- Email: [email protected]
Hippocampal deformity in nonsemantic primary progressive aphasia
P42
Alzheimer’s Imaging Consortium Poster Presentations: IC-P
MMSE¼22.962.4). Thresholds were derived separately for ADNI 1.5 T (N¼89) and 3T (N¼174) data, and applied separately to UCSF 1.5T and 3T data to compare the sensitivity of HV and TPC across AD variants. Results: HV and TPC performed well in discriminating ADNI NC and AD subjects per MRI field strength (FIGURE). For 1.5T, HV had an area under the ROC curve (AUC)¼0.929, sensitivity¼90%, and specificity¼90%, and for 3T, AUC¼0.936, sensitivity¼85%, specificity¼86%. For TPC: AUC¼0.813, sensitivity¼82%, and specificity¼69% for 1.5T; AUC¼0.839, sensitivity¼72%, specificity¼87% for 3T. Overall, both HV and TPC correctly classified 6/7 UCSF LO-AD subjects (sensitivity¼86%). However, HV was poorly sensitive in early-onset and atypical AD variants (overall sensitivity¼32%: 6/12 EO-AD, 2/13 lvPPA, 4/13 PCA, FIGURE), while TPC was significantly more sensitive in these patients (overall sensitivity¼82%: 10/12 EO-AD, 11/13 lvPPA, 10/13 PCA; c 2(2)¼14.4, p<0.001). Conclusions: HV and TPC perform well as neuronal injury biomarkers in late-onset AD. However, TPC is far more sensitive than HV in early-onset and atypical AD and is the preferred MRI biomarker in these populations.
IC-P-070
EVALUATION OF A RADIOLABELLED BUTYRYLCHOLINESTERASE LIGAND, N-METHYL-4-PIPERDINYL-4-[18F]FLUOROBENZOATE, IN HUMAN BRAIN TISSUES
Courtney Jollymore1, Ian Macdonald1, Ian Pottie2, Earl Martin2, Sultan Darvesh1, 1Dalhousie University, Halifax, Nova Scotia, Canada; 2 Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder of the brain. This disease has characteristic brain hallmarks such as b-amyloid (Ab) plaques and neurofibrillary tangles (NFTs). Currently, AD pathology is only discernible by post-mortem examination in order to provide definitive disease diagnosis. AD is also characterized by cholinergic dysfunction due to a decrease in the brain levels of the neurotransmitter acetylcholine. The cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), regulate levels of this neurotransmitter and in AD these enzymes, especially BuChE, have been found to be associated with Ab plaques and NFTs. In addition, cholinesterase activity may distinguish Ab plaques found in AD brain from those present in some cognitively normal individuals. The co-localization of cholinesterase activity with AD pathology may represent a suitable target for diagnosis and treatment monitoring of the disease during life. Currently, positron emission tomography (PET) imaging of Ab deposits is under consideration for use in AD imaging. However, since Ab plaques can be observed in some cognitively normal individuals, such imaging appears to be of limited specificity for AD. Co-localization of BuChE with Ab plaques may be indicative of AD neuropathology thus, fluorine labelled PET imaging agents targeting BuChE could provide a means for non-invasive AD diagnosis during life. Methods: N -Methyl-4-piperidinyl-4-fluorobenzoate has been identified, through enzyme kinetics as being specific for BuChE over AChE. Fluorination of a precursor, N-methyl-4-piperdinyl-4-nitrobenzoate, was achieved through nucleophilic aromatic substitution using literature methodology. As such, efforts are underway to further develop 18 F-labelled N -methyl-4-piperdinyl-4-fluorobenzoate to generate in vitro autoradiographs of BuChE in human brain tissues. Comparisons will be made between AD brains and cognitively normal controls displaying Ab pathology. Results: It is anticipated that the BuChE-specific radioligand will differentiate between AD and non-AD brain tissues. Conclusions: BuChE-specific 18 F imaging agents may differentiate between Ab plaques in AD and cognitively normal brain tissues. As such, development of cholinesterase-specific 18 F imaging agents should facilitate definitive diagnosis of AD during life. IC-P-071
HIPPOCAMPAL DEFORMITY IN NONSEMANTIC PRIMARY PROGRESSIVE APHASIA
Adam Christensen1, Kathryn Alpert2, Emily Rogalski3, Derin Cobia2, Sandra Weintraub2, Marsel Mesulam4, Lei Wang3, 1Northwestern
University, Feinberg School of Medicine, Chicago, Illinois, United States; Northwestern University, Chicago, Illinois, United States; 3Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; 4 Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States. Contact e-mail: [email protected] 2
Background: Primary progressive aphasia (PPA), a clinical dementia syndrome primarily affecting cortical language regions, is associated with both Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) pathology. In the former case, PPA has been associated with hippocampal pathology (1). Here we report the largest neuroimaging study of hippocampal integrity using volume and shape deformation measurements in PPA patients. Methods: T1-weighted MPRAGE images were collected from 37 PPA patients with non-semantic clinical subtypes and 32 healthy controls in the Northwestern PPA Program. We generated the hippocampal surface and corresponding subfields (CA1, CA2-4+GD, subiculum) in all subjects using FS-LDDMM (2) with atlas selection and minor manual correction. Individual subject surfaces were adjusted for intracranial volume. Hippocampal volume was calculated as volume enclosed within its surface, and hippocampal shape measures were obtained using principal component analysis. Group differences and group-by-hemisphere interactions were assessed using repeated-measures ANOVA, covarying for age and education. Finally, we correlated hippocampal shape measures with nonverbal memory scores and a measure of aphasia severity. Results: Shape comparisons revealed significant deformity for PPA subjects compared to controls (F¼2.2,p¼.038), particularly in the left anterior hippocampus (Figure 1). Post-hoc subfield analysis attributed this to deformation of CA1 and CA2-4+GD, but not subiculum. Furthermore, signficant leftward hemispheric asymmetry of shape deformation was found in CA1. Groups did not differ in overall hippocampal volume, irrespective of hemisphere. However, a significant group-by-hemisphere interaction was driven by leftward asymmetry of volume loss within the PPA group (F¼5.1,p¼.027). Correlations of shape with nonverbal memory and aphasia severity scores were not statistically significant. Conclusions: Hippocampal shape analysis revealed significant regional volume loss in CA1 and CA2-4+GD subfields in PPA. Greater, left-ward asymmetrical atrophy in PPA is consistent with known cortical patterns of the disease. These patterns differ from those in dementia of the Alzheimer type (DAT), where there is atrophy of the CA1 and subiculum subfields. This suggests that hippocampal damage in PPA is different from that in DAT, and may reflect disparities in underlying neuropathology. References: 1. Gefen, T., Gasho, K., Rademaker, A., Lalehzari, M., Weintraub, S., Rogalski, E., Wieneke, C., et al. (2012). Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. Brain: a journal of neurology, 135(Pt 5), 1554-65. http://dx.doi.org/10.1093/brain/aws076. 2. Khan, A. R., Wang, L., & Beg, M. F. (2008). FreeSurfer-initiated fully-automated subcortical brain segmentation in MRI using Large Deformation Diffeomorphic Metric Mapping. NeuroImage, 41(3), 735-46. http://dx.doi.org/10.1016/j. neuroimage.2008.03.024.
Figure 1. Shape deformation patterns in the PPA vs. control subjects. Cooler shades represent greater inward deformation of the PPA group relative to controls.
Alzheimer’s Imaging Consortium Poster Presentations: IC-P
MMSE¼22.962.4). Thresholds were derived separately for ADNI 1.5 T (N¼89) and 3T (N¼174) data, and applied separately to UCSF 1.5T and 3T data to compare the sensitivity of HV and TPC across AD variants. Results: HV and TPC performed well in discriminating ADNI NC and AD subjects per MRI field strength (FIGURE). For 1.5T, HV had an area under the ROC curve (AUC)¼0.929, sensitivity¼90%, and specificity¼90%, and for 3T, AUC¼0.936, sensitivity¼85%, specificity¼86%. For TPC: AUC¼0.813, sensitivity¼82%, and specificity¼69% for 1.5T; AUC¼0.839, sensitivity¼72%, specificity¼87% for 3T. Overall, both HV and TPC correctly classified 6/7 UCSF LO-AD subjects (sensitivity¼86%). However, HV was poorly sensitive in early-onset and atypical AD variants (overall sensitivity¼32%: 6/12 EO-AD, 2/13 lvPPA, 4/13 PCA, FIGURE), while TPC was significantly more sensitive in these patients (overall sensitivity¼82%: 10/12 EO-AD, 11/13 lvPPA, 10/13 PCA; c 2(2)¼14.4, p<0.001). Conclusions: HV and TPC perform well as neuronal injury biomarkers in late-onset AD. However, TPC is far more sensitive than HV in early-onset and atypical AD and is the preferred MRI biomarker in these populations.
IC-P-070
EVALUATION OF A RADIOLABELLED BUTYRYLCHOLINESTERASE LIGAND, N-METHYL-4-PIPERDINYL-4-[18F]FLUOROBENZOATE, IN HUMAN BRAIN TISSUES
Courtney Jollymore1, Ian Macdonald1, Ian Pottie2, Earl Martin2, Sultan Darvesh1, 1Dalhousie University, Halifax, Nova Scotia, Canada; 2 Mount Saint Vincent University, Halifax, Nova Scotia, Canada. Contact e-mail: [email protected] Background: Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder of the brain. This disease has characteristic brain hallmarks such as b-amyloid (Ab) plaques and neurofibrillary tangles (NFTs). Currently, AD pathology is only discernible by post-mortem examination in order to provide definitive disease diagnosis. AD is also characterized by cholinergic dysfunction due to a decrease in the brain levels of the neurotransmitter acetylcholine. The cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), regulate levels of this neurotransmitter and in AD these enzymes, especially BuChE, have been found to be associated with Ab plaques and NFTs. In addition, cholinesterase activity may distinguish Ab plaques found in AD brain from those present in some cognitively normal individuals. The co-localization of cholinesterase activity with AD pathology may represent a suitable target for diagnosis and treatment monitoring of the disease during life. Currently, positron emission tomography (PET) imaging of Ab deposits is under consideration for use in AD imaging. However, since Ab plaques can be observed in some cognitively normal individuals, such imaging appears to be of limited specificity for AD. Co-localization of BuChE with Ab plaques may be indicative of AD neuropathology thus, fluorine labelled PET imaging agents targeting BuChE could provide a means for non-invasive AD diagnosis during life. Methods: N -Methyl-4-piperidinyl-4-fluorobenzoate has been identified, through enzyme kinetics as being specific for BuChE over AChE. Fluorination of a precursor, N-methyl-4-piperdinyl-4-nitrobenzoate, was achieved through nucleophilic aromatic substitution using literature methodology. As such, efforts are underway to further develop 18 F-labelled N -methyl-4-piperdinyl-4-fluorobenzoate to generate in vitro autoradiographs of BuChE in human brain tissues. Comparisons will be made between AD brains and cognitively normal controls displaying Ab pathology. Results: It is anticipated that the BuChE-specific radioligand will differentiate between AD and non-AD brain tissues. Conclusions: BuChE-specific 18 F imaging agents may differentiate between Ab plaques in AD and cognitively normal brain tissues. As such, development of cholinesterase-specific 18 F imaging agents should facilitate definitive diagnosis of AD during life. IC-P-071
HIPPOCAMPAL DEFORMITY IN NONSEMANTIC PRIMARY PROGRESSIVE APHASIA
Adam Christensen1, Kathryn Alpert2, Emily Rogalski3, Derin Cobia2, Sandra Weintraub2, Marsel Mesulam4, Lei Wang3, 1Northwestern
University, Feinberg School of Medicine, Chicago, Illinois, United States; Northwestern University, Chicago, Illinois, United States; 3Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; 4 Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States. Contact e-mail: [email protected] 2
Background: Primary progressive aphasia (PPA), a clinical dementia syndrome primarily affecting cortical language regions, is associated with both Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) pathology. In the former case, PPA has been associated with hippocampal pathology (1). Here we report the largest neuroimaging study of hippocampal integrity using volume and shape deformation measurements in PPA patients. Methods: T1-weighted MPRAGE images were collected from 37 PPA patients with non-semantic clinical subtypes and 32 healthy controls in the Northwestern PPA Program. We generated the hippocampal surface and corresponding subfields (CA1, CA2-4+GD, subiculum) in all subjects using FS-LDDMM (2) with atlas selection and minor manual correction. Individual subject surfaces were adjusted for intracranial volume. Hippocampal volume was calculated as volume enclosed within its surface, and hippocampal shape measures were obtained using principal component analysis. Group differences and group-by-hemisphere interactions were assessed using repeated-measures ANOVA, covarying for age and education. Finally, we correlated hippocampal shape measures with nonverbal memory scores and a measure of aphasia severity. Results: Shape comparisons revealed significant deformity for PPA subjects compared to controls (F¼2.2,p¼.038), particularly in the left anterior hippocampus (Figure 1). Post-hoc subfield analysis attributed this to deformation of CA1 and CA2-4+GD, but not subiculum. Furthermore, signficant leftward hemispheric asymmetry of shape deformation was found in CA1. Groups did not differ in overall hippocampal volume, irrespective of hemisphere. However, a significant group-by-hemisphere interaction was driven by leftward asymmetry of volume loss within the PPA group (F¼5.1,p¼.027). Correlations of shape with nonverbal memory and aphasia severity scores were not statistically significant. Conclusions: Hippocampal shape analysis revealed significant regional volume loss in CA1 and CA2-4+GD subfields in PPA. Greater, left-ward asymmetrical atrophy in PPA is consistent with known cortical patterns of the disease. These patterns differ from those in dementia of the Alzheimer type (DAT), where there is atrophy of the CA1 and subiculum subfields. This suggests that hippocampal damage in PPA is different from that in DAT, and may reflect disparities in underlying neuropathology. References: 1. Gefen, T., Gasho, K., Rademaker, A., Lalehzari, M., Weintraub, S., Rogalski, E., Wieneke, C., et al. (2012). Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. Brain: a journal of neurology, 135(Pt 5), 1554-65. http://dx.doi.org/10.1093/brain/aws076. 2. Khan, A. R., Wang, L., & Beg, M. F. (2008). FreeSurfer-initiated fully-automated subcortical brain segmentation in MRI using Large Deformation Diffeomorphic Metric Mapping. NeuroImage, 41(3), 735-46. http://dx.doi.org/10.1016/j. neuroimage.2008.03.024.
Figure 1. Shape deformation patterns in the PPA vs. control subjects. Cooler shades represent greater inward deformation of the PPA group relative to controls.