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A novel MRI-compatible brain ventricle phantom for validation of lateral ventricle segmentation programs
S44 IC-P-086
Alzheimer’s Imaging Consortium: IC-P-Poster Imaging INVESTIGATING THE ASSOCIATION BETWEEN FASTING SERUM GLUCOSE LEVELS AND CEREBRAL METABOLIC RATE FOR GLUCOSE IN BRAIN REGIONS AFFECTED BY ALZHEIMER’S DISEASE
Christine Burns1, Kewei Chen2, Alfred Kaszniak1, Wendy Lee3, Gene Alexander1, Dan Bandy3, Adam Fleisher4, Richard Caselli5, Eric Reiman6, 1University of Arizona, Tucson, Arizona, United States; 2Banner Alzheimer’s Institute; Arizona State University, Phoenix, Arizona, United States; 3 Banner Alzheimer’s Institute, Phoenix, Arizona, United States; 4Banner Alzheimer’s Institute; University of California San Diego, Phoenix, Arizona, United States; 5Mayo Clinic, Scottsdale, Arizona, United States; 6Banner Alzheimer’s Institute; Translational Genomics Research Institue, University of Arizona, Arizona Alzheimer’s Consortium, Phoenix, Arizona, United States. Background: We proposed the use of regional fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) as a pre-symptomatic endophenotype to evaluate genetic and non-genetic risk factors associated with Alzheimer’s disease (AD) (Reiman PNAS 2005, Reiman NeuroImage 2010). Epidemiological studies have implicated high fasting serum glucose (FSG) levels as a risk factor for a variety of changes in cognition that occur later in life, including cognitive changes in healthy older adults, predementia syndrome, and AD. In this study of healthy older adults, we investigate the association between FSG levels and regional CMRgl, as well as an interaction between higher FSG level and genetic risk for AD. This study aims to test the hypothesis that higher FSG levels in cognitively normal, older adults are associated with lower CMRgl measurements in AD-affected brain regions, and to compare these associations in carriers and non-carriers of the apolipoprotein E (APOE) e4 allele , an established genetic risk factor for late-onset AD. Methods: A brain mapping algorithm (SPM8) was used to compute significant correlations between FSG levels and PET CMRgl measurements in 124 healthy, cognitively normal persons 64 6 6 years of age, including 23 APOE e4 homozygotes (HM), 40 e4 heterozygotes (HT), and 61 e4 non-carriers (NC). Results: Higher FSG levels were significantly correlated with lower CMRgl bilaterally in posterior cingulate, precuneus, parietotemporal, and prefrontal brain regions (p <0.005 uncorrected for multiple comparisons) that have previously been reported to be affected by AD. The correlations were significantly stronger in APOE e4 carriers (HM and HT) than NC in precuneus and parietotemporal areas (p <0.005, uncorrected for multiple comparisons). Conclusions: These results further support the use of FDGPET in the evaluation of genetic and non-genetic risk factors for AD. Higher FSG levels in older adults may impart a risk for AD within the context of insulin resistance or other metabolic disorders that have been linked to relevant AD pathology. FDG-PET measurements may prove useful in the future evaluation of important pharmaceutical or lifestyle based intervention studies that target glucose control and AD risk in the older adult. IC-P-087
IN VIVO FOLLOW UP OF CEREBRAL AGING AND SIDE EFFECTS OF ANTI-AMYLOID IMMUNOTHERAPIES IN THE MOUSE LEMUR PRIMATE
Nelly Joseph-Mathurin1, Olene Dorieux1, Audrey Kraska1, Mathieu Santin1, Stephanie Trouche2, Allal Boutajangout3, Philippe Hantraye1, Jean-Michel Verdier2, Einar Sigurdsson3, Nadine Mestre-Frances2, Marc Dhenain1, 1URA CEA-CNRS 2210 MIRCen, Fontenay-aux-Roses, France; 2Inserm U710 - EPHE - Universite Montpellier 2, Montpellier, France; 3NYU School of Medicine, New-York, New York, United States. Background: Active anti-amyloid immunotherapy is a strategy developed against Alzheimer’s disease. Approaches with Aß1-42 or K6Aß1-30 immunogens in an adjuvant decrease amyloid-ß burden and prevent cognitive decline in transgenic mice (Asuni et al, 2006). However, clinical trials of Aß1-42 immunotherapy have induced side effects like encephalitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). Mouse lemurs can develop Aß plaques with age (Mestre-Frances et al, 2000). Such a primate model may be more predictive than rodents of human side effects. We studied,
by magnetic resonance imaging (MRI), immunotherapies in these primates. Methods: A first cohort was used to compare K6Aß1-30 (n ¼ 4; 5.8 6 0.2 years) and Aß1-42 (n ¼ 4; 5.9 6 0.2 years) immunogens in alum adjuvant. A second cohort was used to evaluate K6Aß1-30 (n ¼ 6; 4.6 6 0.2 years) compared to adjuvant alone (n ¼ 6; 4.7 6 0.3 years). All the animals were followed-up by MRI (7T PharmaScan-Bruker) to evaluate neuroinflammation, microhemorrhages and other forms of iron deposition, with T2-weighted and T2*-weighted sequences (resolution ¼ (234x234x234)mm3). The hypointense regions from T2*-weighted images were quantified and evaluate by histology. A complementary study of age effect was performed with twenty other naive animals (1.5 to 4.9 years). Results: The T2-weighted images did not show any neuroinflammation during immunization, irrespective of the immunogen. Microhemorrhages were detected in the cerebral parenchyma at the histological analysis of the first cohort. The animals treated with K6Aß1-30 presented less microhemorrhages compared to those treated with Aß1-42 vaccine (Mann-Whitney, p < 0.05). These small microhemorrhages were not detected on the T2*-weighted images. However hypointense signal was detected on MRI and corresponded to iron deposits in the choroid plexus. Its volume increased with natural aging (r ¼ 0.60; p < 0.001) and with Aß1-42 compared to K6Aß1-30 treatment (ANOVA, p < 0.05). No difference was detected between K6Aß1-30 and adjuvant alone. Conclusions: The immunotherapies studied in the mouse lemur primate did not lead to any MRI sign of neuroinflammation. The K6Aß1-30 strategy appears to be safer than the Aß1-42 strategy as it provokes less microhemorrhages in the cerebral parenchyma and less iron deposits in the choroid plexus. IC-P-088
A NOVEL MRI-COMPATIBLE BRAIN VENTRICLE PHANTOM FOR VALIDATION OF LATERAL VENTRICLE SEGMENTATION PROGRAMS
Amanda Khan1, Robert Ta1, John Drozd1, Robert Moreland2, Michael Borrie3, Robert Bartha1, 1Robarts Research Institute, London, Ontario, Canada; 2Schulich School of Medicine and Dentistry, London, Ontario, Canada; 3Lawson Health Research Institute, London, Ontario, Canada. Background: Patients with Alzheimer’s Disease (AD) demonstrate an increase in ventricle volume as brain tissues atrophy. Software has been developed to quantify ventricular volume using magnetic resonance imaging (MRI) scans. However, they are rarely validated using known standards. The next generation of clinical trials will benefit from ventricle volumetry, to distinguish between disease-modifying effects and symptomatic relief. The purpose of this study was to construct a physical phantom that could be used as a gold standard to validate ventricle segmentation algorithms. Methods: A typical AD subject from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database with a lateral ventricle volume of 48.8 cm3 was identified. Using this subject’s MRI and ITK-SNAP, a mesh of the lateral ventricles was created and used to rapid prototype the ventricle from polycarbonate. The average signal intensity of tissue surrounding the lateral ventricles was measured in 3T T1-weighted MRI images from ten subjects with AD in the ADNI database. The mixture found to replicate this tissue was made of 2% (w/v) agar dissolved in water, containing 0.01% (w/v) NaCl and a gadopentetate dimeglumine concentration of 0.0375 mM. A brain-shaped mold was filled with tissue-mimicking solution and the ventricle positioned in the middle of the brain. The completed phantom was scanned using the ADNI-specific MP-RAGE sequence. Images were analyzed using a fully-automated segmentation tool. Results: The signal intensity difference between the ventricle and agar solution successfully matched in-vivo signal intensity differences. At a resolution of 1.0 x1.0 x1.0 mm3, a volume of 46.6 cm3 was reported, which is only 2.3% smaller than the actual volume. This result illustrates that the software used does a reasonable job of estimating ventricle volume. The use of the ventricle phantom allowed us to also pinpoint ventricular sub-regions where the algorithm failed. Conclusions: A life-sized MRI-compatible brain ventricle phantom was successfully created. Images acquired are available from the authors to groups wishing to use this data for validation. As enlargement of the ventricles is further established as a marker of disease progression and incorporated into clinical trials, careful validation using gold standards must be performed to ensure the integrity of the study.
Alzheimer’s Imaging Consortium: IC-P-Poster Imaging INVESTIGATING THE ASSOCIATION BETWEEN FASTING SERUM GLUCOSE LEVELS AND CEREBRAL METABOLIC RATE FOR GLUCOSE IN BRAIN REGIONS AFFECTED BY ALZHEIMER’S DISEASE
Christine Burns1, Kewei Chen2, Alfred Kaszniak1, Wendy Lee3, Gene Alexander1, Dan Bandy3, Adam Fleisher4, Richard Caselli5, Eric Reiman6, 1University of Arizona, Tucson, Arizona, United States; 2Banner Alzheimer’s Institute; Arizona State University, Phoenix, Arizona, United States; 3 Banner Alzheimer’s Institute, Phoenix, Arizona, United States; 4Banner Alzheimer’s Institute; University of California San Diego, Phoenix, Arizona, United States; 5Mayo Clinic, Scottsdale, Arizona, United States; 6Banner Alzheimer’s Institute; Translational Genomics Research Institue, University of Arizona, Arizona Alzheimer’s Consortium, Phoenix, Arizona, United States. Background: We proposed the use of regional fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of the cerebral metabolic rate for glucose (CMRgl) as a pre-symptomatic endophenotype to evaluate genetic and non-genetic risk factors associated with Alzheimer’s disease (AD) (Reiman PNAS 2005, Reiman NeuroImage 2010). Epidemiological studies have implicated high fasting serum glucose (FSG) levels as a risk factor for a variety of changes in cognition that occur later in life, including cognitive changes in healthy older adults, predementia syndrome, and AD. In this study of healthy older adults, we investigate the association between FSG levels and regional CMRgl, as well as an interaction between higher FSG level and genetic risk for AD. This study aims to test the hypothesis that higher FSG levels in cognitively normal, older adults are associated with lower CMRgl measurements in AD-affected brain regions, and to compare these associations in carriers and non-carriers of the apolipoprotein E (APOE) e4 allele , an established genetic risk factor for late-onset AD. Methods: A brain mapping algorithm (SPM8) was used to compute significant correlations between FSG levels and PET CMRgl measurements in 124 healthy, cognitively normal persons 64 6 6 years of age, including 23 APOE e4 homozygotes (HM), 40 e4 heterozygotes (HT), and 61 e4 non-carriers (NC). Results: Higher FSG levels were significantly correlated with lower CMRgl bilaterally in posterior cingulate, precuneus, parietotemporal, and prefrontal brain regions (p <0.005 uncorrected for multiple comparisons) that have previously been reported to be affected by AD. The correlations were significantly stronger in APOE e4 carriers (HM and HT) than NC in precuneus and parietotemporal areas (p <0.005, uncorrected for multiple comparisons). Conclusions: These results further support the use of FDGPET in the evaluation of genetic and non-genetic risk factors for AD. Higher FSG levels in older adults may impart a risk for AD within the context of insulin resistance or other metabolic disorders that have been linked to relevant AD pathology. FDG-PET measurements may prove useful in the future evaluation of important pharmaceutical or lifestyle based intervention studies that target glucose control and AD risk in the older adult. IC-P-087
IN VIVO FOLLOW UP OF CEREBRAL AGING AND SIDE EFFECTS OF ANTI-AMYLOID IMMUNOTHERAPIES IN THE MOUSE LEMUR PRIMATE
Nelly Joseph-Mathurin1, Olene Dorieux1, Audrey Kraska1, Mathieu Santin1, Stephanie Trouche2, Allal Boutajangout3, Philippe Hantraye1, Jean-Michel Verdier2, Einar Sigurdsson3, Nadine Mestre-Frances2, Marc Dhenain1, 1URA CEA-CNRS 2210 MIRCen, Fontenay-aux-Roses, France; 2Inserm U710 - EPHE - Universite Montpellier 2, Montpellier, France; 3NYU School of Medicine, New-York, New York, United States. Background: Active anti-amyloid immunotherapy is a strategy developed against Alzheimer’s disease. Approaches with Aß1-42 or K6Aß1-30 immunogens in an adjuvant decrease amyloid-ß burden and prevent cognitive decline in transgenic mice (Asuni et al, 2006). However, clinical trials of Aß1-42 immunotherapy have induced side effects like encephalitis and possibly microhemorrhages (Orgogozo et al, 2003; Ferrer et al, 2004). Mouse lemurs can develop Aß plaques with age (Mestre-Frances et al, 2000). Such a primate model may be more predictive than rodents of human side effects. We studied,
by magnetic resonance imaging (MRI), immunotherapies in these primates. Methods: A first cohort was used to compare K6Aß1-30 (n ¼ 4; 5.8 6 0.2 years) and Aß1-42 (n ¼ 4; 5.9 6 0.2 years) immunogens in alum adjuvant. A second cohort was used to evaluate K6Aß1-30 (n ¼ 6; 4.6 6 0.2 years) compared to adjuvant alone (n ¼ 6; 4.7 6 0.3 years). All the animals were followed-up by MRI (7T PharmaScan-Bruker) to evaluate neuroinflammation, microhemorrhages and other forms of iron deposition, with T2-weighted and T2*-weighted sequences (resolution ¼ (234x234x234)mm3). The hypointense regions from T2*-weighted images were quantified and evaluate by histology. A complementary study of age effect was performed with twenty other naive animals (1.5 to 4.9 years). Results: The T2-weighted images did not show any neuroinflammation during immunization, irrespective of the immunogen. Microhemorrhages were detected in the cerebral parenchyma at the histological analysis of the first cohort. The animals treated with K6Aß1-30 presented less microhemorrhages compared to those treated with Aß1-42 vaccine (Mann-Whitney, p < 0.05). These small microhemorrhages were not detected on the T2*-weighted images. However hypointense signal was detected on MRI and corresponded to iron deposits in the choroid plexus. Its volume increased with natural aging (r ¼ 0.60; p < 0.001) and with Aß1-42 compared to K6Aß1-30 treatment (ANOVA, p < 0.05). No difference was detected between K6Aß1-30 and adjuvant alone. Conclusions: The immunotherapies studied in the mouse lemur primate did not lead to any MRI sign of neuroinflammation. The K6Aß1-30 strategy appears to be safer than the Aß1-42 strategy as it provokes less microhemorrhages in the cerebral parenchyma and less iron deposits in the choroid plexus. IC-P-088
A NOVEL MRI-COMPATIBLE BRAIN VENTRICLE PHANTOM FOR VALIDATION OF LATERAL VENTRICLE SEGMENTATION PROGRAMS
Amanda Khan1, Robert Ta1, John Drozd1, Robert Moreland2, Michael Borrie3, Robert Bartha1, 1Robarts Research Institute, London, Ontario, Canada; 2Schulich School of Medicine and Dentistry, London, Ontario, Canada; 3Lawson Health Research Institute, London, Ontario, Canada. Background: Patients with Alzheimer’s Disease (AD) demonstrate an increase in ventricle volume as brain tissues atrophy. Software has been developed to quantify ventricular volume using magnetic resonance imaging (MRI) scans. However, they are rarely validated using known standards. The next generation of clinical trials will benefit from ventricle volumetry, to distinguish between disease-modifying effects and symptomatic relief. The purpose of this study was to construct a physical phantom that could be used as a gold standard to validate ventricle segmentation algorithms. Methods: A typical AD subject from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database with a lateral ventricle volume of 48.8 cm3 was identified. Using this subject’s MRI and ITK-SNAP, a mesh of the lateral ventricles was created and used to rapid prototype the ventricle from polycarbonate. The average signal intensity of tissue surrounding the lateral ventricles was measured in 3T T1-weighted MRI images from ten subjects with AD in the ADNI database. The mixture found to replicate this tissue was made of 2% (w/v) agar dissolved in water, containing 0.01% (w/v) NaCl and a gadopentetate dimeglumine concentration of 0.0375 mM. A brain-shaped mold was filled with tissue-mimicking solution and the ventricle positioned in the middle of the brain. The completed phantom was scanned using the ADNI-specific MP-RAGE sequence. Images were analyzed using a fully-automated segmentation tool. Results: The signal intensity difference between the ventricle and agar solution successfully matched in-vivo signal intensity differences. At a resolution of 1.0 x1.0 x1.0 mm3, a volume of 46.6 cm3 was reported, which is only 2.3% smaller than the actual volume. This result illustrates that the software used does a reasonable job of estimating ventricle volume. The use of the ventricle phantom allowed us to also pinpoint ventricular sub-regions where the algorithm failed. Conclusions: A life-sized MRI-compatible brain ventricle phantom was successfully created. Images acquired are available from the authors to groups wishing to use this data for validation. As enlargement of the ventricles is further established as a marker of disease progression and incorporated into clinical trials, careful validation using gold standards must be performed to ensure the integrity of the study.