- Email: [email protected]
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Poster P2:: Monday Posters INTEGRATED METABOLIC AND NEUROPATHOLOGICAL ANALYSIS OF ALZHEIMER MOUSE BRAIN IN RESPONSE TO ANTI-INFLAMMATORY TREATMENT
Alpaslan Dedeoglu1, Ji-Kyung Choi2, Isabel Carreras3, Sukru Kaymakcalan1, Neil W. Kowall1, Bruce G. Jenkins2, 1Neurology, Boston University, Bedford VA Hospital, Boston, MA, USA; 2Radiology, MGH and Harvard Medical School, Boston, MA, USA; 3Biochemistry, Boston University, Bedford VA Hospital, Boston, MA, USA. Contact e-mail: [email protected] Introduction: Double transgenic mice (PSAPP) expressing mutant human amyloid precursor protein (APP695) and mutant human presenilin-1 (PS1) develop -amyloid (A) plaques throughout the cortex starting at 3 months of age. We examined the neurochemical profile of PSAPP brain by in vivo and in vitro magnetic resonance spectroscopy (NMR) and plaque distribution, size and number by immunohistochemistry. Methods: PSAPP mice were fed chow containing ibuprofen (375 ppm) or celecoxib (120 ppm) between the ages of 3 months to 6 months or 1 month to 18 months. At 6 or 18 months of age PSAPP-treated mice and controls, PSAPP-untreated and wild type mice, were anesthetized with halothane and scanned at 9.4T using T2-weighted imaging (TR/TE ⫽ 3.3/60 ms). Spectroscopy was run using a PRESS sequence with multiple TE values. Brains were then removed, one hemisphere was used to study plaque pathology and the other hemisphere was dissected and the cerebral cortex analyzed by in vitro NMR (600MHz spectra) and by ELISA for A levels. A plaque area and number were analyzed using Stereo Investigator (v 6.55), MicroBrightField and statistics calculated with Neurolucida Explorer. Results: There were significant increases in myo-inositol and glutamine and significant decreases in glutamate and NAA in the cerebral cortex of PSAPP transgenic mice at 18 months of age. Celecoxib significantly raised NAA levels and ibuprofen increased the glutamate. A1-40 and 42 stained plaque area correlated inversely with NAA. A42/40 ratio was altered by ibuprofen at 6 months of age. Discussion: As in human Alzheimer brains, increased brain levels of myo-inositol and decreased NAA levels are consistent with decreased healthy neuron and increased glia cells in PSAPP mouse brain. The significant inverse correlation between A plaque burden and NAA points to NAA as a pathological marker in this mouse model. Supported by: NIA (R21 AG025162-01A1), Alzheimer Association (NIRG 02 3563), Department of Veteran Affairs (Merit Award). P2-312
PET IMAGING OF MICROGLIA IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Sriram Venneti, Brian J. Lopresti, Guoji Wang, Chester A. Mathis, William E. Klunk, Aaron D. Shmookler, Ronald L. Hamilton, Udayan M. Apte, Clayton A. Wiley, University of Pittsburgh, Pittsburgh, PA, USA. Contact e-mail: [email protected] Background: The role of activated microglia in AD pathogenesis is not well understood. A immunization protocols in both animal models and humans have shown prominent microglial activation associated with amyloid clearance and phagocytosis. The ability to determine the extent of microglial activation in vivo could clarify the role of microglia in the pathogenesis of AD and immunization protocols. Objective: We investigated the feasibility of imaging activated microglia using Positron Emission Tomography (PET) by taking advantage of elevated levels of peripheral benzodiazepine receptor expression (PBR) on activated microglia. We tested the hypothesis that PK11195, a selective ligand to PBR, will specifically label activated microglia in vivo using PET in a mouse model of AD. Results: PK11195 binding to microglia was first characterized in vitro and in AD post mortem tissue using filtration binding assays. [H-3]PK11195 binding was significantly higher in lipopolysaccharide activated primary human microglia compared to unactivated microglia, activated astrocytes and unactivated astrocyte controls in culture (n⫽3, p⬍0.001). [H-3]PK11195 was then compared in AD and age matched
control brain tissue (5 AD and 5 controls). Tissue obtained from the frontal cortex showed significantly higher binding in AD than controls (p⫽0.0002). The cerebellum from AD cases did not show any significant difference compared to controls indicating that increased [H-3]PK11195 binding was specific to regions with AD pathology. [C-11]PK11195 microPET imaging was then performed in 7 control and 7 transgenic mice (13-20 mo.) expressing the APP Swedish and PSEN1 mutations (TG), after which mice were sacrificed to assess histopathology. TG mice showed a lesser degree of microglial activation as compared to AD postmortem tissue. However, 4 of the 7 transgenic mice showed moderately increased retention of [C-11]PK11195 in brain, which correlated positively with increasing age in TG mice. Conclusion: Our results indicate that the extent of microglial activation in these TG mice, as assessed by PET imaging and histopathology, is lower than that seen in AD postmortem tissue, suggesting that the neuroinflammatory process is different in TG models and AD. P2-313
PREVALENCE AND SEVERITY OF MICROBLEEDS IN A MEMORY CLINIC SETTING
Charlotte Cordonnier1,2, Wiesje M. van der Flier3, Jasper D. Sluimer4, Didier Leys1, Frederik Barkhof4, Philip Scheltens3, 1Lille University, Lille, France; 2Department of Neurology and Alzheimer Center, VU Medical Center, Amsterdam, The Netherlands; 3Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands; 4Department of Radiology and Image Analysis Center, VU University Medical Center, Amsterdam, The Netherlands. Contact e-mail: [email protected] Objective: To determine prevalence and severity of microbleeds (MBs) in a large cohort of patients attending a memory clinic. Methods: We consecutively included patients attending our memory clinic, between January 2002 and April 2005. We analyzed prevalence and number of MBs according to demographic, diagnostic and MRI data. Results: We included 772 patients (53% men, age 66 ⫾11). One hundred and twenty-seven patients (17%) exhibited at least 1 MB. The prevalence differed according to diagnostic groups (p⬍0.0001): 65% of patients with vascular dementia exhibited MBs versus 18% of Alzheimer (AD) patients, 20% of mild cognitive impairment (MCI), and 10% in patients with subjective complaints. The presence of MBs was associated with age, white matter hyperintensities, lacunar infarcts and infarcts. Conclusions: The prevalence of MBs in a large cohort of patients attending a memory clinic is higher than previously described in community samples and lower than reported in stroke patients. Our finding of a relatively high proportion of MBs in AD and MCI provides further evidence for the involvement of vascular factors in neurodegenerative diseases such as AD. P2-314
HYPOMETABOLISM PRECEDES VOLUME LOSS IN PRESYMPTOMATIC INDIVIDUALS WITH EARLY-ONSET FAMILIAL ALZHEIMER’S DISEASE
Lisa Mosconi1, Alberto Pupi2, Mony de Leon1, Yi Li1, Benedetta Nacmias2, Susan De Santi1, Wai Tsui1, Paul Myoung1, Valentina Bessi2, Mozghan Fayyaz2, Mario Mascalchi2, Sandro Sorbi2, 1 New York University School of Medicine, New York, NY, USA; 2 University of Florence, Florence, Italy. Contact e-mail: [email protected] Background: The aim of the present study is to compare brain atrophy to hypometabolism as preclinical markers of AD by studying presymptomatic individuals from families with early-onset autosomal dominant AD (FAD) carrying mutations in the Presinilin-1 gene. FAD individuals near to the anticipated age of onset may be expected to be in a presymptomatic stage of the disease, providing unique information about preclinical AD-related brain changes. Objective: By using MRI and FDG-PET imaging, the present study compares FAD to age-matched normal non-carrier individuals to examine the hypothesis that the earliest signs of future AD can be found as alterations in brain glucose metabolism (MRglc). Methods:
Poster P2:: Monday Posters INTEGRATED METABOLIC AND NEUROPATHOLOGICAL ANALYSIS OF ALZHEIMER MOUSE BRAIN IN RESPONSE TO ANTI-INFLAMMATORY TREATMENT
Alpaslan Dedeoglu1, Ji-Kyung Choi2, Isabel Carreras3, Sukru Kaymakcalan1, Neil W. Kowall1, Bruce G. Jenkins2, 1Neurology, Boston University, Bedford VA Hospital, Boston, MA, USA; 2Radiology, MGH and Harvard Medical School, Boston, MA, USA; 3Biochemistry, Boston University, Bedford VA Hospital, Boston, MA, USA. Contact e-mail: [email protected] Introduction: Double transgenic mice (PSAPP) expressing mutant human amyloid precursor protein (APP695) and mutant human presenilin-1 (PS1) develop -amyloid (A) plaques throughout the cortex starting at 3 months of age. We examined the neurochemical profile of PSAPP brain by in vivo and in vitro magnetic resonance spectroscopy (NMR) and plaque distribution, size and number by immunohistochemistry. Methods: PSAPP mice were fed chow containing ibuprofen (375 ppm) or celecoxib (120 ppm) between the ages of 3 months to 6 months or 1 month to 18 months. At 6 or 18 months of age PSAPP-treated mice and controls, PSAPP-untreated and wild type mice, were anesthetized with halothane and scanned at 9.4T using T2-weighted imaging (TR/TE ⫽ 3.3/60 ms). Spectroscopy was run using a PRESS sequence with multiple TE values. Brains were then removed, one hemisphere was used to study plaque pathology and the other hemisphere was dissected and the cerebral cortex analyzed by in vitro NMR (600MHz spectra) and by ELISA for A levels. A plaque area and number were analyzed using Stereo Investigator (v 6.55), MicroBrightField and statistics calculated with Neurolucida Explorer. Results: There were significant increases in myo-inositol and glutamine and significant decreases in glutamate and NAA in the cerebral cortex of PSAPP transgenic mice at 18 months of age. Celecoxib significantly raised NAA levels and ibuprofen increased the glutamate. A1-40 and 42 stained plaque area correlated inversely with NAA. A42/40 ratio was altered by ibuprofen at 6 months of age. Discussion: As in human Alzheimer brains, increased brain levels of myo-inositol and decreased NAA levels are consistent with decreased healthy neuron and increased glia cells in PSAPP mouse brain. The significant inverse correlation between A plaque burden and NAA points to NAA as a pathological marker in this mouse model. Supported by: NIA (R21 AG025162-01A1), Alzheimer Association (NIRG 02 3563), Department of Veteran Affairs (Merit Award). P2-312
PET IMAGING OF MICROGLIA IN A MOUSE MODEL OF ALZHEIMER’S DISEASE
Sriram Venneti, Brian J. Lopresti, Guoji Wang, Chester A. Mathis, William E. Klunk, Aaron D. Shmookler, Ronald L. Hamilton, Udayan M. Apte, Clayton A. Wiley, University of Pittsburgh, Pittsburgh, PA, USA. Contact e-mail: [email protected] Background: The role of activated microglia in AD pathogenesis is not well understood. A immunization protocols in both animal models and humans have shown prominent microglial activation associated with amyloid clearance and phagocytosis. The ability to determine the extent of microglial activation in vivo could clarify the role of microglia in the pathogenesis of AD and immunization protocols. Objective: We investigated the feasibility of imaging activated microglia using Positron Emission Tomography (PET) by taking advantage of elevated levels of peripheral benzodiazepine receptor expression (PBR) on activated microglia. We tested the hypothesis that PK11195, a selective ligand to PBR, will specifically label activated microglia in vivo using PET in a mouse model of AD. Results: PK11195 binding to microglia was first characterized in vitro and in AD post mortem tissue using filtration binding assays. [H-3]PK11195 binding was significantly higher in lipopolysaccharide activated primary human microglia compared to unactivated microglia, activated astrocytes and unactivated astrocyte controls in culture (n⫽3, p⬍0.001). [H-3]PK11195 was then compared in AD and age matched
control brain tissue (5 AD and 5 controls). Tissue obtained from the frontal cortex showed significantly higher binding in AD than controls (p⫽0.0002). The cerebellum from AD cases did not show any significant difference compared to controls indicating that increased [H-3]PK11195 binding was specific to regions with AD pathology. [C-11]PK11195 microPET imaging was then performed in 7 control and 7 transgenic mice (13-20 mo.) expressing the APP Swedish and PSEN1 mutations (TG), after which mice were sacrificed to assess histopathology. TG mice showed a lesser degree of microglial activation as compared to AD postmortem tissue. However, 4 of the 7 transgenic mice showed moderately increased retention of [C-11]PK11195 in brain, which correlated positively with increasing age in TG mice. Conclusion: Our results indicate that the extent of microglial activation in these TG mice, as assessed by PET imaging and histopathology, is lower than that seen in AD postmortem tissue, suggesting that the neuroinflammatory process is different in TG models and AD. P2-313
PREVALENCE AND SEVERITY OF MICROBLEEDS IN A MEMORY CLINIC SETTING
Charlotte Cordonnier1,2, Wiesje M. van der Flier3, Jasper D. Sluimer4, Didier Leys1, Frederik Barkhof4, Philip Scheltens3, 1Lille University, Lille, France; 2Department of Neurology and Alzheimer Center, VU Medical Center, Amsterdam, The Netherlands; 3Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands; 4Department of Radiology and Image Analysis Center, VU University Medical Center, Amsterdam, The Netherlands. Contact e-mail: [email protected] Objective: To determine prevalence and severity of microbleeds (MBs) in a large cohort of patients attending a memory clinic. Methods: We consecutively included patients attending our memory clinic, between January 2002 and April 2005. We analyzed prevalence and number of MBs according to demographic, diagnostic and MRI data. Results: We included 772 patients (53% men, age 66 ⫾11). One hundred and twenty-seven patients (17%) exhibited at least 1 MB. The prevalence differed according to diagnostic groups (p⬍0.0001): 65% of patients with vascular dementia exhibited MBs versus 18% of Alzheimer (AD) patients, 20% of mild cognitive impairment (MCI), and 10% in patients with subjective complaints. The presence of MBs was associated with age, white matter hyperintensities, lacunar infarcts and infarcts. Conclusions: The prevalence of MBs in a large cohort of patients attending a memory clinic is higher than previously described in community samples and lower than reported in stroke patients. Our finding of a relatively high proportion of MBs in AD and MCI provides further evidence for the involvement of vascular factors in neurodegenerative diseases such as AD. P2-314
HYPOMETABOLISM PRECEDES VOLUME LOSS IN PRESYMPTOMATIC INDIVIDUALS WITH EARLY-ONSET FAMILIAL ALZHEIMER’S DISEASE
Lisa Mosconi1, Alberto Pupi2, Mony de Leon1, Yi Li1, Benedetta Nacmias2, Susan De Santi1, Wai Tsui1, Paul Myoung1, Valentina Bessi2, Mozghan Fayyaz2, Mario Mascalchi2, Sandro Sorbi2, 1 New York University School of Medicine, New York, NY, USA; 2 University of Florence, Florence, Italy. Contact e-mail: [email protected] Background: The aim of the present study is to compare brain atrophy to hypometabolism as preclinical markers of AD by studying presymptomatic individuals from families with early-onset autosomal dominant AD (FAD) carrying mutations in the Presinilin-1 gene. FAD individuals near to the anticipated age of onset may be expected to be in a presymptomatic stage of the disease, providing unique information about preclinical AD-related brain changes. Objective: By using MRI and FDG-PET imaging, the present study compares FAD to age-matched normal non-carrier individuals to examine the hypothesis that the earliest signs of future AD can be found as alterations in brain glucose metabolism (MRglc). Methods: