trials. The ADNI project provides an example of good practice. IM-06
MULTICENTER PET IMAGING
Karl Herholz1,2, 1Wolfson Molecular Imaging Centre, University of Manchester, United Kingdom; 2Medical Faculty, University of Cologne, Germany. Contact e-mail: [email protected] Positron emission tomography (PET) provides the most sensitive and accurate tools for measuring local brain function (blood flow, metabolism, and receptor binding) in vivo. Some tracers, especially when labeled with the very short-lived isotope carbon-11, depend on local and costly tracer production by an on-site cyclotron, limiting their use to few research centers. In contrast, 18F-2-fluoro-2-deoxy-D-glucose (FDG) and some other tracers labeled by fluorine-18 (110 min half-life) are available more widely, often by commercial suppliers, and can be used easily in multicenter trials. Feasibility of multicenter FDG PET studies in Alzheimer’s Disease (AD) had been demonstrated in 1993 1, showing that with sufficiently homogeneous study conditions, scanning protocols, and procedures for data analysis controls and AD patients can be discriminated with better than 90% accuracy in typical PET study samples. More recent developments include larger samples (more than 1000 subjects in the European Network for Efficiency and Standardisation of Dementia Diagnosis NEST-DD), pooling of autopsy-confirmed cases, voxel-based image analysis, and multivariate methods for discrimination among dementia diseases2-5. FDG PET is sensitive to detect abnormalities in asymptomatic subjects at risk, has a high predictive value for development of dementia in mild cognitive impairment, and regional findings are closely related to neuropsychological deficits and their progression. It therefore has a huge potential for being used as an imaging biomarker for selecting non-demented patients at high risk for development of dementia, and as an outcome parameter. Amyloid
S93
imaging using the thioflavin analogue 11C-PIB has shown consistently 2-3 fold increased tracer retention in patients with AD in many laboratories across the world. Fluorine-18 tracers for easier use in a multicenter setting are currently being evaluated. Multicentre studies using these tracers will provide in-vivo demonstration of amyloid deposition in dementia patients, thus contributing to diagnostic specificity, and are also likely to be useful for monitoring of anti-amyloid therapies. The potential of other tracers targeting cholinergic and serotonergic transmitter pathways as well as microglial activation for multicenter studies is being evaluated within the European Network of Excellence on Diagnostic Molecular Imaging (www.dimi-net.org). IM-07
GENETIC MECHANISMS OF MEMORY
Daniel Weinberger, National Institutes of Health, Bethesda, MD, USA. Contact e-mail: [email protected] Abstract not available. IM-08
IMAGING AND GENES IN THE AGING BRAIN
Susan Bookheimer, Gary Small, Alison Burggren, University of California Los Angeles, Los Angeles, CA, USA. Contact e-mail: [email protected] Combining Imaging and Genetics for Aging Research Novel treatments of Alzheimer’s disease (AD) will likely target disease progression rather than symptom reversal. For this reason, a key focus in AD research is to identify brain changes early in the disease process and if possible, before clinical manifestations of cognitive change. Such efforts may be most beneficial when combined with known risk factors for AD including a family history of the disorder and presence of a known genetic risk marker. The APOE-4 allele is a well documented risk gene for AD which contributed to perhaps 50% of the genetic variance. A series of studies in our lab support the notion that combining genetic risk information with brain imaging reveals brain changes in at-risk individuals perhaps decades before the likely time of disease onset. Functional MRI activation studies indicate that APOE-4 carriers show compensatory increases in fMRI activation during challenging memory tasks but not during tasks relatively unaffected in AD, at a stage in which there is no measurable clinical decline. Structural MRI studies show a characteristic thinning of the cortical ribbon in APOE-4 in regions known to be affected by AD in a pattern of temporal progression consistent with the known pathology. PET measures of glucose metabolism, amyloid binding, and serotonin 1-a receptor binding all show abnormalities characteristic of AD in unaffected or MCI subjects. Together the data suggest that combining genetic risk information with imaging may identify individuals at higher risk for AD, and may be sensitive markers of disease progression. IM-09
ADVANTAGES OF MRI
Stefan J. Teipel1, Christine Born2, Harald Hampel1, 1Alzheimer Memorial Center, Ludwig-Maximilian University, Munich, Germany; 2 Department of Radiology, Ludwig-Maximilian University, Munich, Germany. Contact e-mail: [email protected] Background: The development of new treatment strategies aiming at secondary prevention of Alzheimer’s disease (AD) requires accurate detection of the early stages of the disease and mapping of disease modifying treatment effects. Structural MRI can help to improve diagnosis and to differentiate disease modifying from symptomatic treatment effects. Objective(s): To describe how MRI can be used to determine treatment effects and improve early diagnosis, and how MRI contributes to our understanding of disease pathogenesis. Methods: Methods have been developed to extract MRI features that are useful for early diagnosis and mapping of morphological disease progression, ranging from manual volumetry of vulnerable brain regions, such as the hippocampus, to automated extraction of cortical folding pattern, cortical thickness and volumes, and