Dataset Information

Networks Disrupted in Linguistic Variants of Frontotemporal Dementia.

ABSTRACT: The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and semantic variant (svPPA) of frontotemporal dementia (FTD) are neurodegenerative diseases. Previous works have shown alterations of fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor images (DTIs). This manuscript is aimed at using DTI images to build a global tractography and to identify atrophy patterns of white matter in each variant. Twenty patients with svPPA, 20 patients with nfvPPA, 26 patients with behavioral variant of FTD (bvFTD) and, 33 controls were included. An analysis based on the connectivity of structural networks showed changes in FA and MD in svPPA and nfvPPA with respect to bvFTD. Much damage in the internal networks of the left temporal lobe was found in svPPA patients; in contrast, patients with nfvPPA showed atrophy in networks from the basal ganglia to motor and premotor areas. Those findings support the dual stream model of speech and language.

SUBMITTER: Reyes PA

PROVIDER: S-EPMC6716200 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Networks Disrupted in Linguistic Variants of Frontotemporal Dementia.

Reyes Pablo Alexander PA Rueda Andrea Del Pilar ADP Uriza Felipe F Matallana Diana L DL

Frontiers in neurology 20190823

The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) and semantic variant (svPPA) of frontotemporal dementia (FTD) are neurodegenerative diseases. Previous works have shown alterations of fractional anisotropy (FA) and mean diffusivity (MD) from diffusion tensor images (DTIs). This manuscript is aimed at using DTI images to build a global tractography and to identify atrophy patterns of white matter in each variant. Twenty patients with svPPA, 20 patients with nfvPPA, 26 pat ...[more]

PMID: 31507513

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Project description:Heterozygous mutations in the GRN gene and hexanucleotide repeat expansions in C9orf72 are the two most common genetic causes of Frontotemporal Dementia (FTD) with TDP-43 protein inclusions. The triggers for neurodegeneration in FTD with GRN (FTD-GRN) or C9orf72 (FTD-C9orf72) gene abnormalities are unknown, although evidence from mouse and cell culture models suggests that GRN mutations disrupt lysosomal lipid catabolism. To determine how brain lipid metabolism is affected in familial FTD with TDP-43 inclusions, and how this is related to myelin and lysosomal markers, we undertook comprehensive lipidomic analysis, enzyme activity assays, and western blotting on grey and white matter samples from the heavily-affected frontal lobe and less-affected parietal lobe of FTD-GRN cases, FTD-C9orf72 cases, and age-matched neurologically-normal controls. Substantial loss of myelin-enriched sphingolipids (sulfatide, galactosylceramide, sphingomyelin) and myelin proteins was observed in frontal white matter of FTD-GRN cases. A less-pronounced, yet statistically significant, loss of sphingolipids was also observed in FTD-C9orf72. FTD-GRN was distinguished from FTD-C9orf72 and control cases by increased acylcarnitines in frontal grey matter and marked accumulation of cholesterol esters in both frontal and parietal white matter, indicative of myelin break-down. Both FTD-GRN and FTD-C9orf72 cases showed significantly increased lysosomal and phagocytic protein markers, however galactocerebrosidase activity, required for lysosomal catabolism of galactosylceramide and sulfatide, was selectively increased in FTD-GRN. We conclude that both C9orf72 and GRN mutations are associated with disrupted lysosomal homeostasis and white matter lipid loss, but GRN mutations cause a more pronounced disruption to myelin lipid metabolism. Our findings support the hypothesis that hyperactive myelin lipid catabolism is a driver of gliosis and neurodegeneration in FTD-GRN. Since FTD-GRN is associated with white matter hyperintensities by MRI, our data provides important biochemical evidence supporting the use of MRI measures of white matter integrity in the diagnosis and management of FTD.

Dataset Information

Networks Disrupted in Linguistic Variants of Frontotemporal Dementia.

Publications

Networks Disrupted in Linguistic Variants of Frontotemporal Dementia.

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