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Voxel-based morphometry patterns of atrophy in FTLD with mutations in MAPT or PGRN

From the Departments of Radiology Research (J.L.W., C.R.J.), Neurology (B.F.B., D.S.K., R.C.P., K.A.J.), Information Technology (M.L.S.), and Psychiatry and Psychology (R.J.I.), Mayo Clinic, Rochester, MN; and Departments of Neuroscience (M.B., R.R.) and Neurology (Z.K.W.), Mayo Clinic, Jacksonville, FL.

Address correspondence and reprint requests to Dr. Keith A. Josephs, Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 josephs.keith{at}mayo.edu.

Objective: To compare patterns of gray matter loss in subjects with mutations in the progranulin (PGRN) gene to subjects with mutations in the microtubule-associated protein tau (MAPT) gene.

Methods: We identified all subjects seen at the Mayo Clinic, Rochester, MN, who had screened positive for mutations in PGRN or MAPT and had a head MRI. Twelve cases with mutations in the PGRN gene were matched by time from disease onset to scan to 12 subjects with mutations in the MAPT gene. Voxel-based morphometry was used to assess patterns of gray matter loss in the PGRN and MAPT groups compared to a control cohort, and compared to each other. MAPT subjects were younger than the PGRN subjects; therefore, each group was also compared to a specific age-matched control group.

Results: Both PGRN and MAPT groups showed gray matter loss in frontal, temporal, and parietal lobes compared to controls, although loss was predominantly identified in posterior temporal and parietal lobes in PGRN and anteromedial temporal lobes in MAPT. The MAPT group had greater loss compared to healthy subjects of the same age than the PGRN subjects when compared to healthy subjects of the same age. The MAPT subjects showed greater gray matter loss in the medial temporal lobes, insula, and putamen than the PGRN subjects.

Conclusion: These results increase understanding of the biology of these disorders and suggest that patterns of atrophy on MRI may be useful to aid in the differentiation of groups of PGRN and MAPT mutation carriers.

Abbreviations: AD = Alzheimer disease; ADPR = Alzheimer's Disease Patient Registry; ADRC = Alzheimer's Disease Research Center; bvFTD = behavioral variant frontotemporal dementia; bvFTD+P = bvFTD with parkinsonism; CBS = corticobasal syndrome; CDR-SB = Clinical Dementia Rating scale sum of boxes; DRS = Dementia Rating Scale; FTLD = frontotemporal lobar degeneration; MAPT = microtubule-associated protein tau; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; PGRN = progranulin; PPA = primary progressive aphasia; STMS = Short Test of Mental Status; VBM = voxel-based morphometry.

Supplemental data at www.neurology.org

Supported by the NIH Roadmap Multidisciplinary Clinical Research Career Development Award Grant (K12/NICHD)-HD49078, NIH grants P50-AG16574, U01-AG06786, R01-AG11378, as well as the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Foundation, the NIH Construction Grant (NIH C06 RR018898), and the Pacific Alzheimer's Research Foundation (PARF) grant C06-01. K.A.J. and Z.K.W. are also supported by Morris K. Udall PD Research Center of Excellence (NIH/National Institute of Neurological Disorders and Stroke P50 #NS40256).

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. B.F.B. has been a consultant to GE Healthcare and was an investigator in a clinical trial sponsored by Myriad Pharmaceuticals. R.C.P. has been a consultant to GE Healthcare and has served on a data safety monitoring board in a clinical trial sponsored by Elan Pharmaceuticals. C.R.J. receives research support from Pfizer in the form of research grants.

Received September 15, 2008. Accepted in final form November 24, 2008.

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