Amyloid-beta Positron Emission Tomography Imaging Probes: A Critical Review

The rapidly rising prevalence and cost of Alzheimer’s disease (AD) in recent decades has made the imaging of amyloid- β (A β ) deposits the focus of intense research. Several amyloid imaging probes with purported specificity for A β plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available “amyloid specific” PET imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients.

[1]  C. Jack,et al.  Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers , 2013, The Lancet Neurology.

[2]  Florian Auer,et al.  White matter hyperintensities predict amyloid increase in Alzheimer's disease , 2012, Neurobiology of Aging.

[3]  K. Blennow,et al.  Safety and tolerability of the γ-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. , 2012, Archives of neurology.

[4]  S. Minoshima,et al.  2012 SNM Highlights Lectures. , 2012, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[5]  Keith A. Johnson,et al.  Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy , 2012, Neurology.

[6]  L. Chew,et al.  The Toxicity of Amyloid β Oligomers , 2012, International journal of molecular sciences.

[7]  K. Jellinger,et al.  Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature , 2012, Journal of neuropathology and experimental neurology.

[8]  C. Rowe,et al.  Subacute Ischemic Stroke Is Associated With Focal 11C PiB Positron Emission Tomography Retention But Not With Global Neocortical A&bgr; Deposition , 2012, Stroke.

[9]  Peiying Liu,et al.  Comparison of relative cerebral blood flow maps using pseudo‐continuous arterial spin labeling and single photon emission computed tomography , 2012, NMR in biomedicine.

[10]  Lin Zhu,et al.  Study the pharmacokinetics of AV-45 in rat plasma and metabolism in liver microsomes by ultra-performance liquid chromatography with mass spectrometry. , 2012, Biomedical chromotography.

[11]  Clifford R. Jack,et al.  Ante mortem amyloid imaging and β-amyloid pathology in a case with dementia with Lewy bodies , 2012, Neurobiology of Aging.

[12]  C. Rowe,et al.  Comparison of 11C-PiB and 18F-florbetaben for Aβ imaging in ageing and Alzheimer’s disease , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[13]  Christer Halldin,et al.  Clinical Validation of 18F-AZD4694, an Amyloid-β–Specific PET Radioligand , 2012, The Journal of Nuclear Medicine.

[14]  G. Logroscino,et al.  Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies. , 2012, Immunotherapy.

[15]  A. Alavi,et al.  Amyloid-β imaging with PET in Alzheimer’s disease: is it feasible with current radiotracers and technologies? , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[16]  O. Lopez,et al.  Early AD pathology in a [C-11]PiB-negative case: a PiB-amyloid imaging, biochemical, and immunohistochemical study , 2012, Acta Neuropathologica.

[17]  Keith A. Johnson,et al.  Aβ Imaging: feasible, pertinent, and vital to progress in Alzheimer’s disease , 2012, European Journal of Nuclear Medicine and Molecular Imaging.

[18]  Jacob K. Greenberg,et al.  Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy , 2011, Molecular Neurodegeneration.

[19]  J. Trojanowski,et al.  Association between in vivo fluorine 18-labeled flutemetamol amyloid positron emission tomography imaging and in vivo cerebral cortical histopathology. , 2011, Archives of neurology.

[20]  Kewei Chen,et al.  Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease. , 2011, Archives of neurology.

[21]  David Eisenberg,et al.  Towards a Pharmacophore for Amyloid , 2011, PLoS biology.

[22]  Mark A. Mintun,et al.  Florbetapir-PET Imaging and Postmortem β-Amyloid Pathology—Reply , 2011 .

[23]  John Seibyl,et al.  Cerebral amyloid-β PET with florbetaben (18F) in patients with Alzheimer's disease and healthy controls: a multicentre phase 2 diagnostic study , 2011, The Lancet Neurology.

[24]  G. Small,et al.  Multimodal Imaging of Alzheimer Pathophysiology in the Brain's Default Mode Network , 2011, International journal of Alzheimer's disease.

[25]  S. Lehéricy,et al.  Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl‐11C]‐2‐(4′‐methylaminophenyl)‐ 6‐hydroxybenzothiazole , 2011, Annals of neurology.

[26]  M. Modat,et al.  The importance of appropriate partial volume correction for PET quantification in Alzheimer’s disease , 2011, European Journal of Nuclear Medicine and Molecular Imaging.

[27]  Susan M Resnick,et al.  In vivo fibrillar beta-amyloid detected using [11C]PiB positron emission tomography and neuropathologic assessment in older adults. , 2011, Archives of neurology.

[28]  H. Levine,et al.  PIB binding in aged primate brain: Enrichment of high-affinity sites in humans with Alzheimer's disease , 2011, Neurobiology of Aging.

[29]  C. Flask,et al.  A novel PET marker for in vivo quantification of myelination. , 2010, Bioorganic & medicinal chemistry.

[30]  A. Nordberg,et al.  Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease , 2010, Brain : a journal of neurology.

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

[32]  C. Rowe,et al.  Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging , 2010, Neurobiology of Aging.

[33]  M. Biancalana,et al.  Molecular mechanism of Thioflavin-T binding to amyloid fibrils. , 2010, Biochimica et biophysica acta.

[34]  H. Hall,et al.  [(11)C]PIB-amyloid binding and levels of Abeta40 and Abeta42 in postmortem brain tissue from Alzheimer patients , 2010, Alzheimer's & Dementia.

[35]  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.

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

[37]  N. Cairns,et al.  In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia , 2010, Neurology.

[38]  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.

[39]  Tyler E. Benedum,et al.  Preclinical Properties of 18F-AV-45: A PET Agent for Aβ Plaques in the Brain , 2009, Journal of Nuclear Medicine.

[40]  F. Stossi,et al.  Bibenzyl- and stilbene-core compounds with non-polar linker atom substituents as selective ligands for estrogen receptor beta. , 2009, European journal of medicinal chemistry.

[41]  C. Rowe,et al.  11C-PiB PET studies in typical sporadic Creutzfeldt–Jakob disease , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[42]  C. Rowe,et al.  Characterization of PiB Binding to White Matter in Alzheimer Disease and Other Dementias , 2009, Journal of Nuclear Medicine.

[43]  Yue Feng,et al.  Molecular probes for imaging myelinated white matter in CNS. , 2008, Journal of medicinal chemistry.

[44]  P. Mcgeer Amyloid-β vaccination for Alzheimer's dementia , 2008, The Lancet.

[45]  Sakari Savolainen,et al.  Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B. , 2008, Archives of neurology.

[46]  J H Duyn,et al.  Pittfalls of MRI measurement of white matter perfusion based on arterial spin labeling , 2008, Magnetic resonance in medicine.

[47]  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.

[48]  V. Libri,et al.  PIB is a non-specific imaging marker of amyloid-beta (Abeta) peptide-related cerebral amyloidosis. , 2007, Brain : a journal of neurology.

[49]  Keith A. Johnson,et al.  Imaging of amyloid burden and distribution in cerebral amyloid angiopathy , 2007, Annals of neurology.

[50]  Hyoung-Gon Lee,et al.  Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses , 2007, Journal of Pharmacology and Experimental Therapeutics.

[51]  M. Viitanen,et al.  PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment , 2007, Neurology.

[52]  Lisa A. Weissfeld,et al.  Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease , 2006, NeuroImage.

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

[54]  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.

[55]  Tom R. Miller,et al.  PET: Molecular Imaging and Its Biological Applications. , 2005 .

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

[57]  R. Ramaraj,et al.  Emission of thioflavin T and its control in the presence of DNA , 2004 .

[58]  W. Klunk,et al.  Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. , 2003, Journal of medicinal chemistry.

[59]  William E. Klunk,et al.  The Binding of 2-(4′-Methylaminophenyl)Benzothiazole to Postmortem Brain Homogenates Is Dominated by the Amyloid Component , 2003, The Journal of Neuroscience.

[60]  Y. Shiotsu,et al.  Systemic distribution of steroid sulfatase and estrogen sulfotransferase in human adult and fetal tissues. , 2002, The Journal of clinical endocrinology and metabolism.

[61]  J. Hardy,et al.  The Amyloid Hypothesis of Alzheimer ’ s Disease : Progress and Problems on the Road to Therapeutics , 2009 .

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

[63]  W. Klunk,et al.  Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. , 2001, Life sciences.

[64]  N. Inestrosa,et al.  Thioflavin T Is a Fluorescent Probe of the Acetylcholinesterase Peripheral Site That Reveals Conformational Interactions between the Peripheral and Acylation Sites* , 2001, The Journal of Biological Chemistry.

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

[66]  E. Kato,et al.  Cerebral blood flow and oxygen metabolism in senile dementia of Alzheimer's type and vascular dementia with deep white matter changes , 1998, Neuroradiology.

[67]  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.

[68]  C. Clark,et al.  The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) , 1990, Neurology.

[69]  J. Ringman,et al.  Not all A plaques are created equal , 2012 .

[70]  Charles Duyckaerts,et al.  National Institute on Aging–Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach , 2011, Acta Neuropathologica.

[71]  R. Coleman,et al.  Use of Florbetapir-PET for Imaging-Amyloid Pathology , 2011 .

[72]  B. Ghetti,et al.  Neocortical variation of Abeta load in fully expressed, pure Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[73]  R. Cohen The Role of the Immune System in Alzheimer's Disease , 2009 .

[74]  V. Pike,et al.  Radioligand Development for PET Imaging of β-Amyloid (Aβ)-Current Status , 2007 .

[75]  F. Mottaghy,et al.  Radiosynthesis and evaluation of [11C]BTA-1 and [11C]3'-Me-BTA-1 as potential radiotracers for in vivo imaging of β-amyloid plaques , 2007, Nuklearmedizin.

[76]  Yvette I. Sheline,et al.  Potential antecedent marker of Alzheimer disease , 2006 .

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

[78]  H. Braak,et al.  Sequence of Abeta-protein deposition in the human medial temporal lobe. , 2000, Journal of neuropathology and experimental neurology.

[79]  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.