[F-18]FDDNP microPET imaging correlates with brain Aβ burden in a transgenic rat model of Alzheimer disease: Effects of aging, in vivo blockade, and anti-Aβ antibody treatment

In vivo detection of Alzheimer's disease (AD) neuropathology in living patients using positron emission tomography (PET) in conjunction with high affinity molecular imaging probes for β-amyloid (Aβ) and tau has the potential to assist with early diagnosis, evaluation of disease progression, and assessment of therapeutic interventions. Animal models of AD are valuable for exploring the in vivo binding of these probes, particularly their selectivity for specific neuropathologies, but prior PET experiments in transgenic mice have yielded conflicting results. In this work, we utilized microPET imaging in a transgenic rat model of brain Aβ deposition to assess [F-18]FDDNP binding profiles in relation to age-associated accumulation of neuropathology. Cross-sectional and longitudinal imaging demonstrated that [F-18]FDDNP binding in the hippocampus and frontal cortex progressively increases from 9 to 18months of age and parallels age-associated Aβ accumulation. Specificity of in vivo [F-18]FDDNP binding was assessed by naproxen pretreatment, which reversibly blocked [F-18]FDDNP binding to Aβ aggregrates. Both [F-18]FDDNP microPET imaging and neuropathological analyses revealed decreased Aβ burden after intracranial anti-Aβ antibody administration. The combination of this non-invasive imaging method and robust animal model of brain Aβ accumulation allows for future longitudinal in vivo assessments of potential therapeutics for AD that target Aβ production, aggregation, and/or clearance. These results corroborate previous analyses of [F-18]FDDNP PET imaging in clinical populations.

[1]  M. Staufenbiel,et al.  Comparative Analysis of Amyloid-β Chemical Structure and Amyloid Plaque Morphology of Transgenic Mouse and Alzheimer's Disease Brains* , 2001, The Journal of Biological Chemistry.

[2]  Takashi Morihara,et al.  Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model , 2004, Neuron.

[3]  Juan C. Troncoso,et al.  Limited Clearance of Pre-Existing Amyloid Plaques After Intracerebral Injection of Aβ Antibodies in Two Mouse Models of Alzheimer Disease , 2008, Journal of neuropathology and experimental neurology.

[4]  C. Kuntner,et al.  Limitations of Small Animal PET Imaging with [18F]FDDNP and FDG for Quantitative Studies in a Transgenic Mouse Model of Alzheimer’s Disease , 2009, Molecular Imaging and Biology.

[5]  Kiralee M. Hayashi,et al.  Plaque and tangle imaging and cognition in normal aging and Alzheimer's disease , 2010, Neurobiology of Aging.

[6]  Nelleke Tolboom,et al.  Evaluation of Tracer Kinetic Models for Analysis of [18F]FDDNP Studies , 2009, Molecular Imaging and Biology.

[7]  G. Cole,et al.  Mechanisms of action of non-steroidal anti-inflammatory drugs for the prevention of Alzheimer's disease. , 2010, CNS & neurological disorders drug targets.

[8]  Arthur W. Toga,et al.  A 3D digital map of rat brain , 1995, Brain Research Bulletin.

[9]  W. M. van der Flier,et al.  Molecular imaging in the diagnosis of Alzheimer's disease: visual assessment of [11C]PIB and [18F]FDDNP PET images , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[10]  V. Kepe,et al.  In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile , 2003, Neuroscience.

[11]  J. Barrio,et al.  Correlation of brain amyloid with “aerobic glycolysis”: A question of assumptions? , 2010, Proceedings of the National Academy of Sciences.

[12]  K. Ashe,et al.  Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease , 2000, The Journal of Neuroscience.

[13]  James Robert Brašić,et al.  In Vivo Imaging of Amyloid Deposition in Alzheimer Disease Using the Radioligand 18F-AV-45 (Flobetapir F 18) , 2010, Journal of Nuclear Medicine.

[14]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[15]  E. Salmon,et al.  18F‐flutemetamol amyloid imaging in Alzheimer disease and mild cognitive impairment: A phase 2 trial , 2010, Annals of neurology.

[16]  Patrick L Chow,et al.  A method of image registration for small animal, multi-modality imaging , 2006, Physics in medicine and biology.

[17]  Nelleke Tolboom,et al.  Peripheral metabolism of [(18)F]FDDNP and cerebral uptake of its labelled metabolites. , 2008, Nuclear medicine and biology.

[18]  S. DeKosky,et al.  Binding of the Positron Emission Tomography Tracer Pittsburgh Compound-B Reflects the Amount of Amyloid-β in Alzheimer's Disease Brain But Not in Transgenic Mouse Brain , 2005, The Journal of Neuroscience.

[19]  Yu-Min Kuo,et al.  APP Transgenic Mice Tg2576 Accumulate Aβ Peptides That Are Distinct from the Chemically Modified and Insoluble Peptides Deposited in Alzheimer's Disease Senile Plaques† , 2002 .

[20]  D. Thakker,et al.  Intracerebroventricular amyloid-β antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice , 2009, Proceedings of the National Academy of Sciences.

[21]  J. Mazziotta,et al.  3-(2'-[18F]Fluoroethyl)Spiperone: In vivo Biochemical and Kinetic Characterization in Rodents, Nonhuman Primates, and Humans , 1989, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[22]  Manuel Buttini,et al.  Morphological characterization of Thioflavin-S-positive amyloid plaques in transgenic Alzheimer mice and effect of passive Abeta immunotherapy on their clearance. , 2004, The American journal of pathology.

[23]  Mark A Mintun,et al.  Absence of Pittsburgh compound B detection of cerebral amyloid beta in a patient with clinical, cognitive, and cerebrospinal fluid markers of Alzheimer disease: a case report. , 2009, Archives of neurology.

[24]  J. Thie.  Understanding the standardized uptake value, its methods, and implications for usage. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[25]  A. Luxen,et al.  Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[26]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[27]  Nick C Fox,et al.  11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study , 2010, The Lancet Neurology.

[28]  C. Rowe,et al.  Imaging of amyloid β in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism , 2008, The Lancet Neurology.

[29]  Alan A. Wilson,et al.  In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. , 2004, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[30]  Vladimir Kepe,et al.  High-Yield, Automated Radiosynthesis of 2-(1-{6-[(2-[18F]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP) Ready for Animal or Human Administration , 2006, Molecular Imaging and Biology.

[31]  P. Thompson,et al.  PET of brain amyloid and tau in mild cognitive impairment. , 2006, The New England journal of medicine.

[32]  Michael V. Green,et al.  PET imaging of brain with the β-amyloid probe, [11C]6-OH-BTA-1, in a transgenic mouse model of Alzheimer’s disease , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[33]  C. Rowe,et al.  Imaging β-amyloid burden in aging and dementia , 2007, Neurology.

[34]  Keith A. Johnson,et al.  Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report. , 2007, Archives of neurology.

[35]  D. Flood,et al.  A transgenic rat model of Alzheimer's disease with extracellular Aβ deposition , 2009, Neurobiology of Aging.

[36]  C. Jack,et al.  Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer's disease: implications for sequence of pathological events in Alzheimer's disease , 2009, Brain : a journal of neurology.

[37]  T Greitz,et al.  Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Fusheng Yang,et al.  Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo* , 2005, Journal of Biological Chemistry.

[39]  Claudia Kuntner,et al.  Multimodality Rodent Imaging Chambers for Use Under Barrier Conditions with Gas Anesthesia , 2009, Molecular Imaging and Biology.

[40]  David H. Cribbs,et al.  Aβ Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome , 2004, Neuron.

[41]  Sanjiv Sam Gambhir,et al.  AMIDE: a free software tool for multimodality medical image analysis. , 2003, Molecular imaging.

[42]  Vladimir Kepe,et al.  Specific estrogen sulfotransferase (SULT1E1) substrates and molecular imaging probe candidates , 2010, Proceedings of the National Academy of Sciences.

[43]  S. Siegel,et al.  Performance evaluation of the microPET focus: a third-generation microPET scanner dedicated to animal imaging. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[44]  Dave Morgan,et al.  Intracranially Administered Anti-Αβ Antibodies Reduce β-Amyloid Deposition by Mechanisms Both Independent of and Associated with Microglial Activation , 2003, The Journal of Neuroscience.

[45]  Ottavio Arancio,et al.  A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment , 2008, Neurobiology of Disease.

[46]  Patrick L Chow,et al.  Attenuation correction for small animal PET tomographs , 2005, Physics in medicine and biology.

[47]  G. Small,et al.  Binding Characteristics of Radiofluorinated 6-Dialkylamino-2-Naphthylethylidene Derivatives as Positron Emission Tomography Imaging Probes for β-Amyloid Plaques in Alzheimer's Disease , 2001, The Journal of Neuroscience.

[48]  W. M. van der Flier,et al.  Detection of Alzheimer Pathology In Vivo Using Both 11C-PIB and 18F-FDDNP PET , 2009, Journal of Nuclear Medicine.

[49]  G. Cole,et al.  The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse , 2001, The Journal of Neuroscience.

[50]  Paul M. Thompson,et al.  Fddnp Binding Using Mr Derived Cortical Surface Maps , 2022 .

[51]  G. Small,et al.  Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease. , 2002, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[52]  S. DeKosky,et al.  Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease , 2008, Brain : a journal of neurology.

[53]  Tetsuya Suhara,et al.  Longitudinal, Quantitative Assessment of Amyloid, Neuroinflammation, and Anti-Amyloid Treatment in a Living Mouse Model of Alzheimer's Disease Enabled by Positron Emission Tomography , 2007, The Journal of Neuroscience.

[54]  W. Klunk,et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B , 2004, Annals of neurology.