Frontotemporal lobar degeneration is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes. Common proteinopathies that are found in FTLD include the accumulation of tau proteins and TARDBPs. Mutations in the C9orf72 gene have been established as a major genetic contribution of FTLD, although defects in the GRN and MAPT genes are also associated with it.
Classification
There are 3 main histological subtypes found at post-mortem:
FTLD-TDP is characterised by ubiquitin and TDP-43 positive, tau negative, FUS negative inclusions. The pathological histology of this subtype is so diverse it is subdivided into four subtypes based on the detailed histological findings:
Two physicians independently categorized the various forms of TDP-43 associated disorders. Both classifications were considered equally valid by the medical community, but the physicians in question have jointly proposed a compromise classification to avoid confusion.
Dementia lacking distinctive histology is a rare and controversial entity. New analyses have allowed many cases previously described as DLDH to be reclassified into one of the positively defined subgroups.
Genetics
There have been numerous advances in descriptions of genetic causes of FTLD, and the related disease amyotrophic lateral sclerosis.
Mutations in the Tau gene can cause a FTLD presenting with tau pathology. There are over 40 known mutations at present.
Mutations in the Progranulin gene can cause a FTLD presenting with TDP-43 pathology. Patients with Progranulin mutations have type 3 ubiquitin-positive, TDP-43 positive, tau-negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, however the mutations seen in FTLD-TDP43 produce a haploinsufficiency, meaning that because one of the two alleles is damaged, only half as much Progranulin is produced.
Mutations in the CHMP2B gene are associated with a rare behavioural syndrome akin to bvFTLD, presenting with a tau negative, TDP-43 negative, FUS negative, Ubiquitin positive pathology.
Mutations in the VCP gene cause a TDP-43-positive FTLD which is associated with multisystem proteinopathy, also known as IBMPFD
Mutations in the TDP-43 gene are an exceptionally rare cause of FTLD, despite this protein being present in the pathological inclusions of many cases. However, mutations in TARBP are a more common cause of ALS, which can present with frontotemporal dementia. Since these instances are not considered a pure FTLD they are not included here.
Mutations in all of the above genes cause a very small fraction of the FTLD spectrum. Most of the cases are sporadic.
A proportion of FTLD-TDP43 cases had shown genetic linkage to a region on chromosome 9. This linkage has recently been pinned down to the C9ORF72 gene. Two groups published identical findings back-to-back in the journal Neuron in mid-2011, showing that a hexanucleotide repeat expansion of the GGGGCC genetic sequence within an intron of this gene was responsible. This expansion was found to be present in a large proportion of familial and sporadic cases, particularly in the Finnish population
Diagnosis
For diagnostic purposes, magnetic resonance imaging and positron emission tomography are applied. They measure either atrophy or reductions in glucose utilization. The three clinical subtypes of frontotemporal lobar degeneration, frontotemporal dementia, semantic dementia and progressive nonfluent aphasia, are characterized by impairments in specific neural networks. The first subtype with behavioral deficits, frontotemporal dementia, mainly affects a frontomedian network discussed in the context of social cognition. Semantic dementia is mainly related to the inferior temporal poles and amygdalae; brain regions that have been discussed in the context of conceptual knowledge, semantic information processing, and social cognition, whereas progressive nonfluent aphasia affects the whole left frontotemporal network for phonological and syntactical processing.
Society
Senator Pete Domenici was a known sufferer of FTLD, and the illness was the main reason behind his October 4, 2007 announcement of retirement at the end of his term. American film director, producer, and screenwriter Curtis Hanson died as a result of FTLD on September 20, 2016.
