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Jennifer L. Whitwell, PhD; Clifford R. Jack Jr, MD; Matthew Baker, BS; Rosa Rademakers, PhD; Jennifer Adamson, BS; Bradley F. Boeve, MD; David S. Knopman, MD; Joseph F. Parisi, MD; Ronald C. Petersen, MD; Dennis W. Dickson, MD; Michael L. Hutton, PhD; Keith A. Josephs, MST, MD

Arch Neurol. 2007;64(3):371-376.

Background  Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families.

Objective  To determine whether there is a difference in the patterns of atrophy in FTLD-U cases with and without PGRN mutations.

Design  Case-control study.

Setting  Brain bank of a tertiary care medical center.

Patients  Eight subjects who had screened positive for PGRN mutations (PGRN-positive) and who underwent volumetric magnetic resonance imaging were identified. Subjects were then matched by clinical diagnosis to a group of 8 subjects with a pathological diagnosis of FTLD-U who had screened negative for PGRN mutations (PGRN-negative). All subjects were then age-matched and sex-matched to a control subject.

Main Outcome Measures  Voxel-based morphometry was used to assess the patterns of gray matter atrophy in the PGRN-positive group compared with the PGRN-negative group and compared with controls.

Results  The PGRN-positive group showed a widespread and severe pattern of gray matter loss predominantly affecting the frontal, temporal, and parietal lobes. The PGRN-negative group showed a less severe pattern of gray matter loss restricted mainly to the temporal and frontal lobes. On direct comparison, the PGRN-positive group showed greater gray matter loss in the frontal and parietal lobes compared with the PGRN-negative group.

Conclusion  Findings from this study suggest that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.

Author Affiliations: Department of Radiology (Drs Whitwell and Jack), Divisions of Behavioral Neurology (Drs Boeve, Knopman, Petersen, and Josephs) and Movement Disorders (Dr Josephs), Department of Neurology, and Department of Laboratory Medicine and Pathology (Dr Parisi), Mayo Clinic, Rochester, Minn; and Divisions of Molecular Genetics (Mr Baker, Drs Rademakers and Hutton, and Ms Adamson) and Neuropathology (Dr Dickson), Department of Neuroscience, Mayo Clinic, Jacksonville, Fla.

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