Frontotemporal lobar degeneration
Pathological process causing frontotemporal dementia with brain atrophy.
Frontotemporal lobar degeneration (FTLD) is the underlying disease process behind frontotemporal dementia. It involves shrinkage of the frontal and temporal lobes of the brain, while the parietal and occipital lobes remain unaffected. The condition is marked by abnormal protein buildup, most commonly tau proteins or TAR DNA-binding protein 43 (TDP-43). A major genetic contributor is a mutation in the C9orf72 gene, though defects in the granulin (GRN) and microtubule-associated protein (MAPT) genes are also linked to it.
**Classification**
After death, three main histological subtypes are identified:
- **FTLD-tau**: Defined by tau-positive inclusion bodies, known as Pick bodies. This group includes Pick’s disease, corticobasal degeneration, and progressive supranuclear palsy. - **FTLD-TDP** (also called FTLD-U): Features ubiquitin and TDP-43 positive, tau-negative, FUS-negative inclusions. Its diverse pathology is split into five subtypes based on microscopic findings: - Type A: Many small neurites and neuronal cytoplasmic inclusions in the upper cortical layers, with occasional bar-like neuronal intranuclear inclusions. - Type B: Many neuronal and glial cytoplasmic inclusions in both upper and lower cortical layers, plus lower motor neurons; intranuclear inclusions are rare or absent. Often linked to ALS and C9orf72 mutations. - Type C: Many long neuritic profiles in the superficial cortical layers, with very few or no cytoplasmic or intranuclear inclusions. Often seen in semantic dementia. - Type D: Many neuronal intranuclear inclusions and dystrophic neurites, with a notable absence of inclusions in the hippocampus’s granule cell layer. Associated with VCP mutations. - Type E: Neuronal granulofilamentous inclusions and abundant fine grains in both upper and lower cortical layers. Linked to a rapid clinical course in the behavioral variant of frontotemporal dementia. Two independent groups originally categorized TDP-43 disorders, and both classifications were accepted. A compromise classification was later proposed to reduce confusion. - **FTLD-FUS**: Characterized by FUS-positive cytoplasmic inclusions, intranuclear inclusions, and neuritic threads in the cortex, medulla, hippocampus, and motor cells of the spinal cord and twelfth cranial nerve.
In late 2021, the structure of TDP-43 was resolved using cryo-electron microscopy, but soon afte
- field
- Neuropathology
- known_for
- Pathological process underlying frontotemporal dementia, characterized by frontal and temporal lobe atrophy and protein inclusions
Quick Facts
- Speciality
- Neurology, Psychiatry
- Complications
- Brain death
Facts from the source article.
Lore & Background
FTLD is classified into three main histological subtypes found at post-mortem: FTLD-tau, characterized by tau positive inclusion bodies (Pick-bodies); FTLD-TDP (or FTLD-U), characterized by ubiquitin and TDP-43 positive, tau negative, FUS negative inclusion bodies; and FTLD-FUS, characterized by FUS positive cytoplasmic inclusions. The FTLD-TDP subtype is further subdivided into types A through E based on detailed histological findings, with type D associated with VCP mutations and type E associated with behavioral variant of frontotemporal dementia with a rapid clinical course.
Reader's Guide
Frontotemporal lobar degeneration is significant as the primary pathological process underlying frontotemporal dementia, a major cause of early-onset dementia. Its classification into proteinopathy-based subtypes (FTLD-tau, FTLD-TDP, FTLD-FUS) has guided research into disease mechanisms and genetic causes. The discovery of C9orf72 hexanucleotide repeat expansions as a major genetic contributor, along with mutations in MAPT, PGRN, CHMP2B, and VCP, has advanced understanding of familial and sporadic cases. The legacy of FTLD includes its role in highlighting the heterogeneity of neurodegenerative diseases, with ongoing debate about the precise protein involved in FTLD-TDP (TDP-43 versus TMEM106B). Notable individuals affected include U.S. Senator Pete Domenici, film director Curtis Hanson, and journalist Ian Black.
Did You Know?
- FTLD is characterized by atrophy in the frontal lobe and temporal lobe, with sparing of the parietal and occipital lobes.
- Mutations in the C9orf72 gene have been established as a major genetic contributor to FTLD.
- In FTLD-TDP, the primary pathological protein is TDP-43; while TMEM106B is a risk factor gene and can form amyloid filaments in some diseases, it does not replace TDP-43 as the key protein involved.
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