Frontotemporal lobar degeneration

Dr Henry Knipe and A.Prof Frank Gaillard et al.

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

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

The term frontotemporal dementia (FTD) should be used to denote the clinical syndrome caused by FTLD and should then be followed by the phenotypic variant (behavioral, 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 characterized by Pick bodies (a form of tauopathy). 

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 diseasevascular dementia and Lewy body dementia) accounting for up to 20% of cases.

A convenient division based on clinical presentation is into behavioral 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:

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

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 characterized based on the type of glial and neuronal proteinaceous inclusions or underlying genetic mutation 7,8

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)

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.

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

  • behavioral 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 parietal 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 degenerationprogressive supranuclear palsy (PSP) may be present 8

Neurodegenerative diseases

Neurodegenerative diseases are legion and their classification just as protean. A useful approach is to divide them according to underlying pathological process, although even using this schema, there is much overlap and thus resulting confusion.

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Article information

rID: 3969
Synonyms or Alternate Spellings:
  • Frontotemporal lobar degeneration (FTLD)
  • Fronto-temporal lobar degeneration (FTLD)

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Cases and figures

  • Figure 1: gross pathology
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  • Figure 2: phenotypic overlap
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  • Case 1: temporal variant
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  • Case 2: frontotemporal dementia
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  • Case 3
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  • Case 4
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  • Case 5
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