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Key Points

  • Disease summary:

    • Frontotemporal lobar degeneration (FTLD) is a nonamnestic primary neurodegenerative disorder that is clinically, neuropathologically, and genetically heterogeneous. Characteristic symptoms include progressive behavioral disturbance and/or language impairment, with variable underlying neuropathologic substrates.

    • Clinically FTLD is comprised of two major subtypes:

      • The behavioral variant (bvFTD), a progressive cognitive or behavioral syndrome

      • Primary progressive aphasia (PPA), a degenerative language disorder

      • PPA variants are further subdivided into three variants based on the specific language abnormality present: the nonfluent-agrammatic variant (naPPA), semantic variant (svPPA), and logopenic variant (lvPPA). lvPPA is considered an atypical presentation of Alzheimer disease (AD) and will not be further discussed as an FTLD clinical syndrome.

    • FTLD patients may present with or acquire concomitant motor disorders including parkinsonism or the motor neuron disease, amyotrophic lateral sclerosis (ALS-FTLD). There is also overlap with the extrapyramidal movement disorders progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).

    • FTLD clinical spectrum disorders occur most commonly in patients before the age of 65 years, and have a similar prevalence to AD in this age group.

    • The only known nongenetic risk factor for FTLD is a history of head trauma.

    • Neuropathologically FTLD can be broadly divided into two major categories: tauopathies (FTLD-tau), a class of neurodegenerative diseases which contain aggregations of the abnormally modified microtubule-binding protein tau, and FTLD-TDP, characterized by inclusion bodies formed from the DNA-binding protein, TDP-43.

    • FTLD-tau consists of clinical FTLD-spectrum disorders with neuropathologic diagnoses of Pick disease, corticobasal degeneration (CBD), PSP, argyrophilic grain disease, multisystem tauopathy, or FTLD with parkinsonism linked to chromosome 17 (FTDP-17).

    • FTLD-TDP has four major subtypes (A-D) based on the morphology of TDP-43 positive inclusions and cortical layers involved. All FTLD-spectrum clinical disorders can be associated with each of these subtypes, while most genetic etiologies of FTLD-TDP are generally associated with a specific neuropathologic subtype.

    • A minority of FTLD cases have inclusions composed of the fused in sarcoma (FUS) protein (FTLD-FUS), a RNA-binding protein similar to TDP-43, and in a small number of others the pathologic protein has not yet been identified.

  • Hereditary basis:

    • Approximately 40% of FTLD patients have a family history of dementia and/or movement disorder and in 10% to 30% of cases an autosomal dominant inheritance pattern is detected. The remaining cases are apparent sporadic cases.

    • Autosomal dominant mutations in five genes have been associated with FTLD: MAPT, GRN, C9orf72, VCP, and CHMP2B. Of these, mutations in MAPT, GRN, and a hexanucleotide expansion mutation in C9orf72 are the most common, while mutations in VCP and CHMP2B are rare. Together these genes explain only about 30% of familial FTLD cases suggesting that there are still additional genes to be discovered.

    • Mutations in a few additional genes, TARDBP and FUS, which are primarily associated with ALS phenotypes have been identified in a few FTLD cases.

  • Differential diagnosis:

    • Includes other primary neurodegenerative conditions (AD, dementia with Lewy bodies [DLB], Parkinson disease dementia), nondegenerative primary central nervous system (CNS) ...

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