Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease.

OBJECTIVES To characterize quantitative florbetapir F 18 (hereafter referred to as simply florbetapir) positron emission tomographic (PET) measurements of fibrillar β-amyloid (Aβ) burden in a large clinical cohort of participants with probable Alzheimer disease (AD) or mild cognitive impairment (MCI) and older healthy controls (OHCs). DESIGN Cerebral-to-whole-cerebellar florbetapir standard uptake value ratios (SUVRs) were computed. Mean cortical SUVRs were compared. A threshold of SUVRs greater than or equal to 1.17 was used to reflect pathological levels of amyloid associated with AD based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients. Similarly, a threshold of SUVRs greater than 1.08 was used to signify the presence of any identifiable Aβ because this was the upper limit from a separate set of 46 individuals 18 to 40 years of age who did not carry apolipoprotein E (APOE) ε4. SETTING Multiple research imaging centers. PARTICIPANTS A total of 68 participants with probable AD, 60 participants with MCI, and 82 OHCs who were 55 years of age or older. Main Outcome Measure Florbetapir-PET activity. RESULTS All of the participants (ie, those with probable AD or MCI and those who were OHCs) differed significantly in mean (SD) cortical florbetapir SUVRs (1.39 [0.24], 1.17 [0.27], and 1.05 [0.16], respectively; P < 1.0 × 10⁻⁷), in percentage meeting levels of amyloid associated with AD by SUVR criteria (80.9%, 40.0%, and 20.7%, respectively; P < 1.0 × 10⁻⁷), and in percentage meeting SUVR criteria for the presence of any identifiable Aβ (85.3%, 46.6%, and 28.1%, respectively; P < 1.0 × 10⁻⁷). Among OHCs, the percentage of florbetapir positivity increased linearly by age decile (P = .05). For the 54 OHCs with available APOE genotypes, APOE ε4 carriers had a higher mean (SD) cortical SUVR than did noncarriers (1.14 [0.2] vs 1.03 [0.16]; P = .048). CONCLUSIONS The findings of our analysis confirm the ability of florbetapir-PET SUVRs to characterize amyloid levels in clinically probable AD, MCI, and OHC groups using continuous and binary measures of fibrillar Aβ burden. It introduces criteria to determine whether an image is associated with an intermediate-to-high likelihood of pathologic AD or with having any identifiable cortical amyloid level above that seen in low-risk young controls.

[1]  James Robert Brašić,et al.  P1-284: In vivo imaging of amyloid deposition in Alzheimer's disease using the novel radioligand [18F] Av-45 , 2008, Alzheimer's & Dementia.

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

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

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

[5]  K. Jobst,et al.  Accurate Prediction of Histologically Confirmed Alzheimer's Disease and the Differential Diagnosis of Dementia: The Use of NINCDS-ADRDA and DSM-III-R Criteria, SPECT, X-Ray CT, and Apo E4 in Medial Temporal Lobe Dementias , 1997, International Psychogeriatrics.

[6]  R. Petersen,et al.  Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects , 2009, Annals of neurology.

[7]  H. Braak,et al.  Evolution of the neuropathology of Alzheimer's disease , 1996, Acta neurologica Scandinavica. Supplementum.

[8]  H. Braak,et al.  High Frequency of Apolipoprotein E ϵ4 Allele in Young Individuals with Very Mild Alzheimer's Disease-Related Neurofibrillary Changes , 1998, Experimental Neurology.

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

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

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

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

[13]  A D Roses,et al.  Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer's disease. Alzheimer's Disease Centers Consortium on Apolipoprotein E and Alzheimer's Disease. , 1998, The New England journal of medicine.

[14]  F. LaFerla,et al.  Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease , 2003, Neurobiology of Aging.

[15]  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.

[16]  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.

[17]  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.

[18]  N. Tzourio-Mazoyer,et al.  Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain , 2002, NeuroImage.

[19]  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.

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

[21]  H. Kung,et al.  18F-labeled styrylpyridines as PET agents for amyloid plaque imaging. , 2007, Nuclear medicine and biology.

[22]  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.

[23]  J. Trojanowski,et al.  Editorial on Consensus Recommendations for the Postmortem Diagnosis of Alzheimer Disease from the National Institute on Aging and the Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer Disease , 1997, Journal of neuropathology and experimental neurology.

[24]  G. Linazasoro,et al.  IMAGING β-AMYLOID BURDEN IN AGING AND DEMENTIA , 2008, Neurology.

[25]  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.

[26]  John Q. Trojanowski,et al.  Consensus Recommendations for the Postmortem Diagnosis of Alzheimer’s Disease , 1997, Neurobiology of Aging.

[27]  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.

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

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

[30]  E. Corder,et al.  The role of APOE polymorphisms in late-onset dementias , 1998, Cellular and Molecular Life Sciences CMLS.

[31]  H. Kung,et al.  F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Abeta aggregates in the brain. , 2005, Nuclear medicine and biology.

[32]  Keith A. Johnson,et al.  Imaging amyloid deposition in Lewy body diseases , 2008, Neurology.

[33]  H. Kung,et al.  F-18 stilbenes as PET imaging agents for detecting beta-amyloid plaques in the brain. , 2005, Journal of medicinal chemistry.

[34]  J Bohl,et al.  Staging of Alzheimer-Related Cortical Destruction , 1997, International Psychogeriatrics.

[35]  H. Braak,et al.  The Biphasic Relationship between Regional Brain Senile Plaque and Neurofibrillary Tangle Distributions: Modification by Age, Sex, and APOE Polymorphism , 2004, Annals of the New York Academy of Sciences.

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

[37]  B. Winblad,et al.  Risk factors for late‐ onset Alzheimer's disease: A population‐ based, case‐control study , 1993, Annals of neurology.

[38]  D. Selkoe,et al.  Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior , 2008, Behavioural Brain Research.

[39]  A. Fagan,et al.  APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging , 2010, Annals of neurology.

[40]  Linda S Hynan,et al.  Clinical criteria for the diagnosis of Alzheimer disease: still good after all these years. , 2008, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

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

[42]  E. Reiman,et al.  Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE ε4 allele, the major late-onset Alzheimer's susceptibility gene. , 2010, Journal of Alzheimer's disease : JAD.