Abstract
Frontotemporal dementia (FTD) is a common cause of presenile dementia and is characterized by behavioural and/or language changes and progressive cognitive deficits. Genetics is an important component in the aetiology of FTD, with positive family history of dementia reported for 40% of cases. This review synthesizes current knowledge of the known major FTD genes, including C9orf72 (chromosome 9 open reading frame 72), MAPT (microtubule-associated protein tau) and GRN (granulin), and their impact on neuronal and glial pathology. Further, evidence for white matter dysfunction in the aetiology of FTD and the clinical, neuroimaging and genetic overlap between FTD and leukodystrophy/leukoencephalopathy are discussed. The review highlights the role of common variants and mutations in genes such as CSF1R (colony-stimulating factor 1 receptor), CYP27A1 (cytochrome P450 family 27 subfamily A member 1), TREM2 (triggering receptor expressed on myeloid cells 2) and TMEM106B (transmembrane protein 106B) that play an integral role in microglia and oligodendrocyte function. Finally, pharmacological and non-pharmacological approaches for enhancing remyelination are discussed in terms of future treatments of FTD.
Highlights
Frontotemporal dementia (FTD) syndromes are a heterogeneous group of proteinopathies, characterized by progressive degeneration of the frontal and/or temporal lobes.Clinically, they are divided into three subtypes
Less common causal genes such as those for valosin-containing protein (VCP), chromatin-modifying protein 2B (CHMP2B), TAR-DNAbinding protein 43 (TARDBP), fused in sarcoma (FUS), coiled-coil-helix-coiled-coil-helix domain-containing 10 (CHCHD10) and triggering receptor expressed on myeloid cells 2 (TREM2) are known to contribute to
Over 50% of GRN variant carriers present behavioural variant FTD (bvFTD) followed by progressive non-fluent aphasia (PNFA), and less than 10% are affected by corticobasal syndrome (CBS), Alzheimer’s disease (AD) and schizophrenia [24,60]
Summary
Frontotemporal dementia (FTD) syndromes are a heterogeneous group of proteinopathies, characterized by progressive degeneration of the frontal and/or temporal lobes The main clinical subtype for MAPT mutation carriers is the behavioral variant (bvFTD), which can be concomitant with a dominant Parkinsonism phenotype such as CBS or PSP [22,23,24]. Neuroimaging studies in these patients have shown relatively symmetrical anteromedial temporal lobe and orbito-frontal grey matter atrophy [25,26] that is responsible for the behavioral and semantic deficits in these patients. FTD genes associated with this form of FTD neuropathology include GRN, C9orf and TBK1, whose features will be discussed below
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