Clinicopathologic features of frontotemporal dementia with progranulin sequence variation.

BACKGROUND: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). OBJECTIVE: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). METHODS: Patients underwent a single clinical assessment, MRI, and [(18)F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. RESULTS: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A-->G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A-->G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. CONCLUSIONS: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

Microscopic diagnosis from frozen canine tissues.

Frozen tissues were studied microscopically to determine their value for diagnostic purposes. Sections were taken from lung, liver, kidney, small intestine, and brain of ten diseased dogs that died or were euthanatized. Some tissues were frozen, held for two or seven days, and then formalin-fixed. Tissues that were formalin-fixed immediately served as controls. Freezing changes such as transudate, cell shrinkage, fractures, hemolysis, and hematin formation were a nuisance, but usually did not prevent making a diagnosis. Viral inclusions, microfilaria, fibrosis, and intestinal bacteria remained distinct.

Effects of freezing and frozen storage on histological characteristics of canine tissues.

Frozen tissues were studied histologically to determine what changes were produced by freezing. Samples of brain, lung, liver, small intestine, and kidney from 20 stray dogs were treated in 3 ways: formalin fixation (control), frozen for 2 days plus formalin fixation, or frozen for 7 days plus formalin fixation. Major histological changes caused by freezing were loss of staining, extracellular fluid accumulation, cell shrinkage, fractures, hemolysis, and hematin formation. Lesser changes included loss of bronchial cilia, prominence of collagen in alveolar septa and meninges, and intracellular vacuolization of epithelial cells. Although these changes were annoying, adequate visualization of the tissues was usually possible.