frontotemporal dementia - Humpath.com - Human pathology - Photos - pictures

Definition: Frontotemporal dementia is a group of neurodegenerative disorders characterized by behavioural and personality changes, cognitive impairment and motor defects. NFTs are abundant in the brain of affected individuals.

These are a group of disorders that were first gathered under a single broad term because they shared clinical features (progressive deterioration of language and changes in personality) that corresponded to degeneration and atrophy of temporal and frontal lobes.

Frontotemporal dementias occur in both familial and sporadic forms. Mutations in the tau gene, which codes for tau, a protein associated with microtubules, cause inherited forms of frontotemporal dementia and Pick’s disease.

As with Alzheimer’s disease, about 90 percent of cases of frontotemporal dementia are sporadic, and the rest are familial. Straight filaments composed of hyperphosphorylated mutant tau have been found in the brains of patients with familial frontotemporal dementia.

In some cases, neurofibrillary tangles composed of paired helical filaments have been found; the formation of these filaments seems to depend on the specific mutation and on the specific isoform of the protein.

In sporadic cases of frontotemporal dementia, aggregates of tau are uncommon. Approximately 15 percent of patients with frontotemporal dementia have Pick bodies, which are intracellular collections of partially degraded (ubiquinated) tau fibrils in the brain.

As with frontotemporal dementia, most cases of Pick’s disease are sporadic. Other disorders caused by the misprocessing of tau include progressive supranuclear palsy, progressive subcortical gliosis, and corticobasal degeneration.

Clinical synopsis

Symptoms can be classified (roughly) into two groups which underlie the functions of the frontal lobe: behavioural symptoms (and/or personality change) and symptoms related to problems with executive function.

Behavioural symptoms include lethargy and aspontaneity or oppositely disinhibition. Apathetic patients may become socially withdrawn and stay in bed all day or no longer take care of themselves. Disinhibited patients can make inappropriate (sometimes sexual) comments or perform inappropriate acts.

Patients with FTD can sometimes get into trouble with the police because of inappropriate behaviour such as stealing. Recent findings indicate that psychotic symptoms are rare in FTD, possibly due to limited temporal-limbic involvement in this disorder.

Among the FTD patients, only 2 (2.3%) had delusions, 1 of whom had paranoid ideation; no FTD patient had hallucinations. This was significantly less than the AD patients, 4 (17.4%) of whom had delusions and paranoia.

Executive function is the cognitive skill of planning and organizing. Patients become unable to perform skills that require complex planning or sequencing.

Language skills can be affected in a number of ways with two broad patterns. Some patients remain fluent with normal phonology and syntax but increasing difficulty with naming and word comprehension, known as semantic dementia in which there is atrophy of the anterior temporal lobes, typically with an asymmetric pattern.

Other patients, by contrast, present with a breakdown in speech fluency due to articulation difficulty, phonological and/or syntactic errors but preservation of word comprehension, referred to as progressive nonfluent aphasia.

In addition to the characteristic cognitive dysfunction, a number of primitive reflexes known as frontal release signs are often able to be elicited. Usually the first of these frontal release signs to appear is the palmomental reflex which appears relatively early in the disease course whereas the palmar grasp reflex and rooting reflex appear late in the disease course.

FTD can occur in patients with amyotrophic lateral sclerosis (ALS) in a small number of cases. The prognosis for people with MND is worse when combined with FTD, shortening survival by about a year.

Etiology

Frontotemporal dementia (FTD) can be caused by mutation in the gene encoding microtubule-associated protein tau (MAPT) (MIM.157140) on chromosome 17.

Families with ubiquitin-positive frontotemporal dementia mapping to chromosome 17q21 (FTLDU) (MIM.607485) have mutations in the GRN gene encoding progranulin (MIM.138945).

In one family with FTD, a mutation was identified in the presenilin-1 gene (PSEN1) (MIM.104311) on chromosome 14, which is usually associated with a familial form of early-onset Alzheimer disease (AD3) (MIM.607822).

FTD3 on chromosome 3: mutation in the CHMP2B gene (MIM.609512) at 3p11.2 (MIM.600795)

ALSFTD1 on chromosome 9: amyotrophic lateral sclerosis and/or frontotemporal dementia 1 (ALSFTD1 locus) at 9q21-q22 (MIM.105550).

FTD with MAPT mutations

In 1998, the first mutations in MAPT causing autosomal dominant FTD were identified and 40 different causative MAPT mutations have been reported in 2005.

Nearly all mutations are located in the C-terminus of the protein and include missense, silent and intronic variations in addition to two single codon deletions clustered in or near the microtubule-binding domains.

MAPT disorders are neuropathologically characterized by absence of Aβ deposits but share with AD the invariable presence of different forms of tau aggregates and are therefore called pure tauopathies.

MAPT mutations most typically present with FTD. However, the spectrum of MAPT disease is surprisingly wide and ranges from phenotypes in which FTD is accompanied by severe parkinsonism and motor neuron disease to degenerative disorders that are, as in the case of the MAPT R406W mutation, clinically hardly distinguishable from AD.

FTD without MAPT mutations

Several autosomal dominant FTD families have been described that lack visible tau positive lesions but are still conclusively linked to a chromosomal region that contains MAPT.

In these families, the neuropathological phenotype has been described as either ‘dementia lacking distinctive histopathology’ or ‘FTD with tau-negative and ubiquitin-positive inclusions’, although it is currently unclear if these represent distinct disease entities or are pathological manifestations of the same primary defect.

Consistent with the absence of tau-positive lesions, no causative MAPT mutations have been found in these families, despite extensive sequencing of the whole genomic MAPT locus.

Although this might be explained by a defect in another gene in close proximity to MAPT, others have suggested that this FTD subtype is a ‘no tau tauopathy’ caused by a primary tau defect that leads to loss of brain tau but not tau mRNA. Nevertheless, this finding was not replicated and remains controversial.

MAPT along with several other genes are within a genomic 900-kb region flanked by inverted low-copy repeats (LCRs) that through non-allelic homologous recombination during primate evolution have induced a genomic inversion polymorphism called H1 and H2.

These observations suggest that these LCRs render the MAPT region susceptible to genomic rearrangements and that an as yet unidentified genomic mutation might be the cause of FTD in these families.

Moreover, absence of visible tauopathy does not exclude the possible genetic involvement of MAPT – studies in Drosophila and mouse models have shown that tau-mediated neurodegeneration can be dissociated from visible pathologic tau aggregates.

Because FTD without detectable tau pathology is a frequently observed neuropathological FTD subtype, the identification of the underlying gene defect in MAPT or a neighboring gene is of great importance and will significantly contribute to our understanding of the neurodegenerative process in this type of FTD.

Types (Exemples)

frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)
frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLDU) (MIM.607485)

FTLDU is caused by mutation in the GRN gene encoding progranulin (MIM.138945).