Atrophy of the brain's frontal and temporal lobes
Medical condition
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 TAR DNA-binding protein 43 (TDP-43). Mutations in the "C9orf72" gene have been established as a major genetic contribution of FTLD, although defects in the granulin (GRN) and microtubule-associated proteins (MAPs) are also associated with it.
Classification.
There are 3 main histological subtypes found at post-mortem:
*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.
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.
In December 2021 the structure of TDP-43 was resolved with cryo-EM 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.
Genetics.
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).
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. 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.
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. American film director, producer, and screenwriter Curtis Hanson died as a result of FTLD on September 20, 2016. British journalist Ian Black died from the disease on January 22, 2023.
References.
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