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 andvariants, which in turn overlap with some related motor variantsdegenerative conditions. Most cases are due to the accumulation of glial and neuronal proteinaceous inclusions, on the basis of which FTLDs can be grouped into FTLD-Tau, FTLD-TDP and FTLD-FUS. 

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) is used inconsistently in the literature, sometimes synonymously with behavioural variant frontotemporal dementia and other times to denote frontotemporal lobar degeneration (FTLD) more generally ^2-3.  It should, ideally, should be used to denote the clinical presentationsyndrome caused by FLLD and should then be followed by the typephenotypic 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 ^{3-4, 7}:

• behavioural variant fronto-temporal lobar degeneration dementia (bvFTLD), (behavioural variant frontotemporal dementia) ¹
• language variant fronto-temporal lobar degeneration (lvFTLD), (primary progressive aphasia (PPA) ⁶
  • agrammatic variant primary progressive aphasia, (progressive non-fluent aphasia (PNFA)
  • semantic variant primary progressive aphasia, (semantic dementia)
  • logopaenic variant primary progressive aphasia (rare)
• motor disorders (although these tend to be thought of as separate entities)
  • amyotrophic lateral sclerosis (ALS)
  • corticobasal degeneration
  • progressive supranuclear palsy (PSP)

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. 

Proteinaceous inclusions

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

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: PGRN (progranulin), VCP, TARBP (TDP-43) and C9ofr72 genes.

Radiographic features

Although, as the name suggests, the frontal and temporal lobes are predominantly affected, there is often striking asymmetry both of involvement of frontal vs temporal lobes, and involvement of left and right hemispheres.

In addition, the degree of frontostriatal dysfunction varies between the different FTLD subgroups, with behavioural variant frontotemporal dementia (bvFTD) having the greatest involvement. As a result, the caudate heads tend to be reduced in size in these patients, to a much greater degree than in the language variants of frontotemporal dementia ⁵. This is in keeping with FTLD-tau encompassing both bvFTD and corticobasal degeneration ⁷.