The influence of biological and technical factors on quantitative analysis of amyloid PET: Points to consider and recommendations for controlling variability in longitudinal data

In vivo imaging of amyloid burden with positron emission tomography (PET) provides a means for studying the pathophysiology of Alzheimer's and related diseases. Measurement of subtle changes in amyloid burden requires quantitative analysis of image data. Reliable quantitative analysis of amyloid PET scans acquired at multiple sites and over time requires rigorous standardization of acquisition protocols, subject management, tracer administration, image quality control, and image processing and analysis methods. We review critical points in the acquisition and analysis of amyloid PET, identify ways in which technical factors can contribute to measurement variability, and suggest methods for mitigating these sources of noise. Improved quantitative accuracy could reduce the sample size necessary to detect intervention effects when amyloid PET is used as a treatment end point and allow more reliable interpretation of change in amyloid burden and its relationship to clinical course.

[1]  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.

[2]  W. Oyen,et al.  FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0 , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[3]  W. Jagust,et al.  The Alzheimer's Disease Neuroimaging Initiative positron emission tomography core , 2010, Alzheimer's & Dementia.

[4]  Peter Herscovitch,et al.  Comparison of Bolus and Infusion Methods for Receptor Quantitation: Application to [18F]Cyclofoxy and Positron Emission Tomography , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  H. Engler,et al.  Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. , 2006, Brain : a journal of neurology.

[6]  M. Mintun,et al.  Amyloid-β Imaging with Pittsburgh Compound B and Florbetapir: Comparing Radiotracers and Quantification Methods , 2013, The Journal of Nuclear Medicine.

[7]  Dietmar R. Thal,et al.  Stages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years , 2011, Journal of neuropathology and experimental neurology.

[8]  H. Braak,et al.  Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry , 2006, Acta Neuropathologica.

[9]  J. Andersson,et al.  Accurate attenuation correction despite movement during PET imaging. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

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

[11]  C. Jack,et al.  Comparison of 18F-FDG and PiB PET in Cognitive Impairment , 2009, Journal of Nuclear Medicine.

[12]  Nick C Fox,et al.  The Alzheimer's disease neuroimaging initiative (ADNI): MRI methods , 2008, Journal of magnetic resonance imaging : JMRI.

[13]  Majaz Moonis,et al.  Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees , 2007, The Journal of Neuroscience.

[14]  C. Rowe,et al.  Amyloid Imaging with 18F-Florbetaben in Alzheimer Disease and Other Dementias , 2011, The Journal of Nuclear Medicine.

[15]  Keith A. Johnson,et al.  Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer’s disease , 2011, Alzheimer's & Dementia.

[16]  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.

[17]  R. Boellaard,et al.  Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values: a simulation study. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[18]  Eric Guedj,et al.  Metabolic Networks Underlying Cognitive Reserve in Prodromal Alzheimer Disease: A European Alzheimer Disease Consortium Project , 2013, The Journal of Nuclear Medicine.

[19]  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.

[20]  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.

[21]  W. Klunk,et al.  Progression of Cerebral Amyloid Load Is Associated with the Apolipoprotein E ε4 Genotype in Alzheimer's Disease , 2010, Biological Psychiatry.

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

[23]  Bruno De Man,et al.  Ultra-low dose CT attenuation correction for PET/CT , 2011, Physics in medicine and biology.

[24]  Victor W. Pike,et al.  Radiopharmaceuticals for Positron Emission Tomography , 1993, Developments in Nuclear Medicine.

[25]  R. Petersen,et al.  Mild cognitive impairment , 2006, The Lancet.

[26]  E. Ross,et al.  Philosophy of Science Association , 2022 .

[27]  Paul Kinahan,et al.  Instrumentation factors affecting variance and bias of quantifying tracer uptake with PET/CT. , 2010, Medical physics.

[28]  Masanori Nakagawa,et al.  High striatal amyloid beta-peptide deposition across different autosomal Alzheimer disease mutation types. , 2009, Archives of neurology.

[29]  C. Rowe,et al.  Longitudinal assessment of Aβ and cognition in aging and Alzheimer disease , 2011, Annals of neurology.

[30]  R. Boellaard,et al.  Test-retest variability of quantitative [11C]PIB studies in Alzheimer’s disease , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[31]  Colin L. Masters,et al.  Head-to-Head Comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for β-Amyloid Imaging in Aging and Dementia , 2013, The Journal of Nuclear Medicine.

[32]  J. Trojanowski,et al.  Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre. , 2013, Brain : a journal of neurology.

[33]  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.

[34]  Mark E. Schmidt,et al.  Profiling of hepatic clearance pathways of Pittsburgh compound B and human liver cytochrome p450 phenotyping , 2013, EJNMMI Research.

[35]  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.

[36]  Vijaya L. Melnick,et al.  Alzheimer’s Dementia , 1985, Contemporary Issues in Biomedicine, Ethics, and Society.

[37]  Nick C Fox,et al.  Clinical and biomarker changes in dominantly inherited Alzheimer's disease. , 2012, The New England journal of medicine.

[38]  Keith A. Johnson,et al.  Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease , 2013, Neurobiology of Aging.

[39]  G. Saha Basics Of Pet Imaging: Physics, Chemistry, And Regulations , 2004 .

[40]  Guy B. Williams,et al.  Attenuation Correction Methods Suitable for Brain Imaging with a PET/MRI Scanner: A Comparison of Tissue Atlas and Template Attenuation Map Approaches , 2011, The Journal of Nuclear Medicine.

[41]  S. Arnold,et al.  [18F]Flutemetamol PET imaging and cortical biopsy histopathology for fibrillar amyloid β detection in living subjects with normal pressure hydrocephalus: pooled analysis of four studies , 2012, Acta Neuropathologica.

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

[43]  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.

[44]  G. Alexander,et al.  Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease , 2009, Proceedings of the National Academy of Sciences.

[45]  Bedda L. Rosario,et al.  Consideration of Optimal Time Window for Pittsburgh Compound B PET Summed Uptake Measurements , 2009, Journal of Nuclear Medicine.

[46]  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.

[47]  F. Turkheimer,et al.  Kinetic modeling in positron emission tomography. , 2002, The quarterly journal of nuclear medicine : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology.

[48]  B. Strooper,et al.  The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics , 2011, Nature Reviews Drug Discovery.

[49]  R. Wahl,et al.  PET/CT: comparison of quantitative tracer uptake between germanium and CT transmission attenuation-corrected images. , 2002, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[50]  Denise C. Park,et al.  &bgr;-Amyloid burden in healthy aging: Regional distribution and cognitive consequences , 2012, Neurology.

[51]  C. Jack,et al.  11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. , 2008, Brain : a journal of neurology.

[52]  S Ted Treves,et al.  Dosimetry and adequacy of CT-based attenuation correction for pediatric PET: phantom study. , 2007, Radiology.

[53]  H. Herzog,et al.  Quantitation of Regional Cerebral Blood Flow with 15O-Butanol and Positron Emission Tomography in Humans , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[54]  Paul Kinahan,et al.  Positron emission tomography-computed tomography standardized uptake values in clinical practice and assessing response to therapy. , 2010, Seminars in ultrasound, CT, and MR.

[55]  Ronald Boellaard,et al.  The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[56]  I. Buvat,et al.  A review of partial volume correction techniques for emission tomography and their applications in neurology, cardiology and oncology , 2012, Physics in medicine and biology.

[57]  K. Blennow,et al.  Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer's disease: united we stand, divided we fall , 2010, Clinical chemistry and laboratory medicine.

[58]  Nelleke Tolboom,et al.  Simplified parametric methods for [11C]PIB studies , 2008, NeuroImage.

[59]  R. Coleman,et al.  Use of florbetapir-PET for imaging beta-amyloid pathology. , 2011, JAMA.

[60]  H. Braak,et al.  Gender and age modify the association between APOE and AD-related neuropathology , 2001, Neurology.

[61]  H. Rusinek,et al.  Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer’s disease , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[62]  D. Selkoe,et al.  Diffuse senile plaques occur commonly in the cerebellum in Alzheimer's disease. , 1989, The American journal of pathology.

[63]  M. Groenning,et al.  Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils—current status , 2010, Journal of chemical biology.

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

[65]  Jesper L. R. Andersson,et al.  A RAPID AND ACCURATE METHOD TO REALIGN PET SCANS UTILIZING IMAGE EDGE INFORMATION , 1995 .

[66]  Jeffrey A. Fessler,et al.  Reducing between scanner differences in multi-center PET studies , 2009, NeuroImage.

[67]  C. Jack,et al.  11 C PiB and structural MRI provide complementary information in imaging of Alzheimer ’ s disease and amnestic mild cognitive impairment , 2008 .

[68]  L. Thurfjell,et al.  Phase 1 Study of the Pittsburgh Compound B Derivative 18F-Flutemetamol in Healthy Volunteers and Patients with Probable Alzheimer Disease , 2009, Journal of Nuclear Medicine.

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

[70]  Jeih-San Liow,et al.  Disulfiram Inhibits Defluorination of 18F-FCWAY, Reduces Bone Radioactivity, and Enhances Visualization of Radioligand Binding to Serotonin 5-HT1A Receptors in Human Brain , 2007, Journal of Nuclear Medicine.

[71]  Denise C. Park,et al.  Risk factors for β-amyloid deposition in healthy aging: vascular and genetic effects. , 2013, JAMA neurology.

[72]  M. Wernick,et al.  Emission Tomography: The Fundamentals of PET and SPECT , 2004 .

[73]  L. Thurfjell,et al.  Amyloid PET imaging in Alzheimer’s disease: a comparison of three radiotracers , 2014, European Journal of Nuclear Medicine and Molecular Imaging.

[74]  C. Jack,et al.  Alzheimer's Disease Neuroimaging Initiative , 2008 .

[75]  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.

[76]  Arno Klein,et al.  Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration , 2009, NeuroImage.

[77]  Gunnar Antoni,et al.  Unidirectional Influx and Net Accumulation of PIB , 2008, The open neuroimaging journal.

[78]  K. Welsh-Bohmer,et al.  APOE genotype predicts when — not whether — one is predisposed to develop Alzheimer disease , 1998, Nature Genetics.

[79]  W. Jagust,et al.  Association of lifetime cognitive engagement and low β-amyloid deposition. , 2012, Archives of neurology.

[80]  Andrei G. Vlassenko,et al.  Amyloid‐beta plaque growth in cognitively normal adults: Longitudinal [11C]Pittsburgh compound B data , 2011, Annals of neurology.

[81]  C. Rowe,et al.  11C-PIB binding is increased in patients with cerebral amyloid angiopathy–related hemorrhage , 2010, Neurology.

[82]  A. Gjedde,et al.  Blood-brain transfer of Pittsburgh compound B in humans , 2013, Front. Aging Neurosci..

[83]  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.

[84]  Jurgen Fripp,et al.  Alzheimer's disease detection using 11C-PiB with improved partial volume effect correction , 2009, Medical Imaging.

[85]  Koen Van Laere,et al.  EANM procedure guidelines for PET brain imaging using [18F]FDG, version 2 , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[86]  Rik Ossenkoppele,et al.  Longitudinal Amyloid Imaging Using 11C-PiB: Methodologic Considerations , 2013, The Journal of Nuclear Medicine.

[87]  Lee-Tzuu Chang,et al.  A Method for Attenuation Correction in Radionuclide Computed Tomography , 1978, IEEE Transactions on Nuclear Science.

[88]  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.

[89]  Kengo Ito,et al.  Head motion evaluation and correction for PET scans with 18F-FDG in the Japanese Alzheimer’s disease neuroimaging initiative (J-ADNI) multi-center study , 2011, Annals of Nuclear Medicine.

[90]  Anders M. Dale,et al.  Nonlinear registration of longitudinal images and measurement of change in regions of interest , 2011, Medical Image Anal..

[91]  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.

[92]  J. Anderson A rapid and accurate method to realign PET scans utilizing image edge information. , 1995, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[93]  Jean-Baptiste Thibault,et al.  Ultra low dose CT for attenuation correction in PET/CT , 2008, 2008 IEEE Nuclear Science Symposium Conference Record.

[94]  Cindee M. Madison,et al.  Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. , 2009, Brain : a journal of neurology.

[95]  David T. Jones,et al.  Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity , 2013, Neurology.

[96]  C. Svarer,et al.  Integrated software for the analysis of brain PET/SPECT studies with partial-volume-effect correction. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

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

[98]  L. Ferrucci,et al.  Memory decline shows stronger associations with estimated spatial patterns of amyloid deposition progression than total amyloid burden , 2013, Neurobiology of Aging.

[99]  M. Mintun,et al.  Performance Characteristics of Amyloid PET with Florbetapir F 18 in Patients with Alzheimer's Disease and Cognitively Normal Subjects , 2012, The Journal of Nuclear Medicine.

[100]  L. Kuller,et al.  Arterial stiffness and β-amyloid progression in nondemented elderly adults. , 2014, JAMA neurology.

[101]  Thomas E. Nichols,et al.  Comparative evaluation of MR-based partial-volume correction schemes for PET. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[102]  Nick C Fox,et al.  Carbon-11-Pittsburgh compound B positron emission tomography imaging of amyloid deposition in presenilin 1 mutation carriers. , 2011, Brain : a journal of neurology.

[103]  K. Blennow,et al.  Lessons from Multicenter Studies on CSF Biomarkers for Alzheimer's Disease , 2010, Alzheimer's & Dementia.

[104]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[105]  Clemens Decristoforo,et al.  Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

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

[107]  J. Becker,et al.  A two-year follow-up of cognitive deficits and brain perfusion in mild cognitive impairment and mild Alzheimer's disease. , 2012, Journal of Alzheimer's disease : JAD.

[108]  Jyrki Lötjönen,et al.  Implementation and Validation of an Adaptive Template Registration Method for 18F-Flutemetamol Imaging Data , 2013, The Journal of Nuclear Medicine.

[109]  S. Black,et al.  Vascular Contributions to Cognitive Impairment and Dementia: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association , 2011, Stroke.

[110]  Y. Stern Cognitive reserve in ageing and Alzheimer's disease , 2012, The Lancet Neurology.

[111]  S. Resnick,et al.  Relative Equilibrium Plot Improves Graphical Analysis and Allows Bias Correction of Standardized Uptake Value Ratio in Quantitative 11C-PiB PET Studies , 2012, The Journal of Nuclear Medicine.

[112]  J O Rinne,et al.  Follow-up of [11C]PIB uptake and brain volume in patients with Alzheimer disease and controls , 2009, Neurology.

[113]  Denis Guilloteau,et al.  Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[114]  Claus Svarer,et al.  Attenuation Correction for the HRRT PET-Scanner Using Transmission Scatter Correction and Total Variation Regularization , 2013, IEEE Transactions on Medical Imaging.

[115]  Clifford R. Jack,et al.  Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer’s Association Research Roundtable Workgroup , 2011, Alzheimer's & Dementia.

[116]  Klaus P. Ebmeier,et al.  The influence of ApoE4 on clinical progression of dementia: a meta‐analysis , 2011, International journal of geriatric psychiatry.

[117]  W. Klunk,et al.  Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B , 2012, Alzheimer's & Dementia.

[118]  R. Coleman,et al.  Cerebral PET with florbetapir compared with neuropathology at autopsy for detection of neuritic amyloid-β plaques: a prospective cohort study , 2012, The Lancet Neurology.