- Email: [email protected]
Amygdalar Local Structural Differences in Alzheimer's Patients on 3T MRI
Alzheimer’s Imaging Consotium IC-P: Imaging Posters
IC-P-117
AMYGDALAR LOCAL STRUCTURAL DIFFERENCES IN ALZHEIMER’S PATIENTS ON 3T MRI 1
1
2
Enrica Cavedo , Marina Boccardi , Alberto Beltramello , Carlo Caltagirone3, Paul M. Thompson4, Giovanni B. Frisoni1, 1IRCCS Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy; 2Ospedale Maggiore, Borgo Trento, Verona, Italy; 3IRCCS Fondazione Santa Lucia, Rome, Italy; 4UCLA School of Medicine, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: Histological studies have shown that the amygdala is affected by Alzheimer’s Disease (AD) pathology; its medial aspect is involved the most. Here we aimed to assess the local structural differences in the amygdala in vivo, in AD patients using 3 Tesla high resolution MRI. Methods: 19 AD patients (mean age: 76 6 6 years, Mini Mental State Examination (MMSE) 13 6 4) and 19 healthy elderly subjects (age: 74 6 5 years, MMSE 29 6 1) were enrolled. The Radial Atrophy Mapping technique was used to reconstruct the 3D shape of the amygdala, based on manual segmentation. Permutation tests were run to correct statistical maps for multiple comparisons. A 3D reconstruction from an atlas of the normal amygdala was used to infer which anatomical nuclei were specifically involved. Results: Both right and left amygdalar volumes were significantly smaller in AD patients (right: 1508 6 418 mm3, left: 1646 6 419) than in controls (right: 2129 6 316, left: 2077 6 376; p < 0.002). Dorsally, local tissue deficits were mapped in the medial nucleus, anterior amygdaloid area, and anterior and posterior cortical nuclei, mainly in the medial aspects. Ventrally, the basolateral ventral medial nucleus and the more lateral portions including the lateral nuclei were also involved. These maps were significant after correction for multiple comparisons (permutation test: p < 0.01, corrected. Conclusions: Greater involvement of the medial aspects was confirmed. The affected nuclei are primarily connected to the hippocampus (basolatero-ventro-medial and posterior cortical), and to the olfactory circuitry (medial and anterior cortical nuclei) known to be involved in Alzheimer’s disease.
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Israel; 2Sheba Medical Center, Tel-Aviv, Israel; 3Rabin Medical Center, Tel-Aviv, Israel. Contact e-mail: [email protected] Background: Apolipoprotien E4 (apoE4), the most prevalent genetic risk factor of Alzheimer’s disease (AD), also increases the risk for vascular diseases. It has recently been suggested that in addition to the prominent role of the vascular endothelial growth factors (VEGF) and their receptors in the formation and maintenance of the vascular system, they also play a role in neuroprotection and neurodegenration. The present study investigated the hypothesis that apoE4 impairs the neurovascular unit and that these effects are mediated by the VEGF system. Methods: The effects of apoE4 on the neurovascular unit were studied in the brain following activation of the amyloid cascade in vivo by inhibition of the Ab degrading enzyme neprilyisn, and in retina following induction of angiogenesis by hypoxia Results: Inhibition of neprilyisn resulted in the accumulation of Ab, oligomerized Ab and apoE in CA1 neurons of targeted replacement apoE4 mice but not in the corresponding neurons of apoE3 mice. This was associated with co-localization of Ab, oligomerized Ab and apoE4 with lysosomes and mitochondria and with impairments of these organelles and subsequent neuronal death. Activation of the amyloid cascade by inhibition of neprilyisn also affected the VEGF system and vasculature in the hippocampus. Accordingly, this treatment was associated with abnormal vasculature in the CA1 hippocampal subfield of the apoE4 mice and with concurrent impairments in the expression of the VEGF system (e.g. the expression of VEGF-A and VEGFR1 in the CA1 hippocampal subfield increased in the apoE3 but not the apoE4 mice following treatment). The effects of apoE4 on the vasculature were also studied in the retina. This revealed hypoxia induced abnormal and specifically elevated angiogenesis in the retina of the treated apoE4 mice, which was associated with hyper activation of the VEGF system in these mice. Importantly, in the retina, the levels of expression of VEGF-B and VEGFR2 were most affected by apoE4, whereas in the hippocampus VEGF-A and VEGFR1 were most affected by apoE4. Conclusions: These findings suggest that the VEGF system plays an important role in mediating the neuronal and vascular pathological effects of apoE4 and Ab and provide a novel approach for therapeutic intervention in AD. IC-P-119
A MODEL-BASED APPROACH TO IMPROVE INTRA-INDIVIDUAL COMPARISON OF CLUSTERED BETA-AMYLOID BRAIN PET IMAGING DATA: ACCOUNTING FOR OVERLAPPING IMAGING TIME WINDOWS
Florian Hiemeyer1, John P. Seibyl2, Michael Kunz1, Olivier Barret2, George Zubal2, Henryk Barthel3, Cornelia Reininger1, Osama Sabri3, 1Bayer Healthcare AG, Berlin, Germany; 2Instit Neurodeg Disorders, New Haven, CT, USA; 3University of Leipzig, Leipzig, Germany. Contact e-mail: florian. [email protected]
IC-P-118
THE ROLE OF VEGF IN MEDIATING THE SYNERGISTIC PATHOLOGICAL EFFECTS OF BETA-AMYLOID AND APOE4 ON THE NEUROVASCULAR SYSTEM
Daniel M. Michaelson1, Idit Maharshak1, Moran Frenkel1, Zehavit KarivInbal1, Arie S. Solomon2, Dov Weinberg3, 1Tel-Aviv University, Tel-Aviv,
Background: Data used for the described models was generated from a nonrandomized, global Phase 2 trial evaluating the efficacy of the ß-amyloid targeted PET tracer florbetaben. A total of 150 subjects (69 Healthy volunteers (HV) and 81 probable AD patients) were included in the study. Both visual and quantitative measurements were used to evaluate the efficacy of florbetaben in detecting ß-amyloid in the brain. The quantitative results consisted of decay corrected, standard uptake value (SUV) stemming from various cerebral volumes of interest (VOIs), for 3 different, but overlapping imaging time windows. All SUV were assessed using two different strategies of assigning the boundaries to the VOI. The purpose of the present analysis was to evaluate, whether the second VOI boundary strategy resulted in a higher mean separation in the SUV between AD and HV across different cortical regions. Methods: The proposed analysis is a mixed effects ANOVA model that explains the clustered and repeated SUV measurements by study design (i.e. patient group, imaging window, VOI boundary method) as well as brain VOIs. As the 3 imaging windows overlapped (90 to 110 min., 100 to 120 min. and 110 to 130 min. p.i.), the induced correlation needed to be accounted for. This was done by specifying a sophisticated residual covariance matrix. The results of the ANOVA model were compared with the results of a simplified model which included only data from the 2 non-
IC-P-117
AMYGDALAR LOCAL STRUCTURAL DIFFERENCES IN ALZHEIMER’S PATIENTS ON 3T MRI 1
1
2
Enrica Cavedo , Marina Boccardi , Alberto Beltramello , Carlo Caltagirone3, Paul M. Thompson4, Giovanni B. Frisoni1, 1IRCCS Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy; 2Ospedale Maggiore, Borgo Trento, Verona, Italy; 3IRCCS Fondazione Santa Lucia, Rome, Italy; 4UCLA School of Medicine, Los Angeles, CA, USA. Contact e-mail: [email protected] Background: Histological studies have shown that the amygdala is affected by Alzheimer’s Disease (AD) pathology; its medial aspect is involved the most. Here we aimed to assess the local structural differences in the amygdala in vivo, in AD patients using 3 Tesla high resolution MRI. Methods: 19 AD patients (mean age: 76 6 6 years, Mini Mental State Examination (MMSE) 13 6 4) and 19 healthy elderly subjects (age: 74 6 5 years, MMSE 29 6 1) were enrolled. The Radial Atrophy Mapping technique was used to reconstruct the 3D shape of the amygdala, based on manual segmentation. Permutation tests were run to correct statistical maps for multiple comparisons. A 3D reconstruction from an atlas of the normal amygdala was used to infer which anatomical nuclei were specifically involved. Results: Both right and left amygdalar volumes were significantly smaller in AD patients (right: 1508 6 418 mm3, left: 1646 6 419) than in controls (right: 2129 6 316, left: 2077 6 376; p < 0.002). Dorsally, local tissue deficits were mapped in the medial nucleus, anterior amygdaloid area, and anterior and posterior cortical nuclei, mainly in the medial aspects. Ventrally, the basolateral ventral medial nucleus and the more lateral portions including the lateral nuclei were also involved. These maps were significant after correction for multiple comparisons (permutation test: p < 0.01, corrected. Conclusions: Greater involvement of the medial aspects was confirmed. The affected nuclei are primarily connected to the hippocampus (basolatero-ventro-medial and posterior cortical), and to the olfactory circuitry (medial and anterior cortical nuclei) known to be involved in Alzheimer’s disease.
S47
Israel; 2Sheba Medical Center, Tel-Aviv, Israel; 3Rabin Medical Center, Tel-Aviv, Israel. Contact e-mail: [email protected] Background: Apolipoprotien E4 (apoE4), the most prevalent genetic risk factor of Alzheimer’s disease (AD), also increases the risk for vascular diseases. It has recently been suggested that in addition to the prominent role of the vascular endothelial growth factors (VEGF) and their receptors in the formation and maintenance of the vascular system, they also play a role in neuroprotection and neurodegenration. The present study investigated the hypothesis that apoE4 impairs the neurovascular unit and that these effects are mediated by the VEGF system. Methods: The effects of apoE4 on the neurovascular unit were studied in the brain following activation of the amyloid cascade in vivo by inhibition of the Ab degrading enzyme neprilyisn, and in retina following induction of angiogenesis by hypoxia Results: Inhibition of neprilyisn resulted in the accumulation of Ab, oligomerized Ab and apoE in CA1 neurons of targeted replacement apoE4 mice but not in the corresponding neurons of apoE3 mice. This was associated with co-localization of Ab, oligomerized Ab and apoE4 with lysosomes and mitochondria and with impairments of these organelles and subsequent neuronal death. Activation of the amyloid cascade by inhibition of neprilyisn also affected the VEGF system and vasculature in the hippocampus. Accordingly, this treatment was associated with abnormal vasculature in the CA1 hippocampal subfield of the apoE4 mice and with concurrent impairments in the expression of the VEGF system (e.g. the expression of VEGF-A and VEGFR1 in the CA1 hippocampal subfield increased in the apoE3 but not the apoE4 mice following treatment). The effects of apoE4 on the vasculature were also studied in the retina. This revealed hypoxia induced abnormal and specifically elevated angiogenesis in the retina of the treated apoE4 mice, which was associated with hyper activation of the VEGF system in these mice. Importantly, in the retina, the levels of expression of VEGF-B and VEGFR2 were most affected by apoE4, whereas in the hippocampus VEGF-A and VEGFR1 were most affected by apoE4. Conclusions: These findings suggest that the VEGF system plays an important role in mediating the neuronal and vascular pathological effects of apoE4 and Ab and provide a novel approach for therapeutic intervention in AD. IC-P-119
A MODEL-BASED APPROACH TO IMPROVE INTRA-INDIVIDUAL COMPARISON OF CLUSTERED BETA-AMYLOID BRAIN PET IMAGING DATA: ACCOUNTING FOR OVERLAPPING IMAGING TIME WINDOWS
Florian Hiemeyer1, John P. Seibyl2, Michael Kunz1, Olivier Barret2, George Zubal2, Henryk Barthel3, Cornelia Reininger1, Osama Sabri3, 1Bayer Healthcare AG, Berlin, Germany; 2Instit Neurodeg Disorders, New Haven, CT, USA; 3University of Leipzig, Leipzig, Germany. Contact e-mail: florian. [email protected]
IC-P-118
THE ROLE OF VEGF IN MEDIATING THE SYNERGISTIC PATHOLOGICAL EFFECTS OF BETA-AMYLOID AND APOE4 ON THE NEUROVASCULAR SYSTEM
Daniel M. Michaelson1, Idit Maharshak1, Moran Frenkel1, Zehavit KarivInbal1, Arie S. Solomon2, Dov Weinberg3, 1Tel-Aviv University, Tel-Aviv,
Background: Data used for the described models was generated from a nonrandomized, global Phase 2 trial evaluating the efficacy of the ß-amyloid targeted PET tracer florbetaben. A total of 150 subjects (69 Healthy volunteers (HV) and 81 probable AD patients) were included in the study. Both visual and quantitative measurements were used to evaluate the efficacy of florbetaben in detecting ß-amyloid in the brain. The quantitative results consisted of decay corrected, standard uptake value (SUV) stemming from various cerebral volumes of interest (VOIs), for 3 different, but overlapping imaging time windows. All SUV were assessed using two different strategies of assigning the boundaries to the VOI. The purpose of the present analysis was to evaluate, whether the second VOI boundary strategy resulted in a higher mean separation in the SUV between AD and HV across different cortical regions. Methods: The proposed analysis is a mixed effects ANOVA model that explains the clustered and repeated SUV measurements by study design (i.e. patient group, imaging window, VOI boundary method) as well as brain VOIs. As the 3 imaging windows overlapped (90 to 110 min., 100 to 120 min. and 110 to 130 min. p.i.), the induced correlation needed to be accounted for. This was done by specifying a sophisticated residual covariance matrix. The results of the ANOVA model were compared with the results of a simplified model which included only data from the 2 non-