Chapter 27 - Frontotemporal dementia

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Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive changes in behavior, personality, and language with involvement of the frontal and temporal regions of the brain. About 40% of FTD cases have a positive family history, and about 10% of these cases are inherited in an autosomal-dominant pattern. These gene defects present with distinct clinical phenotypes. As the diagnosis of FTD becomes more recognizable, it will become increasingly important to keep these gene mutations in mind. In this chapter, we review the genes with known associations to FTD. We discuss protein functions, mutation frequencies, clinical phenotypes, imaging characteristics, and pathology associated with these genes.

Introduction

Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by progressive cognitive changes in behavior, personality, and language with distinct involvement of the frontal and temporal regions of the brain. There are three clinical syndromes:

  • 1.

    Behavioral variant FTD (bvFTD) is the most common variant and is characterized by prominent behavioral abnormalities, including behavioral disinhibition, apathy, loss of empathy, stereotyped or compulsive behavior, hyperorality, and dietary changes. There is frontal and/or anterior temporal atrophy on neuroimaging, often worse on the right (Pick, 1892; Rascovsky et al., 2011).

  • 2.

    Nonfluent-agrammatic variant primary progressive aphasia (nfvPPA) is characterized by agrammatism and motor speech deficits with left interior frontal and insular atrophy (Josephs et al., 2006; Ogar et al., 2007; Grossman, 2012).

  • 3.

    Semantic variant primary progressive aphasia (svPPA) is characterized by loss of object and word knowledge with bilateral anterior temporal atrophy (Hodges et al., 1992).

FTD is the second most common cause of dementia in individuals under the age of 65 (Harvey et al., 2003). The age of onset varies within variants. bvFTD normally presents from age 50 to 70s (Johnson et al., 2005), although about 10% of patients will present with symptoms after age 70 (Seelaar et al., 2008). The overall median survival in FTD is about 6–11 years from symptom onset and 3–4 years from diagnosis (Hodges et al., 2003; Rascovsky et al., 2005; Roberson et al., 2005; Ng et al., 2015). Within the variants, bvFTD has been reported to have a median survival of 8.2–8.7 years from onset, nfvPPA has a median survival of 9.4–10.6 years, and svPPA has a median survival of 6.9–11.9 years (Hodges et al., 2003; Roberson et al., 2005). These numbers likely differ among the variants due to differences in underlying pathology (Hodges et al., 2003; Seelaar et al., 2008).

About 40% of cases of FTD have a positive family history (Rohrer et al., 2009), and about 10% of these cases are thought to be inherited in an autosomal-dominant pattern (Goldman et al., 2005; Seelaar et al., 2008). Within the variants, bvFTD is most likely to be inherited (Seelaar et al., 2008; Rohrer et al., 2009), svPPA is most likely to be sporadic, and nfvPPA has an intermediate likelihood of being inherited. The same primary gene defect can present with distinct clinical phenotypes. Genetic factors may also affect the phenotype of FTD in various ways, including age of onset, disease duration, regions and patterns of brain atrophy, and development of associated clinical features such as parkinsonism and psychiatric symptoms.

FTD was rarely diagnosed in prior generations and has a high rate of misdiagnosis, which may mask a family history of disease. In addition, the clinical phenotype of FTD may differ even within the same family, adding to potential difficulty in accurate diagnosis and recognition of a familial syndrome. Even without an obvious familial pattern of inheritance, the clinician should consider referral for genetic testing and counseling, as a genetic cause is found in about 6% of patients without a known family history of FTD (Rademakers et al., 2012).

Currently, testing for genetic causes of FTD in the clinical setting is limited by cost of testing, inconsistent coverage of genetic testing by insurance companies, and concerns regarding genetic privacy (Fong et al., 2012). When pursuing genetic testing, the first step is to obtain a three-generation pedigree that includes any history of FTD, amyotrophic lateral sclerosis (ALS), other dementing illnesses, psychiatric disorders, parkinsonism, and suicide (Fong et al., 2012). If possible, diagnoses should be confirmed through medical records and pathology reports. If there is a family history of FTD or ALS, we recommend testing for chromosome 9 open reading frame 72 (C9ORF72) expansion and would consider testing for progranulin (GRN) and microtubule-associated protein tau (MAPT) mutations (Table 27.1). In cases of very young onset (age < 45 years), we would recommend whole-exome sequencing if financially feasible. Testing for other genetic etiologies can be performed in the research setting. Genetic counselors should be involved throughout the process.

Section snippets

MAPT

MAPT is the gene that encodes the protein tau, which is involved in microtubule stabilization and assembly and intracellular signaling. Mutations in tau can lead to disease through several mechanisms: (1) affect the alternative splicing of tau, resulting in an imbalance of the normal 3R/4R tau ratios (Goedert et al., 1989); (2) promote aggregation of tau in the cytoplasm; and (3) cause errors in the phosphorylation of tau, leading to microtubule instability (Buée and Delacourte, 1999; Goedert

GRN

After the discovery of the MAPT gene as a cause for some cases of autosomal-dominant FTD, there remained many cases with linkage to chromosome 17 that were negative for an MAPT mutation. A GRN gene mutation was first discovered in 2006 by Baker and colleagues in a region that was approximately 6.2 Mb away from the MAPT locus. The GRN gene is located on 17q21.31 and encodes for the protein progranulin, a growth regulation factor that activates signaling cascades that are important for several

C9ORF72

C9ORF72 is a gene located on 9p21.2. Mutation of C9ORF72 leads to a hexanucleotide repeat expansion GGGGCC in a noncoding region of the gene (DeJesus-Hernandez et al., 2011). It encodes for a protein of unknown function. The protein encoded by C9ORF72 is enriched at the presynaptic terminal (DeJesus-Hernandez et al., 2011). There are several mechanisms by which C9ORF72 is proposed to cause FTD and ALS. C9ORF72 mutations likely cause a toxic RNA gain of function, resulting in the accumulation of

VCP

Valosin-containing protein gene (VCP) is located on 9p13.3. It encodes for a protein that is a member of the AAA + (ATPase associated with various activities) family of proteins which are involved in a variety of cellular activities, including cell cycle control, membrane fusion, and the ubiquitin-proteasome degradation pathway (Watts et al., 2004; Weihl, 2009; Nalbandian et al., 2011).

The first reported cases of FTD associated with VCP mutations were described in association with a rare

CHMP2B

The gene encoding chromatin-modifying protein 2B, or charged multivesicular body protein 2B (CHMP2B), is located at 3p11.2. It belongs to a family of proteins that contribute to endosomal sorting complex required for transport III (ESCRT-III). This complex is expressed in neurons, especially in the frontal and temporal lobes, hippocampus, and cerebellum. The ESCRT-III complex participates in the autophagic/late endosome pathway through degradation of cell surface receptor protein during the

TARDBP

TAR DNA-binding protein (TARDBP) is located on 1p36.22 and encodes for TDP-43, a protein that is important for RNA processing and metabolism (Xia et al., 2016). This protein is normally localized to the nucleus, but under stress conditions, a hyperphosphorylated, ubiquitinated and cleaved form of TDP-43 aggregates in the cytoplasm (Neumann et al., 2006; Benajiba et al., 2009).

Mutations were initially identified in ALS. Subsequently, a large French study found TARDBP mutations in 2 patients who

FUS

The FUS gene is located on 16p11.2 and encodes the protein fused in sarcoma, which plays a role in various cellular processes, including cell proliferation (Bertrand et al., 1999), DNA repair (Baechtold et al., 1999), transcription regulation, RNA splicing (Yang et al., 1998), and RNA transport (Zinszner et al., 1997). It may also play a role in neuronal plasticity and maintenance of dendritic integrity (Fujii and Takumi, 2005; Fujii et al., 2005). Mutations in FUS cause redistribution of FUS

SQSTM1

The sequestosome 1 (SQSTM1) gene is located on 5q35.3 and encodes for p62, a ubiquitin binding protein that is important for nuclear factor-κB (NF-κB) signaling, apoptosis, and autophagy. One potential way in which SQSTM1 mutations may lead to disease is through altered autophagy, resulting in pathogenic protein aggregation (Rea et al., 2014).

Mutations in SQSTM1 were first identified in Paget disease of bone. Later, mutations were found in ALS (Fecto et al., 2011; Hirano et al., 2013) and in

UBQLN2

UBQLN2 is located on Xp11.21 and encodes for ubiquilin-2, a member of the ubiquilin family of proteins which are important for proteasomal degradation of ubiquitinated proteins. Mutations in the UBQLN2 gene result in impaired protein degradation (Deng et al., 2011; Hjerpe et al., 2016).

Deng et al. (2011) identified the gene UBQLN2 as a dominant X-linked FTD/ALS gene with incomplete penetrance. The gene was then shown to be associated with a pure FTD phenotype (Synofzik et al., 2012). The

TBK1

Tank-binding kinase 1 (TBK1) is located on 12q14.2 and encodes for a kinase with multiple functions, including degradation of ubiquitinated cargo as a part of the innate immune response (Weidberg and Elazar, 2011). Substrates of TBK1 include p62 and optineurin, which are also involved in autophagy (Freischmidt et al., 2015).

In 2015, Freischmidt and colleagues described eight loss-of-function mutations that resulted in haploinsufficiency of TBK1 that were associated with familial ALS and FTD.

TREM2

Triggering receptor expressed on myeloid cells-2 (TREM2) is located on chromosome 6p21.2 and encodes the TREM2 protein, a membrane protein that forms a receptor-signaling complex with TYRO protein tyrosine kinase-binding protein (TYROBP). This complex is important in activation of the immune response, dendritic cell and osteoclast differentiation, and microglial phagocytosis. Precisely how TREM2 mutations lead to FTD is currently unknown, but it has been hypothesized that lack of TREM2 leads to

CHCHD10

CHCHD10, located on chromosome 22q11.23, encodes for coiled-coil-helix-coiled-coil-helix domain-containing protein 10, which is enriched at mitochondrial cristae junctions (Bannwarth et al., 2014). Mutations in CHCHD10 cause altered structure of the mitochondrial cristae, leading to instability of mitochondrial DNA which in turn causes fragmentation of mitochondria and decreased activities in mitochondrial complex IV (Bannwarth et al., 2014; Ajroud-Driss et al., 2015). The exact manner in which

Genetic risk factors for FTD

Several potential risk factors for FTD have been investigated. Studies on the role of the APOE4 allele in FTD have been mixed. APOE4 has been associated with increased risk for FTD in several studies (Farrer et al., 1995; Helisalmi et al., 1996; Gustafson et al., 1997; Stevens et al., 1997, Fabre et al., 2001; Bernardi et al., 2006), but others have not found this association (Geschwind et al., 1998; Riemenschneider et al., 2002; Short et al., 2002). One study suggested that the E4 allele

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