- Email: [email protected]
Alterations in activation between mild cognitive impaired subjects during a working memory task and resting coherent network
Poster Presentations P3
P366
P3-081
REDUCTION OF CORTICAL ACETYLCHOLINE ESTERASE IN MILD COGNITIVE IMPAIRMENT: CONSISTENCY ACROSS CENTERS AND PET METHODS
Karl Herholz1, Christoph Hohmann2, Ioana Florea3, Andrea Varrone4, Cathleen Haense2, Roman Krais2, Valentina Garibotto3, Elke Kalbe5, Alessandra Bertoldo6, Daniela Perani3, Stefan Vollmar2, Wolf-Dieter Heiss2, 1 University of Manchester, Manchester, United Kingdom; 2Max-PlanckInstitute for Neurological Research, Cologne, Germany; 3Vita Salute San Raffaele University, Milan, Italy; 4Karolinska Institut, Stockholm, Sweden; 5 University of Cologne, Cologne, Germany; 6University of Padova, Padova, Italy. Contact e-mail: [email protected] Background: Previous studies of post-mortem histochemistry and in-vivo assessments of cholinergic markers have yielded conflicting results whether the cholinergic system is impaired in mild cognitive impairment (MCI) and mild Alzheimer´s disease (AD). We therefore compiled PET data from two different centers and used three different methods for data analysis to check the variability of results. Methods: We studied 26 elderly normal controls (NC) (15 men, age: 64.5 6 8.3 yrs., MMSE: 29.5 6 0.7), 32 MCI (20 men, age: 69.2 6 7.8 yrs., MMSE: 26.0 6 2.5), and 15 AD (5 men, age: 66.1 6 7.9 yrs., MMSE: 21.1 6 2.7). All subjects had dynamic PET scans over 60 minutes after injection of C-11-N-methyl-4-piperidyl-acetate (MP4A) and were processed identically including the extraction of a putamen reference activity curve and normalisation to MNI space and an associated set of volumes of interest. Three methods were used for data analysis: (1) a new voxel-based implementation providing full non-linear least squares fits of a three rate-constant model, (2) a new voxel-based implementation of a maximum a-posteriori parameter estimation of hydrolysis rate k3, and (3) a VOI-based implementation of a linearised model as provided in the PMOD software package at two different reconstructed image resolutions. Results: In neocortical regions (frontal, parietal, temporal, occipital) no significant difference of hydrolysis rates was found between centers, while differences between diagnostic groups were highly significant (p0.002 in all regions, most pronounced in temporal cortex: NC 0.08260.007 [SD], MCI 0.06360.013, AD 0.05660.007, p<0.001). All methods produced virtually identical results (all R>0.90). Values obtained in unsmoothed high-resolution scans (method 3) were also highly correlated (all R0.88) and tended to provide a somewhat larger dynamic range. In contrast to neocortical regions, correlations among methods were less close for small deep regions with high hydrolysis rates (e.g., hippocampus, amygdala). Conclusions: The decrease of neocortical AChE activity in MCI and AD has been confirmed consistently across centers and methods. Cooperation supported by an EC FP7 grant on Diagnostic Molecular Imaging (DiMI). P3-082
PET IMAGING FOR MILD COGNITIVE IMPAIRMENT WITH FDG AND BETA-AMYLOID TRACER, 11C-BF-227
Katsutoshi Furukawa, Nobuyuki Okamura, Manabu Tashiro, Shozo Furumoto, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo, Hiroyuki Arai, Tohoku University, Sendai, Japan. Contact e-mail: [email protected] Background: We here applied FDG-PET as well as BF-227 PET, an amyloid tracer, to the same subjects (aged normal (AN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD)) and carefully analyzed and compared the results with these two kinds of PET. Using these data we investigated and compared the specificity and sensitivity of BF-227 PET and FDG-PET in diagnosing AD. Methods: The diagnosis for MCI and probable AD followed the MCI clinical criteria presented by Petersen et al. (Petersen et al. 1999) and National Institute of Neurological and Communication Disorders, Alzheimer’s Disease and Related Disorders Association (McKhann et al. 1984), respectively. [11C]-BF-227 was synthesized from the precursor by N-methylation in dimethyl sulfox-
ide using [11C]-methyl triflate. The [11C]-BF-227 PET study was performed using a PET SET-2400W scanner (Shimadzu Inc., Japan).Cerebral glucose metabolism was measured using 18F-FDG and a PET scanner SET-2400W. Subjects were scanned in a quiet and dimly-lit room with their eyes closed after at least four hours of food restriction. Results: Patients with MCI subjects showed significantly increased accumulation of [11C]-BF-227 compared to AN in frontal, temporal, parietal, and occipital cortices as well as anterior and posterior cingulate gyrus. On the other hand SUV-R of BF-227 was lower in MCI compared to AD in lateral temporal, parietal, and occipital cortices, posterior cingulate gyrus, and striatum. SUV-R of BF-227 was negatively correlated with that of FDG when we analyzed the data from all the subjects (AN, MCI, and AD) together. The specificity and sensitivity for diagnosis of AD with BF-227 were significantly better than those with FDG-PET. Conclusions: We conclude that BF-227 PET is a useful technology in diagnosing MCI or an early stage of AD with very little invasion. These results indicate that MCI has intermediate retention of 11CBF-227 between AN and AD indicating that Ab deposition already started in the stage of MCI before dementia symptoms become obvious. McKhann et al. Neurology. 1984 Jul;34(7):939-44. Petersen et al. Arch Neurol. 1999 Mar;56(3):303-8.
P3-083
ALTERATIONS IN ACTIVATION BETWEEN MILD COGNITIVE IMPAIRED SUBJECTS DURING A WORKING MEMORY TASK AND RESTING COHERENT NETWORK
Arun Bokde1, Michael Ewers1, Yetunde Faluyi1, Catherine Delaney1, Abid Khattack1, Ronan Collins2, Christian Kerskens1, Tara Coughlan2, Siobhain Nibrihain2, Ian Daly2, Greg Swanwick1, Desmond O’Neill1, Harald Hampel1,3, 1Trinity College Dublin, Dublin, Ireland; 2The Adelaide and Meath Hospital incorporating the National Children’s Hospital, Dublin, Ireland; 3Ludwig-Maximilian-University, Munich, Germany. Contact e-mail: [email protected] Background: Mild Cognitive Impairment (MCI) indicates a high risk for conversion to dementia and a clinical diagnosis of Alzheimer’s disease (AD). Memory impairment is one of the cognitive domains indicating higher risk for conversion to AD. We expected different network of activation for the working memory task between the two groups. Methods: The groups were 12 MCI subjects and age-matched 20 health controls (HC). The task design was a delay-match-to-sample and it was analyzed as event related design. There were 3 runs of 5 minutes, 34 sec each. The brain activation maps were computed for corrected performed trials. The coherent default network was measured using a 7 minute resting scan. Brain activation was measured using functional magnetic resonance imaging with a TR ¼ 2 sec. Statistical comparisons were performed at p < 0.05 level, corrected for multiple comparisons. Results: Both groups activated a wide network in the visual striate and extrastriate areas, middle temporal cortices, parietal lobe and frontal areas. During the working memory task there was deactivation of the default network. In the encoding phase of the task, there was higher activation in the HC compared to MCI in left fusiform gyrus and middle temporal gyrus. The MCI group had higher activation compared to HC in the right fusiform gyrus, superior temporal gyrus, middle and medial frontal gyrii and the left hemisphere in precuneus, parahippocampal and fusiform gyrii, and superior frontal gyrus. In the recall phase the HC had higher activation compared to MCI in right hemisphere: posterior cingulate, inferior, medial and superior frontal gyrii whereas in the left hemisphere: cingulate gyrus, fusiform gyrus, precuneus, medial and superior frontal gyrii. The MCI in the recall phase had higher activation compared to HC in the left inferior, middle and superior temporal gyrii and inferior frontal gyrus. The resting default network in the resting scan matched the suppressed default network during the working memory scan. Conclusions: The activation differences between groups indicate compensatory mechanisms within the MCI group for the effects of the putative AD neuropathology.
P366
P3-081
REDUCTION OF CORTICAL ACETYLCHOLINE ESTERASE IN MILD COGNITIVE IMPAIRMENT: CONSISTENCY ACROSS CENTERS AND PET METHODS
Karl Herholz1, Christoph Hohmann2, Ioana Florea3, Andrea Varrone4, Cathleen Haense2, Roman Krais2, Valentina Garibotto3, Elke Kalbe5, Alessandra Bertoldo6, Daniela Perani3, Stefan Vollmar2, Wolf-Dieter Heiss2, 1 University of Manchester, Manchester, United Kingdom; 2Max-PlanckInstitute for Neurological Research, Cologne, Germany; 3Vita Salute San Raffaele University, Milan, Italy; 4Karolinska Institut, Stockholm, Sweden; 5 University of Cologne, Cologne, Germany; 6University of Padova, Padova, Italy. Contact e-mail: [email protected] Background: Previous studies of post-mortem histochemistry and in-vivo assessments of cholinergic markers have yielded conflicting results whether the cholinergic system is impaired in mild cognitive impairment (MCI) and mild Alzheimer´s disease (AD). We therefore compiled PET data from two different centers and used three different methods for data analysis to check the variability of results. Methods: We studied 26 elderly normal controls (NC) (15 men, age: 64.5 6 8.3 yrs., MMSE: 29.5 6 0.7), 32 MCI (20 men, age: 69.2 6 7.8 yrs., MMSE: 26.0 6 2.5), and 15 AD (5 men, age: 66.1 6 7.9 yrs., MMSE: 21.1 6 2.7). All subjects had dynamic PET scans over 60 minutes after injection of C-11-N-methyl-4-piperidyl-acetate (MP4A) and were processed identically including the extraction of a putamen reference activity curve and normalisation to MNI space and an associated set of volumes of interest. Three methods were used for data analysis: (1) a new voxel-based implementation providing full non-linear least squares fits of a three rate-constant model, (2) a new voxel-based implementation of a maximum a-posteriori parameter estimation of hydrolysis rate k3, and (3) a VOI-based implementation of a linearised model as provided in the PMOD software package at two different reconstructed image resolutions. Results: In neocortical regions (frontal, parietal, temporal, occipital) no significant difference of hydrolysis rates was found between centers, while differences between diagnostic groups were highly significant (p0.002 in all regions, most pronounced in temporal cortex: NC 0.08260.007 [SD], MCI 0.06360.013, AD 0.05660.007, p<0.001). All methods produced virtually identical results (all R>0.90). Values obtained in unsmoothed high-resolution scans (method 3) were also highly correlated (all R0.88) and tended to provide a somewhat larger dynamic range. In contrast to neocortical regions, correlations among methods were less close for small deep regions with high hydrolysis rates (e.g., hippocampus, amygdala). Conclusions: The decrease of neocortical AChE activity in MCI and AD has been confirmed consistently across centers and methods. Cooperation supported by an EC FP7 grant on Diagnostic Molecular Imaging (DiMI). P3-082
PET IMAGING FOR MILD COGNITIVE IMPAIRMENT WITH FDG AND BETA-AMYLOID TRACER, 11C-BF-227
Katsutoshi Furukawa, Nobuyuki Okamura, Manabu Tashiro, Shozo Furumoto, Ren Iwata, Kazuhiko Yanai, Yukitsuka Kudo, Hiroyuki Arai, Tohoku University, Sendai, Japan. Contact e-mail: [email protected] Background: We here applied FDG-PET as well as BF-227 PET, an amyloid tracer, to the same subjects (aged normal (AN), mild cognitive impairment (MCI), and Alzheimer’s disease (AD)) and carefully analyzed and compared the results with these two kinds of PET. Using these data we investigated and compared the specificity and sensitivity of BF-227 PET and FDG-PET in diagnosing AD. Methods: The diagnosis for MCI and probable AD followed the MCI clinical criteria presented by Petersen et al. (Petersen et al. 1999) and National Institute of Neurological and Communication Disorders, Alzheimer’s Disease and Related Disorders Association (McKhann et al. 1984), respectively. [11C]-BF-227 was synthesized from the precursor by N-methylation in dimethyl sulfox-
ide using [11C]-methyl triflate. The [11C]-BF-227 PET study was performed using a PET SET-2400W scanner (Shimadzu Inc., Japan).Cerebral glucose metabolism was measured using 18F-FDG and a PET scanner SET-2400W. Subjects were scanned in a quiet and dimly-lit room with their eyes closed after at least four hours of food restriction. Results: Patients with MCI subjects showed significantly increased accumulation of [11C]-BF-227 compared to AN in frontal, temporal, parietal, and occipital cortices as well as anterior and posterior cingulate gyrus. On the other hand SUV-R of BF-227 was lower in MCI compared to AD in lateral temporal, parietal, and occipital cortices, posterior cingulate gyrus, and striatum. SUV-R of BF-227 was negatively correlated with that of FDG when we analyzed the data from all the subjects (AN, MCI, and AD) together. The specificity and sensitivity for diagnosis of AD with BF-227 were significantly better than those with FDG-PET. Conclusions: We conclude that BF-227 PET is a useful technology in diagnosing MCI or an early stage of AD with very little invasion. These results indicate that MCI has intermediate retention of 11CBF-227 between AN and AD indicating that Ab deposition already started in the stage of MCI before dementia symptoms become obvious. McKhann et al. Neurology. 1984 Jul;34(7):939-44. Petersen et al. Arch Neurol. 1999 Mar;56(3):303-8.
P3-083
ALTERATIONS IN ACTIVATION BETWEEN MILD COGNITIVE IMPAIRED SUBJECTS DURING A WORKING MEMORY TASK AND RESTING COHERENT NETWORK
Arun Bokde1, Michael Ewers1, Yetunde Faluyi1, Catherine Delaney1, Abid Khattack1, Ronan Collins2, Christian Kerskens1, Tara Coughlan2, Siobhain Nibrihain2, Ian Daly2, Greg Swanwick1, Desmond O’Neill1, Harald Hampel1,3, 1Trinity College Dublin, Dublin, Ireland; 2The Adelaide and Meath Hospital incorporating the National Children’s Hospital, Dublin, Ireland; 3Ludwig-Maximilian-University, Munich, Germany. Contact e-mail: [email protected] Background: Mild Cognitive Impairment (MCI) indicates a high risk for conversion to dementia and a clinical diagnosis of Alzheimer’s disease (AD). Memory impairment is one of the cognitive domains indicating higher risk for conversion to AD. We expected different network of activation for the working memory task between the two groups. Methods: The groups were 12 MCI subjects and age-matched 20 health controls (HC). The task design was a delay-match-to-sample and it was analyzed as event related design. There were 3 runs of 5 minutes, 34 sec each. The brain activation maps were computed for corrected performed trials. The coherent default network was measured using a 7 minute resting scan. Brain activation was measured using functional magnetic resonance imaging with a TR ¼ 2 sec. Statistical comparisons were performed at p < 0.05 level, corrected for multiple comparisons. Results: Both groups activated a wide network in the visual striate and extrastriate areas, middle temporal cortices, parietal lobe and frontal areas. During the working memory task there was deactivation of the default network. In the encoding phase of the task, there was higher activation in the HC compared to MCI in left fusiform gyrus and middle temporal gyrus. The MCI group had higher activation compared to HC in the right fusiform gyrus, superior temporal gyrus, middle and medial frontal gyrii and the left hemisphere in precuneus, parahippocampal and fusiform gyrii, and superior frontal gyrus. In the recall phase the HC had higher activation compared to MCI in right hemisphere: posterior cingulate, inferior, medial and superior frontal gyrii whereas in the left hemisphere: cingulate gyrus, fusiform gyrus, precuneus, medial and superior frontal gyrii. The MCI in the recall phase had higher activation compared to HC in the left inferior, middle and superior temporal gyrii and inferior frontal gyrus. The resting default network in the resting scan matched the suppressed default network during the working memory scan. Conclusions: The activation differences between groups indicate compensatory mechanisms within the MCI group for the effects of the putative AD neuropathology.