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.
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, 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.
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:
- behavioral variant frontotemporal dementia (bvFTD)
- primary progressive aphasia (PPA) aka language variant frontotemporal dementia (lvFTD)
- motor disorders
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:
- 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 (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
- 1. Neary D, Snowden JS, Gustafson L et-al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998;51 (6): 1546-54. Neurology (full text) - doi:10.1212/WNL.51.6.1546 - Pubmed citation
- 2. The neuropathology of dementia. Cambridge University Press. ISBN:0521819156. Read it at Google Books - Find it at Amazon
- 3. Krishnamoorthy ES, Prince MJ, Cummings JL. Dementia, A Global Approach. Cambridge University Press. (2010) ISBN:0521857767. Read it at Google Books - Find it at Amazon
- 4. Growdon JH, Rossor M. The Dementias 2. Butterworth-Heinemann. (2007) ISBN:075067542X. Read it at Google Books - Find it at Amazon
- 5. Looi JC, Lindberg O, Zandbelt BB et-al. Caudate nucleus volumes in frontotemporal lobar degeneration: differential atrophy in subtypes. AJNR Am J Neuroradiol. 2008;29 (8): 1537-43. doi:10.3174/ajnr.A1168 - Pubmed citation
- 6. Gorno-tempini ML, Hillis AE, Weintraub S et-al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76 (11): 1006-14. doi:10.1212/WNL.0b013e31821103e6 - Free text at pubmed - Pubmed citation
- 7. Irwin DJ, Cairns NJ, Grossman M, McMillan CT, Lee EB, Van Deerlin VM, Lee VM, Trojanowski JQ. Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. (2015) Acta neuropathologica. 129 (4): 469-91. doi:10.1007/s00401-014-1380-1 - Pubmed
- 8. Meeter LH, Kaat LD, Rohrer JD, van Swieten JC. Imaging and fluid biomarkers in frontotemporal dementia. (2017) Nature reviews. Neurology. 13 (7): 406-419. doi:10.1038/nrneurol.2017.75 - Pubmed
- Whitwell JL, Josephs KA. Recent advances in the imaging of frontotemporal dementia. (2012) Current neurology and neuroscience reports. 12 (6): 715-23. doi:10.1007/s11910-012-0317-0 - Pubmed
Related Radiopaedia articles
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.
neurodegenerative MRI brain (an approach)
- measurements and ratios
- midbrain to pons area ratio (for PSP)
- Magnetic Resonance Parkinsonism Index (MRPI) (for PSP)
- frontal horn width to intercaudate distance ratio (FH/CC) (for Huntington disease)
- intercaudate distance to inner table width ratio (CC/IT) (for Huntington disease)
- scoring systems
- measurements and ratios
- typical/classical Alzheimer disease
- variant (e.g. posterior cortical atrophy)
- chronic traumatic encephalopathy (CTE)
- corticobasal degeneration
- frontotemporal lobar degeneration (FTLD) (not all are tau)
- Pick disease
- progressive supranuclear palsy (PSP)
- Alzheimer disease
- cerebral amyloid angiopathy (CAA)
- transthyretine-associated cerebral amyloidosis
- neuronal intranuclear hyaline inclusion disease (NIHID)
- TDP-43 proteinopathies
- spinocerebellar ataxias
- Huntington disease
- hereditary spastic paraplegia
- clinically unclassifiable parkinsonism (CUP)
- Unverricht-Lundborg disease
- prion diseases (not always included as neurodegenerative)