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A human brain showing frontotemporal lobar degeneration causing frontotemporal dementia.

Frontotemporal lobar degeneration (FTLD) is a form of dementia. In the over 65 age group it is probably the fourth most common type of dementia after Alzheimer's disease, Dementia with Lewy bodies and vascular dementia. In the below 65 age group it is the second most common cause after Alzheimer's disease.

There are three clinical variants of FTLD:

• frontotemporal dementia (or behavioural variant FTLD)
• semantic dementia
• progressive nonfluent aphasia

There are a number of possible pathological findings at post-mortem:

• tau inclusions (either with Pick bodies or without)
• ubiquitin positive (tau-negative) inclusions - these ubiquitinated inclusions have recently been found to be a protein called TDP-43. There are three subtypes of this type of pathology. Mackenzie et al (and subsequently Davidson et al) describe the following: type 1 with intranuclear inclusions; type 2 with neurites predominantly and type 3 with cytoplasmic inclusions predominantly.
• dementia lacking distinctive histology (DLDH)

Many cases (possibly up to 50%) of FTLD are genetic rather than sporadic. Mutations in the Tau gene (on chromosome 17q21 - known as MAPT or Microtubule Associated Protein Tau) can cause FTLD and there are over 40 known mutations at present. A series of new mutations associated with FTLD has been recently described in the progranulin gene which is remarkably also on chromosome 17q21. Patients with progranulin mutations have type 1 TDP-43 positive, tau negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, whereas the mutations seen in the progranulin gene associated with FTLD suggests a deficit in progranulin may be the problem.

• Mackenzie IR, Baborie A, Pickering-Brown S, Plessis DD, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM. Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol (Berl). 2006 Nov;112(5):539-49. Epub 2006 Sep 26.
• Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DM. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl). 2007 Jan 12; [Epub ahead of print]
• Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. "Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria." 'Neurology' (1998) 51(6):1546-54. Available: [1]

• Frontotemporal dementia
• Semantic dementia
• Progressive nonfluent aphasia
• Alzheimer's disease
• Corticobasal degeneration

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