- Email: [email protected]
Mild to moderate Alzheimer's disease (AD) clinical trials: The role of hippocampal atrophy as an inclusion criterion
Poster Presentations P1 temporal volume was associated with approximately 1.5 times (95% CI 1.1 to 2.0) greater risk of AD. The area under the ROC curve for FreeSurfer medial temporal, LEAP hippocampal, and Ab:tau (logarithmic) were 0.688, 0.604, and 0.572, respectively. Conclusions: We found that the 3 biomarkers (hippocampal volume, medial temporal lobe volume, and CSF Ab:tau) significantly and independently predict the development of AD from MCI. A particular level of Ab:tau ratio enhances the predictive accuracy of MRI biomarkers. These biomarkers are associated with different aspects of AD pathology. P1-385
ALTERED VISUOSPATIAL WORKING MEMORY PROCESS IN PATIENTS WITH ALZHEIMER’S DISEASE: FMRI INVESTIGATION
Chang- Uk Lee, Hyun-Kook Lim, Catholic University, Seoul, Korea, Republic of. Contact e-mail: [email protected] Background: Impaired visuospatial working memory processing is one of the broad ranges of cognitive deficits in patients with Alzheimer’s disease (AD). We aimed to elucidate the differences in brain activities involved in the process of visuospatial working memory between AD patients and healthy comparison subjects. Methods: Twelve patients with AD were recruited along with twelve healthy volunteers as a comparison group. Functional magnetic resonance imaging (fMRI) was employed to assess cortical activities during the performance of a 1-back and 2-back visuospatial working memory paradigm using various shapes as mnemonic content. Subsequently, the difference in neural activities between the two groups was analyzed. Results: The AD group performed the tasks with reduced accuracy. Group comparison analysis revealed that the AD group showed decreased brain activity in the right precuneus(BA7), the right insula(BA13), and the right premotor cortex(BA6) during the performance of the 1-back task, the right dorsolateral prefrontal cortex(BA46) during the 2-back task, compared to the control group. The AD group showed increased activation in the right parahippocampal gyrus(BA28), left fusiform gyrus during the 1-back task, compared to the control group. No increased activities were observed during the 2-back task in the AD patients as compared to controls. Conclusions: A decreased level of activation in the prefrontal cortex and an increased level of activation in the parietal neural networks from the patient group may document altered visuospatial working memory process in the patients with AD. P1-386
VOXEL-BASED ASSESSMENT OF ASYMMETRICAL HIPPOCAMPAL AND ENTORHINAL ATROPHY IN MCI: A LONGITUDINAL MRI INVESTIGATION FROM THE ADDNEUROMED STUDY
Simon Brunton1, Matthew Kempton2,3, Eric Westman4, Sebastian Muehlboeck5, Lars-Olof Wahlund4, Magda Tsolaki6, Hilkka Soininen7, Patrizia Mecocci8, Iwona Kloszewska9, Bruno Vellas10, Simon Lovestone11,3, Christian Spenger12, Andrew Simmons11,3, 1King’s College London, Centre for Neuroimaging Sciences, London, United Kingdom; 2King’s College London, Center for Neuroimaging Sciences, London, United Kingdom; 3NIHR Biomedical Research Centre for Mental Health, London, United Kingdom; 4Department of Neurobiology, Care Sciences and Society, Stockholm, Sweden; 5Department of Clinical Science, Intervention and Technology, Stockholm, Sweden; 6Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece; 7Department of Neurology, University and University Hospital of Kuopio, Kuopio, Finland; 8Institute Gerontology and Geriatrics, University of Perugia, Perugia, Italy; 9 Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland; 10Department of Internal and Geriatrics Medicine, Hopitaux de Toulouse, Toulouse, France; 11King’s College London, Institute of Psychiatry, London, United Kingdom; 12Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden. Contact e-mail: [email protected] Background: Previous studies have demonstrated the importance of early changes in the hippocampus, parahippocampal and entrorhinal cortex in mild cognitive impairment (MCI). We investigated the rate of change of these
S285
structures and the degree of lateralisation using voxel-based morphometry (VBM) as part of the AddNeuroMed study, comparing MCI subjects that converted from mild cognitive impairment (MCI-c) to Alzheimer’s disease (AD) with stable MCI subjects (MCI-s). Methods: 14 MCI-c (mean age 72.10(5.6)) and 45 MCI-s (74.54 (5.8)) patients were scanned on 1.5T MRI scanners as part of the AddNeuroMed study. MRI acquisition was designed to be compatible with ADNI and included a high resolution sagittal 3D T1weighted MPRAGE volume. Each subject underwent scans at baseline and 1 year. VBM was used for a region of interest-based analysis of grey matter atrophy in the hippocampus, parahippocampus, anterior ERC and posterior ERC using SPM-5. Group differences were assessed at p < 0.05, with volumetric comparisons performed using SPSS. Results: VBM analysis showed greatest atrophy in hippocampus (head, body and tail) and anterior ERC in the right hemisphere in MCI-c patients. Reductions in the left hemisphere were localised to the head of the hippocampus, with sparing of the anterior ERC. At one year, the MCI-c group was found to have a higher rate of decline in volume than the MCI-s group (MCI-c hippocampus L ¼ 3.6%; R ¼ 3.6%, anterior ERC L ¼ 2.8%; R ¼ 2.8%; MCI-s hippocampus L ¼ 2.2%; R ¼ 2.2%, anterior ERC L ¼ 1.8%; R ¼ 2.1%). Differences in volumetric asymmetries were observed at baseline and were characterised by a left > right bias in the hippocampus of 12.7% in MCI-c compared to 7.8% in MCI-s, and anterior ERC of 5.4% in MCI-c compared to 1.3% in MCI-s. This pattern of asymmetry remained consistent at the one year follow up scan. Conclusions: Our study has used VBM to demonstrate consistent asymmetrical patterns of atrophy between MCI-c and MCI-s patients over time. The rate at which the hippocampus and anterior ERC changes over time was greater for the MCI-c group than the MCI-s group. Knowledge of atrophy rates and asymmetries in MCI is important for predicting which subjects with MCI will convert to AD and for future pharmacological interventions. P1-387
MILD TO MODERATE ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: THE ROLE OF HIPPOCAMPAL ATROPHY AS AN INCLUSION CRITERION
Robert Risinger1, Robert M Berman1, Vlad Coric1, Jian Han1, Stephen Kaplita1, Leah Burns1, Zubin Bhagwagar1, Derek Hill2, Robin Wolz3, Daniel Rueckert3, Howard Feldman1, 1Bristol - Myers Squibb, Wallingford, CT, USA; 2IXICO, London, United Kingdom; 3Imperial College, London, United Kingdom. Contact e-mail: [email protected] Background: Volumetric measurement of regions involved in AD has relied on manual definition of the hippocampus and temporal lobe structures using MRI. The potential utility of automated MRI region of interest definition to improve the accurate identification of AD or as an inclusion criterion for randomized controlled trials in AD has not been systematically investigated. The objective of this study was to investigate whether automated hippocampal volumetric definition using MRI could be a useful inclusion criterion for mild to moderate AD trials. We examined the correlation of baseline hippocampal volume (HV) with (a) rate of clinical decline and (b) baseline CSF Ab1-42 and t-tau:Ab1-42 levels. Methods: A retrospective analysis was performed on the subset of subjects with mild AD from ADNI (MMSE score 18-28) and who had up to 2 years’ follow up and automated MRI hippocampal volumetric analysis at baseline (n ¼ 128). HV was calculated using the Learning Embeddings for Atlas Propagation (LEAP)-framework (Wolz et al, 2010) in which a set of manually labeled brain atlases are automatically propagated to a diverse population, increasing the accuracy of standard multi-atlas segmentation (Hechemann et al, 2006). HV for each subject was normalized to intracranial volume and multiplied by 106 for ease of review. The AD study population was evaluated as an entire group and by age cohorts (55-71, 72-79, and 80-91 years). All patients had a lumbar puncture for estimation of Ab1-42 or t-tau:Ab1-42. Clinical decline was measured as the change in ADAS-cog from baseline. Descriptive statistics and correlational analyses were determined. Results: Baseline characteristics of this cohort included: mean age of 75.3 years (standard deviation [SD]: 7.5); 47.2% female; MMSE score of 23.4 (2.1); ADAS-cog of 18.6 (6.3); and CDR-sb of 4.3 (1.6). Based on patients with available HV, the normalized HV range was 651-2007 with a mean of 1264.8 (214.5). There were no consistent
S286
Poster Presentations P1
significant correlations between baseline HV and either rate of clinical decline or baseline CSF measures (Ab1-42 or t-tau:Ab1-42). Conclusions: The use of baseline HV as an inclusion criterion for mild to moderate AD clinical trials is not supported by these data P1-388
IMAGING OF CHOLINERGIC TERMINALS IN THE NON-HUMAN PRIMATE BRAIN USING 18F-FEOBV PET: DEVELOPMENT OF A TOOL TO ASSESS CHOLINERGIC LOSSES IN ALZHEIMER’S DISEASE
Jean-Paul Soucy1, Pedro Rosa1, Gassan Massarweh1, Antonio Aliaga1, Esther Schirrmacher1, Marc-Andre´ Be´dard2, Margarita Sanchez-Legaspi3, Paul Gravel1, Andrew Reader1, 1Montreal Neurological Institute, Montreal, QC, Canada; 2Universite´ du Que´bec a` Montre´al, Montreal, QC, Canada; 3 INRS - Experimental Biology Center, Laval, QC, Canada. Contact e-mail: [email protected] Background: Loss of ACh cells is is seen at early stages in Alzheimer’s disease. Different approaches have been tried to assess this loss as a biomarker for diagnosing the disease during the very first stages of its development, as well as to follow its progression. Radioactive tracers derived from the acetylcholine vesicular transporter vesamicol have been proposed for in vivo imaging with either SPECT or PET. We have characterized and validated a potential PET ligand of that category, 18F-FEOBV, in rodents. However, doubts have been raised by others about the stability (defluorination) of this class of agents in primates. Here, we have evaluated this tracer in non-human primates to assess its suitability for PET imaging. Methods: Two Macaca fascicularis (1 female; 5,7 kg; 1 male: 5,5 kg) were imaged. The animals were fasted overnight, sedated using a mixture of Ketamine and Acepromazine, and intubated prior to scanning. Vital signs were monitored/adjusted at all time. We used a Siemens HRRT scanner with an isotropic resolution of 2.3 - 3.4 mm FWHM; this scanner operates in list mode acquisition. High specific activity 18F-FEOBV (92 and 78 MBq) was injected and acquisition was performed for 75 min. post IV. Reconstruction was with OPOSEM+PSF, 10 iterations, 16 subsets. BP images and TAC’s were generated for multiple regions. Results: Good quality scans (see figure) were obtained. No major defluorination (which would have been inferred from significant bone uptake) was observed, even at the end of the scanning session. There was well defined uptake of the tracer in brain regions rich in cholinergic terminals, with the highest binding potentials being detected in the caudate and thalamus. Evaluation of time-activity curves (see figure) from different regions showed a profile compatible with an essentially irreversible binding in the striatum and cortex. Monitoring of the animals during the imaging phase and for a period of 1 week thereafter revealed no untoward effect. Conclusions: 18F-FEOBV can be used for PET imaging in primates, and appears to be a promising agent to evaluate cholinergic systems status using this
technique. No problems of stability nor toxicity were observed in this experiment. P1-389
HIPPOCAMPAL ATROPHY IN YOUNG VETERANS WITH PTSD AND COGNITIVE IMPAIRMENT: A POTENTIAL LINK BETWEEN PTSD AND DEMENTIA
Linda L. Chao, Kristine Yaffe, Thomas C. Neylan, Johannes C. Rothlind, Dieter J. Meyerhoff, Michael W. Weiner, University of California, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: We recently reported that older veterans with post-traumatic stress disorder (PTSD) are nearly twice as likely to develop dementia compared to veterans without PTSD (Yaffe et al., 2009). The goal of this study is to examine potential links between these two disorders in a group of younger veterans with and without PTSD. Methods: We examined brain structural magnetic resonance imaging (MRI) and neuropsychological data of 34 veterans of the first Gulf War (mean age: 41.7 years). All of the veterans had PTSD, defined as a Clinical Administered PTSD Scale (CAPS) score > 40 and chronic multi-symptom illness based on the criteria described by Fukuda et al. (1998). Ten veterans also had cognitive impairments (CI), defined as > 1 SD below the mean on a cognitive domain (i.e., memory, executive function, or attention). MRI data were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray and white matter, cerebrospinal fluid (CSF) and the hippocampus. Results: Veterans with and without PTSD were similar in age, education, CAPS score, and % male (p > 0.33). As expected, there were significant group differences in memory (p < 0.0001), executive function (p < 0.0001), and attention (p ¼ 0.004) domain scores. There was also a significant difference in hippocampal volume (p ¼ 0.02). Spearman’s correlation showed that CAPS scores were negatively associated with memory domain scores (r ¼ -0.35, p ¼ 0.03) in Differences between PTSD+ veterans with and without CI PTSD with CI (N ¼ 10)
PTSD without CI (N ¼ 24)
p-value
male:female Age (years) Education (years) CAPS
9:1 41.3 (6.9) 14.5 (2.5) 63.8 (18.6)
19:6 41.8 (9.6) 14.3 (2.1) 63.4 (14.6)
0.33 0.88 0.80 0.94
Domain scores Memory Executive Function Attention
-0.87 (1.02) -0.81 (0.67) -0.80 (0.92)
0.25 (0.60) 0.22 (0.56) 0.50 (1.10)
<0.0001 <0.0001 0.004
MRI volumes Hippocampus Total gray matter Total white matter Ventricular CSF
4.89 (0.61) 659.08 (57.81) 556.84 (53.18) 25.74 (12.44)
5.26 (0.55) 636.39 (79.31) 544.74 (70.20) 19.23 (7.25)
0.02 0.97 0.52 0.11
MRI volumes analyzed with total intracranial volume as covariate all veterans. Conclusions: Previous studies have reported reduced hippocampal volume in individuals with PTSD (e.g., Bremner et al., 1995). In this study, we found that hippocampal volume is further reduced in PTSD+ subjects with CI. We also found a negative association between PTSD severity (i.e., CAPS) and memory scores. Because hippocampal atrophy and memory impairment are both risk factors for Alzheimer’s disease (AD), this may be a potential link between the two disorders. P1-390
PET AMYLOID IMAGING IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE USING NOVEL AMYLOID LIGAND [18F]FACT - THE HYDROXYLATED BF-227 DERIVATIVE
He Shao1, Nobuyuki Okamura1, Shozo Furumoto1, Katsutoshi Furukawa2, Masaaki Waragai2, Hiroyuki Arai2, Yukitsuka Kudo3, Kazuhiko Yanai1,
ALTERED VISUOSPATIAL WORKING MEMORY PROCESS IN PATIENTS WITH ALZHEIMER’S DISEASE: FMRI INVESTIGATION
Chang- Uk Lee, Hyun-Kook Lim, Catholic University, Seoul, Korea, Republic of. Contact e-mail: [email protected] Background: Impaired visuospatial working memory processing is one of the broad ranges of cognitive deficits in patients with Alzheimer’s disease (AD). We aimed to elucidate the differences in brain activities involved in the process of visuospatial working memory between AD patients and healthy comparison subjects. Methods: Twelve patients with AD were recruited along with twelve healthy volunteers as a comparison group. Functional magnetic resonance imaging (fMRI) was employed to assess cortical activities during the performance of a 1-back and 2-back visuospatial working memory paradigm using various shapes as mnemonic content. Subsequently, the difference in neural activities between the two groups was analyzed. Results: The AD group performed the tasks with reduced accuracy. Group comparison analysis revealed that the AD group showed decreased brain activity in the right precuneus(BA7), the right insula(BA13), and the right premotor cortex(BA6) during the performance of the 1-back task, the right dorsolateral prefrontal cortex(BA46) during the 2-back task, compared to the control group. The AD group showed increased activation in the right parahippocampal gyrus(BA28), left fusiform gyrus during the 1-back task, compared to the control group. No increased activities were observed during the 2-back task in the AD patients as compared to controls. Conclusions: A decreased level of activation in the prefrontal cortex and an increased level of activation in the parietal neural networks from the patient group may document altered visuospatial working memory process in the patients with AD. P1-386
VOXEL-BASED ASSESSMENT OF ASYMMETRICAL HIPPOCAMPAL AND ENTORHINAL ATROPHY IN MCI: A LONGITUDINAL MRI INVESTIGATION FROM THE ADDNEUROMED STUDY
Simon Brunton1, Matthew Kempton2,3, Eric Westman4, Sebastian Muehlboeck5, Lars-Olof Wahlund4, Magda Tsolaki6, Hilkka Soininen7, Patrizia Mecocci8, Iwona Kloszewska9, Bruno Vellas10, Simon Lovestone11,3, Christian Spenger12, Andrew Simmons11,3, 1King’s College London, Centre for Neuroimaging Sciences, London, United Kingdom; 2King’s College London, Center for Neuroimaging Sciences, London, United Kingdom; 3NIHR Biomedical Research Centre for Mental Health, London, United Kingdom; 4Department of Neurobiology, Care Sciences and Society, Stockholm, Sweden; 5Department of Clinical Science, Intervention and Technology, Stockholm, Sweden; 6Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece; 7Department of Neurology, University and University Hospital of Kuopio, Kuopio, Finland; 8Institute Gerontology and Geriatrics, University of Perugia, Perugia, Italy; 9 Department of Old Age Psychiatry & Psychotic Disorders, Medical University of Lodz, Lodz, Poland; 10Department of Internal and Geriatrics Medicine, Hopitaux de Toulouse, Toulouse, France; 11King’s College London, Institute of Psychiatry, London, United Kingdom; 12Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden. Contact e-mail: [email protected] Background: Previous studies have demonstrated the importance of early changes in the hippocampus, parahippocampal and entrorhinal cortex in mild cognitive impairment (MCI). We investigated the rate of change of these
S285
structures and the degree of lateralisation using voxel-based morphometry (VBM) as part of the AddNeuroMed study, comparing MCI subjects that converted from mild cognitive impairment (MCI-c) to Alzheimer’s disease (AD) with stable MCI subjects (MCI-s). Methods: 14 MCI-c (mean age 72.10(5.6)) and 45 MCI-s (74.54 (5.8)) patients were scanned on 1.5T MRI scanners as part of the AddNeuroMed study. MRI acquisition was designed to be compatible with ADNI and included a high resolution sagittal 3D T1weighted MPRAGE volume. Each subject underwent scans at baseline and 1 year. VBM was used for a region of interest-based analysis of grey matter atrophy in the hippocampus, parahippocampus, anterior ERC and posterior ERC using SPM-5. Group differences were assessed at p < 0.05, with volumetric comparisons performed using SPSS. Results: VBM analysis showed greatest atrophy in hippocampus (head, body and tail) and anterior ERC in the right hemisphere in MCI-c patients. Reductions in the left hemisphere were localised to the head of the hippocampus, with sparing of the anterior ERC. At one year, the MCI-c group was found to have a higher rate of decline in volume than the MCI-s group (MCI-c hippocampus L ¼ 3.6%; R ¼ 3.6%, anterior ERC L ¼ 2.8%; R ¼ 2.8%; MCI-s hippocampus L ¼ 2.2%; R ¼ 2.2%, anterior ERC L ¼ 1.8%; R ¼ 2.1%). Differences in volumetric asymmetries were observed at baseline and were characterised by a left > right bias in the hippocampus of 12.7% in MCI-c compared to 7.8% in MCI-s, and anterior ERC of 5.4% in MCI-c compared to 1.3% in MCI-s. This pattern of asymmetry remained consistent at the one year follow up scan. Conclusions: Our study has used VBM to demonstrate consistent asymmetrical patterns of atrophy between MCI-c and MCI-s patients over time. The rate at which the hippocampus and anterior ERC changes over time was greater for the MCI-c group than the MCI-s group. Knowledge of atrophy rates and asymmetries in MCI is important for predicting which subjects with MCI will convert to AD and for future pharmacological interventions. P1-387
MILD TO MODERATE ALZHEIMER’S DISEASE (AD) CLINICAL TRIALS: THE ROLE OF HIPPOCAMPAL ATROPHY AS AN INCLUSION CRITERION
Robert Risinger1, Robert M Berman1, Vlad Coric1, Jian Han1, Stephen Kaplita1, Leah Burns1, Zubin Bhagwagar1, Derek Hill2, Robin Wolz3, Daniel Rueckert3, Howard Feldman1, 1Bristol - Myers Squibb, Wallingford, CT, USA; 2IXICO, London, United Kingdom; 3Imperial College, London, United Kingdom. Contact e-mail: [email protected] Background: Volumetric measurement of regions involved in AD has relied on manual definition of the hippocampus and temporal lobe structures using MRI. The potential utility of automated MRI region of interest definition to improve the accurate identification of AD or as an inclusion criterion for randomized controlled trials in AD has not been systematically investigated. The objective of this study was to investigate whether automated hippocampal volumetric definition using MRI could be a useful inclusion criterion for mild to moderate AD trials. We examined the correlation of baseline hippocampal volume (HV) with (a) rate of clinical decline and (b) baseline CSF Ab1-42 and t-tau:Ab1-42 levels. Methods: A retrospective analysis was performed on the subset of subjects with mild AD from ADNI (MMSE score 18-28) and who had up to 2 years’ follow up and automated MRI hippocampal volumetric analysis at baseline (n ¼ 128). HV was calculated using the Learning Embeddings for Atlas Propagation (LEAP)-framework (Wolz et al, 2010) in which a set of manually labeled brain atlases are automatically propagated to a diverse population, increasing the accuracy of standard multi-atlas segmentation (Hechemann et al, 2006). HV for each subject was normalized to intracranial volume and multiplied by 106 for ease of review. The AD study population was evaluated as an entire group and by age cohorts (55-71, 72-79, and 80-91 years). All patients had a lumbar puncture for estimation of Ab1-42 or t-tau:Ab1-42. Clinical decline was measured as the change in ADAS-cog from baseline. Descriptive statistics and correlational analyses were determined. Results: Baseline characteristics of this cohort included: mean age of 75.3 years (standard deviation [SD]: 7.5); 47.2% female; MMSE score of 23.4 (2.1); ADAS-cog of 18.6 (6.3); and CDR-sb of 4.3 (1.6). Based on patients with available HV, the normalized HV range was 651-2007 with a mean of 1264.8 (214.5). There were no consistent
S286
Poster Presentations P1
significant correlations between baseline HV and either rate of clinical decline or baseline CSF measures (Ab1-42 or t-tau:Ab1-42). Conclusions: The use of baseline HV as an inclusion criterion for mild to moderate AD clinical trials is not supported by these data P1-388
IMAGING OF CHOLINERGIC TERMINALS IN THE NON-HUMAN PRIMATE BRAIN USING 18F-FEOBV PET: DEVELOPMENT OF A TOOL TO ASSESS CHOLINERGIC LOSSES IN ALZHEIMER’S DISEASE
Jean-Paul Soucy1, Pedro Rosa1, Gassan Massarweh1, Antonio Aliaga1, Esther Schirrmacher1, Marc-Andre´ Be´dard2, Margarita Sanchez-Legaspi3, Paul Gravel1, Andrew Reader1, 1Montreal Neurological Institute, Montreal, QC, Canada; 2Universite´ du Que´bec a` Montre´al, Montreal, QC, Canada; 3 INRS - Experimental Biology Center, Laval, QC, Canada. Contact e-mail: [email protected] Background: Loss of ACh cells is is seen at early stages in Alzheimer’s disease. Different approaches have been tried to assess this loss as a biomarker for diagnosing the disease during the very first stages of its development, as well as to follow its progression. Radioactive tracers derived from the acetylcholine vesicular transporter vesamicol have been proposed for in vivo imaging with either SPECT or PET. We have characterized and validated a potential PET ligand of that category, 18F-FEOBV, in rodents. However, doubts have been raised by others about the stability (defluorination) of this class of agents in primates. Here, we have evaluated this tracer in non-human primates to assess its suitability for PET imaging. Methods: Two Macaca fascicularis (1 female; 5,7 kg; 1 male: 5,5 kg) were imaged. The animals were fasted overnight, sedated using a mixture of Ketamine and Acepromazine, and intubated prior to scanning. Vital signs were monitored/adjusted at all time. We used a Siemens HRRT scanner with an isotropic resolution of 2.3 - 3.4 mm FWHM; this scanner operates in list mode acquisition. High specific activity 18F-FEOBV (92 and 78 MBq) was injected and acquisition was performed for 75 min. post IV. Reconstruction was with OPOSEM+PSF, 10 iterations, 16 subsets. BP images and TAC’s were generated for multiple regions. Results: Good quality scans (see figure) were obtained. No major defluorination (which would have been inferred from significant bone uptake) was observed, even at the end of the scanning session. There was well defined uptake of the tracer in brain regions rich in cholinergic terminals, with the highest binding potentials being detected in the caudate and thalamus. Evaluation of time-activity curves (see figure) from different regions showed a profile compatible with an essentially irreversible binding in the striatum and cortex. Monitoring of the animals during the imaging phase and for a period of 1 week thereafter revealed no untoward effect. Conclusions: 18F-FEOBV can be used for PET imaging in primates, and appears to be a promising agent to evaluate cholinergic systems status using this
technique. No problems of stability nor toxicity were observed in this experiment. P1-389
HIPPOCAMPAL ATROPHY IN YOUNG VETERANS WITH PTSD AND COGNITIVE IMPAIRMENT: A POTENTIAL LINK BETWEEN PTSD AND DEMENTIA
Linda L. Chao, Kristine Yaffe, Thomas C. Neylan, Johannes C. Rothlind, Dieter J. Meyerhoff, Michael W. Weiner, University of California, San Francisco, San Francisco, CA, USA. Contact e-mail: [email protected] Background: We recently reported that older veterans with post-traumatic stress disorder (PTSD) are nearly twice as likely to develop dementia compared to veterans without PTSD (Yaffe et al., 2009). The goal of this study is to examine potential links between these two disorders in a group of younger veterans with and without PTSD. Methods: We examined brain structural magnetic resonance imaging (MRI) and neuropsychological data of 34 veterans of the first Gulf War (mean age: 41.7 years). All of the veterans had PTSD, defined as a Clinical Administered PTSD Scale (CAPS) score > 40 and chronic multi-symptom illness based on the criteria described by Fukuda et al. (1998). Ten veterans also had cognitive impairments (CI), defined as > 1 SD below the mean on a cognitive domain (i.e., memory, executive function, or attention). MRI data were analyzed using automated and semi-automated image processing techniques that produced volumetric measurements of gray and white matter, cerebrospinal fluid (CSF) and the hippocampus. Results: Veterans with and without PTSD were similar in age, education, CAPS score, and % male (p > 0.33). As expected, there were significant group differences in memory (p < 0.0001), executive function (p < 0.0001), and attention (p ¼ 0.004) domain scores. There was also a significant difference in hippocampal volume (p ¼ 0.02). Spearman’s correlation showed that CAPS scores were negatively associated with memory domain scores (r ¼ -0.35, p ¼ 0.03) in Differences between PTSD+ veterans with and without CI PTSD with CI (N ¼ 10)
PTSD without CI (N ¼ 24)
p-value
male:female Age (years) Education (years) CAPS
9:1 41.3 (6.9) 14.5 (2.5) 63.8 (18.6)
19:6 41.8 (9.6) 14.3 (2.1) 63.4 (14.6)
0.33 0.88 0.80 0.94
Domain scores Memory Executive Function Attention
-0.87 (1.02) -0.81 (0.67) -0.80 (0.92)
0.25 (0.60) 0.22 (0.56) 0.50 (1.10)
<0.0001 <0.0001 0.004
MRI volumes Hippocampus Total gray matter Total white matter Ventricular CSF
4.89 (0.61) 659.08 (57.81) 556.84 (53.18) 25.74 (12.44)
5.26 (0.55) 636.39 (79.31) 544.74 (70.20) 19.23 (7.25)
0.02 0.97 0.52 0.11
MRI volumes analyzed with total intracranial volume as covariate all veterans. Conclusions: Previous studies have reported reduced hippocampal volume in individuals with PTSD (e.g., Bremner et al., 1995). In this study, we found that hippocampal volume is further reduced in PTSD+ subjects with CI. We also found a negative association between PTSD severity (i.e., CAPS) and memory scores. Because hippocampal atrophy and memory impairment are both risk factors for Alzheimer’s disease (AD), this may be a potential link between the two disorders. P1-390
PET AMYLOID IMAGING IN MILD COGNITIVE IMPAIRMENT AND ALZHEIMER’S DISEASE USING NOVEL AMYLOID LIGAND [18F]FACT - THE HYDROXYLATED BF-227 DERIVATIVE
He Shao1, Nobuyuki Okamura1, Shozo Furumoto1, Katsutoshi Furukawa2, Masaaki Waragai2, Hiroyuki Arai2, Yukitsuka Kudo3, Kazuhiko Yanai1,