Frontotemporal lobar degeneration

Frontotemporal lobar degeneration
Classification and external resources
OMIM 600274
DiseasesDB 10034
MeSH D003704

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.

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.[1]


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.

There are 3 main histological subtypes found at post-mortem:

  • Type A presents with many small neurites and neuronal cytoplasmic inclusions in the upper (superficial) cortical layers. Bar-like neuronal intranuclear inclusions can also be seen they are fewer in number.
  • Type B presents with lots of 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 lots of neuronal intranuclear inclusions and dystrophic neurites, and an unusual absence of inclusions in the granual cell layer of the hippocampus. Type 4 is associated with VCP mutations.

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.[2]

Dementia lacking distinctive histology (DLDH) is a rare and controversial entity. New analyses has allowed many cases previously described as DLDH to be reclassified into one of the positively defined subgroups.


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

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).


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.[8] 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.


United States Senator Pete Domenici (R-NM) is a known sufferer of FTLD, and the illness is the main reason behind his October 4, 2007 announcement of retirement at the end of his term.

See also


  1. van der Zee, Julie; Van Broeckhoven, Christine (7 January 2014). "Dementia in 2013: Frontotemporal lobar degeneration—building on breakthroughs". Nature Reviews Neurology. 10 (2): 70–72. doi:10.1038/nrneurol.2013.270. PMID 24394289.
  2. Ian R. A. Mackenzie; Manuela Neumann (corresponding author); Atik Baborie; Deepak M. Sampathu; Daniel Du Plessis; Evelyn Jaros; Robert H. Perry; John Q. Trojanowski; David M. A. Mann & Virginia M. Y. Lee (July 2011). "A harmonized classification system for FTLD-TDP pathology". Acta Neuropathol. 122 (1): 111–113. doi:10.1007/s00401-011-0845-8. PMC 3285143Freely accessible. PMID 21644037.
  3. Goedert, M.; et al. (1989). "Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain.". The EMBO Journal. 8 (2): 393–9.
  4. Cruts, M.; et al. (2006). "Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.". Nature. 442 (7105): 920–4. doi:10.1038/nature05017. PMID 16862115.
  5. Kimonis, V.E.; et al. (2008). "VCP disease associated with myopathy, Paget disease of bone and frontotemporal dementia: review of a unique disorder.". Biochim Biophys Acta. 1782 (12): 744–8. doi:10.1016/j.bbadis.2008.09.003.
  6. Borroni, B.; et al. (2010). "TARDBP mutations in frontotemporal lobar degeneration: frequency, clinical features, and disease course". Rejuvenation Res. 13 (5): 509–17. doi:10.1089/rej.2010.1017.
  7. Dejesus-Hernandez, M.; et al. (2011). "Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS.". Neuron. 72 (2): 245–56. doi:10.1016/j.neuron.2011.09.011. PMC 3202986Freely accessible. PMID 21944778.
  8. Schroeter ML, Raczka KK, Neumann J, von Cramon DY (2007). "Towards a nosology for frontotemporal lobar degenerations – A meta-analysis involving 267 subjects.". NeuroImage. 36 (3): 497–510. doi:10.1016/j.neuroimage.2007.03.024. PMID 17478101.


Further reading

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