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Progressive aphasia secondary to Alzheimer disease vs FTLD pathology

From the Departments of Neurology (Divisions of Behavioral Neurology [K.A.J., W.T.H., B.F.B., D.S.K., R.C.P.] and Speech Pathology [J.R.D., E.A.S.]), Radiology (J.L.W., C.R.J.), Neuropsychology (W.A.V.), and Laboratory Medicine and Pathology (J.E.P.), Mayo Clinic, Rochester, MN; and Departments of Neurology and Neuroscience (N.R.G.-R.) (Neuropathology [D.W.D.]), Mayo Clinic, Jacksonville, FL.

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

Background: The pathology causing progressive aphasia is typically a variant of frontotemporal lobar degeneration, especially with ubiquitin-positive inclusions (FTLD-U). Less commonly the underlying pathology is Alzheimer disease (AD).

Objective: To compare clinicopathologic and MRI features of subjects with progressive aphasia and AD pathology to subjects with aphasia and FTLD-U pathology and subjects with typical AD.

Methods: We identified 5 subjects with aphasia and AD pathology and 5 with aphasia and FTLD-U pathology with an MRI from a total of 216 aphasia subjects. Ten subjects with typical AD clinical features and AD pathology were also identified. All subjects with AD pathology underwent pathologic reanalysis with TDP-43 immunohistochemistry. Voxel-based morphometry (VBM) was used to assess patterns of gray matter atrophy in the aphasia cases with AD pathology, aphasia cases with FTLD-U, and typical AD cases with AD pathology, compared with a normal control group.

Results: All aphasic subjects had fluent speech output. However, those with AD pathology had better processing speed than those with FTLD-U pathology. Immunohistochemistry with TDP-43 antibodies was negative. VBM revealed gray matter atrophy predominantly in the temporoparietal cortices, with notable sparing of the hippocampus in the aphasia with AD subjects. In comparison, the aphasic subjects with FTLD-U showed sparing of the parietal lobe. Typical AD subjects showed temporoparietal and hippocampal atrophy.

Conclusions: A temporoparietal pattern of atrophy on MRI in patients with progressive fluent aphasia and relatively preserved processing speed is suggestive of underlying Alzheimer disease pathology rather than frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes.

GLOSSARY: AD = Alzheimer disease; ADPR = Alzheimer's Disease Patient Registry; ADRC = Alzheimer's Disease Research Center; aphasia–AD = subjects with progressive aphasia and Alzheimer disease pathology; aphasia–FTLD-U = subjects with progressive aphasia and frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes pathology; CDR = Clinical Dementia Rating; DCT = discrete cosine transformation; FTLD = frontotemporal lobar degeneration; FTLD-U = frontotemporal lobar degeneration with ubiquitin-only immunoreactive changes; FWHM = full-width at half-maximum; GM = gray matter; MMSE = Mini-Mental State Examination; MNI = Montreal Neurological Institute; NA = not applicable; NIA = National Institute on Aging; NR = not reported; NS = not significant; PPA = primary progressive aphasia; typical AD = subjects with a clinical and pathologic diagnosis of Alzheimer disease; VBM = voxel-based morphometry; WAIS-R = Wechsler Adult Intelligence Scale–Revised; WM = white matter; WMS-R = Wechsler Memory Scale–Revised.

Received February 27, 2007. Accepted in final form June 20, 2007.

Supplemental data at www.neurology.org.

Supported by the NIH Roadmap Multidisciplinary Clinical Research Career Development Award Grant (K12/NICHD)-HD49078; grants P50 AG16574, U01 AG06786, and R01 AG11378 from the National Institute on Aging, Bethesda, MD; and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program of the Mayo Foundation, USA.

Disclosure: D.S.K. has been a consultant to GE Healthcare, GlaxoSmithKline, and Myriad Pharmaceuticals; has served on a data safety monitoring board for Sanofi-Aventis and 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 has served on a data safety monitoring board in a clinical trial sponsored by Elan Pharmaceuticals. B.F.B. and N.G.R. receive grant support as investigators in a clinical trial sponsored by Myriad Pharmaceuticals.

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