Microglial activation in Alzheimer's disease: an (R)-[11C]PK11195 positron emission tomography study

UNLABELLED Inflammatory mechanisms, like microglial activation, could be involved in the pathogenesis of Alzheimer's disease (AD). (R)-[(11)C]PK11195 (1-(2-chlorophenyl)-N-methyl-N-1(1-methylpropyl)-3-isoquinolinecarboxamide), a positron emission tomography (PET) ligand, can be used to quantify microglial activation in vivo. The purpose of this study was to assess whether increased (R)-[(11)C]PK11195 binding is present in AD and mild cognitive impairment (MCI), currently also known as "prodromal AD." METHODS Nineteen patients with probable AD, 10 patients with prodromal AD (MCI), and 21 healthy control subjects were analyzed. Parametric images of binding potential (BP(ND)) of (R)-[(11)C]PK11195 scans were generated using receptor parametric mapping (RPM) with supervised cluster analysis. Differences between subject groups were tested using mixed model analysis, and associations between BP(ND) and cognition were evaluated using Pearson correlation coefficients. RESULTS Voxel-wise statistical parametric mapping (SPM) analysis showed small clusters of significantly increased (R)-[(11)C]PK11195 BP(ND) in occipital lobe in AD dementia patients compared with healthy control subjects. Regions of interest (ROI)-based analyses showed no differences, with large overlap between groups. There were no differences in (R)-[(11)C]PK11195 BP(ND) between clinically stable prodromal AD patients and those who progressed to dementia, and BP(ND) did not correlate with cognitive function. CONCLUSION Microglial activation is a subtle phenomenon occurring in AD.

[1]  C. Duyckaerts,et al.  Microglia, amyloid and dementia in Alzheimer disease A correlative study , 2000, Neurobiology of Aging.

[2]  D. Holtzman,et al.  Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease , 2008, Nature.

[3]  H. Malcolm Hudson,et al.  Accelerated image reconstruction using ordered subsets of projection data , 1994, IEEE Trans. Medical Imaging.

[4]  Janet B W Williams.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[5]  M. V. van Breemen,et al.  Amyloid beta plaque-associated proteins C1q and SAP enhance the Abeta1-42 peptide-induced cytokine secretion by adult human microglia in vitro. , 2003, Acta neuropathologica.

[6]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[7]  Martin Rossor,et al.  Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study , 2008, Neurobiology of Disease.

[8]  Gerald Q. Maguire,et al.  Comparison and evaluation of retrospective intermodality brain image registration techniques. , 1997, Journal of computer assisted tomography.

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

[10]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[11]  Ronald Boellaard,et al.  Evaluation of Methods for Generating Parametric (R)-[11C]PK11195 Binding Images , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  E. Walker,et al.  Diagnostic and Statistical Manual of Mental Disorders , 2013 .

[13]  Vladimir V. Frolkis,et al.  Neurobiology of Aging , 2019, Psychobiology of Behaviour.

[14]  A. Lammertsma,et al.  Monitoring response to therapy in cancer using [18F]-2-fluoro-2-deoxy-d-glucose and positron emission tomography: an overview of different analytical methods , 2000, European Journal of Nuclear Medicine.

[15]  Tony Wyss-Coray,et al.  Inflammation in Alzheimer disease: driving force, bystander or beneficial response? , 2006, Nature Medicine.

[16]  E. Tangalos,et al.  Neuropathologic features of amnestic mild cognitive impairment. , 2006, Archives of neurology.

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

[18]  Nick C Fox,et al.  Revising the definition of Alzheimer's disease: a new lexicon , 2010, The Lancet Neurology.

[19]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

[20]  Ronald Boellaard,et al.  Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[11C]PK11195 brain PET studies , 2012, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  Mark Lubberink,et al.  In vivo Validation of Reconstruction-Based Resolution Recovery for Human Brain Studies , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[22]  Dick J. Veltman,et al.  SPM analysis of parametric (R)-[11C]PK11195 binding images: Plasma input versus reference tissue parametric methods , 2007, NeuroImage.

[23]  J. Morris,et al.  Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease , 1999, Annals of neurology.

[24]  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.

[25]  Frederik Barkhof,et al.  Microglial activation in healthy aging , 2012, Neurobiology of Aging.

[26]  W. Scheper,et al.  Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease , 2005, Journal of Neuroinflammation.

[27]  M. V. van Breemen,et al.  Amyloid β plaque-associated proteins C1q and SAP enhance the Aβ1–42 peptide-induced cytokine secretion by adult human microglia in vitro , 2003, Acta Neuropathologica.

[28]  E. Tangalos,et al.  Mild Cognitive Impairment Clinical Characterization and Outcome , 1999 .

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

[30]  F. Turkheimer,et al.  Reference and target region modeling of [11C]-(R)-PK11195 brain studies. , 2007, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[31]  J. Price,et al.  Mild cognitive impairment represents early-stage Alzheimer disease. , 2001, Archives of neurology.

[32]  Olaf B. Paulson,et al.  MR-based automatic delineation of volumes of interest in human brain PET images using probability maps , 2005, NeuroImage.

[33]  C. Plata-salamán,et al.  Inflammation and Alzheimer’s disease , 2000, Neurobiology of Aging.

[34]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[35]  F. Barkhof,et al.  New Research Criteria for the Diagnosis of Alzheimer’s Disease Applied in a Memory Clinic Population , 2010, Dementia and Geriatric Cognitive Disorders.

[36]  P. Eikelenboom,et al.  Microglial cells around amyloid plaques in Alzheimer's disease express leucocyte adhesion molecules of the LFA-1 family , 1989, Neuroscience Letters.

[37]  S. Hume,et al.  Synthesis of the enantiomers of [N-methyl-11C]PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats. , 1994, Nuclear medicine and biology.

[38]  G Brix,et al.  Performance evaluation of a whole-body PET scanner using the NEMA protocol. National Electrical Manufacturers Association. , 1997, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[39]  Guy Marchal,et al.  Multimodality image registration by maximization of mutual information , 1997, IEEE Transactions on Medical Imaging.

[40]  R. Petersen.  Mild cognitive impairment as a diagnostic entity , 2004, Journal of internal medicine.

[41]  PROCEssIng magazInE.  IEEE Signal Processing Magazine , 2004 .

[42]  Bin Zhang,et al.  Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model , 2007, Neuron.

[43]  D. Perani,et al.  Faculty Opinions recommendation of Microglial activation and amyloid deposition in mild cognitive impairment: a PET study. , 2009 .

[44]  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.

[45]  D. Nutt,et al.  Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. , 2006, Trends in pharmacological sciences.

[46]  G. Muehllehner,et al.  Positron emission tomography , 2006, Physics in medicine and biology.

[47]  J Nucl Med , 2010 .

[48]  David J. Schlyer,et al.  Graphical Analysis of Reversible Radioligand Binding from Time—Activity Measurements Applied to [N-11C-Methyl]-(−)-Cocaine PET Studies in Human Subjects , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[49]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

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

[51]  B. Gelman,et al.  Microglial Cell Activation in Aging and Alzheimer Disease: Partial Linkage with Neurofibrillary Tangle Burden in the Hippocampus , 1997, Journal of neuropathology and experimental neurology.

[52]  Julie Price,et al.  Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. , 2009, Archives of neurology.

[53]  Mitsuru Kikuchi,et al.  In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease , 2011, European Journal of Nuclear Medicine and Molecular Imaging.