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Epidemiology and subtypes of dementia
Published in Marjolein de Vugt, Janet Carter, Understanding Young Onset Dementia, 2021
FTD is pathologically heterogeneous and the histopathology of FTD is broadly grouped by the type of cellular inclusions present: frontotemporal lobar degeneration with tau, transactive response DNA‐binding protein with Mr 43 kD (TDP‐43) or FET protein accumulation (Mackenzie & Neumann, 2016; Mackenzie et al., 2011). Correlating FTD clinical phenotypes with their underlying molecular pathology is notoriously difficult and the precise role of the pathogenic deposition of these proteins in causing neurodegeneration and cell death continue to be defined (Mackenzie & Neumann, 2016). Although FTD is mostly sporadic, approximately 30–40% of patients with FTD report a family history (Rohrer et al., 2009; Wood et al., 2013). Roughly 20% of FTD cases are thought to be associated with identifiable genetic mutations, the most common genetic causes of FTD are progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) and account for 15% of cases (Wood et al., 2013). The remaining 5% are associated with a multitude of gene mutations: VCP (2004), CHMP2B (2005), TARDBP (2008), FUS (2009), SQSTM1 (2012), CHCHD10 (2014), TBK1 (2015), OPTN (2015), CCNF (2016), TIA1 (2017) (Greaves & Rohrer, 2019; Rohrer et al., 2009; Warren et al., 2013).
Applications of imaging genomics beyond oncology
Published in Ruijiang Li, Lei Xing, Sandy Napel, Daniel L. Rubin, Radiomics and Radiogenomics, 2019
Xiaohui Yao, Jingwen Yan, Li Shen
One GWAS has identified a novel gene transmembrane protein 106B (TMEM106B) associated with FTD-TDP, as well as increased risk of FTLD-TDP in individuals with GRN mutations [89]. Several other rare FTD risk genes, including charged multivesicular body protein 2B (CHMP2B), valosin containing protein (VCP), sequestosome 1 (SQSTM1), transactive response DNA-binding protein (TARDP), FUS, Tank-binding kinase 1 gene (TBK1), and coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), have also been reported in small family studies [81, 86–88, 90–92]. Diekstra et al. [93] performed a meta-analysis of GWAS and reported two shared genetic associations of FTD and ALS including C9orf72 and a novel gene unc-13 homolog A (UNC13A). Although the above common and rare genetic findings have contributed to the risk of different types of FTLD, some portion of disease heritability is still unexplained. In addition, the molecular mechanism of disease is not fully understood due to limited statistical power of case-control study and complex pathology of FTD.
Genetics of frontotemporal dementia in China
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Yaling Jiang, Bin Jiao, Xuewen Xiao, Lu Shen
CHCHD10 is a mitochondrial protein located in the intermembrane space and enriched at cristae junctions. Various mutations of CHCHD10 have been identified in a broad spectrum of neurological disorders, including FTD, ALS, Alzheimer’s disease (AD), and motor neuron diseases (MND) (63–65). Previous studies of mutant CHCHD10 protein have implicated both loss-of-function and gain-of-toxic-function mechanisms (66–72). The S59L mutation was a well-known ALS-FTD associated mutation of the CHCHD10 gene, which was reported in patients with mitochondrial myopathy associated with MND at first (73). In vitro and in vivo studies showed that overexpression of the S59L mutation led to mitochondrial dysfunction (72–74). However, many patients who carried CHCHD10 mutations did not have characteristics of mitochondrial disorders (5,66). Woo, J. A. et. al (75) demonstrated that CHCHD10 mutations (R15L and S59L) resulted in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation, suggesting that the pathogenic mechanism of CHCHD10 mutations may be closely related to TDP-43 abnormalities (66,75).