Frontotemporal lobar degeneration
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Frontotemporal lobar degeneration (FTLD) is the pathological description of a group of neurodegenerative disorders characterized by focal atrophy of the frontal and/or temporal cortices. These results in variable clinical manifestations collectively known as frontotemporal dementia (FTD) syndromes.
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 that 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 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 disease, usually with onset between 40 to 60 years of age (60%) and 10% being diagnosed <45 years old. Prevalence is estimated at between 1-26 cases per 100,000 population 10.
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.
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:
primary progressive aphasia (PPA) or language variant frontotemporal dementia (lvFTD)
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 diseases 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:
FTLD-tau: misfolded tau protein (see tauopathies)
FTLD-TDP: transactive response DNA binding protein 43 (TDP-43)
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 (granulin), C9ofr72, VCP, and TARBP (TDP-43) 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
History and etymology
Frontotemporal dementia was first described by Arnold Pick (1851-1924), Czech psychiatrist, neurologist and neuropathologist, in 1892 11,12.