Furthermore, the discovery that TDP-43 is a component of the neuronal inclusions seen in the most common neuropathological subtype has also helped expand the biochemical pathways that are the focus of much FTLD research.
Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis.
Frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) is characterized by the presence of ubiquitin and TDP-43 positive aggregates which are likely related to specific gene expression profiles.
Immunohistochemical and biochemical studies of TDP-43 have helped to clarify the relationship between different sub-types of FTLD-U and related conditions.
Recently, the heterogeneous pathologic substrate of corticobasal syndrome has been further expanded to include cases with pathologic diagnosis of frontotemporal lobar degeneration with ubiquitin/TDP-43 (TAR DNA binding protein 43)-positive inclusions associated with progranulin (PGRN) mutations.
Newton showed tau-negative ubiquitin-positive histology consistent with frontotemporal lobar degeneration (FTLD) and a mutation in the progranulin (PGRN) gene.
The neuropathology associated with each of the known non-MAPT FTLD genes and loci (PGRN, valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of FTLD-U.
Recently, the heterogeneous pathologic substrate of corticobasal syndrome has been further expanded to include cases with pathologic diagnosis of frontotemporal lobar degeneration with ubiquitin/TDP-43 (TAR DNA binding protein 43)-positive inclusions associated with progranulin (PGRN) mutations.
Twenty-eight patients with frontotemporal dementia, including 9 with GRN mutations (4 autopsy cases and 5 with only clinical information) and 19 with the identical pathologic diagnosis--frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (FTLD-U)--and no GRN mutations.
First, mutations in the progranulin gene (PGRN) were recognized as a major cause of FTLD with ubiquitin-positive and tau-negative inclusions (FTLD-U), and subsequently the TAR DNA-binding protein-43 (TDP-43) was identified as a key protein within the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS).
In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau.
Furthermore, we determined the frequency of PGRN mutations in familial cases recruited from a large population-based study of frontotemporal lobar degeneration carried out in The Netherlands.
First, mutations in the progranulin gene (PGRN) were recognized as a major cause of FTLD with ubiquitin-positive and tau-negative inclusions (FTLD-U), and subsequently the TAR DNA-binding protein-43 (TDP-43) was identified as a key protein within the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS).
To determine whether MAPT gene copy number variation is involved in FTLD, 70 patients with clinical diagnosis of FTLD and no MAPT mutation (including 12 patients with pathologically proven tau-positive FTLD) were screened by using multiplex ligation probe amplification (MLPA) with specific oligonucleotide probes.
Whereas, in the past, most attention focused on FTLD associated with tau-based pathology and microtubule associated protein tau gene (MAPT) mutations, there has recently been greater attention paid to non-tau FTLD.
Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS.
Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS.
The neuropathology associated with each of the known non-MAPT FTLD genes and loci (PGRN, valosin-containing protein gene, CHMP2B and 9p), has been shown to be a specific subtype of FTLD-U.