Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease.

BACKGROUND Alzheimer disease (AD) is defined neuropathologically by the presence of neurofibrillary tangles and plaques associated with tau and beta-amyloid protein deposition. The colocalization of microglia and beta-amyloid plaques has been widely reported in pathological examination of AD and suggests that neuroinflammation may play a role in pathogenesis and/or progression. Because postmortem histopathological analyses are limited to single end-stage assessment, the time course and nature of this relationship are not well understood. OBJECTIVE To image microglial activation and beta-amyloid deposition in the brains of subjects with and without AD. DESIGN, SETTING, AND PARTICIPANTS Using two carbon 11 ([11C])-labeled positron emission tomographic imaging agents, Pittsburgh Compound B (PiB) and (R)-PK11195, we examined the relationship between amyloid deposition and microglial activation in different stages of AD using 5 control subjects, 6 subjects diagnosed with mild cognitive impairment, and 6 patients with mild to moderate AD. RESULTS Consistent with prior reports, subjects with a clinical diagnosis of probable AD showed significantly greater levels of [11C]PiB retention than control subjects, whereas patients with mild cognitive impairment spanned a range from control-like to AD-like levels of [11C]PiB retention. Additionally, 2 asymptomatic control subjects also exhibited evidence of elevated PiB retention in regions associated with the early emergence of plaques in AD and may represent prodromal cases of AD. We observed no differences in brain [11C](R)-PK11195 retention when subjects were grouped by clinical diagnosis or the presence or absence of beta-amyloid pathological findings as indicated by analyses of [11C]PiB retention. CONCLUSIONS These findings suggest that either microglial activation is limited to later stages of severe AD or [11C](R)-PK11195 is too insensitive to detect the level of microglial activation associated with mild to moderate AD.

[1]  B. Lopresti,et al.  The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: From pathology to imaging , 2006, Progress in Neurobiology.

[2]  T. Guilarte,et al.  Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS , 2005, Journal of NeuroVirology.

[3]  R. Butterworth,et al.  Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex , 1991, Neurobiology of Aging.

[4]  G. Reynolds,et al.  Increased peripheral benzodiazepine binding sites in the brain of patients with Huntington's disease , 1998, Neuroscience Letters.

[5]  J. Becker,et al.  Incidence of dementia in mild cognitive impairment in the cardiovascular health study cognition study. , 2007, Archives of neurology.

[6]  William E. Klunk,et al.  PK11195 labels activated microglia in Alzheimer's disease and in vivo in a mouse model using PET , 2009, Neurobiology of Aging.

[7]  N L Foster,et al.  PET of peripheral benzodiazepine binding sites in the microgliosis of Alzheimer's disease. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[8]  S. DeKosky,et al.  Kinetic Modeling of Amyloid Binding in Humans using PET Imaging and Pittsburgh Compound-B , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  P. Mcgeer,et al.  Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR , 1987, Neuroscience Letters.

[10]  Gina N. LaRossa,et al.  [11C]PIB in a nondemented population , 2006, Neurology.

[11]  J. Rabe-Jabłońska,et al.  [Affective disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association -- diagnostic and statistical manual of mental disorders]. , 1993, Psychiatria polska.

[12]  Ronald Boellaard,et al.  Evaluation of Reference Regions for (R)-[11C]PK11195 Studies in Alzheimer's Disease and Mild Cognitive Impairment , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[14]  K. Henke,et al.  Antibodies against β-Amyloid Slow Cognitive Decline in Alzheimer's Disease , 2003, Neuron.

[15]  Alexander Gerhard,et al.  Microglial activation in presymptomatic Huntington's disease gene carriers. , 2005, Brain : a journal of neurology.

[16]  Vincent J. Cunningham,et al.  Parametric Imaging of Ligand-Receptor Binding in PET Using a Simplified Reference Region Model , 1997, NeuroImage.

[17]  C. Holmes,et al.  Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report , 2003, Nature Medicine.

[18]  Roger N Gunn,et al.  In-vivo measurement of activated microglia in dementia , 2001, The Lancet.

[19]  K. Conant,et al.  Neurodegenerative disease and the neuroimmune axis (Alzheimer's and Parkinson's disease, and viral infections) , 2004, Journal of Neuroimmunology.

[20]  Patrick L. McGeer,et al.  Inflammatory processes in Alzheimer's disease , 2003, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[21]  O L Lopez,et al.  Research evaluation and diagnosis of probable Alzheimer’s disease over the last two decades: I , 2000, Neurology.

[22]  S. DeKosky,et al.  Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[23]  S. Wisniewski,et al.  PET imaging of brain macrophages using the peripheral benzodiazepine receptor in a macaque model of neuroAIDS. , 2004, The Journal of clinical investigation.

[24]  V. Chan‐Palay,et al.  Increased monoamine oxidase b activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography , 1994, Neuroscience.

[25]  Eric Achten,et al.  Assessment of Neuroinflammation and Microglial Activation in Alzheimer’s Disease with Radiolabelled PK11195 and Single Photon Emission Computed Tomography , 2003, European Neurology.

[26]  Michel Baudry,et al.  Systemic injection of kainic acid: Gliosis in olfactory and limbic brain regions quantified with [3H]PK 11195 binding autoradiography , 1990, Experimental Neurology.

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

[28]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease: Report of the NINCDS—ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease , 2011, Neurology.

[29]  I. Ferrer,et al.  Neuropathology and Pathogenesis of Encephalitis following Amyloid β Immunization in Alzheimer's Disease , 2004, Brain pathology.

[30]  S. Wisniewski,et al.  Research evaluation and diagnosis of possible Alzheimer’s disease over the last two decades: II , 2000, Neurology.

[31]  Paul Maruff,et al.  β-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease , 2007 .

[32]  H. Braak,et al.  Phases of Aβ-deposition in the human brain and its relevance for the development of AD , 2002, Neurology.

[33]  G. V. Van Hoesen,et al.  The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease. , 1991, Cerebral cortex.

[34]  Paul Maruff,et al.  Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease. , 2007, Brain : a journal of neurology.

[35]  Jeffrey A. James,et al.  Frequent amyloid deposition without significant cognitive impairment among the elderly. , 2008, Archives of neurology.

[36]  K. Henke,et al.  Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. , 2003, Neuron.

[37]  S. M. Sumi,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1991, Neurology.

[38]  C. Wiley,et al.  The high affinity peripheral benzodiazepine receptor ligand DAA1106 binds to activated and infected brain macrophages in areas of synaptic degeneration: Implications for PET imaging of neuroinflammation in lentiviral encephalitis , 2008, Neurobiology of Disease.

[39]  B. Hyman,et al.  Neuropathological changes in Down's syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. , 1995, Archives of neurology.