- Email: [email protected]
Increased Expression of the Lysosomal Cholesterol Transporter NPC1 in Alzheimer's Disease
e68
Hot Topics
changes in brain blood flow at rest reflect a specific response to cholinesterase inhibitor (ChEI) treatment or are simply a systemic response to cholinergic enhancement. Methods: Twenty four patients with probable AD were recruited for the study. All had psychiatric, neurological and neuropsychological assessments and structural MRI scanning. A perfusion MRI scan was acquired before and after 20 weeks of ChEI treatment. Post treatment scans were compared to pre treatment scans. Patients was also classified into responders and non responders based on clinical and neuropsychological criteria. Post treatment scans of each sub-group were then compared to pre treatment scans. Results: Assessing treatment response in the entire group of patients with AD revealed increases in perfusion in the bilateral temporal regions and the posterior cingulate. Decreases in perfusion were detected in left frontal and temporal regions. At retest, in the sub-group of patients who responded to treatment, increased perfusion was recorded in the right caudate (tail and body), but there were decreases in bilateral frontal regions, the right caudate head and the left cuneus. Non responders had increases in perfusion in bilateral temporal regions, but decreases in the right caudate body. Conclusions: Increases in brain blood flow in cortical regions after treatment most likely reflect a systemic response to cholinergic enhancement rather than a specific response to treatment. Perfusion changes in the left caudate nucleus were the only ones which paralleled clinical and cognitive response. This finding suggests that increases in cortical brain blood flow or metabolism do not accurately reflect a specific clinically relevant effect of treatment.
P4-151
THE DIAGNOSTIC ACCURACY OFAN INCIDENTAL MEMORY TEST IN DIFFERENTIATING BETWEEN NORMAL AGING AND MILD ALZHEIMER’S DISEASE
Mira Karrasch1,2, Anna Myllyniemi1, Linda Latvasalo1, Carina So¨derholm1,2, Ulla Ellfolk1,2, Matti Laine1, 1A˚bo Akademi University, Turku, Finland; 2University of Turku, Turku, Finland. Contact e-mail: [email protected]. Background: Most episodic memory tests assess intentional memory, i.e. the instruction is to try to memorize something. Both dementing disorders and normal ageing affect the performance in intentional episodic memory tests. There are only a few tests tapping incidental episodic memory, although this form of memory test would in fact be more ecologically valid and replicate ordinary life situations where individuals rarely put conscious effort into memorizing events. The aim of the study was to examine the diagnostic accuracy of an incidental memory test (the memo-BNT) in differentiating between healthy old controls and mild AD patients. Methods: There were three groups in the study, young controls (n ¼ 22, mean age 21.7, SD¼4.4), normally aged old controls (n ¼ 23, mean age 70.6, SD ¼ 7.3) and patients diagnosed with mild AD (n ¼ 23, mean age 74.0, SD ¼ 4.7). The memo-BNT is an incidental memory test based on the BNT. After naming items 30-60 according to the standard administration of the BNT, a free recall task and a recognition task were introduced without prior warning, i.e. the subjects were not informed that they would have to recall the items after naming. Results: There were no statistically significant differences on any of the incidental memory measures between the healthy older and younger subjects. There were however, statistically significant differences between the AD patients and the normal healthy old controls, as well as between the AD patients and the young healthy controls in the incidental memory measures. This difference was due to the fact that the AD patient’s performance was much poorer. ROC-analysis revealed that incidental free recall was the best measure in discriminating between the healthy aged controls and the AD patients (area under curve¼.939). Conclusions: The results indicate that the memo-BNT has high sensitivity and specificity for memory impairment in AD. In the future, the applicability of this incidental memory test for differentiating between normal ageing and other dementing disorders (vascular dementia and dementia related to
Parkinso’s disease) or between different dementing disorders should be studied.
P4-152
SYNTHESIS OF META- [18F]FLUORO-DONEPEZIL AND META- [18F]FLUORO-CP118,954 FROM IODONIUM SALT PRECURSORS AS NEW PET IMAGING PROBES FOR ACHE
Byung Chul Lee1, Byung Seok Moon1, Yearn Seong Choe2, Yu Kyeong Kim1, Sang Eun Kim1, 1Seoul National University Bundang Hospital, Seongnam, Korea, Republic of; 2Samsung Medical Center, Seoul, Korea, Republic of. Contact e-mail: [email protected]. Background: Acetylcholinesterase (AChE) inhibitiors, which are Donepezil and CP118,954, have been developed and evaluated to manifest biochemical differences between Alzheimer’s disease (AD) and normal brain. Among the fluorine substituted Donepezil/CP118,954) analogs, meta-fluorine-substitued Donepezil (IC50 ¼ 3.1 nM)/CP118,954 (IC50 ¼ 0.2 nM) showed the highest anti-acetylcholinesterase activity. These fluorine-18 labeled analogs were not reported due to the limitation of labeling methods at meta-position of phenyl ring. We herein describe the synthesis of meta- [18F]fluoro-Donepezil/CP118,954 analogs using iodonium salt precursors as AChE imaging probes. Methods: To prepare of meta- [18F]fluoro-Donepezil/CP118,954, we designed two synthetic routes: one is that fluorine-18 could be directly introduced to iodonium salt precursor at a very late step and another proceeds through the prosthetic group (3[18F]fluorobenzaldehyde) for the desired target compounds. Iodonium salt precursors were prepared by the reaction of 3-tributylstannyl-DP (for direct fluorination) and 3-tributylstannylbenzaldehyde (for indirect fluorination) with hydroxyl(tosyloxy)iodobenzene (Koser’s reagent). The aromatic radiofluorination was carried out with microwave or oil-bath in different solvents. In case of prosthetic pathway, meta- [18F]fluoro-Donepezil/CP118,954 analogs were synthesized by reductive-alkylation with 3- [18F]fluorobenzaldehyde. Results: The direct radiofluorination of meta- [18F]fluoro-Donepezil showed in 1-15% of radiochemical yield with low reproducibility. On the other hand, the radiofluorination of 3- [18F]fluorobenzaldehyde showed 20-40% and reductive-alkylation step was achieved about 50-70% yield. Consequently, meta- [18F]fluoro-Donepezil/CP118,954 analogs obtained about 10-15% of radiochemical yield (decay-corrected) with high radiochemical purity over 95% within approximately 80 min. Conclusions: meta- [18F]Fluoro-Donepezil/CP118,954 analogs successfully obtained from iodonium salt precursors as a reasonable yield for the biological evaluation. Further, these radiotracers are ongoing to the biological evaluation as AChE imaging probes.
P4-153
INCREASED EXPRESSION OF THE LYSOSOMAL CHOLESTEROL TRANSPORTER NPC1 IN ALZHEIMER’S DISEASE
Katarina Ka˚gedal1, Woojin Kim2, Hanna Appelqvist1, Sharon Chan2, Danni Cheng2, Lotta Hellstro¨m1, Kevin Barnham3, Heather McCann2, Glenda Halliday2, Brett Garner2, 1Linko¨ping University, Linko¨ping, Sweden; 2Prince of Wales Medical Research Institute, Sydney, Australia; 3 University of Melbourne, Melbourne, Australia. Contact e-mail: katarina. [email protected]. Background: The Niemann-Pick type C1 (NPC1) protein regulates the trafficking of cholesterol from lysosomes to other organelles. Mutations of NPC1 lead to the retention of cholesterol and other lipids in the lysosomal compartment, and such defects are the basis of NPC1 disease. Several parallels exist between NPC1 disease and Alzheimer’s disease (AD), including altered cholesterol homeostasis, changes in the lysosomal system, neurofibrillary tangles and increased amyloid-beta generation. How the expression of NPC1 in the human brain is affected in AD has not
Hot Topics been investigated so far. Methods: We measured NPC1 mRNA (qPCR) and protein expression (western blot) in distinct regions of healthy individuals and AD patients or mice. Results: NPC1 expression is upregulated at both mRNA and protein levels in the hippocampus and frontal cortex of AD patients compared to control individuals. In the cerebellum, a brain region that is relatively spared in AD, no difference in NPC1 expression was detected. Similarly, murine NPC1 mRNA levels were increased in the hippocampus of 12 month old transgenic mice expressing a familial AD form of human amyloid-beta precursor protein (APP) and presenilin-1 (APP/PS1tg) compared to 2 month old APP/PS1tg or wild type mice whereas no change in NPC1 was detected in mouse cerebellum. Immunohistochemical analysis of human hippocampus indicated that NPC1 expression was strongest in neurons. However, in vitro studies revealed that NPC1 expression was not induced by transfecting SK-N-SH neurons with human APP nor by treating them with oligomeric amyloid-beta peptide. Total cholesterol levels were reduced in hippocampus from AD patients compared to control individuals. Conclusions: It is possible that the increased expression of NPC1 is linked to perturbed cholesterol homeostasis in AD.
P4-154
GENOME-WIDE ASSOCIATION OF CEREBROVASCULAR AND NEURODEGENERATIVE QUANTITATIVE MRI TRAITS IN ALZHEIMER’S DISEASE
Antonio R. Parrado1, Mark Logue1, Kathryn L. Lunetta1, Adrienne Cupples1, Charles DeCarli2, Clinton T. Baldwin1, Lindsay A. Farrer1, 1Boston University, Boston, MA, USA; 2University of California Davis Center for Neuroscience, Davis, CA, USA. Contact e-mail: [email protected]. Background: Most genetic association studies of Alzheimer’s disease (AD) have focused on the dichotomous AD diagnosis as an outcome. Recently, using a candidate gene approach we showed significant associations between SORL1 (a robustly confirmed AD locus) and MRI-based semiquantitative measures of white matter hyperintensities (WMH), generalized cerebral atrophy (CA), cerebrovascular disease (CD) and hippocampal atrophy (HA), thus encouraging use of these endophenotypes for AD (Cuenco et al. 2008). Objective: To identify additional genes related to AD, we performed a GWAS of WMH, CA, CD and HA measured in a Caucasian sample of 431 affected and 516 cognitively healthy members of 501 sibships from the MIRAGE Study. Methods: Association analyses were performed using Generalized Estimating Equations to account for sib correlations and adjusted for age at MRI, sex, disease duration, ancestry measured by genetic principal components, and presence of APOE e4. Results: Several chromosomal regions revealed suggestive evidence of association (P < 10-5) with each semi-quantitative measure. We identified strong evidence for association (P < 10-7) for SNPs in or near several genes with CA (SAP30BP), HA (rs12608393 on chromosome 18q23) and CD (PTPRK and HMGB1). SNP rs820218 in SAP30BP showed a noteworthy association with CA (p ¼ 6.1 x 10-9, OR 0.03, 95% CI 0.01-0.09). SAP30BP produces a transcriptional regulator protein that may be involved in cellular corepression of transcription and inhibition of cell survival. Conclusions: Because neuronal loss is a distinguishing characteristic of AD, SAP30BP represents a new and interesting candidate AD risk locus. These results emphasize the potential importance of neuroimaging endophenotypes as biological markers for discovering genes influencing the etiology of AD.
P4-155
NEUROPSYCHIATRIC PROFILES OF DEMENTIA
David K. Johnson1, Amber Watts1, Jeffrey M. Burns2, 1University of Kansas, Lawrence, KS, USA; 2University of Kansas Medical Center, Kansas City, KS, USA. Contact e-mail: [email protected].
e69
Background: Our objective was to compare patterns of neuropsychiatric symptoms across several types of dementia to discern patterns of psychiatric symptoms that are unique to the specific neuropathologic conditions. Methods: We used confirmatory factor analysis to compare the neuropsychiatric profiles of 4 dementia types and 2 mixed diagnosis types using the Neuropsychiatric Inventory (NPI-Q). The sample of 2,963 individuals are from the 2003 National Alzheimer Coordinating Committee (NACC) with diagnosis types of AD, VAD, DLB, PDD, and two mixed groups AD-VAD, and AD-DLB. We included patients with Clinical Dementia Rating (CDR) scores of 1 or higher. Results: The factor structure was comparable across dementia types, indicating that the NPI could be used to compare groups. Examination of group difference indicated the groups differed significantly in their mean levels of mood, psychotic, and frontal symptoms suggesting different profiles of neuropsychiatric symptoms that differed by dementia type. Conclusions: Psychiatric profiles differ across dementia types and may provide useful information regarding the non-cognitive symptoms of dementia that may contribute to knowledge about pathological origins, disease course, and appropriate treatments.
P4-156
SYNTHESIS AND EVALUATION OF BUTYRYLCHOLINESTERASE LIGANDS FOR NEUROIMAGING ALZHEIMER’S DISEASE
Ian Macdonald1, Ian Pottie2, Edward E. Joy1, Gilbert Matte1, Steven Burrell1, George Mawko1, Earl Martin2, Sultan Darvesh1, 1Dalhousie University, Halifax, NS, Canada; 2Mount Saint Vincent University, Halifax, NS, Canada. Contact e-mail: [email protected]. Background: Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. Increased levels of BuChE are observed in Alzheimer’s disease brain especially in neuritic plaques and neurofibrillary tangles, characteristic of the disease. This makes BuChE a suitable target for diseasespecific neuroimaging. Cholinesterase ligands currently being investigated for imaging have the radioisotope in that part of the molecule that is the initial leaving group in the enzyme catalyzed hydrolysis. This may be, in part, responsible for poorly defined images with these ligands. We propose that BuChE-specific radiopharmaceuticals, having the radioisotope in the part of the molecule that forms the ligand-enzyme intermediate, can be used in PET and SPECT imaging to detect this enzyme in vivo, and thus the neuritic plaques and neurofibrillary tangles associated with AD. Imaging the AD plaques and tangles may provide an early diagnosis as well as a method for treatment monitoring. Methods: Piperidinols and pyrrolidinols were reacted with various acid chlorides and isocyanates to produce corresponding esters and carbamates, respectively. These compounds were evaluated using enzyme kinetics for their affinity towards both BuChE and AChE. BuChE-specific ligands were then transformed into intermediates suitable for incorporation of a radiolabel, either 123I for SPECT or 18F for PET imaging. Carrier free radiolabeled ligands were then administered to experimental animals and the distribution of BuChE in vivo determined. Results: Several piperidinols and pyrrolidinols proved to be specific ligands for BuChE. These ligands were successfully transformed into both tin and tosylate intermediates. 123I was successfully incorporated into these molecules. Preliminary animal imaging indicated regional distribution of ligands. Conclusions: BuChE has been previously demonstrated to be involved in the pathology of AD. We have synthesized several BuChE-specific ligands that have been successfully radiolabeled. Preliminary animal imaging with these ligands indicated that there is regional distribution in the body and that these ligands are taken up into the brain. Further refinement of imaging methodology is underway. The imaging of BuChE in vivo may facilitate early diagnosis and treatment monitoring of AD.
Hot Topics
changes in brain blood flow at rest reflect a specific response to cholinesterase inhibitor (ChEI) treatment or are simply a systemic response to cholinergic enhancement. Methods: Twenty four patients with probable AD were recruited for the study. All had psychiatric, neurological and neuropsychological assessments and structural MRI scanning. A perfusion MRI scan was acquired before and after 20 weeks of ChEI treatment. Post treatment scans were compared to pre treatment scans. Patients was also classified into responders and non responders based on clinical and neuropsychological criteria. Post treatment scans of each sub-group were then compared to pre treatment scans. Results: Assessing treatment response in the entire group of patients with AD revealed increases in perfusion in the bilateral temporal regions and the posterior cingulate. Decreases in perfusion were detected in left frontal and temporal regions. At retest, in the sub-group of patients who responded to treatment, increased perfusion was recorded in the right caudate (tail and body), but there were decreases in bilateral frontal regions, the right caudate head and the left cuneus. Non responders had increases in perfusion in bilateral temporal regions, but decreases in the right caudate body. Conclusions: Increases in brain blood flow in cortical regions after treatment most likely reflect a systemic response to cholinergic enhancement rather than a specific response to treatment. Perfusion changes in the left caudate nucleus were the only ones which paralleled clinical and cognitive response. This finding suggests that increases in cortical brain blood flow or metabolism do not accurately reflect a specific clinically relevant effect of treatment.
P4-151
THE DIAGNOSTIC ACCURACY OFAN INCIDENTAL MEMORY TEST IN DIFFERENTIATING BETWEEN NORMAL AGING AND MILD ALZHEIMER’S DISEASE
Mira Karrasch1,2, Anna Myllyniemi1, Linda Latvasalo1, Carina So¨derholm1,2, Ulla Ellfolk1,2, Matti Laine1, 1A˚bo Akademi University, Turku, Finland; 2University of Turku, Turku, Finland. Contact e-mail: [email protected]. Background: Most episodic memory tests assess intentional memory, i.e. the instruction is to try to memorize something. Both dementing disorders and normal ageing affect the performance in intentional episodic memory tests. There are only a few tests tapping incidental episodic memory, although this form of memory test would in fact be more ecologically valid and replicate ordinary life situations where individuals rarely put conscious effort into memorizing events. The aim of the study was to examine the diagnostic accuracy of an incidental memory test (the memo-BNT) in differentiating between healthy old controls and mild AD patients. Methods: There were three groups in the study, young controls (n ¼ 22, mean age 21.7, SD¼4.4), normally aged old controls (n ¼ 23, mean age 70.6, SD ¼ 7.3) and patients diagnosed with mild AD (n ¼ 23, mean age 74.0, SD ¼ 4.7). The memo-BNT is an incidental memory test based on the BNT. After naming items 30-60 according to the standard administration of the BNT, a free recall task and a recognition task were introduced without prior warning, i.e. the subjects were not informed that they would have to recall the items after naming. Results: There were no statistically significant differences on any of the incidental memory measures between the healthy older and younger subjects. There were however, statistically significant differences between the AD patients and the normal healthy old controls, as well as between the AD patients and the young healthy controls in the incidental memory measures. This difference was due to the fact that the AD patient’s performance was much poorer. ROC-analysis revealed that incidental free recall was the best measure in discriminating between the healthy aged controls and the AD patients (area under curve¼.939). Conclusions: The results indicate that the memo-BNT has high sensitivity and specificity for memory impairment in AD. In the future, the applicability of this incidental memory test for differentiating between normal ageing and other dementing disorders (vascular dementia and dementia related to
Parkinso’s disease) or between different dementing disorders should be studied.
P4-152
SYNTHESIS OF META- [18F]FLUORO-DONEPEZIL AND META- [18F]FLUORO-CP118,954 FROM IODONIUM SALT PRECURSORS AS NEW PET IMAGING PROBES FOR ACHE
Byung Chul Lee1, Byung Seok Moon1, Yearn Seong Choe2, Yu Kyeong Kim1, Sang Eun Kim1, 1Seoul National University Bundang Hospital, Seongnam, Korea, Republic of; 2Samsung Medical Center, Seoul, Korea, Republic of. Contact e-mail: [email protected]. Background: Acetylcholinesterase (AChE) inhibitiors, which are Donepezil and CP118,954, have been developed and evaluated to manifest biochemical differences between Alzheimer’s disease (AD) and normal brain. Among the fluorine substituted Donepezil/CP118,954) analogs, meta-fluorine-substitued Donepezil (IC50 ¼ 3.1 nM)/CP118,954 (IC50 ¼ 0.2 nM) showed the highest anti-acetylcholinesterase activity. These fluorine-18 labeled analogs were not reported due to the limitation of labeling methods at meta-position of phenyl ring. We herein describe the synthesis of meta- [18F]fluoro-Donepezil/CP118,954 analogs using iodonium salt precursors as AChE imaging probes. Methods: To prepare of meta- [18F]fluoro-Donepezil/CP118,954, we designed two synthetic routes: one is that fluorine-18 could be directly introduced to iodonium salt precursor at a very late step and another proceeds through the prosthetic group (3[18F]fluorobenzaldehyde) for the desired target compounds. Iodonium salt precursors were prepared by the reaction of 3-tributylstannyl-DP (for direct fluorination) and 3-tributylstannylbenzaldehyde (for indirect fluorination) with hydroxyl(tosyloxy)iodobenzene (Koser’s reagent). The aromatic radiofluorination was carried out with microwave or oil-bath in different solvents. In case of prosthetic pathway, meta- [18F]fluoro-Donepezil/CP118,954 analogs were synthesized by reductive-alkylation with 3- [18F]fluorobenzaldehyde. Results: The direct radiofluorination of meta- [18F]fluoro-Donepezil showed in 1-15% of radiochemical yield with low reproducibility. On the other hand, the radiofluorination of 3- [18F]fluorobenzaldehyde showed 20-40% and reductive-alkylation step was achieved about 50-70% yield. Consequently, meta- [18F]fluoro-Donepezil/CP118,954 analogs obtained about 10-15% of radiochemical yield (decay-corrected) with high radiochemical purity over 95% within approximately 80 min. Conclusions: meta- [18F]Fluoro-Donepezil/CP118,954 analogs successfully obtained from iodonium salt precursors as a reasonable yield for the biological evaluation. Further, these radiotracers are ongoing to the biological evaluation as AChE imaging probes.
P4-153
INCREASED EXPRESSION OF THE LYSOSOMAL CHOLESTEROL TRANSPORTER NPC1 IN ALZHEIMER’S DISEASE
Katarina Ka˚gedal1, Woojin Kim2, Hanna Appelqvist1, Sharon Chan2, Danni Cheng2, Lotta Hellstro¨m1, Kevin Barnham3, Heather McCann2, Glenda Halliday2, Brett Garner2, 1Linko¨ping University, Linko¨ping, Sweden; 2Prince of Wales Medical Research Institute, Sydney, Australia; 3 University of Melbourne, Melbourne, Australia. Contact e-mail: katarina. [email protected]. Background: The Niemann-Pick type C1 (NPC1) protein regulates the trafficking of cholesterol from lysosomes to other organelles. Mutations of NPC1 lead to the retention of cholesterol and other lipids in the lysosomal compartment, and such defects are the basis of NPC1 disease. Several parallels exist between NPC1 disease and Alzheimer’s disease (AD), including altered cholesterol homeostasis, changes in the lysosomal system, neurofibrillary tangles and increased amyloid-beta generation. How the expression of NPC1 in the human brain is affected in AD has not
Hot Topics been investigated so far. Methods: We measured NPC1 mRNA (qPCR) and protein expression (western blot) in distinct regions of healthy individuals and AD patients or mice. Results: NPC1 expression is upregulated at both mRNA and protein levels in the hippocampus and frontal cortex of AD patients compared to control individuals. In the cerebellum, a brain region that is relatively spared in AD, no difference in NPC1 expression was detected. Similarly, murine NPC1 mRNA levels were increased in the hippocampus of 12 month old transgenic mice expressing a familial AD form of human amyloid-beta precursor protein (APP) and presenilin-1 (APP/PS1tg) compared to 2 month old APP/PS1tg or wild type mice whereas no change in NPC1 was detected in mouse cerebellum. Immunohistochemical analysis of human hippocampus indicated that NPC1 expression was strongest in neurons. However, in vitro studies revealed that NPC1 expression was not induced by transfecting SK-N-SH neurons with human APP nor by treating them with oligomeric amyloid-beta peptide. Total cholesterol levels were reduced in hippocampus from AD patients compared to control individuals. Conclusions: It is possible that the increased expression of NPC1 is linked to perturbed cholesterol homeostasis in AD.
P4-154
GENOME-WIDE ASSOCIATION OF CEREBROVASCULAR AND NEURODEGENERATIVE QUANTITATIVE MRI TRAITS IN ALZHEIMER’S DISEASE
Antonio R. Parrado1, Mark Logue1, Kathryn L. Lunetta1, Adrienne Cupples1, Charles DeCarli2, Clinton T. Baldwin1, Lindsay A. Farrer1, 1Boston University, Boston, MA, USA; 2University of California Davis Center for Neuroscience, Davis, CA, USA. Contact e-mail: [email protected]. Background: Most genetic association studies of Alzheimer’s disease (AD) have focused on the dichotomous AD diagnosis as an outcome. Recently, using a candidate gene approach we showed significant associations between SORL1 (a robustly confirmed AD locus) and MRI-based semiquantitative measures of white matter hyperintensities (WMH), generalized cerebral atrophy (CA), cerebrovascular disease (CD) and hippocampal atrophy (HA), thus encouraging use of these endophenotypes for AD (Cuenco et al. 2008). Objective: To identify additional genes related to AD, we performed a GWAS of WMH, CA, CD and HA measured in a Caucasian sample of 431 affected and 516 cognitively healthy members of 501 sibships from the MIRAGE Study. Methods: Association analyses were performed using Generalized Estimating Equations to account for sib correlations and adjusted for age at MRI, sex, disease duration, ancestry measured by genetic principal components, and presence of APOE e4. Results: Several chromosomal regions revealed suggestive evidence of association (P < 10-5) with each semi-quantitative measure. We identified strong evidence for association (P < 10-7) for SNPs in or near several genes with CA (SAP30BP), HA (rs12608393 on chromosome 18q23) and CD (PTPRK and HMGB1). SNP rs820218 in SAP30BP showed a noteworthy association with CA (p ¼ 6.1 x 10-9, OR 0.03, 95% CI 0.01-0.09). SAP30BP produces a transcriptional regulator protein that may be involved in cellular corepression of transcription and inhibition of cell survival. Conclusions: Because neuronal loss is a distinguishing characteristic of AD, SAP30BP represents a new and interesting candidate AD risk locus. These results emphasize the potential importance of neuroimaging endophenotypes as biological markers for discovering genes influencing the etiology of AD.
P4-155
NEUROPSYCHIATRIC PROFILES OF DEMENTIA
David K. Johnson1, Amber Watts1, Jeffrey M. Burns2, 1University of Kansas, Lawrence, KS, USA; 2University of Kansas Medical Center, Kansas City, KS, USA. Contact e-mail: [email protected].
e69
Background: Our objective was to compare patterns of neuropsychiatric symptoms across several types of dementia to discern patterns of psychiatric symptoms that are unique to the specific neuropathologic conditions. Methods: We used confirmatory factor analysis to compare the neuropsychiatric profiles of 4 dementia types and 2 mixed diagnosis types using the Neuropsychiatric Inventory (NPI-Q). The sample of 2,963 individuals are from the 2003 National Alzheimer Coordinating Committee (NACC) with diagnosis types of AD, VAD, DLB, PDD, and two mixed groups AD-VAD, and AD-DLB. We included patients with Clinical Dementia Rating (CDR) scores of 1 or higher. Results: The factor structure was comparable across dementia types, indicating that the NPI could be used to compare groups. Examination of group difference indicated the groups differed significantly in their mean levels of mood, psychotic, and frontal symptoms suggesting different profiles of neuropsychiatric symptoms that differed by dementia type. Conclusions: Psychiatric profiles differ across dementia types and may provide useful information regarding the non-cognitive symptoms of dementia that may contribute to knowledge about pathological origins, disease course, and appropriate treatments.
P4-156
SYNTHESIS AND EVALUATION OF BUTYRYLCHOLINESTERASE LIGANDS FOR NEUROIMAGING ALZHEIMER’S DISEASE
Ian Macdonald1, Ian Pottie2, Edward E. Joy1, Gilbert Matte1, Steven Burrell1, George Mawko1, Earl Martin2, Sultan Darvesh1, 1Dalhousie University, Halifax, NS, Canada; 2Mount Saint Vincent University, Halifax, NS, Canada. Contact e-mail: [email protected]. Background: Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. Increased levels of BuChE are observed in Alzheimer’s disease brain especially in neuritic plaques and neurofibrillary tangles, characteristic of the disease. This makes BuChE a suitable target for diseasespecific neuroimaging. Cholinesterase ligands currently being investigated for imaging have the radioisotope in that part of the molecule that is the initial leaving group in the enzyme catalyzed hydrolysis. This may be, in part, responsible for poorly defined images with these ligands. We propose that BuChE-specific radiopharmaceuticals, having the radioisotope in the part of the molecule that forms the ligand-enzyme intermediate, can be used in PET and SPECT imaging to detect this enzyme in vivo, and thus the neuritic plaques and neurofibrillary tangles associated with AD. Imaging the AD plaques and tangles may provide an early diagnosis as well as a method for treatment monitoring. Methods: Piperidinols and pyrrolidinols were reacted with various acid chlorides and isocyanates to produce corresponding esters and carbamates, respectively. These compounds were evaluated using enzyme kinetics for their affinity towards both BuChE and AChE. BuChE-specific ligands were then transformed into intermediates suitable for incorporation of a radiolabel, either 123I for SPECT or 18F for PET imaging. Carrier free radiolabeled ligands were then administered to experimental animals and the distribution of BuChE in vivo determined. Results: Several piperidinols and pyrrolidinols proved to be specific ligands for BuChE. These ligands were successfully transformed into both tin and tosylate intermediates. 123I was successfully incorporated into these molecules. Preliminary animal imaging indicated regional distribution of ligands. Conclusions: BuChE has been previously demonstrated to be involved in the pathology of AD. We have synthesized several BuChE-specific ligands that have been successfully radiolabeled. Preliminary animal imaging with these ligands indicated that there is regional distribution in the body and that these ligands are taken up into the brain. Further refinement of imaging methodology is underway. The imaging of BuChE in vivo may facilitate early diagnosis and treatment monitoring of AD.