Frontotemporal lobar degeneration
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 TAR DNA-binding protein 43. Mutations in the C9orf72 gene have been established as a major genetic contribution of FTLD, although defects in the granulin and microtubule-associated proteins are also associated with it.
Classification
There are 3 main histological subtypes found at post-mortem:- FTLD-tau is characterised by tau positive inclusion bodies often referred to as Pick-bodies. Examples of FTLD-tau include; Pick's disease, corticobasal degeneration, progressive supranuclear palsy.
- FTLD-TDP is characterised by ubiquitin and TDP-43 positive, tau negative, FUS negative inclusion bodies. The pathological histology of this subtype is so diverse it is subdivided into four subtypes based on the detailed histological findings:
- FTLD-FUS; which is characterised by FUS positive cytoplasmic inclusions, intra nuclear inclusions, and neuritic threads. All of which are present in the cortex, medulla, hippocampus, and motor cells of the spinal cord and XIIth cranial nerve.
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.
- Hypermorphic mutations in the VCP gene cause a TDP-43-positive FTLD which is associated with multisystem proteinopathy, also known as IBMPFD
- A hypomorphic mutation in the VCP gene cause a unique type of FTLD-tau called vacuolar tauopathy with neurofibrillary tangles and neuronal vacuoles
- 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.
- 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
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, frontotemporal dementia, mainly affects a frontomedian network and impairs social cognition. Semantic dementia is mainly related to the inferior temporal poles and amygdalae; brain regions enabling conceptual knowledge, semantic information processing, and social cognition, whereas progressive nonfluent aphasia affects the entire left frontotemporal network for phonological and syntactical processing.