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From the Departments of Radiology (J.L.W., K.K., P.V., C.R.J.), Neurology (Behavioral Neurology) (K.A.J., D.S.K., B.F.B., R.C.P.), Biostatistics (S.A.P., S.D.W.), Information Technology (M.L.S.) and Laboratory Medicine and Pathology (J.E.P.), Mayo Clinic, Rochester, MN; and Department of Neuroscience (Neuropathology) (M.E.M., D.W.D.), Mayo Clinic, Jacksonville, FL.
Address correspondence and reprint requests to Dr. Clifford R. Jack, Jr., Department of Radiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 jack.clifford{at}mayo.edu
Background: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology.
Methods: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II).
Results: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden.
Conclusions: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.
Abbreviations: AD = Alzheimer disease; AGD = argyrophilic grains disease; aMCI = amnestic mild cognitive impairment; CDR-SB = Clinical Dementia Rating scale sum of boxes; DLB = dementia with Lewy bodies; FDR = false-discovery rate; MMSE = Mini-Mental State Examination; NFT = neurofibrillary tangle; NIA = National Institute on Aging; SPGR = spoiled gradient echo; VBM = voxel-based morphometry.
Supported by grants P50 AG16574, U01 AG06786, and R01 AG11378 from the National Institute on Aging (NIA), Bethesda, MD; the NIH Roadmap Multidisciplinary Clinical Research Career Development Award Grant (K12/NICHD)-HD49078; the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program; the Paul B. Beeson Career Development Award in Aging K23 AG030935 from the NIH/NIA; the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation, USA; and the NIH Construction Grant (NIH C06 RR018898).
Disclosure: D.S.K. has been a consultant to GE HealthCare, GlaxoSmithKline, and Myriad Pharmaceuticals; has served on a Data Safety Monitoring Board for Neurochem Pharmaceuticals; and is an investigator in a clinical trial sponsored by Elan Pharmaceuticals. R.C.P. has been a consultant to GE Healthcare and is on a Treatment Effects Monitoring Committee for a clinical trial sponsored by Elan Pharmaceuticals. B.F.B. is an investigator in a clinical trial sponsored by Myriad Pharmaceuticals. C.R.J. receives research support from Pfizer in the form of research grants.
Received September 17, 2007. Accepted in final form May 29, 2008.
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