Frontotemporal lobar degeneration

Frontotemporal lobar degeneration
Neuropathologic analysis of brain tissue from FTLD-TDP patients. Ubiquitin immunohistochemistry in cases of familial FTLD-TDP demonstrates staining of (a) neurites and neuronal cytoplasmic inclusions in the superficial cerebral neocortex, (b) neuronal cytoplasmic inclusions in hippocampal dentate granule cells, and (c) neuronal intranuclear inclusions in the cerebral neocortex (arrows). Scale bar; (a) and (b) 40 μm, (c) 25 μm, insert 6 μm.
Specialty	Neurology, Psychiatry
Complications	Brain death

Frontotemporal lobar degeneration (FTLD) 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.^[1][2]

Common

• FTLD-tau is characterised by
  Pick's disease, corticobasal degeneration, progressive supranuclear palsy
  .
• FTLD-TDP (or FTLD-U ) is characterised by
  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:

• Type A presents with many small neurites and neuronal cytoplasmic inclusion bodies in the upper (superficial) cortical layers. Bar-like neuronal intranuclear inclusions can also be seen they are fewer in number.
• Type B presents with many neuronal and
  glial cytoplasmic inclusions in both the upper (superficial) and lower (deep) cortical layers, and lower motor neurons. However neuronal intranuclear inclusions are rare or absent. This is often associated with ALS and C9ORF72
  mutations (see next section).
• Type C presents many long neuritic profiles found in the superficial cortical laminae, very few or no neuronal cytoplasmic inclusions, neuronal intranuclear inclusions or glial cytoplasmic inclusions. This is often associated with semantic dementia.
• Type D presents with many neuronal intranuclear inclusions and dystrophic neurites, and an unusual absence of inclusions in the granule cell layer of the hippocampus. Type D is associated with VCP mutations.
• Type E presents with neuronal granulofilamentous inclusions and abundant fine grains involving upper (superficial) and lower (deep) cortical layers. This has been associated with behavioral variant of frontotemporal dementia with a rapid clinical course.^[5]

Two groups independently categorized the various forms of TDP-43 associated disorders. Both classifications were considered equally valid by the medical community, but the physicians and researchers in question have jointly proposed a compromise classification to avoid confusion.^[6]

• FTLD-FUS; which is characterised by
  cranial nerve
  .

In December 2021 the structure of TDP-43 was resolved with cryo-EM^[7][8] but shortly after it was argued that in the context of FTLD-TDP the protein involved could be TMEM106B (which has been also resolved with cryo-EM), rather than of TDP-43.^[9][10]

Genetics

There have been numerous advances in descriptions of genetic causes of FTLD, and the related disease

• Mutations in the
  MAPT or Microtubule Associated Protein Tau) can cause a FTLD presenting with tau pathology (FTLD-tau).^[11]
  There are over 40 known mutations at present.
• Mutations in the
  alleles is damaged, only half as much progranulin is produced.^[12]
• Mutations in the
  FUS negative, Ubiquitin
  positive pathology.
• Hypermorphic mutations in the VCP gene cause a TDP-43-positive FTLD which is associated with multisystem proteinopathy (MSP), also known as IBMPFD (inclusion body myopathy, Paget's disease and frontotemporal dementia)^[13]
• A hypomorphic mutation in the VCP gene cause a unique type of FTLD-tau called vacuolar tauopathy with neurofibrillary tangles and neuronal vacuoles ^[14]
• Mutations in the TDP-43 gene (known as
  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 (no known genetic cause).

• A proportion of FTLD-TDP43 [with
  ALS] cases had shown genetic linkage to a region on chromosome 9 (FTLD-TDP43/Ch9). 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^[16]

For diagnostic purposes, magnetic resonance imaging (MRI) and ([18F]fluorodeoxyglucose) positron emission tomography (FDG-PET) 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.^[17] 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.^{[citation needed]}

This article may be confusing or unclear to readers. In particular, The repeated use of "discussed in the context of" makes this passage confusing. The phrase appears to be meant to connect a brain region with a function without committing to that connection with certaintly. This is awkward and confusing for an encyclopedia. Please help clarify the article. There might be a discussion about this on the talk page. (October 2021) (Learn how and when to remove this template message)

Society

United States Senator Pete Domenici (R-NM) 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.^[18] American film director, producer, and screenwriter Curtis Hanson died as a result of FTLD on September 20, 2016.^[19] British journalist Ian Black died from the disease on January 22, 2023.^[20]

See also

• Frontotemporal dementia and parkinsonism linked to chromosome 17

References