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.
FTLD-TDP (or FTLD-U ) 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:
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
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.
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
amyotrophic lateral sclerosis.
Mutations in the
Tau gene (known as
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
progranulin gene (PGRN) can cause a FTLD presenting with TDP-43 pathology (FTLD-TDP43). 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.[12]
Mutations in the
CHMP2B gene are associated with a rare behavioural syndrome akin to bvFTLD (mainly in a large Jutland cohort), 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 (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
TARBP or TAR DNA-binding protein) are an exceptionally rare cause of FTLD, despite this protein being present in the pathological inclusions of many cases (FTLD-TDP43).[15] 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 (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]
Diagnosis
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]
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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]