- Email: [email protected]
DETECTION OF TAU TANGLES IN THE RETINA
Poster Presentations: Wednesday, July 19, 2017
Figure 3. Simulated shape change in the most discriminant direction from Normal Controls (top panel) to Alzheimer’s disease (bottom panel). Volume decrease can be observed in the lower panel and especially a thinning in the CA1 region (red arrows) is evident.
P1535
to investigate hippocampal anatomy in AD and aging and to serve as a reference for in vivo morphometry. Methods: 0.2x0.2x0.2 mm3 9.4T MR images from 31 ex vivo hippocampal specimens (13 normal controls (NC), 18 cases with a clinical diagnosis of dementia; of whom 9 AD; mean age at death: 75 years) and histological sections with Kluver-Barrera staining at 0.2 mm intervals from 9 of the 31 specimens were combined into a probabilistic atlas of the hippocampus (Figure 1-2). Results: All subfields were smaller in AD compared to NC (Table 1), with the largest decrease in CA1 and stratum radiatum lacunosum moleculare (SRLM). Consistent with the preferential effect of AD on CA1 over DG, the DG/CA1 ratio was significantly larger in AD than CN. Figure 3 shows the shape change from NC and AD, illustrating thinning of CA1. Additionally, T-statistic maps (Figure 4) reveal that SRLM is affected throughout its length, but show localized effects in the grey matter in middle and posterior regions. An association with age was found for all subfields, with the strongest effect for DG. Conclusions: This probabilistic post-mortem atlas of the hippocampus allowed us for the first time to investigate AD- and agerelated effects on hippocampal subfield morphometry, derived from histology, in a 3-dimensional manner. These results can be translated directly to in vivo MRI studies and support the hypothesis of differential involvement of hippocampal subfields in aging and AD, providing further impetus for studying hippocampal subfields during life.
P4-508
DETECTION OF TAU TANGLES IN THE RETINA
Umur A. Kayabasi1 and Marco Rispoli2, 1Istinye University, Istanbul, Turkey; 2University of Rome, Rome, Italy. Contact e-mail: [email protected] Background: Imaging Tau tangles and amyloid beta via retinal ex-
Figure 4. T-Statistics map of the NC-AD effect on the thickness of the dentate gyrus, stratum radiatum lacunosum moleculare (SRLM) and outer layers. Black curves outline the clusters that are statistically significant using an FDR threshold of 0.05.
a definitive reference model describing regional effects of AD pathology on the hippocampus. Histological studies (e.g. Rossler et al, Acta Neuropathol, 2002; Simic et al., JOCN, 1997) provide limited reference information due to their 2D nature, use of a measure like cell count rather than volume or thickness, and inconsistency between studies. We therefore built a 3D probabilistic atlas of the hippocampus combining post-mortem MRI and histology
amination is a breakthrough method since it is non-invasive, quick, easy and cheap. Spectral Domain Optical CoherenceTomography (SD- OCT) is extremely useful for this purpose with the addition of Fundus Autofluorescence (FAF) technology. Methods: 30 patients with early or advanced Alzheimer’s Disease (AD) had OCT and FAF tests. Mean age was 71. Retinal regions with hyper or hypofluorescence were inspected by OCT and neurofibrillary filaments or advanced Tau tangles were detected in a masked fashion. Results: In patients with early disease, only thin neurofibrillary filaments were detected , but retinal imaging revealed thick tangles in patients who had advanced AD. Both authors agreed on the nature of the Tau images. Conclusions: Staging of AD may
Table 1 Description of hippocampal anatomy in the NC and AD group with statistical analyses for NC vs. AD and the associations with age NC vs. AD*
Age association in NC
Measure
NC Mean (SD)
AD Mean (SD)
%
X
p
%/year
X2
p
CA1 CA2 CA3 SRLM DG Hippocampus DG/CA1 ratio
762 (161) 89 (17) 271 (47) 423 (68) 496 (117) 2553 (414) 0.66 (0.12)
451 (130) 66 (21) 239 (32) 254 (98) 381 (43) 1717 (366) 0.88 (0.15)
-40.8 -25.5 -11.7 -39.8 -23.3 -32.7 33.2
17.6 13.9 6.5 20.2 8.9 17.9 11
2.80E-05 0.0002 0.01 6.8E-06 0.003 2.30E-05 0.001
-2.8 -1.1 -1.9 -1.7 -3.4 -2.3 -0.3
7.5 1.3 5.1 4.6 8.3 8.7 0.12
0.01 0.26 0.02 0.03 0.004 0.003 0.73
2
*Corrected for age. NC¼Normal controls, AD¼Alzheimer’s Disease, CA¼cornu ammonis; SRLM¼stratum radiatum lacunosum moleculare, DG¼dentate gyrus.
P1536
Poster Presentations: Wednesday, July 19, 2017
endproducts (RAGE).1 The aim of this work is to establish the potential of RAGE as new PET biomarker of AD diagnosis and monitoring. Methods: Carbon-11-labelled RAGE inhibitor ([11C]FPS-ZM1) was radiosynthesised by palladium-mediated carbonylation via [11C]CO.2 In vitro brain autoradiography using [11C]FPS-ZM1 (1-10 nM; n¼3) was conducted with 8month-old wild-type (WT) and 17-month-old AD-model mice. Images were developed on a phosphor-imaging plate followed by qualitative and quantitative analyses to compare specific to non-specific binding (SB/NSB) in cerebellar and extracerebellar brain regions. Results: fdb 9.1.450/W Unicode [11C]FPS-ZM1 was radiosynthesised with a good radiochemical yield (30.2 6 5.3%; n¼12) and high purity (>99%) for pre-clinical studies. Autoradiography experiments highlighted high NSB in both WT and AD mice with negligible signal at concentrations below 5 nM. No statistically significant differences between the brain regions, animal types or [11C]FPS-ZM1 concentrations were observed despite overall greater SB/NSB in AD mice. Conclusions: fdb 9.1.450/W UnicodeThis study utilised an effective radiosynthesis method to produce a novel radiotracer for RAGE in AD. The low SB/NSB ratio exhibited by [11C]FPS-ZM1 may be due to lipophilicity-driven non-specific binding and warrants future structural optimisation. Our findings are in line with previously reported NSB of 18Flabelled-FPS-ZM1 in AD post-mortem tissues, rats and primates.3 References 1. Sasaki, N.; Toki, S.; Chowei, H.; Saito, T.; Nakano, N.; Hayashi, Y.; et al. Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease. Brain Res 2001,888,256-262. 2. Taddei, C.; Bongarzone, S.; Haji Dheere, A. K.; Gee, A. D. [(11)C]CO2 to [(11)C]CO conversion mediated by [(11)C]silanes: a novel route for [(11)C]carbonylation reactions. Chem Commun (Camb) 2015,51,11795-7. 3. Cary, B. P.; Brooks, A. F.; Fawaz, M. V.; Drake, L. R.; Desmond, T. J.; Sherman, P.; et al. Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts. ACS Chem Neurosci 2016,7,391-8. be possible by retinal examination and detecting Tau in different development status. OCT and FAF are novel and reliable biomarkers for this purpose.
P4-509
DEVELOPMENT AND EVALUATION OF A NOVEL POSITRON EMISSION TOMOGRAPHY RADIOTRACER FOR IMAGING THE RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS IN ALZHEIMER’S DISEASE
Vilius Savickas1, Salvatore Bongarzone2, Federico Luzi2, Nisha Singh2, Tony D. Gee3, 1National Institute for Health Research Biomedical Research Centre and Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, United Kingdom; 2King’s College London, London, United Kingdom; 3King’s College London, London, United Kingdom. Contact e-mail: [email protected] Background: Existing positron emission tomography (PET) radio-
tracers for Alzheimer’s disease (AD) target its late stage pathologies (e.g. beta amyloid plaques) and lack diagnostic specificity. This study aimed to develop a radiotracer for the receptor of beta amyloid oligomers known as the receptor for advanced glycation
Figure 1. Images from brain autoradiography experiments with sagittal brain sections of 8-month-old wild-type and 17-month-old transgenic (Tg2576) Alzheimer’s disease mice in the presence of 5 nM of [11C]FPSZM1 (75 mM of FPS-ZM1 for non-specific binding (NSB)). Note the high level of NSB in either cerebellar or extracerebellar regions of the brain in each species. Specific binding is obtained by subtracting NSB from total binding (TB). Greater binding is denoted by red colour.
Figure 3. Simulated shape change in the most discriminant direction from Normal Controls (top panel) to Alzheimer’s disease (bottom panel). Volume decrease can be observed in the lower panel and especially a thinning in the CA1 region (red arrows) is evident.
P1535
to investigate hippocampal anatomy in AD and aging and to serve as a reference for in vivo morphometry. Methods: 0.2x0.2x0.2 mm3 9.4T MR images from 31 ex vivo hippocampal specimens (13 normal controls (NC), 18 cases with a clinical diagnosis of dementia; of whom 9 AD; mean age at death: 75 years) and histological sections with Kluver-Barrera staining at 0.2 mm intervals from 9 of the 31 specimens were combined into a probabilistic atlas of the hippocampus (Figure 1-2). Results: All subfields were smaller in AD compared to NC (Table 1), with the largest decrease in CA1 and stratum radiatum lacunosum moleculare (SRLM). Consistent with the preferential effect of AD on CA1 over DG, the DG/CA1 ratio was significantly larger in AD than CN. Figure 3 shows the shape change from NC and AD, illustrating thinning of CA1. Additionally, T-statistic maps (Figure 4) reveal that SRLM is affected throughout its length, but show localized effects in the grey matter in middle and posterior regions. An association with age was found for all subfields, with the strongest effect for DG. Conclusions: This probabilistic post-mortem atlas of the hippocampus allowed us for the first time to investigate AD- and agerelated effects on hippocampal subfield morphometry, derived from histology, in a 3-dimensional manner. These results can be translated directly to in vivo MRI studies and support the hypothesis of differential involvement of hippocampal subfields in aging and AD, providing further impetus for studying hippocampal subfields during life.
P4-508
DETECTION OF TAU TANGLES IN THE RETINA
Umur A. Kayabasi1 and Marco Rispoli2, 1Istinye University, Istanbul, Turkey; 2University of Rome, Rome, Italy. Contact e-mail: [email protected] Background: Imaging Tau tangles and amyloid beta via retinal ex-
Figure 4. T-Statistics map of the NC-AD effect on the thickness of the dentate gyrus, stratum radiatum lacunosum moleculare (SRLM) and outer layers. Black curves outline the clusters that are statistically significant using an FDR threshold of 0.05.
a definitive reference model describing regional effects of AD pathology on the hippocampus. Histological studies (e.g. Rossler et al, Acta Neuropathol, 2002; Simic et al., JOCN, 1997) provide limited reference information due to their 2D nature, use of a measure like cell count rather than volume or thickness, and inconsistency between studies. We therefore built a 3D probabilistic atlas of the hippocampus combining post-mortem MRI and histology
amination is a breakthrough method since it is non-invasive, quick, easy and cheap. Spectral Domain Optical CoherenceTomography (SD- OCT) is extremely useful for this purpose with the addition of Fundus Autofluorescence (FAF) technology. Methods: 30 patients with early or advanced Alzheimer’s Disease (AD) had OCT and FAF tests. Mean age was 71. Retinal regions with hyper or hypofluorescence were inspected by OCT and neurofibrillary filaments or advanced Tau tangles were detected in a masked fashion. Results: In patients with early disease, only thin neurofibrillary filaments were detected , but retinal imaging revealed thick tangles in patients who had advanced AD. Both authors agreed on the nature of the Tau images. Conclusions: Staging of AD may
Table 1 Description of hippocampal anatomy in the NC and AD group with statistical analyses for NC vs. AD and the associations with age NC vs. AD*
Age association in NC
Measure
NC Mean (SD)
AD Mean (SD)
%
X
p
%/year
X2
p
CA1 CA2 CA3 SRLM DG Hippocampus DG/CA1 ratio
762 (161) 89 (17) 271 (47) 423 (68) 496 (117) 2553 (414) 0.66 (0.12)
451 (130) 66 (21) 239 (32) 254 (98) 381 (43) 1717 (366) 0.88 (0.15)
-40.8 -25.5 -11.7 -39.8 -23.3 -32.7 33.2
17.6 13.9 6.5 20.2 8.9 17.9 11
2.80E-05 0.0002 0.01 6.8E-06 0.003 2.30E-05 0.001
-2.8 -1.1 -1.9 -1.7 -3.4 -2.3 -0.3
7.5 1.3 5.1 4.6 8.3 8.7 0.12
0.01 0.26 0.02 0.03 0.004 0.003 0.73
2
*Corrected for age. NC¼Normal controls, AD¼Alzheimer’s Disease, CA¼cornu ammonis; SRLM¼stratum radiatum lacunosum moleculare, DG¼dentate gyrus.
P1536
Poster Presentations: Wednesday, July 19, 2017
endproducts (RAGE).1 The aim of this work is to establish the potential of RAGE as new PET biomarker of AD diagnosis and monitoring. Methods: Carbon-11-labelled RAGE inhibitor ([11C]FPS-ZM1) was radiosynthesised by palladium-mediated carbonylation via [11C]CO.2 In vitro brain autoradiography using [11C]FPS-ZM1 (1-10 nM; n¼3) was conducted with 8month-old wild-type (WT) and 17-month-old AD-model mice. Images were developed on a phosphor-imaging plate followed by qualitative and quantitative analyses to compare specific to non-specific binding (SB/NSB) in cerebellar and extracerebellar brain regions. Results: fdb 9.1.450/W Unicode [11C]FPS-ZM1 was radiosynthesised with a good radiochemical yield (30.2 6 5.3%; n¼12) and high purity (>99%) for pre-clinical studies. Autoradiography experiments highlighted high NSB in both WT and AD mice with negligible signal at concentrations below 5 nM. No statistically significant differences between the brain regions, animal types or [11C]FPS-ZM1 concentrations were observed despite overall greater SB/NSB in AD mice. Conclusions: fdb 9.1.450/W UnicodeThis study utilised an effective radiosynthesis method to produce a novel radiotracer for RAGE in AD. The low SB/NSB ratio exhibited by [11C]FPS-ZM1 may be due to lipophilicity-driven non-specific binding and warrants future structural optimisation. Our findings are in line with previously reported NSB of 18Flabelled-FPS-ZM1 in AD post-mortem tissues, rats and primates.3 References 1. Sasaki, N.; Toki, S.; Chowei, H.; Saito, T.; Nakano, N.; Hayashi, Y.; et al. Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease. Brain Res 2001,888,256-262. 2. Taddei, C.; Bongarzone, S.; Haji Dheere, A. K.; Gee, A. D. [(11)C]CO2 to [(11)C]CO conversion mediated by [(11)C]silanes: a novel route for [(11)C]carbonylation reactions. Chem Commun (Camb) 2015,51,11795-7. 3. Cary, B. P.; Brooks, A. F.; Fawaz, M. V.; Drake, L. R.; Desmond, T. J.; Sherman, P.; et al. Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts. ACS Chem Neurosci 2016,7,391-8. be possible by retinal examination and detecting Tau in different development status. OCT and FAF are novel and reliable biomarkers for this purpose.
P4-509
DEVELOPMENT AND EVALUATION OF A NOVEL POSITRON EMISSION TOMOGRAPHY RADIOTRACER FOR IMAGING THE RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS IN ALZHEIMER’S DISEASE
Vilius Savickas1, Salvatore Bongarzone2, Federico Luzi2, Nisha Singh2, Tony D. Gee3, 1National Institute for Health Research Biomedical Research Centre and Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, United Kingdom; 2King’s College London, London, United Kingdom; 3King’s College London, London, United Kingdom. Contact e-mail: [email protected] Background: Existing positron emission tomography (PET) radio-
tracers for Alzheimer’s disease (AD) target its late stage pathologies (e.g. beta amyloid plaques) and lack diagnostic specificity. This study aimed to develop a radiotracer for the receptor of beta amyloid oligomers known as the receptor for advanced glycation
Figure 1. Images from brain autoradiography experiments with sagittal brain sections of 8-month-old wild-type and 17-month-old transgenic (Tg2576) Alzheimer’s disease mice in the presence of 5 nM of [11C]FPSZM1 (75 mM of FPS-ZM1 for non-specific binding (NSB)). Note the high level of NSB in either cerebellar or extracerebellar regions of the brain in each species. Specific binding is obtained by subtracting NSB from total binding (TB). Greater binding is denoted by red colour.