- Email: [email protected]
A NOVEL RADIOLIGAND FOR ASSESSING BACE OCCUPANCY IN P-GP KO MOUSE BRAIN
P108
Poster Presentations: IC-P
Figure 1. Individual subjects (1-28) left and right thalamus volumes (mm3) obtained using different automated techniques, relative to the gold standard segmentations (in black).
heimer’s Disease (AD), however patterns of propagation remains debatable. Modeling structural and functional brain regional associations allows for examining patterns of propagation and accumulations of AD pathophysiological processes in the living human brain. Dynamics of large-scale organization might serve as a sensitive metric to quantify patterns of amyloidosis or degenerative changes present in individuals at risk of developing AD dementia. Methods: Twenty four month longitudinal structure MRIs, [18F] FDG and [18F]Florbetapir PET images obtained from 206 subjects (60 Healthy Controls, 108 Early Cognitive Impairment, 19 Late Cognitive Impairment, 19 Alzheimer’s Disease) were downloaded from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Surfaces were acquired using CIVET. The respective standardized uptake value ratio (SUVR) maps were subsequently generated using the median counts at cerebellar grey matter and pons for [18F]Florbetapir and [18F]FDG PET images, respectively. The SUVR at the cortex were projected using the mid brain surface of each subject. Vertex values were down sampled using kmeans clustering algorithm. Regional Association Maps (RAMs) were then generated by using the correlation matrix and Bonferroni corrected regional association density maps were calculated for [18F]FDG and [18F]florbetapir. Results: Comparing the baseline and follow-up regional associations, Amyloid accumulation ([18F]Florbetapir SUVR) shows a decrease over time in all the disease stages. A decrease in regional association can also be observed in Amyloid accumulation with the disease severity. Hypometabolism ([18F]FDG SUVR) shows an opposite variation (increase) when comparing the baseline and follow-up regional associations but decreases with disease severity. However, the regions that shows association in their rate of Amyloid accumulation and hypometabolism decrease with the disease severity [Figure 1]. Conclusions: Regional Association Maps capture the dynamic architecture of amyloid and hypometabolism propagation, occurring as the disease progresses. Regional associations decline for Amyloid accumulation as a function of the disease progression can be attributed to the non-linear rate of amyloidosis (reaching a plateau). This behavior is also supported by the reduction in regional associations for the rate of amyloid accumulation with the increase in disease severity.
Table 1 Results for the Overlap Accuracy of MAPS vs. Gold Standard Segmentations: Average Dice Values and 95% Confidence Intervals (CI). MAPS-sba
MAPS-STAPLE
Thalamus L Mean Dice [95% CI] 0.92 [0.91 - 0.93] 0.92 [0.91 - 0.93] Thalamus R [Mean Dice [95% CI] 0.92 [0.91 - 0.93] 0.92 [0.91 - 0.93]
IC-P-194
REGIONAL ASSOCIATION MAPS DESCRIBE DYNAMIC ARCHITECTURE OF AMYLOIDOSIS AND HYPOMETABOLISM IN ALZHEIMER’S DISEASE
Sulantha Sanjeewa Mathotaarachchi1, Sara Mohades2, Eduardo Rigon Zimmer3, Felix Carbonell4, Thomas Beaudry1, Maxime Parent5, Andrea Lessa Benedet1, Seqian Wang1, Monica Shin1, Vladimir S. Fonov1, Laksanun Cheewakriengkrai5, Antoine Leuzy5, Lucas Porcello Schilling1, Sarinporn Manitsirikul1, Simon Eskildsen6, Min Su Kang7, Serge Gauthier3, Pedro Rosa-Neto8, 1McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; 2McGill Center-McGill Centre for Studies in Aging, Montreal, Quebec, Canada; 3McGill Center for Studies in Aging, Montreal, Quebec, Canada; 4Biospective Inc., Montreal, Quebec, Canada; 5McGill Centre for Studies in Aging, Montreal, Quebec, Canada; 6McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; 7McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; 8McGill University, Porto Alegre, Brazil. Contact e-mail: [email protected] Background: It has been accepted that amyloidosis and hypometabolism propagates over time and accumulate across brain regions in the Alz-
Figure 1. Longitudinal variation of regional associativity. IC-P-195
A NOVEL RADIOLIGAND FOR ASSESSING BACE OCCUPANCY IN P-GP KO MOUSE BRAIN
Zhizhen Zeng1, Patricia Miller2, Stacey O’Malley3, Shaun Stauffer4, Shawn Stachel5, Idriss Bennacef5, Eric Hostetler5, David Williamson5, Cyrille Sur6, 1Merck Research Laboratories, West Point, Pennsylvania, United States; 2Merck Research Laboratories, West Point, Pennsylvania, United States; 3Merck Research Laboratories, West Point, Pennsylvania, United States; 4Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee, United States; 5Merck, West Point, Pennsylvania, United States; 6Merck Research Laboratories, West Point, Pennsylvania, United States. Contact e-mail: [email protected] Background: A beta-site amyloid precursor protein cleaving enzyme (BACE) is a key enzyme in generation of amyloid-b peptides that aggregate to form amyloid plaques found in Alzheimer’s disease (AD) brains. Inhibition of BACE is
Poster Presentations: IC-P a potential approach for the treatment of AD and a BACE radioligand could be valuable for assessing target occupancy and therapeutic responses to BACE inhibition. Methods: Mdr1a/b (P-gp 3 and 1 deficient, termed P-gp KO), FVB wild type (wt), BACE1 knockout (KO), and BACE1 wt mice, were purchased from Taconic. Mdr1a/b and FVB WT mice were 8 weeks old, while BACE1 KO and BACE1 WT mice were two years old when used in the studies. The unlabeled compounds and [3 H]Compound-A (75.3Ci/mmol) were synthesized in house. Autoradiography was performed using frozen brain slices. In vitro binding assays were done with brain membranes or homogenates. In vivo brain occupancy was performed in Mdr1a/b, FVB and BACE1 KO mice by i.p. administration of BACE inhibitor or vehicle and then followed by i.v. dosing of the radioligand. Results: In mouse brain homogenates, [3 H]Compound-A showed binding site densities (B max) from 6.5 nM to 8.4 nM and high binding affinity (K d ¼ 0.5 nM), yielding good binding potentials (B max/K d). In autoradiography of BACE1 wt mice, [3 H]Compound-A binding sites were widely distributed across the brain with different binding densities in various regions, and the non-displaceable binding was low and homogenous among all the brain slices. In contrast, [3 H]Compound-A failed to show specific binding in the brain slices of BACE1 KO mice. Furthermore, the in vivo brain occupancy studies demonstrated that [3 H]Compound-A binding to Mdr1a/b brains was dose-dependent and displaceable by pre-administration of a selective, brain penetrant BACE inhibitor. In FVB mouse brains, [3 H]Compound-A did not show specific brain uptake following i.v. administration of [3 H]CompoundA. Conclusions: These results demonstrate that [3 H]Compound-A binding is specific to BACE which is widely distributed in mouse brain. In vivo brain uptake of [3 H]-Compound-A only occurred in P-gp KO mice, not in wild type and BACE1 KO mice. Together, these data suggest that a compound with no P-gp liability could be developed into a PET tracer for BACE. IC-P-196
ADVANCING THE ACCURACY OF AUTOMATED FDG-PET MEASUREMENTS USING HIGHDIMENSIONAL IMAGE NORMALIZATION
Michel J. Grothe1, Marina Boccardi2, Martina Bocchetta3, Giovanni Frisoni4, Stefan Teipel5, 1German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; 2IRCCS S.Giovanni di Dio Fatebenefratelli, Brescia, Italy; 3IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy; 4IRCCS, Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy; 5University Medicine Rostock and DZNE Rostock, Rostock, Germany. Contact e-mail: [email protected] Background: Fluorodeoxyglucose (FDG)-PET imaging is among the most important imaging modalities for in-vivo research on Alzheimer’s disease. The gold standard for regional quantification of PET signal relies on manual delineation of anatomical regions-of-interest (ROIs) on coregistered high-resolution structural MRI scans of the same subject. Analysis of large-scale imaging datasets has been made possible through the development of automated image analysis techniques employing spatial normalization of the PET images to a standardized reference space with associated atlases of anatomical ROIs. Novel high-dimensional image warping algorithms for MRI allow matching individual images to a given reference template with much higher accuracy compared to earlier low-dimensional implementations. The potential benefits of these novel normalization procedures for the accuracy of automated FDGPET measurements have not yet been investigated. Methods: Hand-drawn hippocampus labels based on a harmonized delineation protocol were recently published for a subset of 100 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Coincident FDG-PET scans were available for 38 of these subjects and were rigidly coregistered to their corresponding MRIs. Quantification of hippocampal tracer-uptake was carried out using SPM8 software and the VBM8-toolbox and followed 4 different analysis approaches: (i) the "gold standard" of direct signal extraction within individual hippocampus labels in native space, as well as automated extraction within harmonized hippocampus labels in standard reference space using (ii) direct low-dimensional normalization of the PET scans to SPM’s default H2O-PET template ("standard direct"), (iii) indirect normalization using parameters from standard lowdimensional normalization of the coregistered MRI ("standard indirect"), and (iii) indirect normalization using parameters from high-dimensional normalization of the coregistered MRI ("DARTEL"). Results: Automatically
P109
estimated values for hippocampal FDG-uptake using "DARTEL" were highly correlated with the values extracted using the "gold standard" method (R2(left/ right) ¼ 0.94/0.93), with a mean percentage divergence below 3%. The correlations were significantly higher compared to those using "standard direct" (R2(left/right) ¼ 0.85/0.87, p(difference) < 0.001/0.05) and "standard indirect" (R2(left/right) ¼ 0.91/0.84, p(difference) < 0.01/0.0001) normalization strategies. Conclusions: Even though PET images are generally limited by relatively low spatial resolution, novel high-dimensional image normalization techniques may still significantly improve the accuracy of automated regional signal measurements compared to more traditional normalization strategies. IC-P-197
MICROHEMORRHAGE FINDINGS ON BASELINE ROSAS MRI DATA
Hubert Basselerie1, Luc Bracoud2, Hans-Martin Schneble3, Sylvain Gouttard2, Isabelle Guignot3, Audrey Istace2, Florent Roche2, Joel Schaerer2, Maria Pueyo3, Chahin Pachai2, Bruno Vellas1, Fabrice Bonneville1, 1CHU Casselardit, Toulouse, France; 2BioClinica, Lyon, France; 3IRIS, Suresnes, France. Contact e-mail: luc.bracoud@ bioclinica.com Background: Cerebral microhemorrhages, although common among the elderly, are known to be related to the presence of amyloid in the brain, cognitive impairment and dementia severity. This work assesses the prevalence of microhemorrhages in ROSAS, a monocentric observational study which includes normal controls as well as MCI and AD subjects. Methods: 408 subjects 65 years and older were enrolled, including 110 Normal Controls (NC, no memory complaints, MMSE26 and CDR¼0), 100 Mild Cognitive Impairment (MCI, MMSE24 and CDR¼0.5, memory impairment based on RAVLT and that did not meet DSM IV criteria for AD dementia) and 198 AD (12MMSE26 and CDR0.5 and meeting DSM IV criteria). Susceptibility-Weighted (SWI) MRI scans were collected up to 3 times between Baseline and Month 48, at one site using a Philips Achieva 3T scanner, for consenting subjects (n¼153, including 51 NC, 41 MCI and 61 AD). Baseline SWI data were reviewed by one rater, looking at native 0.5 mm thick images along with minimum Intensity Projection (minIP) reconstructed slices (6 mm thick, with 3 mm overlap). Bleeds were categorized as deep, lobar and infratentorial, and further subdivided as <5 mm, between 5 and 10 mm (so-called large microhemorrhages), and >10 mm in size. Descriptive statistics were computed for each group. Pearson Chi-Square tests were used to assess differences between groups. Results: Microhemorrhages (10mm) were reported on 56.9% NC, 68.3% MCI and 65.6% AD. Only 2.0% NC had more than 4 microhemorrhages, as compared to 22.0% MCI and 11.5% AD. Significant differences between groups were found for the presence of intratentorial microhemorrhages (p¼0.035) and of >4 microhemorrhages (p¼0.01), and between NC and non-NC for the presence of large microhemorrhages (p¼0.045) and >4 lobar microhemorrhages (p¼0.029). Bleeds >10 mm were found on only 2 MCI and 2 AD. Conclusions: A majority of ROSAS subjects from all clinical categories had >1 microhemorrhage. Multiple Table 1 Proportion of microhemorrhages by group, classified by number # Microhemorrhages (10 mm)
NC (%)
MCI (%)
AD (%)
1 0 [1-4] >4 >4 lobar
56.9 43.1 54.9 2.0 2.0
68.3 31.7 46.3 22.0 17.1
65.6 34.4 54.1 11.5 9.8
Table 2 Proportion of microhemorrhages by group, classified by location Microhemorrhage location
NC (%)
MCI (%)
AD (%)
Deep Lobar Infratentorial
9.8 54.9 7.8
24.4 63.4 26.8
18.0 57.4 13.1
Poster Presentations: IC-P
Figure 1. Individual subjects (1-28) left and right thalamus volumes (mm3) obtained using different automated techniques, relative to the gold standard segmentations (in black).
heimer’s Disease (AD), however patterns of propagation remains debatable. Modeling structural and functional brain regional associations allows for examining patterns of propagation and accumulations of AD pathophysiological processes in the living human brain. Dynamics of large-scale organization might serve as a sensitive metric to quantify patterns of amyloidosis or degenerative changes present in individuals at risk of developing AD dementia. Methods: Twenty four month longitudinal structure MRIs, [18F] FDG and [18F]Florbetapir PET images obtained from 206 subjects (60 Healthy Controls, 108 Early Cognitive Impairment, 19 Late Cognitive Impairment, 19 Alzheimer’s Disease) were downloaded from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Surfaces were acquired using CIVET. The respective standardized uptake value ratio (SUVR) maps were subsequently generated using the median counts at cerebellar grey matter and pons for [18F]Florbetapir and [18F]FDG PET images, respectively. The SUVR at the cortex were projected using the mid brain surface of each subject. Vertex values were down sampled using kmeans clustering algorithm. Regional Association Maps (RAMs) were then generated by using the correlation matrix and Bonferroni corrected regional association density maps were calculated for [18F]FDG and [18F]florbetapir. Results: Comparing the baseline and follow-up regional associations, Amyloid accumulation ([18F]Florbetapir SUVR) shows a decrease over time in all the disease stages. A decrease in regional association can also be observed in Amyloid accumulation with the disease severity. Hypometabolism ([18F]FDG SUVR) shows an opposite variation (increase) when comparing the baseline and follow-up regional associations but decreases with disease severity. However, the regions that shows association in their rate of Amyloid accumulation and hypometabolism decrease with the disease severity [Figure 1]. Conclusions: Regional Association Maps capture the dynamic architecture of amyloid and hypometabolism propagation, occurring as the disease progresses. Regional associations decline for Amyloid accumulation as a function of the disease progression can be attributed to the non-linear rate of amyloidosis (reaching a plateau). This behavior is also supported by the reduction in regional associations for the rate of amyloid accumulation with the increase in disease severity.
Table 1 Results for the Overlap Accuracy of MAPS vs. Gold Standard Segmentations: Average Dice Values and 95% Confidence Intervals (CI). MAPS-sba
MAPS-STAPLE
Thalamus L Mean Dice [95% CI] 0.92 [0.91 - 0.93] 0.92 [0.91 - 0.93] Thalamus R [Mean Dice [95% CI] 0.92 [0.91 - 0.93] 0.92 [0.91 - 0.93]
IC-P-194
REGIONAL ASSOCIATION MAPS DESCRIBE DYNAMIC ARCHITECTURE OF AMYLOIDOSIS AND HYPOMETABOLISM IN ALZHEIMER’S DISEASE
Sulantha Sanjeewa Mathotaarachchi1, Sara Mohades2, Eduardo Rigon Zimmer3, Felix Carbonell4, Thomas Beaudry1, Maxime Parent5, Andrea Lessa Benedet1, Seqian Wang1, Monica Shin1, Vladimir S. Fonov1, Laksanun Cheewakriengkrai5, Antoine Leuzy5, Lucas Porcello Schilling1, Sarinporn Manitsirikul1, Simon Eskildsen6, Min Su Kang7, Serge Gauthier3, Pedro Rosa-Neto8, 1McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; 2McGill Center-McGill Centre for Studies in Aging, Montreal, Quebec, Canada; 3McGill Center for Studies in Aging, Montreal, Quebec, Canada; 4Biospective Inc., Montreal, Quebec, Canada; 5McGill Centre for Studies in Aging, Montreal, Quebec, Canada; 6McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; 7McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; 8McGill University, Porto Alegre, Brazil. Contact e-mail: [email protected] Background: It has been accepted that amyloidosis and hypometabolism propagates over time and accumulate across brain regions in the Alz-
Figure 1. Longitudinal variation of regional associativity. IC-P-195
A NOVEL RADIOLIGAND FOR ASSESSING BACE OCCUPANCY IN P-GP KO MOUSE BRAIN
Zhizhen Zeng1, Patricia Miller2, Stacey O’Malley3, Shaun Stauffer4, Shawn Stachel5, Idriss Bennacef5, Eric Hostetler5, David Williamson5, Cyrille Sur6, 1Merck Research Laboratories, West Point, Pennsylvania, United States; 2Merck Research Laboratories, West Point, Pennsylvania, United States; 3Merck Research Laboratories, West Point, Pennsylvania, United States; 4Vanderbilt Center for Neuroscience Drug Discovery, Nashville, Tennessee, United States; 5Merck, West Point, Pennsylvania, United States; 6Merck Research Laboratories, West Point, Pennsylvania, United States. Contact e-mail: [email protected] Background: A beta-site amyloid precursor protein cleaving enzyme (BACE) is a key enzyme in generation of amyloid-b peptides that aggregate to form amyloid plaques found in Alzheimer’s disease (AD) brains. Inhibition of BACE is
Poster Presentations: IC-P a potential approach for the treatment of AD and a BACE radioligand could be valuable for assessing target occupancy and therapeutic responses to BACE inhibition. Methods: Mdr1a/b (P-gp 3 and 1 deficient, termed P-gp KO), FVB wild type (wt), BACE1 knockout (KO), and BACE1 wt mice, were purchased from Taconic. Mdr1a/b and FVB WT mice were 8 weeks old, while BACE1 KO and BACE1 WT mice were two years old when used in the studies. The unlabeled compounds and [3 H]Compound-A (75.3Ci/mmol) were synthesized in house. Autoradiography was performed using frozen brain slices. In vitro binding assays were done with brain membranes or homogenates. In vivo brain occupancy was performed in Mdr1a/b, FVB and BACE1 KO mice by i.p. administration of BACE inhibitor or vehicle and then followed by i.v. dosing of the radioligand. Results: In mouse brain homogenates, [3 H]Compound-A showed binding site densities (B max) from 6.5 nM to 8.4 nM and high binding affinity (K d ¼ 0.5 nM), yielding good binding potentials (B max/K d). In autoradiography of BACE1 wt mice, [3 H]Compound-A binding sites were widely distributed across the brain with different binding densities in various regions, and the non-displaceable binding was low and homogenous among all the brain slices. In contrast, [3 H]Compound-A failed to show specific binding in the brain slices of BACE1 KO mice. Furthermore, the in vivo brain occupancy studies demonstrated that [3 H]Compound-A binding to Mdr1a/b brains was dose-dependent and displaceable by pre-administration of a selective, brain penetrant BACE inhibitor. In FVB mouse brains, [3 H]Compound-A did not show specific brain uptake following i.v. administration of [3 H]CompoundA. Conclusions: These results demonstrate that [3 H]Compound-A binding is specific to BACE which is widely distributed in mouse brain. In vivo brain uptake of [3 H]-Compound-A only occurred in P-gp KO mice, not in wild type and BACE1 KO mice. Together, these data suggest that a compound with no P-gp liability could be developed into a PET tracer for BACE. IC-P-196
ADVANCING THE ACCURACY OF AUTOMATED FDG-PET MEASUREMENTS USING HIGHDIMENSIONAL IMAGE NORMALIZATION
Michel J. Grothe1, Marina Boccardi2, Martina Bocchetta3, Giovanni Frisoni4, Stefan Teipel5, 1German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; 2IRCCS S.Giovanni di Dio Fatebenefratelli, Brescia, Italy; 3IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy; 4IRCCS, Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy; 5University Medicine Rostock and DZNE Rostock, Rostock, Germany. Contact e-mail: [email protected] Background: Fluorodeoxyglucose (FDG)-PET imaging is among the most important imaging modalities for in-vivo research on Alzheimer’s disease. The gold standard for regional quantification of PET signal relies on manual delineation of anatomical regions-of-interest (ROIs) on coregistered high-resolution structural MRI scans of the same subject. Analysis of large-scale imaging datasets has been made possible through the development of automated image analysis techniques employing spatial normalization of the PET images to a standardized reference space with associated atlases of anatomical ROIs. Novel high-dimensional image warping algorithms for MRI allow matching individual images to a given reference template with much higher accuracy compared to earlier low-dimensional implementations. The potential benefits of these novel normalization procedures for the accuracy of automated FDGPET measurements have not yet been investigated. Methods: Hand-drawn hippocampus labels based on a harmonized delineation protocol were recently published for a subset of 100 subjects from the Alzheimer’s Disease Neuroimaging Initiative. Coincident FDG-PET scans were available for 38 of these subjects and were rigidly coregistered to their corresponding MRIs. Quantification of hippocampal tracer-uptake was carried out using SPM8 software and the VBM8-toolbox and followed 4 different analysis approaches: (i) the "gold standard" of direct signal extraction within individual hippocampus labels in native space, as well as automated extraction within harmonized hippocampus labels in standard reference space using (ii) direct low-dimensional normalization of the PET scans to SPM’s default H2O-PET template ("standard direct"), (iii) indirect normalization using parameters from standard lowdimensional normalization of the coregistered MRI ("standard indirect"), and (iii) indirect normalization using parameters from high-dimensional normalization of the coregistered MRI ("DARTEL"). Results: Automatically
P109
estimated values for hippocampal FDG-uptake using "DARTEL" were highly correlated with the values extracted using the "gold standard" method (R2(left/ right) ¼ 0.94/0.93), with a mean percentage divergence below 3%. The correlations were significantly higher compared to those using "standard direct" (R2(left/right) ¼ 0.85/0.87, p(difference) < 0.001/0.05) and "standard indirect" (R2(left/right) ¼ 0.91/0.84, p(difference) < 0.01/0.0001) normalization strategies. Conclusions: Even though PET images are generally limited by relatively low spatial resolution, novel high-dimensional image normalization techniques may still significantly improve the accuracy of automated regional signal measurements compared to more traditional normalization strategies. IC-P-197
MICROHEMORRHAGE FINDINGS ON BASELINE ROSAS MRI DATA
Hubert Basselerie1, Luc Bracoud2, Hans-Martin Schneble3, Sylvain Gouttard2, Isabelle Guignot3, Audrey Istace2, Florent Roche2, Joel Schaerer2, Maria Pueyo3, Chahin Pachai2, Bruno Vellas1, Fabrice Bonneville1, 1CHU Casselardit, Toulouse, France; 2BioClinica, Lyon, France; 3IRIS, Suresnes, France. Contact e-mail: luc.bracoud@ bioclinica.com Background: Cerebral microhemorrhages, although common among the elderly, are known to be related to the presence of amyloid in the brain, cognitive impairment and dementia severity. This work assesses the prevalence of microhemorrhages in ROSAS, a monocentric observational study which includes normal controls as well as MCI and AD subjects. Methods: 408 subjects 65 years and older were enrolled, including 110 Normal Controls (NC, no memory complaints, MMSE26 and CDR¼0), 100 Mild Cognitive Impairment (MCI, MMSE24 and CDR¼0.5, memory impairment based on RAVLT and that did not meet DSM IV criteria for AD dementia) and 198 AD (12MMSE26 and CDR0.5 and meeting DSM IV criteria). Susceptibility-Weighted (SWI) MRI scans were collected up to 3 times between Baseline and Month 48, at one site using a Philips Achieva 3T scanner, for consenting subjects (n¼153, including 51 NC, 41 MCI and 61 AD). Baseline SWI data were reviewed by one rater, looking at native 0.5 mm thick images along with minimum Intensity Projection (minIP) reconstructed slices (6 mm thick, with 3 mm overlap). Bleeds were categorized as deep, lobar and infratentorial, and further subdivided as <5 mm, between 5 and 10 mm (so-called large microhemorrhages), and >10 mm in size. Descriptive statistics were computed for each group. Pearson Chi-Square tests were used to assess differences between groups. Results: Microhemorrhages (10mm) were reported on 56.9% NC, 68.3% MCI and 65.6% AD. Only 2.0% NC had more than 4 microhemorrhages, as compared to 22.0% MCI and 11.5% AD. Significant differences between groups were found for the presence of intratentorial microhemorrhages (p¼0.035) and of >4 microhemorrhages (p¼0.01), and between NC and non-NC for the presence of large microhemorrhages (p¼0.045) and >4 lobar microhemorrhages (p¼0.029). Bleeds >10 mm were found on only 2 MCI and 2 AD. Conclusions: A majority of ROSAS subjects from all clinical categories had >1 microhemorrhage. Multiple Table 1 Proportion of microhemorrhages by group, classified by number # Microhemorrhages (10 mm)
NC (%)
MCI (%)
AD (%)
1 0 [1-4] >4 >4 lobar
56.9 43.1 54.9 2.0 2.0
68.3 31.7 46.3 22.0 17.1
65.6 34.4 54.1 11.5 9.8
Table 2 Proportion of microhemorrhages by group, classified by location Microhemorrhage location
NC (%)
MCI (%)
AD (%)
Deep Lobar Infratentorial
9.8 54.9 7.8
24.4 63.4 26.8
18.0 57.4 13.1