Frontotemporal lobar degeneration
Encyclopedia
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 lobe
s.
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:
There are currently 2 other known genes that can cause FTLD:
These 2 genes only account for a tiny proportion of cases.
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.
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.
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
and temporal lobe
Temporal lobe
The temporal lobe is a region of the cerebral cortex that is located beneath the Sylvian fissure on both cerebral hemispheres of the mammalian brain....
of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, with sparing of the parietal
Parietal lobe
The parietal lobe is a part of the Brain positioned above the occipital lobe and behind the frontal lobe.The parietal lobe integrates sensory information from different modalities, particularly determining spatial sense and navigation. For example, it comprises somatosensory cortex and the...
and occipital lobe
Occipital lobe
The occipital lobe is the visual processing center of the mammalian brain containing most of the anatomical region of the visual cortex. The primary visual cortex is Brodmann area 17, commonly called V1...
s.
In the over 65 age group, FTLD is probably the fourth most common cause of dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
after Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, dementia with Lewy bodies
Dementia with Lewy bodies
Dementia with Lewy bodies , also known under a variety of other names including Lewy body dementia, diffuse Lewy body disease, cortical Lewy body disease, and senile dementia of Lewy type, is a type of dementia closely allied to both Alzheimers and Parkinson's Diseases...
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 dementiaFrontotemporal dementiaFrontotemporal dementia is a clinical syndrome caused by degeneration of the frontal lobe of the brain and may extend back to the temporal lobe...
- semantic dementiaSemantic dementiaSemantic dementia is a progressive neurodegenerative disorder characterized by loss of semantic memory in both the verbal and non-verbal domains...
- progressive nonfluent aphasiaProgressive nonfluent aphasiaProgressive nonfluent aphasia is one of three clinical syndromes associated with frontotemporal lobar degeneration. The major symptom is progressive difficulties with the production of speech.-Clinical features:...
.
Histology
There are 3 main histological subtypes found at post-mortem:- tauTau proteinTau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
inclusions (Pick's diseasePick's diseasePick's disease, is a rare neurodegenerative disease that causes progressive destruction of nerve cells in the brain. Symptoms include loss of speech , and dementia. While some of the symptoms can initially be alleviated, the disease progresses and patients often die within two to ten years...
, MAPT mutations, corticobasal degenerationCorticobasal degenerationCorticobasal degeneration or Corticobasal Ganglionic Degeneration is a rare progressive neurodegenerative disease involving the cerebral cortex and the basal ganglia. It is characterized by marked disorders in movement and cognitive dysfunction...
, progressive supranuclear palsyProgressive supranuclear palsyProgressive supranuclear palsy is a degenerative disease involving the gradual deterioration and death of specific areas of the brain....
) - ubiquitinUbiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
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 FUSFUSRNA-binding protein FUS is a protein that in humans is encoded by the FUS gene.- Function :The N-terminal end of FUS appears to be involved in transcriptional activation, while the C-terminal end is involved in protein and RNA binding...
. - 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:
- 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).
These 2 genes only account for a tiny proportion of cases.
A locus on chromosome 9 is associated with FTD-MND (or FTD-ALS) i.e. frontotemporal dementia associated with motor neurone disease
Motor neurone disease
The motor neurone diseases are a group of neurological disorders that selectively affect motor neurones, the cells that control voluntary muscle activity including speaking, walking, breathing, swallowing and general movement of the body. They are generally progressive in nature, and can cause...
(or amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
) - 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 StatesUnited States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
Senator Pete Domenici
Pete Domenici
Pietro Vichi "Pete" Domenici is an American Republican politician, who served six terms as a United States Senator from New Mexico, from 1973 to 2009, the longest tenure in the state's history....
(R
Republican Party (United States)
The Republican Party is one of the two major contemporary political parties in the United States, along with the Democratic Party. Founded by anti-slavery expansion activists in 1854, it is often called the GOP . The party's platform generally reflects American conservatism in the U.S...
-NM
New Mexico
New Mexico is a state located in the southwest and western regions of the United States. New Mexico is also usually considered one of the Mountain States. With a population density of 16 per square mile, New Mexico is the sixth-most sparsely inhabited U.S...
) 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.
Further reading
- Hodges, John R. The Frontotemporal Dementia Syndromes. Cambridge University Press. 2007 ISBN 978-0-521-85477-1