- Email: [email protected]
Predicting brain amyloidosis in MCI using clinical, cognitive, imaging and peripheral blood protein measures
Developing Topics: P4 Posters DEVELOPING TOPICS: P4 POSTERS P4-251
DYSPHAGIA IN INDIVIDUALS WITH ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW OF THE EVIDENCE
Rebecca Affoo, Ruth Martin, Western University, London, Ontario, Canada. Background: Dementia is a syndrome that can be caused by a number of neurodegenerative disorders that affect memory, thinking, behavior, and the ability to perform activities of daily living. Alzheimer’s disease is the most common type of dementia and currently affects approximately 250,000 Canadians. Individuals with dementia of the Alzheimer’s type may experience swallowing impairment, or dysphagia, during the progression of the disease. Swallowing function is controlled in part by the parasympathetic branch of the autonomic nervous system. The primary objective of this study was to review studies of dysphagia in individuals with Alzheimer’s disease. Secondary objectives included identification and review of the literature concerning autonomic dysfunction in individuals with Alzheimer’s disease. Methods: Systematic searches of the PubMed, EBSCOhost, PsychINFO, Cochrane, EMBASE, and Scopus databases were completed. Search terms included dementia, Alzheimer’s disease, swallowing, deglutition disorders, autonomic nervous system, and parasympathetic nervous system. Published studies and grey literature describing dysphagia or autonomic dysfunction in the context of Alzheimer’s disease were identified. Studies were reviewed and organized into categories according to type. These categories included clinical reports, physiologic studies, and brain imaging studies. Results: The literature contains evidence that dementia of the Alzheimer’s type results in distinct dysphagia or dysautonomia profiles, even in the early stages of the disease process. Conclusions: Although the prevalence and incidence of dysphagia or dysautonomia in the Alzheimer’s population is unknown, there is preliminary evidence to suggest that dysphagia or autonomic dysfunction can occur in dementia of the Alzheimer’s type. P4-252
BLOOD ASSAY TO DETECT OLIGOMERIC BETAAMYLOID WITH HIGH SENSITIVITY AND SPECIFICITY
Seong An1, Kuntaek Lim2, Byoung Sub Lee2, Gwang Je Kim2, Ji Sun Yu2, JeongEun Kim3, Sung Min Kang2, Youngsoon Yang4, Young Chul Youn5, SangYun Kim6, 1Gachon University., Singnam-si, South Korea; 2PeopleBio Inc., Seoul, South Korea; 3Seoul National University, Bundang Hospital, Sungnam, South Korea; 4Veteran’s Hospital, Seoul, South Korea; 5 Department of Neurology, College of Medicine, Chung-Ang University, Seoul, South Korea; 6Seoul National University College of Medicine, Seoul National Bundang Hospital, Seongnam-si, Kyungki-do, South Korea. Background: The number of Alzheimer’s Diseases (AD) patients is exponentially increasing without ultimate cure or accurate diagnosis. Recently, imaging methods and CSF assay with triple markers could help diagnose AD and monitor the progression of the disease. However, the cost of these assays, confined availability of the materials, and invasiveness of CSF tap could limit a wide use for the early diagnosis and monitoring test.Originally, multimer detection system (MDS) was designed to detect specific oligomer form of pathologic prion protein in blood; in the mixture of pathologic and normal prion protein. After having developed the scrapie blood test, MDS was applied to AD diagnostics. Here, we present the preliminary data of MDS for detecting oligomers of beta amyloid in blood to diagnose AD, as MDS-AD-Blood.The objective of this study was to improve the sensitivity and specificity of the MDS-AD as a possible option for new AD blood diagnostics. Methods: We collected blood samples from 30 patients with probable AD, 15 with SMI, 20 of normal healthy control. MDS-AD-Blood was repeatedly done for these samples with modification of many fundamental experimental elements, as like antibodies, anticoagulant, incubation time, volume of samples, and buffers. Results: MDS-AD distinguished AD blood samples from normal samples with approximately 90 % sensitivity and specificity. Furthermore, MDS-AD detected the amyloid-beta oligomer
S747
from some patients’ samples with subjective memory impairment. Conclusions: The results from MDS-AD-Blood test suggested the possibility to be used for the early diagnostic test. Also, the development of the sensitive detection methods for Ab aggregates or oligomers in blood could be important for the therapeutic strategy and for the evaluation of the drugs, especially with upcoming releases of disease-modifying-drug candidates.
P4-253
HILAR GABAERGIC INTERNEURON ACTIVITY CONTROLS SPATIAL LEARNING AND MEMORY RETRIEVAL
Yaisa Andrews-Zwilling1, Anna Gillespie1, Alexxai Kravitz1, Alexandra Nelson1, Nino Devidze1, Iris Lo1, Seo Yeon Yoon1, Nga BienLy2, Karen Ring1, Daniel Zwilling1, Gregory Potter2, John Rubenstein2, Anatol Kreitzer1, Yadong Huang1, 1Gladstone Institute of Neurological Disease, San Francisco, California, United States; 2University of California, San Francisco, San Francisco, California, United States. Background: Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer’s disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. Methods: Using transgenic mice specifically expressing Cre recombinase in GABAergic inhibitory neurons, we explored the function of hilar GABAergic interneurons in spatial learning and memory. We inhibited their activity by Cre-depena lightdent viral expression of enhanced halorhodopsin (eNpHR3.0)Z during spatial learning and memory tests. Results: driven chloride pumpZ We found that, in GABAergic specific Cre mice injected with eNpHR3.0 virus in the hilus of the dentate gyrus, in vitro and in vivo illumination with yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in CA3 and CA1 regions of the hippocampus. Optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity. Conclusions: Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD. P4-254
PREDICTING BRAIN AMYLOIDOSIS IN MCI USING CLINICAL, COGNITIVE, IMAGING AND PERIPHERAL BLOOD PROTEIN MEASURES
Liana Apostolova1, Kristy Hwang1, Omid Kohannim1, Clifford Jack2, Leslie Shaw3, John Trojanowski4, Michael Weiner5, Paul Thompson6, 1 UCLA, Los Angeles, California, United States; 2Mayo Clinic, Rochester, Minnesota, United States; 3University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, United States; 4University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 5Center for Imaging of Neurodegenerative Diseases; VA Medical Center and UCSF, San Francisco, California, United States; 6UCLA, Los Angeles, California, United States. Background: Randomized, double-blind clinical trials for the latent stages of Alzheimer’s disease are now being planned. To identify enough amyloid positive cognitively normal subjects, these trials would need to screen tens of thousands of asymptomatic individuals using amyloid positron emission tomography (PET) imaging. Identifying people highly likely to be amyloidpositive without relying on amyloid PET could save time and resources. We investigated the accuracy of a novel unsupervised multimodal biomarker classifier for predicting brain amyloidosis in MCI subjects. By combining the predictive information of cognitive, imaging and peripheral blood protein biomarkers, we expected to achieve high accuracy in differentiating Pittsburgh compound B (PIB) positive (SUVR>1.6) from PIB negative (SUVR<1.6) subjects. Methods: Using the baseline cognitive, imaging
S748
Developing Topics: P4 Posters
and proteomic data of 60 ADNI MCI participants (mean age¼75.2 68.1, mean MMSE¼27.2 62.2) we developed automated unimodal and multimodal classifiers based on support vector machines. The pool of features provided to the classifiers included MMSE, Trails B, AVLT delayed recall, plasma levels of ApoE, BDNF, TNF alpha, IL13, IL6 and clusterin, and hippocampal volume. All classifiers included age and sex. Three separate classifiers were built to predict mean cortical, lateral parietal and precuneal SUVR as the outcome variable. Results: All classifiers consistently ranked ApoE genotype as the most powerful predictor of brain amyloidosis. ApoE genotype alone predicted brain amyloidosis with 75-77% accuracy (AUC¼0.67-0.75). When cognitive, imaging and peripheral blood protein variables were added, classifier performance improved. Greatest classifier accuracy in predicting PIB+ vs. PIB- subjects was seen for the lateral parietal (accuracy¼85%, AUC¼0.87) and precuneal regions (accuracy¼85%, AUC¼0.89). The variables selected by these classifiers included ApoE genotype, MMSE, Trails B, AVLT delayed recall, clusterin, TNF alpha and BDNF. The precuneal classifier also included IL13 and ApoE protein. The average cortical classifier used ApoE genotype, MMSE, Trails B, hippocampal volume, clusterin, BDNF and IL6 and achieved 80% accuracy (AUC¼0.81). Conclusions: Automated classifiers based on ApoE4 genotype, cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with high accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.
P4-255
DEVELOPING A NATIONAL INSTITUTIONAL REVIEW BOARD FOR NEURODEGENERATIVE DISEASES
Peter J. Snyder1, Maria Carrillo2, David S. Knopman3, Ara S. Khachaturian4, 1The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States; 2Alzheimer’s Association, Chicago, Illinois, United States; 3Mayo Clinic, Rochester, Minnesota, United States; 4The Campaign to Prevent Alzheimer’s Disease by 2020, Rockville, Maryland, United States. Background: Since World War II, federal governments across the globe have fostered vital and robust systems to safeguard the conduct of studies involving human participants. One of the important regulatory mechanisms to assure protection has been the development of the institutional review board (IRB). Although local community representation in the United States has been a key feature of IRB reviews for clinical research, more complex study designs often involving multiple research sites and extending over large geographical distances is complicating the review process. The problems associated with multisite IRB reviews are particularly relevant for neurodegenerative disease research. A key consensus recommendation to overcome this hurdle in the United States is the launch of a National Institutional Review Board for Neurodegenerative Diseases (NIRB-ND). The purpose of this new ethical oversight panel would be to increase the efficiency in the conduct of large-scale multi-site trials and to serve as an international model for global prevention studies. Methods: The Campaign to Prevent Alzheimer’s Disease by 2020, in partnership with the Alzheimer’s Association, the Alzheimer’s Disease Cooperative Study (ADCS), Mayo Clinic, Rhode Island Hospital and the Alpert Medical School of Brown University has assembled an advisory board comprising members from the National Institutes of Health, the Canadian Institutes for Health Research, academia and industry to provide technical oversight and opinion on several topics and functions related to the development and operation of the NIRBND. Results: The NIRB-ND be incorporated as a 501c(3) not-for-profit cor-
poration. The entity will provide centralized IRB services to support of all phases of clinical drug, device, and biologics development for national or multi-center studies as the IRB of record. The NIRB-ND will initially accept protocols for studies of Alzheimer’s disease, dementia, and related disorders effecting memory, movement and mood in late 2012. Conclusions: The NIRB-ND will build upon on the experiences of the National Cancer Institute and the NeuroNEXT central IRBs for prevention trials of neurodegenerative diseases. The project will explore the possibility of using facilitated review model in an international context with partnerships starting in Canada. P4-256
ASTROCYTES MAY DRIVE A BETA-AMYLOID CONTAGION IN HUMAN ALZHEIMER’S DISEASE BRAINS
Ilaria Dal Pra1, Anna Chiarini1, Balu Chakravarthy2, Raffaella Pacchiana1, Clara Bonafini1, James Whitfield2, Ubaldo Armato1, 1University of Verona Medical School, Verona, Italy; 2National Research Council of Canada, Ottawa, Ontario, Canada. Background: Reportedly, astrocytes gap-junctionally interconnected with neurons enwrap synapses to form “tripartite synapses” and their products directly impact on synaptic signalling. Until recently, astrocytes were thought to act just as janitors sweeping up any Ab peptides released by neurons in AD brains. Here, we present evidence that astrocytes’ role is much more complex and important as they are involved in the development of AD. Methods: Normal adult human astrocytes (NAHAs) isolated from tissue fragments of temporal lobe cortex of patients with perforating head trauma were set into cultures and used experimentally in their early passages. Cultures were treated with Ab(25-35) or reverse Ab(35-25) for up to 72 hrs. Protein lysates and conditioned growth media were sampled every 24 hrs. Ab(1-42) levels were assayed by immunoblotting in lysates and via ELISA in medium samples. UPS (ubiquitin-proteasome system) enzyme activities were assessed by standard biochemical methods. Results: The administration of the Ab(1-42) surrogate Ab(25-35) induced normal human adult astrocytes to produce and secrete significant amounts of Ab(1-42) peptides extracellularly. Reverse Ab(35-25) was instead totally inactive.This increased production/release of Ab peptides was due to a reduced activity of the UPS (ubiquitin-proteasome system) caused by an Ab(25-35)-stimulated CaSRs’ (Calcium-Sensing Receptors’) signaling. In fact, the calcilytic (CaSR-inhibitor) NPS-2143 agent reactivated the UPS activity, which destroyed the low molecular weight Ab peptides otherwise produced in excess and hence totally suppressed their extracellular secretion by the astrocytes. Conclusions: These results indicate that in AD brains the astrocytes are stimulated by exogenously accumulating Ab peptides to make Ab(1-42) and can dump these endogenous toxic oligomers directly onto the neuronal synapses they enwrap, triggering synaptic destruction. Indeed, we have shown that the Ab peptides released by astrocytes can kill neurons but not their astrocyte producers. Moreover, since there are 10 times more cerebral astrocytes than neurons, the Ab oligomers they hugely produce/release could, just like “infectious agents”, spread widely and "infect"increasing numbers of neurons and astrocytes, both of which would also start producing/releasing Ab. This self-sustaining mounting “contagion” may explain the inexorable advance of AD. Hence, calcilytics originally intended to cure osteoporosis would likely stop human AD progression. P4-257
CHANGES IN FMRI RESTING STATE FUNCTIONAL CONNECTIVITY IN RATS AFTER ACUTE AND REPEAT DOSING WITH PIOGLITAZONE
Karen Asin1, Donna Crenshaw2, Kirby Gottschalk2, Nanyin Zhang3, Zifeng Liang3, Allen Roses2, 1Takeda Global Research & Development Center, Inc., Deerfield, Illinois, United States; 2Zinfandel Pharmaceuticals, Inc., Research Triangle Park, North Carolina, United States; 3Center for Comparative Neuroimaging (CCNI), Worcester, Massachusetts, United States. Background: Pioglitazone HCl (PIO) is a thiazolidinedione (TZD) PPAR g receptor agonist used to treat type 2 diabetes (T2D). Accumulating evidence
DYSPHAGIA IN INDIVIDUALS WITH ALZHEIMER’S DISEASE: A SYSTEMATIC REVIEW OF THE EVIDENCE
Rebecca Affoo, Ruth Martin, Western University, London, Ontario, Canada. Background: Dementia is a syndrome that can be caused by a number of neurodegenerative disorders that affect memory, thinking, behavior, and the ability to perform activities of daily living. Alzheimer’s disease is the most common type of dementia and currently affects approximately 250,000 Canadians. Individuals with dementia of the Alzheimer’s type may experience swallowing impairment, or dysphagia, during the progression of the disease. Swallowing function is controlled in part by the parasympathetic branch of the autonomic nervous system. The primary objective of this study was to review studies of dysphagia in individuals with Alzheimer’s disease. Secondary objectives included identification and review of the literature concerning autonomic dysfunction in individuals with Alzheimer’s disease. Methods: Systematic searches of the PubMed, EBSCOhost, PsychINFO, Cochrane, EMBASE, and Scopus databases were completed. Search terms included dementia, Alzheimer’s disease, swallowing, deglutition disorders, autonomic nervous system, and parasympathetic nervous system. Published studies and grey literature describing dysphagia or autonomic dysfunction in the context of Alzheimer’s disease were identified. Studies were reviewed and organized into categories according to type. These categories included clinical reports, physiologic studies, and brain imaging studies. Results: The literature contains evidence that dementia of the Alzheimer’s type results in distinct dysphagia or dysautonomia profiles, even in the early stages of the disease process. Conclusions: Although the prevalence and incidence of dysphagia or dysautonomia in the Alzheimer’s population is unknown, there is preliminary evidence to suggest that dysphagia or autonomic dysfunction can occur in dementia of the Alzheimer’s type. P4-252
BLOOD ASSAY TO DETECT OLIGOMERIC BETAAMYLOID WITH HIGH SENSITIVITY AND SPECIFICITY
Seong An1, Kuntaek Lim2, Byoung Sub Lee2, Gwang Je Kim2, Ji Sun Yu2, JeongEun Kim3, Sung Min Kang2, Youngsoon Yang4, Young Chul Youn5, SangYun Kim6, 1Gachon University., Singnam-si, South Korea; 2PeopleBio Inc., Seoul, South Korea; 3Seoul National University, Bundang Hospital, Sungnam, South Korea; 4Veteran’s Hospital, Seoul, South Korea; 5 Department of Neurology, College of Medicine, Chung-Ang University, Seoul, South Korea; 6Seoul National University College of Medicine, Seoul National Bundang Hospital, Seongnam-si, Kyungki-do, South Korea. Background: The number of Alzheimer’s Diseases (AD) patients is exponentially increasing without ultimate cure or accurate diagnosis. Recently, imaging methods and CSF assay with triple markers could help diagnose AD and monitor the progression of the disease. However, the cost of these assays, confined availability of the materials, and invasiveness of CSF tap could limit a wide use for the early diagnosis and monitoring test.Originally, multimer detection system (MDS) was designed to detect specific oligomer form of pathologic prion protein in blood; in the mixture of pathologic and normal prion protein. After having developed the scrapie blood test, MDS was applied to AD diagnostics. Here, we present the preliminary data of MDS for detecting oligomers of beta amyloid in blood to diagnose AD, as MDS-AD-Blood.The objective of this study was to improve the sensitivity and specificity of the MDS-AD as a possible option for new AD blood diagnostics. Methods: We collected blood samples from 30 patients with probable AD, 15 with SMI, 20 of normal healthy control. MDS-AD-Blood was repeatedly done for these samples with modification of many fundamental experimental elements, as like antibodies, anticoagulant, incubation time, volume of samples, and buffers. Results: MDS-AD distinguished AD blood samples from normal samples with approximately 90 % sensitivity and specificity. Furthermore, MDS-AD detected the amyloid-beta oligomer
S747
from some patients’ samples with subjective memory impairment. Conclusions: The results from MDS-AD-Blood test suggested the possibility to be used for the early diagnostic test. Also, the development of the sensitive detection methods for Ab aggregates or oligomers in blood could be important for the therapeutic strategy and for the evaluation of the drugs, especially with upcoming releases of disease-modifying-drug candidates.
P4-253
HILAR GABAERGIC INTERNEURON ACTIVITY CONTROLS SPATIAL LEARNING AND MEMORY RETRIEVAL
Yaisa Andrews-Zwilling1, Anna Gillespie1, Alexxai Kravitz1, Alexandra Nelson1, Nino Devidze1, Iris Lo1, Seo Yeon Yoon1, Nga BienLy2, Karen Ring1, Daniel Zwilling1, Gregory Potter2, John Rubenstein2, Anatol Kreitzer1, Yadong Huang1, 1Gladstone Institute of Neurological Disease, San Francisco, California, United States; 2University of California, San Francisco, San Francisco, California, United States. Background: Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer’s disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear. Methods: Using transgenic mice specifically expressing Cre recombinase in GABAergic inhibitory neurons, we explored the function of hilar GABAergic interneurons in spatial learning and memory. We inhibited their activity by Cre-depena lightdent viral expression of enhanced halorhodopsin (eNpHR3.0)Z during spatial learning and memory tests. Results: driven chloride pumpZ We found that, in GABAergic specific Cre mice injected with eNpHR3.0 virus in the hilus of the dentate gyrus, in vitro and in vivo illumination with yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in CA3 and CA1 regions of the hippocampus. Optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity. Conclusions: Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD. P4-254
PREDICTING BRAIN AMYLOIDOSIS IN MCI USING CLINICAL, COGNITIVE, IMAGING AND PERIPHERAL BLOOD PROTEIN MEASURES
Liana Apostolova1, Kristy Hwang1, Omid Kohannim1, Clifford Jack2, Leslie Shaw3, John Trojanowski4, Michael Weiner5, Paul Thompson6, 1 UCLA, Los Angeles, California, United States; 2Mayo Clinic, Rochester, Minnesota, United States; 3University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, United States; 4University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States; 5Center for Imaging of Neurodegenerative Diseases; VA Medical Center and UCSF, San Francisco, California, United States; 6UCLA, Los Angeles, California, United States. Background: Randomized, double-blind clinical trials for the latent stages of Alzheimer’s disease are now being planned. To identify enough amyloid positive cognitively normal subjects, these trials would need to screen tens of thousands of asymptomatic individuals using amyloid positron emission tomography (PET) imaging. Identifying people highly likely to be amyloidpositive without relying on amyloid PET could save time and resources. We investigated the accuracy of a novel unsupervised multimodal biomarker classifier for predicting brain amyloidosis in MCI subjects. By combining the predictive information of cognitive, imaging and peripheral blood protein biomarkers, we expected to achieve high accuracy in differentiating Pittsburgh compound B (PIB) positive (SUVR>1.6) from PIB negative (SUVR<1.6) subjects. Methods: Using the baseline cognitive, imaging
S748
Developing Topics: P4 Posters
and proteomic data of 60 ADNI MCI participants (mean age¼75.2 68.1, mean MMSE¼27.2 62.2) we developed automated unimodal and multimodal classifiers based on support vector machines. The pool of features provided to the classifiers included MMSE, Trails B, AVLT delayed recall, plasma levels of ApoE, BDNF, TNF alpha, IL13, IL6 and clusterin, and hippocampal volume. All classifiers included age and sex. Three separate classifiers were built to predict mean cortical, lateral parietal and precuneal SUVR as the outcome variable. Results: All classifiers consistently ranked ApoE genotype as the most powerful predictor of brain amyloidosis. ApoE genotype alone predicted brain amyloidosis with 75-77% accuracy (AUC¼0.67-0.75). When cognitive, imaging and peripheral blood protein variables were added, classifier performance improved. Greatest classifier accuracy in predicting PIB+ vs. PIB- subjects was seen for the lateral parietal (accuracy¼85%, AUC¼0.87) and precuneal regions (accuracy¼85%, AUC¼0.89). The variables selected by these classifiers included ApoE genotype, MMSE, Trails B, AVLT delayed recall, clusterin, TNF alpha and BDNF. The precuneal classifier also included IL13 and ApoE protein. The average cortical classifier used ApoE genotype, MMSE, Trails B, hippocampal volume, clusterin, BDNF and IL6 and achieved 80% accuracy (AUC¼0.81). Conclusions: Automated classifiers based on ApoE4 genotype, cognitive and peripheral blood protein variables can identify the presence of brain amyloidosis with high accuracy. Such methods could have implications for clinical trial design and enrollment in the near future.
P4-255
DEVELOPING A NATIONAL INSTITUTIONAL REVIEW BOARD FOR NEURODEGENERATIVE DISEASES
Peter J. Snyder1, Maria Carrillo2, David S. Knopman3, Ara S. Khachaturian4, 1The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States; 2Alzheimer’s Association, Chicago, Illinois, United States; 3Mayo Clinic, Rochester, Minnesota, United States; 4The Campaign to Prevent Alzheimer’s Disease by 2020, Rockville, Maryland, United States. Background: Since World War II, federal governments across the globe have fostered vital and robust systems to safeguard the conduct of studies involving human participants. One of the important regulatory mechanisms to assure protection has been the development of the institutional review board (IRB). Although local community representation in the United States has been a key feature of IRB reviews for clinical research, more complex study designs often involving multiple research sites and extending over large geographical distances is complicating the review process. The problems associated with multisite IRB reviews are particularly relevant for neurodegenerative disease research. A key consensus recommendation to overcome this hurdle in the United States is the launch of a National Institutional Review Board for Neurodegenerative Diseases (NIRB-ND). The purpose of this new ethical oversight panel would be to increase the efficiency in the conduct of large-scale multi-site trials and to serve as an international model for global prevention studies. Methods: The Campaign to Prevent Alzheimer’s Disease by 2020, in partnership with the Alzheimer’s Association, the Alzheimer’s Disease Cooperative Study (ADCS), Mayo Clinic, Rhode Island Hospital and the Alpert Medical School of Brown University has assembled an advisory board comprising members from the National Institutes of Health, the Canadian Institutes for Health Research, academia and industry to provide technical oversight and opinion on several topics and functions related to the development and operation of the NIRBND. Results: The NIRB-ND be incorporated as a 501c(3) not-for-profit cor-
poration. The entity will provide centralized IRB services to support of all phases of clinical drug, device, and biologics development for national or multi-center studies as the IRB of record. The NIRB-ND will initially accept protocols for studies of Alzheimer’s disease, dementia, and related disorders effecting memory, movement and mood in late 2012. Conclusions: The NIRB-ND will build upon on the experiences of the National Cancer Institute and the NeuroNEXT central IRBs for prevention trials of neurodegenerative diseases. The project will explore the possibility of using facilitated review model in an international context with partnerships starting in Canada. P4-256
ASTROCYTES MAY DRIVE A BETA-AMYLOID CONTAGION IN HUMAN ALZHEIMER’S DISEASE BRAINS
Ilaria Dal Pra1, Anna Chiarini1, Balu Chakravarthy2, Raffaella Pacchiana1, Clara Bonafini1, James Whitfield2, Ubaldo Armato1, 1University of Verona Medical School, Verona, Italy; 2National Research Council of Canada, Ottawa, Ontario, Canada. Background: Reportedly, astrocytes gap-junctionally interconnected with neurons enwrap synapses to form “tripartite synapses” and their products directly impact on synaptic signalling. Until recently, astrocytes were thought to act just as janitors sweeping up any Ab peptides released by neurons in AD brains. Here, we present evidence that astrocytes’ role is much more complex and important as they are involved in the development of AD. Methods: Normal adult human astrocytes (NAHAs) isolated from tissue fragments of temporal lobe cortex of patients with perforating head trauma were set into cultures and used experimentally in their early passages. Cultures were treated with Ab(25-35) or reverse Ab(35-25) for up to 72 hrs. Protein lysates and conditioned growth media were sampled every 24 hrs. Ab(1-42) levels were assayed by immunoblotting in lysates and via ELISA in medium samples. UPS (ubiquitin-proteasome system) enzyme activities were assessed by standard biochemical methods. Results: The administration of the Ab(1-42) surrogate Ab(25-35) induced normal human adult astrocytes to produce and secrete significant amounts of Ab(1-42) peptides extracellularly. Reverse Ab(35-25) was instead totally inactive.This increased production/release of Ab peptides was due to a reduced activity of the UPS (ubiquitin-proteasome system) caused by an Ab(25-35)-stimulated CaSRs’ (Calcium-Sensing Receptors’) signaling. In fact, the calcilytic (CaSR-inhibitor) NPS-2143 agent reactivated the UPS activity, which destroyed the low molecular weight Ab peptides otherwise produced in excess and hence totally suppressed their extracellular secretion by the astrocytes. Conclusions: These results indicate that in AD brains the astrocytes are stimulated by exogenously accumulating Ab peptides to make Ab(1-42) and can dump these endogenous toxic oligomers directly onto the neuronal synapses they enwrap, triggering synaptic destruction. Indeed, we have shown that the Ab peptides released by astrocytes can kill neurons but not their astrocyte producers. Moreover, since there are 10 times more cerebral astrocytes than neurons, the Ab oligomers they hugely produce/release could, just like “infectious agents”, spread widely and "infect"increasing numbers of neurons and astrocytes, both of which would also start producing/releasing Ab. This self-sustaining mounting “contagion” may explain the inexorable advance of AD. Hence, calcilytics originally intended to cure osteoporosis would likely stop human AD progression. P4-257
CHANGES IN FMRI RESTING STATE FUNCTIONAL CONNECTIVITY IN RATS AFTER ACUTE AND REPEAT DOSING WITH PIOGLITAZONE
Karen Asin1, Donna Crenshaw2, Kirby Gottschalk2, Nanyin Zhang3, Zifeng Liang3, Allen Roses2, 1Takeda Global Research & Development Center, Inc., Deerfield, Illinois, United States; 2Zinfandel Pharmaceuticals, Inc., Research Triangle Park, North Carolina, United States; 3Center for Comparative Neuroimaging (CCNI), Worcester, Massachusetts, United States. Background: Pioglitazone HCl (PIO) is a thiazolidinedione (TZD) PPAR g receptor agonist used to treat type 2 diabetes (T2D). Accumulating evidence