Frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is the pathological description of a group of neurodegenerative disorders characterised by focal atrophy of the frontal and temporal cortices. FTLD results in variable clinical manifestation as one of the frontotemporal dementias (FTD) with behavioural and language variants, which in turn overlap with some related motor degenerative conditions.

Terminology

The conditions grouped under this term vary from publication to publication, depending on whether clinical, pathological or genetic factors are used in the classification and when they were published. More recent publications, due to the recognition that the type of proteinaceous accumulation correlates with clinical manifestations of FTLDs, has lead to the inclusion of motor variants which encompass amyotrophic lateral sclerosis (ALS), corticobasal degeneration and progressive supranuclear palsy (PSP) ^7,8. 

Terms to use with care

The term frontotemporal dementia (FTD) should be used to denote the clinical syndrome caused by FLLD and should then be followed by the phenotypic variant (behavioural, language etc...). 

Older terms, such as Pick disease should probably be avoided especially when discussing the clinical presentation. Rather it should be reserved for the pathological entity characterised by Pick bodies (a form of tauopathy). 

Epidemiology

The majority of cases are sporadic, however, 20-40% may relate to an autosomal gene. Typically FTLDs occurs in younger patients than Alzheimer, usually with onset between 40 to 60 years of age.

Given the difficulty in clearly defining this group, the incidence is similarly fuzzy, however, it is thought to be the fourth most common cause of progressive dementia (after Alzheimer disease, vascular dementia and Lewy body dementia) accounting for up to 20% of cases.

Clinical presentation

A convenient division based on clinical presentation is into behavioural and language variants. The former demonstrates predominantly frontal lobe changes whereas the latter has a predilection for the temporal lobe (particularly the left), and is further subdivided into a number of clinical distinct entities. As such frontotemporal lobar degeneration can be divided as follows ^3--7:

• behavioural variant frontotemporal dementia (bvFTD)
• primary progressive aphasia (PPA) aka language variant frontotemporal dementia (lvFTD)
  • non-fluent variant primary progressive aphasia (nfvPPA)
  • semantic variant primary progressive aphasia (svPPA)
  • logopaenic variant primary progressive aphasia (lvPPA)
• motor disorders
  • amyotrophic lateral sclerosis (ALS)
  • corticobasal degeneration
  • progressive supranuclear palsy (PSP)

It should be noted that the motor disorders are generally considered separate entities but, however, frequently have features of FTD ⁸. 

Pathology

Over the past decade or two, it has become apparent that FTLD is an umbrella term for a heterogeneous group of disease that can be characterised based on the type of glial and neuronal proteinaceous inclusions or underlying genetic mutation ^7,8. 

Proteinaceous inclusions

Three major types of FTLD can be defined histologically/biochemically on the basis of the type of proteinaceous inclusions ⁸: 

1. FTLD-Tau: misfolded tau protein (see tauopathies)
2. FTLD-TDP: transactive response DNA binding protein 43 (TDP-43)
3. FTLD-FUS: fused in sarcoma protein (rare)

Genetic mutation

Numerous genetic mutations have been identified that usually correlate with both phenotypic and histological/biochemical variants. 

• FTLD-tau: MAPT gene (tau)
• FTLD-TDP: GRN (progranulin), VCP, TARBP (TDP-43) and C9ofr72 genes.

Radiographic features

Although, as the name suggests, the frontal and temporal lobes are predominantly affected, depending on the genetic and clinical phenotype, individuals demonstrate very variable regional atrophy.

As a general rule the following dominant patterns of regional loss are demonstrated ⁸: 

• behavioural variant FTD: bilateral frontal lobes
• semantic variant of PPA: left temporal lobe
• non-fluent variant of PPA: left insula and frontal operculum (including Broca's area)
• FTLD-FUS: bilateral caudate nuclei
• FTLD-TDP due to GRN mutation: right frontal, lateral temporal and temporalparietal lobes, often markedly asymmetric when comparing hemispheres ⁹
• FTLD-TDP due to C9orf72 mutation: bilateral hemispheres (generalized)
• FTLD-tau: due to MAPT mutation: bilateral temporal lobes

In addition to these features that overlap with amyotrophic lateral sclerosis (ALS), corticobasal degeneration, progressive supranuclear palsy (PSP) may be present ⁸.