Frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is the name for a group of clinically, pathologically and genetically heterogeneous disorders associated with atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.

In the over 65 age group, FTLD is probably the fourth most common cause 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. In some patients the symptoms of FTLD and Alzheimer's may overlap

There are three clinical subtypes described:
 * behavioural-variant frontotemporal dementia
 * semantic dementia
 * progressive nonfluent aphasia.

Histology
There are 3 main histological subtypes found at post-mortem:
 * tau inclusions (Pick's disease, MAPT mutations, corticobasal degeneration, progressive supranuclear palsy)
 * ubiquitin positive (tau-negative) inclusions - in the majority of cases that have this type of pathology the ubiquitinated inclusions contain a protein called TDP-43. There are four subtypes of this type of pathology described in the recent consensus criteria by Cairns et al.: type 1 with neurites predominantly, type 2 with cytoplasmic inclusions predominantly; type 3 with intranuclear inclusions and type 4 associated with VCP mutations. Not all ubiquitin-positive, tau negative cases stain for TDP-43 e.g. the CHMP2B cases but also other cases: many of these have been very recently recognized to contain the protein FUS.
 * Dementia lacking distinctive histology (DLDH) - a rare and controversial entity - new analyses have allowed many cases to be reclassified into one of the positively-defined subgroups.

Genetics
Many cases (possibly up to 40%) of FTLD are genetic rather than sporadic. There are 2 major genes in which mutations cause FTLD:
 * 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 3 ubiquitin-positive, TDP-43 positive, tau-negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, however the mutations seen in the progranulin gene associated with FTLD suggests a deficit in progranulin may be the problem.

There are currently 2 other known genes that can cause FTLD: These 2 genes only account for a tiny proportion of cases.
 * CHMP2B (on chromosome 3) which is associated with a behavioural syndrome (mainly in a large Jutland cohort)
 * VCP (valosin-containing protein, on chromosome 9) which is associated with the IBMPFD syndrome (inclusion body myopathy, Paget's disease and frontotemporal dementia).

A locus on chromosome 9 is associated with FTD-MND (or FTD-ALS) i.e. frontotemporal dementia associated with motor neurone disease (or amyotrophic lateral sclerosis) - the hunt for this gene is currently the focus of a number of research labs around the world.

Imaging
For diagnostic purposes, magnetic resonance imaging (MRI) and ([18F]fluorodeoxyglucose) positron emission tomography (FDG-PET) are applied. They measure either atrophy or reductions in glucose utilization. The three clinical subtypes of frontotemporal lobar degeneration, frontotemporal dementia, semantic dementia and progressive nonfluent aphasia, are characterized by impairments in specific neural networks. The first subtype with behavioral deficits, frontotemporal dementia, mainly affects a frontomedian network discussed in the context of social cognition. Semantic dementia is mainly related to the inferior temporal poles and amygdalae; brain regions that have been discussed in the context of conceptual knowledge, semantic information processing, and social cognition, whereas progressive nonfluent aphasia affects the whole left frontotemporal network for phonological and syntactical processing.

Examples
United States Senator Pete Domenici (R-NM) is a known sufferer of FTLD, and the illness is the main reason behind his October 4, 2007 announcement of retirement at the end of his term.