Our study suggests that pro-inflammatory changes observed in the early symptomatic phase of FTLD are associated with distinct clinical profiles and a more rapid disease progression, and that the C9orf72 repeat expansion and gender may also affect the inflammatory profile in FTLD.
Because phosphorylated (p) TDP-43 has been identified as a component of ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), it is considered to play a major role in neurodegenerative processes.
Frontotemporal lobar degeneration with TDP-43 immunoreactive (TDP-ir) inclusions (FTLD-TDP) is sub-classified based on the pattern of neocortical pathology, with each subtype showing clinical and genetic correlations.
Progranulin gene (GRN) mutations are among the leading causes of frontotemporal lobar degeneration, a group of neurodegenerative diseases characterized by remarkable clinical heterogeneity.
This variant is in high LD with the TMEM106B non-synonymous variant p.T185S (rs3173615; r<sup>2</sup> = 0.98) which was previously identified as a protective variant for frontotemporal lobar degeneration (FTLD).
Here, we review the current status of research pursued to identify specific indicators to predict or exclude TDP-43 pathology in the ALS-FTLD spectrum disorders and findings on candidates for prognosis and monitoring of disease progression in TDP-43 proteinopathies with a focus on TDP-43 with its pathological forms, neurochemical and imaging biomarkers.
Heterogeneous Nuclear Ribonucleoprotein E2 (hnRNP E2) Is a Component of TDP-43 Aggregates Specifically in the A and C Pathological Subtypes of Frontotemporal Lobar Degeneration.
We assessed the prevalence and distribution of GVD in cases with TDP-43-related frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS-TDP).
We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy.
The aim of this study was to determine the prevalence of C9orf72 G<sub>4</sub>C<sub>2</sub>-repeat expansion in a Turkish population with FTLD and to determine its effects on the phenotype.
We included individuals for whom frontal cortex tissue was available: FTLD and FTLD/MND patients with (n = 34) or without (n = 44) an expanded C9orf72 repeat as well as control subjects (n = 24).
This study not only supports the scenario that loss-of-function of TDP-43 in mice may recapitulate key behaviour features of the FTLD diseases, but also provides a list of TDP-43 target genes/transcript isoforms useful for future therapeutic research.
To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72).
Heterozygous loss-of-function mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A).
Suppression of Progranulin Expression Leads to Formation of Intranuclear TDP-43 Inclusions In Vitro: A Cell Model of Frontotemporal Lobar Degeneration.
Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL).
Wild type TDP-43 inclusions are a pathological hallmark of >95% of patients with sporadic ALS and of the majority of familial ALS cases, and they are also found in a significant proportion of FTLD cases.
In PPA, FTLD-TDP and FTLD-Tau have divergent anatomic distributions of left-lateralized postmortem pathology that relate to antemortem structural imaging and distinct language deficits.