Clinical and Molecular Aspects of Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disease and next to Alzheimer’s disease and vascular dementia, the third most common cause of early-onset progressive dementia. FTD leads to neurodegeneration in the frontal and temporal neocortex and usually encompasses both sides of the frontal and anterior temporal lobes. Psychologically, FTD is characterized by personality changes such as lack of insight, inappropriate behaviour, disinhibition, apathy, executive disabilities and a decline in cognitive functions, with large clinical and neuropathological variations among cases. Neuropathological characteristics include gliosis or microvacuolation of cortical nerve cells. Inclusions staining for tau protein and/or ubiquitin are also common findings. Both sporadic and hereditary forms of FTD have been identified and 30–50% of the FTD cases have a familial background. So far, at least three genetic loci for FTD have been identified, at human chromosomes 3, 9 and 17 in familial forms of the disease. A large number of the familial forms have been linked to chromosome 17q21 and referred to as frontotemporal dementia and Parkinsonism linked to chromosome 17. In the majority of these families, pathogenic mutations in the tau gene were identified. However, tau mutations seem to be a rare cause of disease in the general FTD population. Thus, other genes and/or environmental factors are yet to be identified, which will give further clues to this complex and heterogeneous disorder.

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

“…However, a cause-effect relationship between Aβ deposition, and tau pathology and synaptic dysfunction, may not apply to all cases of AD, and certainly does not apply to patients with frontotemporal lobe dementia who exhibit abundant tau pathology, but no Aβ pathology (Froelich-Fabre et al, 2004). In our study, paroxetine treatment lessened the amount of Aβ in the hippocampus in both males and females.…”

Immunotherapy for neurodegenerative diseases: Focus on α-synucleinopathies

“…Abundant tau-positive neurofibrillary lesions constitute a defining neuropathological characteristic of AD (Grundke-Iqbal et al, 1986; Lee et al, 1988; Mandelkow & Mandelkow, 1993; Wolozin et al, 1986), but filamentous tau pathology is also central to a number of other disorders, such as progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17 (Buée & Delacourte, 1999; Robert & Mathuranath, 2007; Spillantini & Goedert, 1998). FTD is the clinical syndrome caused by degeneration of the frontal lobe of the brain, degeneration that may also extend to the temporal lobe (Froelich-Fabre et al, 2004; Neary et al, 2005; Snowden et al, 2007). Approximately 30–50% of FTD cases present with tau pathology at post-mortem (Froelich-Fabre et al, 2004; Seelaar et al, 2011; Shi et al, 2005; Taniguchi et al, 2004).…”

“…FTD is the clinical syndrome caused by degeneration of the frontal lobe of the brain, degeneration that may also extend to the temporal lobe (Froelich-Fabre et al, 2004; Neary et al, 2005; Snowden et al, 2007). Approximately 30–50% of FTD cases present with tau pathology at post-mortem (Froelich-Fabre et al, 2004; Seelaar et al, 2011; Shi et al, 2005; Taniguchi et al, 2004). In AD, FTD, and other tauopathies, hyperphosphorylated tau accumulates within neurons forming intracellular neurofibrillary tangles (Grundke-Iqbal et al, 1986; Hampel & Teipel, 2004; Iwatsubo et al, 1994; Lee et al, 1988; Mandelkow & Mandelkow, 1993; Wolozin et al, 1986).…”

Management of Frontotemporal Dementia: Targeting Symptom Management in Such a Heterogeneous Disease Requires a Wide Range of Therapeutic Options

“…In addition, brainstem, spinal cord and striatal involvement can produce a myriad of coexistent symptoms including bulbar, corticospinal and extrapyramidal dysfunction that further add to the heterogeneity of clinical phenotypes in FTD and complicate the treatment of FTD [2,6–9,11,14–16,24,25,27–29]. The focal predilection of FTD pathology for discrete brain areas remains a mystery.…”