- Email: [email protected]
IC-P3-186: Alzheimers diseases
Alzheimer’s Imaging Consortium IC-P3: Poster Presentations Background: Exercise and physical fitness have been shown to moderate age-related brain changes in healthy adults although this has never been assessed in AD. Objective: Thus, we investigated the relationship of cardiorespiratory fitness with regional brain atrophy using Voxel Based Morphometry (VBM) and the role of APOE4 genotype in modulating this relationship. Methods: Nondemented (n⫽56) and early-stage AD subjects (n⫽63) aged 60 and over had MRI and fitness assessments. Peak oxygen consumption (VO2peak) was assessed during a symptom-limited graded treadmill test. MPRAGE images were processed using the VBM5 toolbox (http://dbm.neuro.uni-jena.de), and SPM5 algorithms (Wellcome Department of Cognitive Neurology, London, UK) including the Hidden Markov Field model (HMRF), producing modulated, smoothed (10mm) gray (GMV) and white matter (WMV) maps for analyses. First, nondemented and AD subjects were compared to identify areas of AD-related atrophy (p⬍.05, family-wise error (FWE) corrected) and create atrophy masks (i.e., “disease regions”). Next, we regressed VO2peak across WMV and GMV within groups. Results were masked with “disease regions” to assess for fitness-related preservation of brain volume in areas most affected by AD-related atrophy. Finally, we analyzed a groupxAPOE4 interaction to look for differential fitness-brain relationships in APOE4 carriers and noncarriers (p⬍.001 uncorrected, exploratory). All analyses were covaried for age, gender, education and whole brain volume. Results: As expected, AD-related atrophy was present in the hippocampus, temporal cortex, and parietal cortices. In “disease regions”, VO2peak in early AD subjects was significantly positively associated with WMV in the hippocampus (p⫽0.02), inferior temporal gyrus (p⫽0.038), and precentral gyrus (p⫽0.047). Positive trends existed in AD subjects relating GMV with VO2peak in whole-brain analyses in the superior and inferior temporal, prefrontal, and parietal cortices. A significant interaction for groupxAPOE4 genotype was present in the bilateral middle temporal cortices. APOE4 noncarriers had a stronger fitness-brain volume relationship than APOE4 carriers. Conclusions: In early-stage AD, cardiorespiratory fitness is associated with regional brain volumes in the hippocampus, temporal, and parietal cortices suggesting that maintaining cardiorespiratory fitness may positively modify AD-related brain atrophy. The presence of an APOE ⑀4 allele may limit the positive affect of fitness on brain volume in early AD. IC-P3-184
LOBAR GRAY AND WHITE MATTER ATROPHY IN ALZHEIMER’S DISEASE: PRELIMINARY RESULTS FROM THE ADNI PUBLIC DATABASE
Juebin Huang1, Alexander P. Auchus1,2, 1University of Tennessee Health Science Center, Memphis, TN, USA; 2Memphis Veterans Affairs Medical Center, Memphis, TN, USA. Contact e-mail: [email protected] Background: Regional brain volume loss beyond the medial temporal lobe has not been extensively studied in AD, particularly in the white matter. Recent studies suggest that white matter pathology may underlie regional dissociations between medial temporal volume loss and metabolic reductions in posterior association cortices in AD patients. The present study investigates lobar gray and white matter volume loss in AD using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Methods: 1.5 Tesla MR brain images from 18 subjects with AD and 18 age- and sex-matched subjects with normal cognition (NC) were obtained from the ADNI public database (www.loni.ucla.eduADNI). T1-weighted, 3-D volumetric MP-RAGE images were analyzed in a multi-step process. Brain parenchyma was segmented into gray matter and white matter using an automated program. Lobar gray and white matter volumes in frontal, temporal, parietal and occipital lobes were delineated using a landmarkbased, manual method and normalized to total intracranial volume. Between-group differences in lobar gray and white matter volumes were compared using student’s t-test. Results: AD subjects (mean age ⫽ 75, mean MMSE ⫽ 23.4, all CDR ⫽ 1) demonstrated significantly reduced gray matter volumes vs. NC (mean age ⫽ 75, mean MMSE ⫽ 29.1, all CDR ⫽ 0) in frontal (10.39 vs. 11.60, p⬍0.01), temporal (6.91 vs. 8.44,
T81
p⬍0.01) and parietal (6.14 vs.7.10, p⬍0.01) lobes. There was no difference between groups in occipital gray matter volume (3.46 vs. 3.60, p⫽0.30). White matter volume in the parietal lobe was significantly decreased in AD vs. NC (10.09 vs. 10.94, p⬍0.05). Conclusions: This analysis from the ADNI public database reveals AD-associated gray matter volume loss in brain regions serving higher functions (frontal, temporal and parietal lobes), but not in regions serving primary functions (occipital lobe). Furthermore, we observed white matter volume loss in the parietal lobe of AD, a novel finding which has not been previously described. This new finding may represent axonal loss from degenerating neurons in multimodal association cortices, or reduced integrity of fibers in the posterior cingulate bundle connecting medial temporal lobe structures to posterior cingulate gyrus. IC-P3-185
A METHOD TO QUANTITATE AMYLOID PLAQUE LOAD IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
George Iordanescu1,2, Palamadai N. Venkatasubramanian1,2, Marina V. Yasvoina1,3, Jason C. Pych1,4, Alice M. Wyrwicz1,5, 1ENH Research Institute, Evanston, IL, USA; 2Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3NUIN, Northwestern University, Evanston, IL, USA; 4Neurobiology and Physiology, Northwestern University Weinberg College of Arts and Sciences, Evanston, IL, USA; 5Radiology, Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Contact email: [email protected] Background: Although successful visualization of amyloid deposits in the APP transgenic mouse brain with MR imaging has been reported recently, there is no suitable method to measure plaque load (PL). We present a novel method based on simulated flooding (watersheds) to segment amyloid plaques in mouse brain images. In this method, the image is segmented into catchment basins (CB) associated with local minima and CBs that correspond to plaques are selected using the data Laplacian as a feature describing local variation. Besides PL (volume fraction) estimation, our method can be also used to analyze other plaque characteristics such as size, shape and distribution. Methods: The automatic plaque segmentation algorithm has two steps: First, simulated flooding is used to extract regions with low intensities completely surrounded by higher intensity neighbors. The resulting map defines the CBs of the MR local minima. Second, the image Laplacian L(I) ⫽ div (grad (I)) is used to model the plaque cores, defined as regions with small derivatives, surrounded by rapidly increasing neighbors. Plaques are segmented by taking the CBs that have maximum Laplacians larger than the background noise. The algorithm was used to compute PL in the subiculum of 2 and 10 months old 5XFAD APP/PS1 transgenic mice. RARE 3D-images of fixed brains acquired on a 14.1T microimager using TR/TEeff 2500ms/40ms and pixel size 35m x35m x35m were analyzed. The algorithm was applied to histology data from the same brains and PL results were compared for validation. Results: The computed PL values increased with age for the 5XFAD mice from 1.25% at 2 months to 25.0% at 10 months. A non-transgenic control mouse had a PL of nearly 0% as expected. Our results are consistent with the known evolution of plaque deposition in this strain. Amyloid plaques begin to appear in the subiculum of 2 month old 5XFAD mice and by 10 months of age numerous plaques are found in subiculum, hippocampus and deep layers of the cortex. Conclusions: Our automatic computational method for the quantitation of plaques can be applied to evaluate disease progression and efficacy of therapy in transgenic mouse models of AD. IC-P3-186
ALZHEIMERS DISEASES
Mwambu Margaret Nil Jane, Mwambu Margaret Nil Jane, Nkumba University, Kampala, Uganda. Contact e-mail: [email protected]
N W A HDR
Background: I was born in Uganda, by Mr and Mrs Mukata, who past away when l was 5 years, l started that orphage life from then to to day, my
WIT
T82
Alzheimer’s Imaging Consortium IC-P3: Poster Presentations
education was very poor, l started P.1 at Kamonkoli primary school, l joined secondary school, then joined Nkumba college of commerce, l completed my diploma in secretary. Methods: To acquire more training to how people in my community can avoid getting some diseases, training them how to eat, drinck etc. Results: To be voice & help the aged/people suffering with diseases in my community. Conclusions: I pray God should open a way for me to attend that conference, such that l can aquire knowledge and l teach the people in my community.
N W A HDR
WIT
IC-P3-187
ACCELERATED CORTICAL THINNING IN FTD-3 CHMP2B MUTATION CARRIERS
Peter Johannsen1, Simon F. Eskildsen2, Jørgen E. Nielsen1,3, Adrian Isaacs4, Dora Zeidler5, Leif Østergaard5, 1Memory Research Group, Copenhagen University Hospital, Copenhagen, Denmark; 2 Department of Health Science and Technology, Aalborg University, Aalborg, Denmark; 3Section of Neurogenetics, Institute of Medical Biochemistry & Genetics, Copenhagen University, Copenhagen, Denmark; 4MRC Prion Unit, Institute of Neurology, London, United Kingdom; 5Center for Functionally Integrative Neuroscience, Aarhus University Hospital, Aarhus, Denmark. Contact e-mail: [email protected] Background: Frontotemporal dementia linked to chromosome 3 (FTD-3) (1) is caused by mutations in the CHMP2B gene in the endosomal ESCRTIII complex (2). Objective: To prospectively study changes over time of cortical thickness in structural neuroimaging MR data from the large Danish FTD-3 family with a pathogenic G-to-C transition in the acceptor splice site of CHMP2B exon 6. Methods: Nine presymptomatic CHMP2B mutation carriers (mean age 55.8 ⫾ SD 5.6) and 7 mutation negative (MN) (mean age 54.3 ⫾ SD 6.0) family members were scanned twice, 1.3 years apart, using a 3T MRI FSPGR 3D sequence. Cortical thickness was calculated with an updated previously published method (3) where 3D non-parametric surfaces were iteratively fitted to the inner and outer boundary of the cortex. The method calculates the cortical thickness with sub-voxel accuracy at more than 85.000 vertices equally distributed over the cortical surface. For this abstract results were pooled for right and left cortical lobes as defined by a stereotaxic atlas. Results: Paired t-tests between cortical thicknesses at the two time points showed that for CHMP2B mutation carriers all lobes except the parietal and the right temporal were significantly thinner at time point 2 compared to 1. In the MN group only the left occipital lobe was significantly thinner at time point 2. Annualized thinning rates (mean⫾SD) as percent decline of thickness at time point 1 are listed in Table.
CHMP2Bmutation MN p-value
Frontal Lobe Left
Right
Temporal Lobe Left
Right
Parietal Lobe Left
Right
Occipital Lobe Left
Right
4.18⫾3.73
3.42⫾3.51
3.74⫾3.16
1.37⫾3.75
1.52⫾5.30
3.14⫾6.87
6.15⫾4.03
3.91⫾2.97
0.50⫾3.51 0.032
1.15⫾2.86 0.088
1.44⫾1.96 0.048
0.48⫾2.86 0.141
0.81⫾4.57 0.388
1.59⫾4.89 0.303
4.77⫾5.53 0.295
0.84⫾3.78 0.052
Conclusions: The cortical thinning rate is significantly higher in the left frontal and left temporal lobe in CHMP2B mutation carriers compared to the mutation negative subjects. Supported by Danish MRC: 22-04-0458. References: (1) Gydesen et al. Neurology 2002; 59: 1585-94. (2) Skibinski et al. Nature Genetics 2005; 37: 806-8. (3) Eskildsen et al. LNCS 2006; 4191: 823-830. IC-P3-188
EARLY DETECTION OF HEREDITARY CEREBRAL AMYLOID ANGIOPATHY WITH PITTSBURGH COMPOUND B
K. A. Johnson1, T. J. Grabowski2, M. E. Gurol2, M. E. Skehan1, R. N. K. Nandigam1, J. A. Becker1, M. Garcia-Alloza1, C. Prada1, M. P. Frosch1, J. Rosand1, E. E. Smith1, S. M. Greenberg1, 1 Massachusetts General Hospital, Boston, MA, USA; 2University of Iowa, Iowa City, IA, USA. Contact e-mail: [email protected]
Background: Patients with advanced cerebrovascular deposition of betaamyloid (cerebral amyloid angiopathy, CAA) show increased PiB retention in an occipital predominant pattern (Johnson, Ann. Neurol. 2007). There is no definitive proof, however, that this PiB signal represents CAA rather than accompanying Alzheimer’s disease (AD) plaque pathology. Methods: PiB-PET, CT, MRI, and genetic testing were evaluated in a 42 year-old man with Iowa-type hereditary CAA (ICAA), a condition with severe CAA, but little or no fibrillar plaque amyloid. The subject presented clinically with a 10-year history of tremor and atypical migraine, but no dementia. Post-mortem brain from a first-degree relative with ICAA was stained with PiB. PET DVR values were compared to AD and normal control groups. Results: Amyloid precursor protein exon 17 sequencing showed the characteristic Iowa mutation, substitution of asparagine for aspartic acid at position 23. Marked PiB retention (DVR⬎1.8) was seen in occipital cortex, whereas regions typically involved in AD had low retention. PiB staining of post-mortem tissue showed exclusively vascular labeling, supporting the inference that the PiB-PET signal in the patient represented CAA rather than AD plaque pathology. CT demonstrated occipital calcifications characteristic of ICAA. Conclusions: These findings offer strong evidence that PiB-PET detects vascular as well as plaque amyloid and can identify the vascular deposits as an early manifestation of CAA. Advanced cerebrovascular amyloid deposition appears to precede other manifestations of CAA such as extensive hemorrhage or white matter damage. IC-P3-189
DECREASED BINDING OF [11C] DONEPEZIL AS SHOWN BY PET CORRELATED WITH CLINICAL EFFECT OF DONEPEZIL ADMINISTRATION IN ALZHEIMER’S DISEASE: THE OSAKI-TAJIRI PROJECT (4)
Masashi Kasuya1,2, Hiroyasu Ishikawa1, Nobuyuki Okamura3, Motohisa Kato3, Yumi Sasaki1, Eriko Nakata1, Yoichi Ishikawa4, Yoshihito Funaki4, Naofumi Tanaka1, Ren Iwata4, Kazuhiko Yanai3, Kenichi Meguro1, 1Department of Geriatric Behavioral Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; 2 Miyagi University, Miyagi, Japan; 3Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan; 4 Cyclotron RI Center, Tohoku University, Sendai, Japan. Contact e-mail: [email protected] Background: Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and has widely been used for Alzheimer’s disease (AD). Positron emission tomography (PET) with the 5-11C-methoxy donepezil ([11C] donepezil) can visualize the distribution of donepezil in human brain. We previously reported that AD patients exhibited about 20⬃30% reductions of donepezil binding in neocortex and hippocampus compared with normal subjects. We herein evaluated longitudinal changes by orally administered donepezil with clinical effects. Methods: Patients: Seven patients with probable AD (NINCDS-ADRDA) were studied. After the first PET study, 5 mg of donepezil was orally administered. After 6 months, they received the second PET study. Informed consent was received from family members of all patients. PET: After i.v. administration of 7⬃9 mCi of [11C] donepezil, a dynamic scan was performed for 60 min. Arterialized venous blood samples were obtained from a hand vein for assessing blood RI activity. Standard uptake value images were obtained by normalizing tissue concentration by injected dose and body mass. Circular region of interest was put to evaluate regional distributions of the cerebellum, striatum, thalamus, frontal, temporal, parietal, occipital, anterior and posterior cingulate, and hippocampus. The distribution volume (DV), the ratio of the concentration in tissue to that in plasma at equilibrium, was calculated by Logan’s graphical analysis. The reduction rate was calculated by (PET1-PET2)/PET1*100. Clinical effects: The Mini-Mental State Examination (MMSE) was used for assessing global cognitive function, the Cognitive Abilities Screening Instrument (CASI) was used for evaluate nine domains such as recent memory, orientation, the frontal domains (attention, list-generating fluency concentration/mental
LOBAR GRAY AND WHITE MATTER ATROPHY IN ALZHEIMER’S DISEASE: PRELIMINARY RESULTS FROM THE ADNI PUBLIC DATABASE
Juebin Huang1, Alexander P. Auchus1,2, 1University of Tennessee Health Science Center, Memphis, TN, USA; 2Memphis Veterans Affairs Medical Center, Memphis, TN, USA. Contact e-mail: [email protected] Background: Regional brain volume loss beyond the medial temporal lobe has not been extensively studied in AD, particularly in the white matter. Recent studies suggest that white matter pathology may underlie regional dissociations between medial temporal volume loss and metabolic reductions in posterior association cortices in AD patients. The present study investigates lobar gray and white matter volume loss in AD using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Methods: 1.5 Tesla MR brain images from 18 subjects with AD and 18 age- and sex-matched subjects with normal cognition (NC) were obtained from the ADNI public database (www.loni.ucla.eduADNI). T1-weighted, 3-D volumetric MP-RAGE images were analyzed in a multi-step process. Brain parenchyma was segmented into gray matter and white matter using an automated program. Lobar gray and white matter volumes in frontal, temporal, parietal and occipital lobes were delineated using a landmarkbased, manual method and normalized to total intracranial volume. Between-group differences in lobar gray and white matter volumes were compared using student’s t-test. Results: AD subjects (mean age ⫽ 75, mean MMSE ⫽ 23.4, all CDR ⫽ 1) demonstrated significantly reduced gray matter volumes vs. NC (mean age ⫽ 75, mean MMSE ⫽ 29.1, all CDR ⫽ 0) in frontal (10.39 vs. 11.60, p⬍0.01), temporal (6.91 vs. 8.44,
T81
p⬍0.01) and parietal (6.14 vs.7.10, p⬍0.01) lobes. There was no difference between groups in occipital gray matter volume (3.46 vs. 3.60, p⫽0.30). White matter volume in the parietal lobe was significantly decreased in AD vs. NC (10.09 vs. 10.94, p⬍0.05). Conclusions: This analysis from the ADNI public database reveals AD-associated gray matter volume loss in brain regions serving higher functions (frontal, temporal and parietal lobes), but not in regions serving primary functions (occipital lobe). Furthermore, we observed white matter volume loss in the parietal lobe of AD, a novel finding which has not been previously described. This new finding may represent axonal loss from degenerating neurons in multimodal association cortices, or reduced integrity of fibers in the posterior cingulate bundle connecting medial temporal lobe structures to posterior cingulate gyrus. IC-P3-185
A METHOD TO QUANTITATE AMYLOID PLAQUE LOAD IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE
George Iordanescu1,2, Palamadai N. Venkatasubramanian1,2, Marina V. Yasvoina1,3, Jason C. Pych1,4, Alice M. Wyrwicz1,5, 1ENH Research Institute, Evanston, IL, USA; 2Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 3NUIN, Northwestern University, Evanston, IL, USA; 4Neurobiology and Physiology, Northwestern University Weinberg College of Arts and Sciences, Evanston, IL, USA; 5Radiology, Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Contact email: [email protected] Background: Although successful visualization of amyloid deposits in the APP transgenic mouse brain with MR imaging has been reported recently, there is no suitable method to measure plaque load (PL). We present a novel method based on simulated flooding (watersheds) to segment amyloid plaques in mouse brain images. In this method, the image is segmented into catchment basins (CB) associated with local minima and CBs that correspond to plaques are selected using the data Laplacian as a feature describing local variation. Besides PL (volume fraction) estimation, our method can be also used to analyze other plaque characteristics such as size, shape and distribution. Methods: The automatic plaque segmentation algorithm has two steps: First, simulated flooding is used to extract regions with low intensities completely surrounded by higher intensity neighbors. The resulting map defines the CBs of the MR local minima. Second, the image Laplacian L(I) ⫽ div (grad (I)) is used to model the plaque cores, defined as regions with small derivatives, surrounded by rapidly increasing neighbors. Plaques are segmented by taking the CBs that have maximum Laplacians larger than the background noise. The algorithm was used to compute PL in the subiculum of 2 and 10 months old 5XFAD APP/PS1 transgenic mice. RARE 3D-images of fixed brains acquired on a 14.1T microimager using TR/TEeff 2500ms/40ms and pixel size 35m x35m x35m were analyzed. The algorithm was applied to histology data from the same brains and PL results were compared for validation. Results: The computed PL values increased with age for the 5XFAD mice from 1.25% at 2 months to 25.0% at 10 months. A non-transgenic control mouse had a PL of nearly 0% as expected. Our results are consistent with the known evolution of plaque deposition in this strain. Amyloid plaques begin to appear in the subiculum of 2 month old 5XFAD mice and by 10 months of age numerous plaques are found in subiculum, hippocampus and deep layers of the cortex. Conclusions: Our automatic computational method for the quantitation of plaques can be applied to evaluate disease progression and efficacy of therapy in transgenic mouse models of AD. IC-P3-186
ALZHEIMERS DISEASES
Mwambu Margaret Nil Jane, Mwambu Margaret Nil Jane, Nkumba University, Kampala, Uganda. Contact e-mail: [email protected]
N W A HDR
Background: I was born in Uganda, by Mr and Mrs Mukata, who past away when l was 5 years, l started that orphage life from then to to day, my
WIT
T82
Alzheimer’s Imaging Consortium IC-P3: Poster Presentations
education was very poor, l started P.1 at Kamonkoli primary school, l joined secondary school, then joined Nkumba college of commerce, l completed my diploma in secretary. Methods: To acquire more training to how people in my community can avoid getting some diseases, training them how to eat, drinck etc. Results: To be voice & help the aged/people suffering with diseases in my community. Conclusions: I pray God should open a way for me to attend that conference, such that l can aquire knowledge and l teach the people in my community.
N W A HDR
WIT
IC-P3-187
ACCELERATED CORTICAL THINNING IN FTD-3 CHMP2B MUTATION CARRIERS
Peter Johannsen1, Simon F. Eskildsen2, Jørgen E. Nielsen1,3, Adrian Isaacs4, Dora Zeidler5, Leif Østergaard5, 1Memory Research Group, Copenhagen University Hospital, Copenhagen, Denmark; 2 Department of Health Science and Technology, Aalborg University, Aalborg, Denmark; 3Section of Neurogenetics, Institute of Medical Biochemistry & Genetics, Copenhagen University, Copenhagen, Denmark; 4MRC Prion Unit, Institute of Neurology, London, United Kingdom; 5Center for Functionally Integrative Neuroscience, Aarhus University Hospital, Aarhus, Denmark. Contact e-mail: [email protected] Background: Frontotemporal dementia linked to chromosome 3 (FTD-3) (1) is caused by mutations in the CHMP2B gene in the endosomal ESCRTIII complex (2). Objective: To prospectively study changes over time of cortical thickness in structural neuroimaging MR data from the large Danish FTD-3 family with a pathogenic G-to-C transition in the acceptor splice site of CHMP2B exon 6. Methods: Nine presymptomatic CHMP2B mutation carriers (mean age 55.8 ⫾ SD 5.6) and 7 mutation negative (MN) (mean age 54.3 ⫾ SD 6.0) family members were scanned twice, 1.3 years apart, using a 3T MRI FSPGR 3D sequence. Cortical thickness was calculated with an updated previously published method (3) where 3D non-parametric surfaces were iteratively fitted to the inner and outer boundary of the cortex. The method calculates the cortical thickness with sub-voxel accuracy at more than 85.000 vertices equally distributed over the cortical surface. For this abstract results were pooled for right and left cortical lobes as defined by a stereotaxic atlas. Results: Paired t-tests between cortical thicknesses at the two time points showed that for CHMP2B mutation carriers all lobes except the parietal and the right temporal were significantly thinner at time point 2 compared to 1. In the MN group only the left occipital lobe was significantly thinner at time point 2. Annualized thinning rates (mean⫾SD) as percent decline of thickness at time point 1 are listed in Table.
CHMP2Bmutation MN p-value
Frontal Lobe Left
Right
Temporal Lobe Left
Right
Parietal Lobe Left
Right
Occipital Lobe Left
Right
4.18⫾3.73
3.42⫾3.51
3.74⫾3.16
1.37⫾3.75
1.52⫾5.30
3.14⫾6.87
6.15⫾4.03
3.91⫾2.97
0.50⫾3.51 0.032
1.15⫾2.86 0.088
1.44⫾1.96 0.048
0.48⫾2.86 0.141
0.81⫾4.57 0.388
1.59⫾4.89 0.303
4.77⫾5.53 0.295
0.84⫾3.78 0.052
Conclusions: The cortical thinning rate is significantly higher in the left frontal and left temporal lobe in CHMP2B mutation carriers compared to the mutation negative subjects. Supported by Danish MRC: 22-04-0458. References: (1) Gydesen et al. Neurology 2002; 59: 1585-94. (2) Skibinski et al. Nature Genetics 2005; 37: 806-8. (3) Eskildsen et al. LNCS 2006; 4191: 823-830. IC-P3-188
EARLY DETECTION OF HEREDITARY CEREBRAL AMYLOID ANGIOPATHY WITH PITTSBURGH COMPOUND B
K. A. Johnson1, T. J. Grabowski2, M. E. Gurol2, M. E. Skehan1, R. N. K. Nandigam1, J. A. Becker1, M. Garcia-Alloza1, C. Prada1, M. P. Frosch1, J. Rosand1, E. E. Smith1, S. M. Greenberg1, 1 Massachusetts General Hospital, Boston, MA, USA; 2University of Iowa, Iowa City, IA, USA. Contact e-mail: [email protected]
Background: Patients with advanced cerebrovascular deposition of betaamyloid (cerebral amyloid angiopathy, CAA) show increased PiB retention in an occipital predominant pattern (Johnson, Ann. Neurol. 2007). There is no definitive proof, however, that this PiB signal represents CAA rather than accompanying Alzheimer’s disease (AD) plaque pathology. Methods: PiB-PET, CT, MRI, and genetic testing were evaluated in a 42 year-old man with Iowa-type hereditary CAA (ICAA), a condition with severe CAA, but little or no fibrillar plaque amyloid. The subject presented clinically with a 10-year history of tremor and atypical migraine, but no dementia. Post-mortem brain from a first-degree relative with ICAA was stained with PiB. PET DVR values were compared to AD and normal control groups. Results: Amyloid precursor protein exon 17 sequencing showed the characteristic Iowa mutation, substitution of asparagine for aspartic acid at position 23. Marked PiB retention (DVR⬎1.8) was seen in occipital cortex, whereas regions typically involved in AD had low retention. PiB staining of post-mortem tissue showed exclusively vascular labeling, supporting the inference that the PiB-PET signal in the patient represented CAA rather than AD plaque pathology. CT demonstrated occipital calcifications characteristic of ICAA. Conclusions: These findings offer strong evidence that PiB-PET detects vascular as well as plaque amyloid and can identify the vascular deposits as an early manifestation of CAA. Advanced cerebrovascular amyloid deposition appears to precede other manifestations of CAA such as extensive hemorrhage or white matter damage. IC-P3-189
DECREASED BINDING OF [11C] DONEPEZIL AS SHOWN BY PET CORRELATED WITH CLINICAL EFFECT OF DONEPEZIL ADMINISTRATION IN ALZHEIMER’S DISEASE: THE OSAKI-TAJIRI PROJECT (4)
Masashi Kasuya1,2, Hiroyasu Ishikawa1, Nobuyuki Okamura3, Motohisa Kato3, Yumi Sasaki1, Eriko Nakata1, Yoichi Ishikawa4, Yoshihito Funaki4, Naofumi Tanaka1, Ren Iwata4, Kazuhiko Yanai3, Kenichi Meguro1, 1Department of Geriatric Behavioral Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan; 2 Miyagi University, Miyagi, Japan; 3Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan; 4 Cyclotron RI Center, Tohoku University, Sendai, Japan. Contact e-mail: [email protected] Background: Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and has widely been used for Alzheimer’s disease (AD). Positron emission tomography (PET) with the 5-11C-methoxy donepezil ([11C] donepezil) can visualize the distribution of donepezil in human brain. We previously reported that AD patients exhibited about 20⬃30% reductions of donepezil binding in neocortex and hippocampus compared with normal subjects. We herein evaluated longitudinal changes by orally administered donepezil with clinical effects. Methods: Patients: Seven patients with probable AD (NINCDS-ADRDA) were studied. After the first PET study, 5 mg of donepezil was orally administered. After 6 months, they received the second PET study. Informed consent was received from family members of all patients. PET: After i.v. administration of 7⬃9 mCi of [11C] donepezil, a dynamic scan was performed for 60 min. Arterialized venous blood samples were obtained from a hand vein for assessing blood RI activity. Standard uptake value images were obtained by normalizing tissue concentration by injected dose and body mass. Circular region of interest was put to evaluate regional distributions of the cerebellum, striatum, thalamus, frontal, temporal, parietal, occipital, anterior and posterior cingulate, and hippocampus. The distribution volume (DV), the ratio of the concentration in tissue to that in plasma at equilibrium, was calculated by Logan’s graphical analysis. The reduction rate was calculated by (PET1-PET2)/PET1*100. Clinical effects: The Mini-Mental State Examination (MMSE) was used for assessing global cognitive function, the Cognitive Abilities Screening Instrument (CASI) was used for evaluate nine domains such as recent memory, orientation, the frontal domains (attention, list-generating fluency concentration/mental