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Mapping the progression of progranulin-associated frontotemporal lobar degeneration.

ABSTRACT: BACKGROUND:A 55-year-old woman was followed over a 13-year period as part of a longitudinal study of people at risk for familial dementia. She was a member of a family with an autosomal dominant familial dementia that fulfilled consensus criteria for frontotemporal lobar degeneration. The patient was initially asymptomatic but developed progressive behavioral and cognitive decline characterized by apathy, impaired emotion recognition, mixed aphasia and parietal lobe dysfunction. INVESTIGATIONS:Clinical assessments, neuropsychometry, volumetric brain MRI, and genetic mutation screening. DIAGNOSIS:Progranulin-associated frontotemporal lobar degeneration. MANAGEMENT:Explanation of the patient's condition and genetic counseling for her family.

SUBMITTER: Rohrer JD

PROVIDER: S-EPMC2567307 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Mapping the progression of progranulin-associated frontotemporal lobar degeneration.

Rohrer Jonathan D JD Warren Jason D JD Barnes Josephine J Mead Simon S Beck Jonathan J Pepple Tracey T Boyes Richard R Omar Rohani R Collinge John J Stevens John M JM Warrington Elizabeth K EK Rossor Martin N MN Fox Nick C NC

Nature clinical practice. Neurology 20080722 8

<h4>Background</h4>A 55-year-old woman was followed over a 13-year period as part of a longitudinal study of people at risk for familial dementia. She was a member of a family with an autosomal dominant familial dementia that fulfilled consensus criteria for frontotemporal lobar degeneration. The patient was initially asymptomatic but developed progressive behavioral and cognitive decline characterized by apathy, impaired emotion recognition, mixed aphasia and parietal lobe dysfunction.<h4>Inves ...[more]

PMID: 18648346

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Project description:ObjectiveTo identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72).MethodsWe performed quantitative neuropathologic comparison of 17 FTLD-C9ORF72 and 15 FTLD-GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD-GRN and 13 FTLD-C9ORF72). Neuropathological analyses were limited to TDP-43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD-GRN and 11 FTLD-C9ORF72). FTLD cases were also compared to age- and sex-matched normal controls. Immunohistochemistry was performed for pTDP-43, IBA-1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information.ResultsFTLD-GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD-C9ORF72 had greater hippocampal tau pathology and more TDP-43 neuronal cytoplasmic inclusions. FTLD-GRN had more neocortical microvacuolation, as well as more IBA-1-positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD-GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD-GRN and FTLD-C9ORF72 differed from controls.InterpretationOur findings underscore differences in microglial response in FTLD-C9ORF72 and FTLD-GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD-GRN and FTLD-C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

Dataset Information

Mapping the progression of progranulin-associated frontotemporal lobar degeneration.

Publications

Mapping the progression of progranulin-associated frontotemporal lobar degeneration.

Similar Datasets

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