Frontotemporal dementia

Handbook of Clinical Neurology, Vol. 167 (3rd series) Geriatric Neurology S.T. DeKosky and S. Asthana, Editors https://doi.org/10.1016/B978-0-12-804766-8.00015-7 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 15

Frontotemporal dementia EMMA M. DEVENNEY1†, REBEKAH M. AHMED2†, AND JOHN R. HODGES1* 1 Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia 2

Department of Clinical Neuroscience, Royal Prince Alfred Hospital, Sydney, NSW, Australia

Abstract Frontotemporal dementia (FTD) is the second commonest cause of young onset dementia. Our understanding of FTD and its related syndromes has advanced significantly in recent years. Among the most prominent areas of progress is the overlap between FTD, MND, and other neurodegenerative conditions at a clinicopathologic and genetic level. In parallel major advances in neuroimaging techniques, the discovery of new genetic mutations as well as the development of potential biomarkers may serve to further expand knowledge of the biologic processes at play in FTD and may in turn propel research toward identifying curative and preventative pharmacologic therapies. The aim of this chapter is to discuss the clinical, pathologic, and genetic complexities of FTD and related disorders.

Frontotemporal dementia (FTD) is the second commonest cause of young onset dementia (Ratnavalli et al., 2002; Rosso et al., 2003). The term FTD refers to a group of progressive neurodegenerative disorders characterized by atrophy of the frontal and anterior temporal lobes, most commonly associated with the intraneuronal deposition of Tau (τ) or TAR DNA-binding protein 43 (TDP-43 protein). There are two main clinical syndromes of FTD, which are classified based on their predominant clinical presentation: behavioral variant FTD (bvFTD), where there is deterioration in social function and personality; and primary progressive aphasia (PPA), where there is an insidious decline in language skills. PPA is further divided based on the pattern of language breakdown into semantic dementia (semantic variant; PPA-S), nonfluent or agrammatic aphasia (PPA-G), and logopenic aphasia (PPA-L) (Hodges and Patterson, 2007; Gorno-Tempini et al., 2011) (Table 15.1). Each of these syndromes has distinct clinical symptoms, imaging, and pathologic findings; however, in clinical practice there is considerable overlap and heterogeneity. It should be noted that although language and behavioral features can overlap within the various subtypes the

consensus criteria state that for a diagnosis of PPA to be made the language disorder should be the predominant cause of disability for at least 2 years. Increasingly it is also being recognized that a number of overlap syndromes exist including the motor neuron disease (MND)-FTD spectrum (Devenney et al., 2015) and the presence of behavioral and language presentations in parkinsonian plus syndromes (Kertesz and McMonagle, 2010).

CLINICAL SYNDROMES OF FRONTOTEMPORAL DEMENTIA Behavioral variant FTD bvFTD is a progressive syndrome characterized by changes in personality and behavior. The age of onset is typically less than 65 years with an average age of 58 years (Johnson et al., 2005) although in our experience about a third of cases present over the age of 65. It is characterized by an alteration in personality and social conduct into which patients have little or no insight, but is a cause of considerable distress for carers (Mioshi et al., 2009). The diagnosis hinges on a detailed carer

*Correspondence to: John R. Hodges, M.D., NeuRA, Barker Street, Randwick, New South Wales 2031, Australia. Tel: +02-9114-4336, E-mail: [email protected] † The authors contributed equally to the work.

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Table 15.1 Key clinical features, pathology, and genetic associations of FTD syndromes FTD syndrome Clinical features

Structural imaging

bvFTD

PPA-S

Change in personality and behavior, emotional blunting, loss of empathy, dietary changes Atrophy in the orbito-medial frontal and anterior temporal lobes TDP-43, τ, FUS

Fluent speech with loss Nonfluent spontaneous of word meaning speech, agrammatism, Right sided cases: apraxia of speech, prosopagnosia, anomia prominent behavioral features

Predominant pathology Genetic C9orf72, MAPT, associations GRN

PPA-G

FTD-MND Features of FTD with associated limb weakness, muscle atrophy, or bulbar symptoms including dysarthria and dysphagia

Frontal and anterior temporal lobe Asymmetric changes Atrophy of anterior atrophy widening of left sylvian temporal lobe, fissure typically asymmetric TDP-43 type C

τ or TDP-43 type A

TDP-43

Least genetic association of all FTD syndromes

MAPT, GRN

C9orf72

interview to elicit key behavioral features—notably apathy, alterations in social conduct and inhibitory control, loss of empathy, mental rigidity, stereotypic speech and motor behaviors, a change in eating habits leaning toward sweet cravings, and a lack of satiety. The neuropsychologic profile is said to be characterized by deficits in executive function with relative sparing of episodic memory and visuospatial skills (Rascovsky et al., 2011). Recently the consensus criteria for the diagnosis of bvFTD have been updated to rank the degree of diagnostic certainty as possible, probable, or definite (Rascovsky et al., 2011). To reach a diagnosis of possible bvFTD, three of six core criteria must be met (Table 15.2). To reach probable criteria patients must have first met possible criteria and then also show changes in the frontal or temporal regions on neuroimaging. Only when pathologic or genetic confirmation has been made is the diagnosis considered definite. We now review a number of specific clinical symptoms of bvFTD.

EMOTION PROCESSING AND SOCIAL DYSFUNCTION Social dysfunction represents one of the hallmark features of FTD, with caregivers reporting prominent changes in social comportment, appropriateness, and reduced social interest leading progressively to social withdrawal (Piguet et al., 2011). Altered emotion processing is widely documented in FTD patients, with recognition of negative emotions such as anger, fear, and disgust, predominantly affected (Werner et al., 2007; Kumfor et al., 2013). These difficulties with emotion processing extend beyond the recognition of facial emotional expressions and lead to a marked inability to empathize or to share

Table 15.2 bvFTD consensus criteria 1. Possible bvFTD (at least three of the following core features) a. Disinhibition b. Apathy c. Lack of sympathy/empathy d. Stereotypic/ritualistic behaviors e. Change in dietary preferences f. Frontal dysexecutive cognitive profile 2. Probable bvFTD (all of the following features) a. Meet criteria for possible (above) b. Functional disability/decline c. Frontal and or temporal abnormalities on neuroimaging 3. Definite bvFTD (either a or b) FTLD pathology at autopsy Known pathogenic genetic mutation

the emotional experience of others (Rankin et al., 2005). In addition, FTD patients are unable to consider or infer the thoughts and beliefs of others with so-called loss of theory of mind (Adenzato et al., 2010), resulting in an apparent lack of regard for the thoughts and feelings of others (Lough et al., 2006; Hsieh et al., 2013). Mounting evidence suggests that these theory of mind and empathy deficits map onto medial prefrontal and temporal lobe pathology (Rankin et al., 2006; Irish et al., 2014a).

MEMORY DYSFUNCTION While difficulties in memory function have been thought to be related to Alzheimer’s disease (AD), evidence from neuropsychologic and neuroimaging studies converges

FRONTOTEMPORAL DEMENTIA to reveal clear-cut episodic memory deficits in FTD (Hornberger and Piguet, 2012). Such patients display memory impairments equivalent to that of AD cases across standardized tests of verbal and visual, immediate and delayed, recall (Hornberger et al., 2010a; Pennington et al., 2011) as well as the retrieval of autobiographical events from the past (Irish et al., 2011). These deficits extend to the domain of source memory, with bvFTD cases unable to correctly retrieve the spatial or temporal context of previously presented items (S€ oderlund et al., 2008; Irish et al., 2012). Initially it was assumed that episodic memory difficulties in bvFTD reflect retrieval problems and stem from the degeneration of prefrontal cortical regions (Simons et al., 2002; Pennington et al., 2011); however, it is becoming increasingly clear that anterior and medial temporal regions including the hippocampi are heavily involved in FTD (Frisch et al., 2013; Irish et al., 2014b). It should be noted that orientation is typically well preserved in bvFTD, which is in contrast to the early temporal and spatial memory deficits seen in AD.

CHANGES IN EATING BEHAVIOR Hyperorality and dietary changes form one of the six criteria for the diagnosis of bvFTD (Rascovsky et al., 2011) and are reported in over 60% of patients at initial presentation (Piguet et al., 2009). These features are extremely helpful in diagnosing bvFTD and in discriminating this condition from other dementias such as AD (Mendez et al., 2008a). The changes in eating habits vary across the clinical subtypes of FTD. Alterations in bvFTD patients have been characterized by gluttony, hyperphagia, indiscriminate eating, and increased preference for sweet foods (Miller et al., 1995; Snowden et al., 2001; Woolley et al., 2007), as well as changes in food preference, eating habits, and other oral behaviors, compared to patients with AD (Ikeda et al., 2002). It is accepted that these changes in eating behavior in FTD are complex and may be further confounded by cultural and ethnic factors that may influence eating behavior (Shinagawa et al., 2009). Recent studies have suggested involvement of complex networks including hypothalamic and neuroendocrine factors controlling intake (Ahmed et al., 2015, 2016).

PSYCHOSIS Psychotic symptoms, including hallucinations and delusions, were previously considered rare in FTD (Mendez et al., 2008b). This view has been challenged recently with the discovery that FTD patients, with the chromosome 9 open reading frame 72 (C9orf72) nucleotide repeat expansion, often present with florid psychosis and, in some cases, are misdiagnosed with psychiatric

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disorders (Snowden et al., 2012; Devenney et al., 2014b). In our experience these delusions are often of a persecutory nature and the hallucinations span the full spectrum of the senses to include auditory, visual, and somatic hallucinations. Moreover, recent systematic reviews suggest that psychotic symptoms may be experienced by over one quarter of FTD patients (Hall and Finger, 2015). The similarities between FTD and schizophrenia have already been raised and the finding of psychosis in FTD patients has prompted renewed interest in this overlap, and it seems likely that future studies will address this issue (Cooper and Ovsiew, 2013).

bvFTD PHENOCOPY SYNDROME Although the current consensus criteria have provided a useful framework to make accurate diagnoses by ranking the level of certainty as possible, probable, and definite (Rascovsky et al., 2011), the early diagnosis of bvFTD can be challenging. In particular a subgroup of patients have emerged who are predominantly male and present with a collection of behavioral features indistinguishable from true bvFTD yet do not show significant brain atrophy (Hornberger et al., 2008, 2009; Kipps et al., 2009; Mioshi et al., 2010). Furthermore, these patients show normal patterns of metabolism on fluorodeoxyglucose positron emission tomography (FDG-PET) and a recent pathologic report of two cases show that they do not exhibit frontotemporal lobar degeneration (FTLD) pathology or significant brain atrophy at autopsy (Devenney et al., 2016). It has been hypothesized that this presentation represents a decompensated developmental disorder in the Autism spectrum appearing in later life. In keeping with this hypothesis, such patients, although scoring normally on tests such as the Addenbrooke’s Cognitive Examination-Revised and measures of memory, may show mild deficits on tests of inhibitory control and emotion processing (Kumfor et al., 2014a) as do patients on the Autism spectrum (Ashwin et al., 2006; Happe et al., 2006). A recent study comparing phenocopy and probable bvFTD cases showed a high rate of adverse life events, relationship problems, and cluster C personality traits comprising the avoidant, dependent, and obsessive-compulsive personality traits (Gossink et al., 2015). Putting these findings together it seems highly likely that the phenocopy syndrome is a final common pathway for a complex interaction of a number of personality and psychiatric factors.

Primary progressive aphasia A progressive disorder affecting language was first described by Pick in the early 1890s (Kertesz, 2004). Since then there have been multiple refinements of the

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description of the clinical presentation and advancements in the understanding of the imaging and underlying pathology, and three distinct clinical syndromes of semantic dementia (PPA-S), progressive nonfluent aphasia (PPA-G), and logopenic aphasia (PPA-L) have been described (Hodges and Patterson, 2007; Grossman, 2010) (Table 15.3).

Table 15.3 PPA consensus criteria 1. PPA—all of the following must be met (a–d) a. Language disturbance is the most prominent clinical feature b. Language impairment is the cause of impairment in activities of daily living c. Aphasia should be the most prominent deficit at symptom onset and for the initial phases of the disease d. No other condition should better account for the presentation 2. PPA-S (semantic variant) Both of the following must be met a. Poor confrontation naming (pictures/objects) particularly for low familiarity items b. Impaired single word comprehension Plus at least three of the following must be met a. Poor object and/or person knowledge, particularly for low frequency or low familiarity objects b. Surface dyslexia c. Spared single word repetition d. Spared motor speech, melody and phrase length Plus neuroimaging abnormality—Predominant anterior temporal lobe 3. PPA-G (agrammatic/nonfluent variant) At least one of the following must be met a. Grammatical errors and simplification in language production b Effortful, halting speech with speech sound errors consistent with apraxia of speech Plus at least three of the following must be met a. Impaired naming, particularly of action verbs b. Impaired comprehension of syntactically complex sentences c. Spared content word comprehension d. Spared object knowledge Plus neuroimaging abnormality—Predominant left posterior fronto-insular PPA-L (logopenic variant) Both of the following must be met a. Impaired single word retrieval in spontaneous speech and confrontational naming b. Impaired repetition of sentences and phrases At least three of the following must be met a. Phonologic errors in spontaneous speech and naming b. Spared motor speech c. Spared single word comprehension d. Spared object knowledge Plus neuroimaging abnormality—Predominant left posterior perisylvian or parietal

Semantic dementia (PPA-S) PPA-S is characterized by the progressive breakdown of the semantic memory (the memory system that stores knowledge about objects and words). Speech is fluent with normal grammar and speech sounds, but increasingly empty of content and circumlocutory, and there is prominent anomia and impaired comprehension of word meanings involving, initially, less common words such as violin, caterpillar, and catastrophe. Often words are replaced with more common terms such as “thing.” As the disease progresses patients develop impaired recognition and use of objects and worsening behavioral symptoms of the type seen in bvFTD (Hodges and Patterson, 2007). Such patients have asymmetric atrophy of the anterior temporal lobes involving the left more than the right side. Patients with the less common variant in which the right temporal lobe is most involved present with prosopagnosia and prominent changes in personality (Thompson et al., 2003).

Progressive nonfluent aphasia (PPA-G) In contrast to PPA-S, speech in PPA-G is strikingly nonfluent with speech distortion, pauses, groping, and agrammatism (Gorno-Tempini et al., 2011). The distortion of speech is due to breakdown in motor planning, referred to as speech apraxia, causing impairment of rhythm and the normal stress patterns of speech. These deficits occur in the presence of spared word comprehension. Sentence comprehension, however, can be impaired due to problems understanding the grammatical elements of sentences. Word repetition is often impaired due to articulatory errors (Josephs et al., 2006a; Ash et al., 2009).

Logopenic aphasia (PPA-L) The criteria for the relatively recently described logopenic variant of PPA are described in Table 15.2. PPA-L is characterized by frequent word finding pauses that results in a nonfluent speech disorder rather than impairment in speech articulation, prosody, and grammar seen in PPA-G. It can, however, be difficult to distinguish from PPA-G since some patients with PPA-L produce phonologic errors. Naming is impaired but to a lesser extent than that seen in PPA-S, and single word comprehension is intact. Another hallmark is the marked impairment in sentence and phrase repetition secondary to problems with auditory verbal short-term memory. Comprehension of sentences is also poor due to subjects’ poor short-term memory. Behavioral features in this group are similar to those found in AD and include low mood, apathy, irritability, and anxiety (Mesulam et al., 2008; Rohrer and Warren, 2010).

FRONTOTEMPORAL DEMENTIA

THE FTD OVERLAP SYNDROMES FTD and Parkinsonian syndromes The FTD syndrome can overlap with a number of the parkinsonian plus syndromes, particularly progressive supranuclear palsy (PSP), in which there is increasing evidence for prominent behavioral change including apathy (Borroni et al., 2009; Gerstenecker et al., 2013), impaired social engagement (Gerstenecker et al., 2013), and impaired emotional expression (Ghosh et al., 2009) of the type seen in bvFTD, which may be the major presenting feature in up to 30% of PSP patients (Kobylecki et al., 2015). The corticobasal syndrome (CBS) also overlaps considerably with FTD. Most, if not all, patients with CBS have changes in social behavior and/or speech production as well as the parkinsonism and asymmetric apraxia that characterize CBS (Kumfor et al., 2014b). The underlying pathology in CBS is extremely heterogeneous and there is considerable interest currently in the development of biomarkers that can diagnose the pathology in vivo (Eller and Williams, 2009; Burrell et al., 2013). Patients with progressive nonfluent aphasia (PPA-G) may go on to develop a CBS-like syndrome characterized by extrapyramidal symptoms including dystonia, rigidity, limb apraxia, and atypical parkinsonism. A syndrome resembling PSP can also be seen with symptoms associated with progressive supranuclear palsy including vertical gaze palsy, balance and gait problems, and axial rigidity (Rohrer et al., 2010a) (Table 15.3).

Motor neuron disease and FTD There is increasing evidence for overlap between FTD with MND at a clinical and pathologic level (Mitsuyama and Inoue, 2009), which has gained impetus with the discovery of the C9orf72 gene expansion in cases with familial FTD, FTD-MND, and MND (Hodges, 2012) leading to suggestions that FTD and MND represent extremes of a single disease spectrum (Clark and Forman, 2006). Behavioral and cognitive symptoms typical of bvFTD can occur in MND, while FTD patients can develop limb weakness and bulbar dysfunction. Around 10%–15% of FTD patients develop full-blown MND, while 30%–60% have evidence of motor neuron dysfunction insufficient to reach criteria for MND (Lomen-Hoerth et al., 2002; Josephs et al., 2006b; Burrell et al., 2011). In one of the largest studies of patients with sporadic MND, cognitive and/or behavioral impairment was found in 50% of patients, and 15% of patients met the criteria for a diagnosis of FTD (Ringholz et al., 2005). Cognitive dysfunction in MND patients involves predominantly frontal executive abilities (Ringholz et al., 2005). Language deficits are also common, including progressive

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nonfluent PPA-G (Caselli et al., 1993) and apraxia of speech (Duffy et al., 2007) and prominent behavioral features, most notably apathy, loss of empathy, emotional lability, and less commonly gluttony, behavioral stereotypes, and compulsions (Gibbons et al., 2008). Imaging studies support an overlap between FTD and MND. Voxel-based morphometry MRI in patients with MND and with FTD-MND shows frontal atrophy involving bilateral motor/premotor cortices, the left middle and inferior frontal gyri, the anterior portion of the superior frontal gyri, the superior temporal gyri, the temporal poles, and the left posterior thalamus. The frontal regions were more significantly atrophied in those with FTD/MND, than MND alone (Chang et al., 2005). FTD and MND also share a common pathology with TDP-43 inclusions present in up to 50% of cases of FTD (including, bvFTD, PPA-S, and PPA-G), most sporadic cases of MND, and MND associated with FTD (Mackenzie et al., 2010). TDP-43 pathology and the genetic abnormalities associated with it are described in more detail in the following sections.

PATHOLOGY The pathology in FTD is characterized by severe focal atrophy of frontal and temporal regions, subcortical gliosis, and neuronal loss. FTLD is the accepted umbrella term for the pathologic classification of FTD subtypes. The classification of subtypes depends upon the presence of intraneuronal protein inclusions, which are typically either phosphorylated τ protein or ubiquitinated TAR DNA-binding protein (TDP-43). These two account for over 90% of cases with fused in sarcoma (FUS) positive pathology and ubiquitin proteasome system pathology due to CHMP2B mutations (FTD-3) in a small proportion of cases. The distinction between the various subtypes of FTD is not purely academic since the underlying neuropathology is, to some extent, predictable especially in those with PPA. Those with the semantic variant PPA-S typically have TDP-43 type C, and these are rarely genetic. In those with PPA-G, apraxia of speech is said to be associated with τ pathology, which may conform to the pattern seen in PSP and corticobasal degeneration (CBD) pathology (Josephs et al., 2006c; Deramecourt et al., 2010). It has also been suggested that PPA-G without apraxia of speech is associated with TDP 43 type A pathology (Josephs et al., 2011; Mackenzie et al., 2011). The logopenic form of PPA (PPA-L) is strongly associated with Alzheimer’s pathology (Mesulam et al., 2008; Gorno-Tempini et al., 2011). In bvFTD, however, the pathology remains heterogeneous with an approximate 50–50 split between FTD-τ and FTD-TDP43 (Fig. 15.1).

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Fig. 15.1. Clinical and pathologic subtypes of frontotemporal dementia. Weighted lines represent the approximate frequency of pathology for each variant.

FTLD-τ can be further classified depending on the species of τ protein accumulation. Alternative splicing in exon 10 results in either three (3R) or four (4R) repeats of 32 amino acids in the microtubule binding domain, which in turn are associated with distinct FTD phenotypes (Stanford et al., 2003; Mackenzie et al., 2009). Pick’s disease, associated with 3R τ, is the archetypal pathology associated with FTD and comprises round, silver staining inclusions, also known as “Pick’s bodies” predominantly found in the cortex and limbic regions (Onari, 1926). In some instances, the term Pick’s disease has been used instead of FTD, which led to a controversy concerning the term Pick’s disease, which was applied by some to the clinical entity and by others to a distinctive pathologic appearance that is present in a minority of cases with the clinical syndrome (Hodges et al., 2004). FTLD-τ due to an abnormality in the microtubuleassociated τ (MAPT) gene can be associated with either 3R τ or 4R τ. In cases of PSP and CBD, 4R τ predominates, with protein accumulation predominantly in the basal ganglia, brainstem, and cerebellum in PSP, and in the cortex and basal ganglia in CBD (Dickson et al., 2011). The identification of the DNA/RNA-binding protein TDP-43 as the pathologic protein in the majority of MND, τ-negative FTLD with ubiquitin inclusions (FTLD-U) and MND-FTD was a significant development in cementing the overlap between FTD and MND, and propelled the discovery of TDP-43 associated genes—TARDBP, C9orf72, and Ubiquilin 2 (Neumann et al., 2006). TDP-43 is an RNA-binding protein with functions in transcriptional repression, pre-mRNA

splicing, and translational regulation (Buratti and Baralle, 2010). The pathologic classification of FTLDTDP underwent numerous iterations until 2011 when a consensus was reached, and FTLD-TDP 43 was classified into four distinct subtypes (Mackenzie et al., 2011). These subtypes are based on the anatomical localization and morphology of neuronal inclusions and dystrophic neurites (DNs) and have been linked to specific FTD phenotypes. FTLD-TDP type A is characterized by numerous neuronal cytoplasmic inclusions (NCIs) and DNs mainly in the upper cortical layers and is most frequently found in PPA-G, while type B has numerous NCIs and sparse DNs throughout all cortical layers and is associated with FTD-MND. Type C is associated with PPA-S and pathologically show long DNs. Type D have few NCIs but moderate DNs and neuronal intranuclear inclusions (NIIs). The bvFTD phenotype is the most heterogeneous in terms of FTLDTDP43 subtypes and has not been consistently linked with any one type (Mackenzie et al., 2006; Snowden et al., 2007; Josephs et al., 2011). There is also an association between the pattern of TDP-43 staining and certain gene defects, in that the C9orf72 expansion is associated with TDP-43 types A and B, the progranulin (GRN) mutation with Type B, and the rare valosin-containing protein (VCP) mutation with type D (see following text). Moreover, the C9orf72 genetic expansion has certain other distinctive pathologic features including numerous p62 positive TDP-43 negative inclusions in the hippocampus and cerebellum. Within the hippocampus, globular and star-shaped p62 positive NCIs and p62 TDP-43 negative

FRONTOTEMPORAL DEMENTIA NIIs are abundant in the pyramidal layer. In the cerebellum, p62 positive NCIs are present in the granular and molecular layers and the majority are also found in the Purkinje cells, while p62 positive TDP-43 negative NIIs are present in the granular layer in almost one half of cases (Al-Sarraj et al., 2011). The discovery of TDP-43 provided an avenue for the development of disease models and biomarker assays. It also encouraged researchers to explore the chromosome 16 region, which led to the eventual identification of the fused sarcoma protein gene (FUS). FUS has been identified as the pathologic protein in ubiquitinated positive but TDP-43 negative cases of FTLD-U, as well as the TDP-43 negative SOD-1 negative MND. FUS mutations account for around 4% of familial MND cases and less than 1% of sporadic cases, while they are rarely found in cases with FTD. The majority of MND patients with FUS protein pathology have been found to harbor 1 of at least 35 pathogenic mutations in the FUS gene (Blair et al., 2010). In contrast, FTD patients with underlying FUS pathology appear to be sporadic in nature as DNA and RNA sequencing has failed to identify FUS mutations in this cohort (Van Langenhove et al., 2010). Within FTLD-FUS three distinct pathologic subtypes have emerged. In addition to the typical frontal and temporal atrophy of FTLD, atypical FTLD-U (aFTLD-U) is characterized by severe atrophy of the caudate and hippocampal sclerosis; patients typically present below the age of 40 years and do not have a family history thus enabling distinction from the other pathologic proteinopathies (Seelaar et al., 2010). Furthermore, FUS proteinopathy has been found in basophilic inclusion body disease (BIBD), a rare entity with characteristic pathologic findings including NCIs that are inconsistently ubiquitin immunoreactive (Sasaki et al., 2001). In FTD, the phenotype associated with BIBD is almost exclusively bvFTD. Neuronal intermediate filament inclusion disease is also rare and this subtype is characterized by the presence of neuronal inclusions immunoreactive for all class IV intermediate filaments and presents as an early onset bvFTD with movement disorders.

GENETICS Approximately 20%–30% of FTD sufferers have a firstdegree relative with a relevant neurodegenerative disorder. Within a single pedigree, family members can suffer from the spectrum of MND-FTD disorders including pure MND, pure FTD, and a combination of both.

FTD genes The first gene to be associated with FTD in the late 1980s was the microtubule-associated protein τ (MAPT) gene, and over 40 mutations, which are associated with

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underlying τ pathology, have since been described and account for approximately 20%–30% of familial FTD (Rosso et al., 2003; Stanford et al., 2003). The second major gene defect involving the progranulin or GRN gene, was identified in 2006, and around 50 mutations have been described, which together account for perhaps 10%–20% of familial FTD. These cases were associated exclusively with TDP-43 pathology (Goedert et al., 1998; Baker et al., 2006; Cruts et al., 2006; Le Ber et al., 2007). Both gene mutations show an autosomal dominant pattern of inheritance (Foster et al., 1997). MAPT mutation carriers can present initially with either a predominant parkinsonian syndrome or a dementia (Tsuboi et al., 2002; Baba et al., 2005), with the precise mutation determining the clinical phenotype; the N279K mutation has a predominant parkinsonian presentation (Wszolek et al., 2000), personality and behavioral changes characterize the P301L and 10 + 16 mutation (Kodama et al., 2000; Janssen et al., 2002) and the S305S mutation does not appear to favor either (Stanford et al., 2000; Reed et al., 2001). Although the reported age of onset ranges from 25 to 65 years in MAPT carriers, the majority of patients first exhibit signs in their 40s, and live for 3–10 years with the disease (Boeve and Hutton, 2008; Espay and Litvan, 2011). An exception to this is the R406W mutation carriers, who have a much longer disease duration with reports of patient surviving into their 70s (Van Swieten et al., 1999). Patients with GRN mutations tend to present later than those with MAPT mutations, with most patients developing symptoms after 50 years of age with a mean disease duration of 5 years (3–22 years) and a shorter disease duration in late-onset disease (Van Swieten and Heutink, 2008). The MAPT mutation is almost fully penetrant, although there are reports of asymptomatic individuals living into old age (Hutton et al., 1998). In contrast, GRN carriers exhibit incomplete penetrance, with 10% of carriers remaining asymptomatic at 70 years (Gass et al., 2006; Boeve and Hutton, 2008). Parkinsonism has been reported in approximately 40% of GRN cases (Le Ber et al., 2007). In common with MAPT mutation carriers, the parkinsonism is generally symmetric with bradykinesia, rigidity, rarely resting tremor, and with modest or little response to levodopa (Tsuboi et al., 2002). Features typically associated with PSP have all been reported in MAPT mutation carriers (Stanford et al., 2000) while features of MND are very rare in both MAPT and GRN carriers (Seelaar et al., 2007; Pickering-Brown et al., 2008; Tsuboi, 2006). Severe behavioral disorders are found in the majority of carriers of both mutations, in addition to frontal dysexecutive cognitive deficits (Le Ber et al., 2007; Boeve and Hutton, 2008). Psychotic features have been reported

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Table 15.4 Comparison of clinical features—MAPT vs GRN

Age at onset Disease duration Penetrance

MAPT

GRN

25–65 years, usually in 40s 3–10 years, mean 5 years >95%

>50 years

Clinical features Parkinsonism Infrequent Apraxia Very rare ALS features Very rare Psychosis Infrequent Imaging Symmetry Distribution of atrophy

Symmetrical Anteromedial temporal lobe and orbitofrontal cortex

1–15 years, mean 7 years 90% by 70 years Frequent Infrequent Never Frequent Asymmetrical Inferior fontal, inferior temporal and inferior parietal lobes

in up to a quarter of GRN carriers and include hallucinations and/or delusions, which in some cases has led to misdiagnosis as schizophrenia. Visual hallucinations (animals and people) were reported in 25% in one series and tactile hallucinations (insects crawling over the skin) in another series (Le Ber et al., 2007; Beck et al., 2008). Psychotic features are also reported in MAPT carriers but appear to be less common (Saito et al., 2002; Spina et al., 2007). Nonfluent aphasia often accompanies the behavioral and personality deficits in GRN carriers but is rarely the predominant feature (Pickering-Brown et al., 2008). A dynamic aphasia has also been documented in a number of patients, characterized by a decreased output of speech without evidence of a motor speech disorder or agrammatism, and resulting in mutism in some patients (Beck et al., 2008) (Table 15.4).

MND-FTD genes C9ORF72 GENETIC EXPANSION The discovery of the C9orf72 expansion as the most common genetic abnormality in MND-FTD was a critical genetic breakthrough. A link between FTD and MND at chromosome 9p21.3–9p21.1 was first reported in 2006, and linkage was confirmed by genome-wide association studies. In 2011 the gene responsible for chromosome 9p21 linked FTD-MND was reported (DeJesusHernandez et al., 2011; Renton et al., 2011). This genetic expansion, now known as C9orf72, is a hexanucleotide GGGGCC repeat found on the noncoding region of chromosome 9, and is pathogenic at greater than 30 repeats, with most affected patients having repeat lengths in the

thousands (DeJesus-Hernandez et al., 2011; Renton et al., 2011). The length of repeats in the cerebellum of FTD patients shows a negative correlation with survival, in that a longer repeat size is associated with shorter survival (van Blitterswijk et al., 2013b). This correlation has not been identified in MND cases. Penetrance is likely to be incomplete as healthy adults of 80 years and over have been identified with the expansion, although the majority of expansion carriers have manifested the disease by 70 years (Galimberti et al., 2014). Studies of affected carriers, asymptomatic carriers, and their family members may provide further insight into this gene, which, similar to other repeat disorders, may be prone to the anticipation phenomenon. Studies have linked C9orf72 to other clinical phenotypes outside of FTD and MND, including Parkinson’s disease, multiple system atrophy (MSA) and AD, although the rates are low and may merely reflect the background population risk in combination with variability in diagnostic specificity and cooccurrence of multiple pathologies (Majounie et al., 2012a, b; Cruts et al., 2013; Lesage et al., 2013; Goldman et al., 2014). These studies lack neuropathologic confirmation and their findings have been refuted by a number of pathologic studies: one such study did not identify the expansion in 100 pathologically confirmed MSA patients, while another failed to link the expansion with autopsy-confirmed Parkinson’s disease (Nuytemans et al., 2014; Scholz et al., 2014). Nonetheless, there does appear to be clinical heterogeneity, particularly in relation to AD phenotypes, which extends beyond clinical to pathologic heterogeneity, with autopsy cases showing one of three distinct pathologic classifications of either FTLD-TDP, FTLDMND, or MND (Murray et al., 2011). Three pathologic mechanisms have been proposed to cause disease in C9orf72 carriers: loss of function of the protein encoded by the gene, toxic effects of RNA products which aggregate in the cell, and toxicity caused by dipeptide repeat proteins. The C9orf72 expansion has also been identified together with mutations in other well-known causative genes in FTD including GRN and MAPT (Lashley et al., 2013; van Blitterswijk et al., 2013a); the significance of these so-called “double mutations” is unclear. This expansion accounts for approximately one-third of familial FTD and 40%–50% of familial MND cases (Chio, 1999; Renton et al., 2011; Majounie et al., 2012c; Devenney et al., 2014b). The rate is even higher for familial FTD-MND cases, with rates reported to be as high as 88% in one cohort, although the average appears to center around 70%–80% (Smith et al., 2012; Stewart et al., 2012; Cruts et al., 2013; van der Zee et al., 2013). Notably, it is also found in a significant proportion (5%–20%) of patients with apparently sporadic disease, especially those with bvFTD.

FRONTOTEMPORAL DEMENTIA It is possible that in these cases gene-carrying family members may have died before reaching the age of disease onset; however, another possibility is that the genetic expansion may have manifested as another disorder. There is marked geographical variation in prevalence, with high rates of the expansion reported in European countries, while remaining rare in Asian populations (Zou et al., 2013). Across the clinical spectrum of FTD, the predominant phenotype associated with the C9orf72 expansion is bvFTD, often occurring with features of MND, although PPA-G has also been reported to varying degrees. In contrast, MND expansion carriers conform to the classic adult-onset MND, although more patients present with bulbar disease (40%). Only very rarely have progressive muscle atrophy and primary lateral sclerosis been associated with the expansion (Snowden et al., 2013; Williams et al., 2013). Survival in expansion-positive FTD is variable, reported to be between 1 and 24 years, but when MND develops, the course is usually rapid with death in less than 2 years. Prognosis for MND patients with the expansion is poorer than for their C9orf72 expansionnegative counterparts, but is on a par with that for FUS mutation carriers, with survival range reported between 1 and 96 months. More recently evidence has emerged for C9orf72 hypermethylation as a protective factor in FTD but not in MND (Russ et al., 2015). Features that distinguish C9orf72 positive cases include a family history of MND, parkinsonism, and prominent psychosis (Snowden et al., 2012; Devenney et al., 2014b). Delusions and hallucinations have emerged as a frequent presenting feature of the C9orf72 expansion. In some instances, C9orf72 carriers were initially diagnosed with late-onset psychiatric illnesses because of prominent psychotic features at onset. A distinctive neuroanatomical signature has also emerged, with posterior and thalamic atrophy, in addition to the typical frontal and temporal atrophy of FTD (Mahoney et al., 2012a; Whitwell et al., 2012; Devenney et al., 2014b) although the degree of cortical atrophy is variable, with some patients manifesting very little frontal or temporal atrophy (Devenney et al., 2014a, b). Prior to the C9orf72 discovery, the diagnosis remained unknown or unconfirmed for many years in some patients, and others were considered “slow-progressors” or “phenocopy” cases (Khan et al., 2012; Devenney et al., 2014a). Imaging studies in MND cohorts identified a pattern of cortical and subcortical atrophy similar to that seen in FTD in those carrying the C9orf72 expansion in parallel with cognitive changes (Byrne et al., 2012; Bede et al., 2013). It remains to be determined whether specific features of the expansion, including the anticipation phenomenon or the admixture of a variety of gene effects, have a part to play in terms of clinical variability.

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TARDBP MUTATION When NCIs were found to contain TDP-43 protein, research turned to the analysis of TARDBP, the gene that encodes this protein. Mutations in this gene were identified in 2008 and result in the abnormal redistribution of TDP-43 from the nucleus to the cytoplasm in neurons and glia of the spinal cord (Andersen and Al-Chalabi, 2011). Mutations in this gene account for 4% of familial MND as well as a lesser proportion (1%–2%) of sporadic MND (Kabashi et al., 2008; Sreedharan et al., 2008). The phenotype is classic MND with bulbar, limb, and respiratory involvement, although disease duration and age of onset can be variable. Outside of its presentation in MND, the phenotype is heterogeneous with rare reports of bvFTD, semantic dementia, MND with chorea, and supranuclear gaze palsy and Parkinson’s disease. Mutations remain rare in FTD and when present are usually in association with MND.

UBIQUILIN2 (UBQLN2) MUTATION In 2011 a five generation family with 19 affected MND individuals were identified with an X-linked dominant transmission in association with a mutation in the ubiquilin2 (UBQLN2) gene (Deng et al., 2011). Subsequent analysis of a larger cohort identified 3 further mutations of Ubiquilin2; in total 40 individuals with 4 mutation variants were identified. Although this analysis was carried out in a primarily MND cohort, 23% of the cases had evidence of MND-FTD. Dementia manifested with the behavioral and executive abnormalities of FTD. In most cases, dementia was present before the motor disorder. The age at diagnosis was variable, ranging from 16 to 71 years and the penetrance was 90% at 70 years, with males affected earlier than females. This gender difference probably reflects the genetic burden in homozygous males vs heterozygous females (Andersen and Al-Chalabi, 2011). UBQLN2 encodes an ubiquitin-like protein, ubiquilin2, and leads to an impairment of protein degradation. Not only are ubiquilin2 inclusions found in UBQLN2-positive cases but they were also found in all of the 47 UBQLN2 negative MND and MND-FTD cases, suggesting that Ubiquilin2 pathology may be a common final pathway for all MND.

NEUROIMAGING Structural Imaging Findings Associated With FTD Clinical Phenotypes BEHAVIOURAL VARIANT FTD On MRI imaging (Fig. 15.2) patients typically exhibit atrophy involving mesial frontal, orbitofrontal, and anterior insula cortices (Hornberger et al., 2010b), most evident on coronal T1 images, although this can be difficult

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Fig. 15.2. Imaging changes in frontotemporal dementia. (A) Coronal T1 images showing early frontal lobe atrophy with widening of the interhemispheric fissure (white arrow) and atrophy of the superior aspects of the frontal lobe in a patient with bvFTD. (B) Imaging changes in PPA-S. Coronal T1 image demonstrating atrophy predominantly affecting the anterior left temporal lobe, especially the fusiform gyrus (white arrow) in a case of anomic PPA-S. (C) Coronal T1 image showing predominant right anteroinferior (white arrow) temporal lobe atrophy in a right sided PPA-S case with prominent prosopagnosic deficits and behavioral changes. (D) MRI changes in PPA-G. Coronal T1 MRI image showing predominant left anterior perisylvian atrophy (white arrow) in a case of PPA-G.

to identify without reference to comparable age matched controls. As the disease progresses there is involvement of the other frontal neocortex gray matter regions—the striatum, hippocampi, posterior insula, and parietal lobes (Seeley et al., 2008). A clinically based grading system validated against quantitative methods has been published and used in a number of studies (Kipps et al., 2007). Functional neuroimaging techniques including single-photon emission computed tomography (SPECT) and FDG-PET can be beneficial in early cases by revealing frontal hypometabolism, which typically exceeds the extent of atrophic changes seen on MRI (Varma et al., 2002; Kanda et al., 2008).

SEMANTIC DEMENTIA Patients show bilateral, typically asymmetrical (usually left more than right) atrophy of the anterior temporal lobes, involving the polar and perirhinal cortices and anterior fusiform gyri (Rosen et al., 2002). As the disease progresses, this degeneration extends caudally into the posterior temporal lobes and rostrally into the posterior, inferior frontal lobes. Rarer patients with prosopagnosia show the reverse pattern, with right > left atrophy.

PROGRESSIVE NONFLUENT APHASIA The imaging findings in PPA-G (Fig. 15.2) are heterogeneous, and at a clinical level images may be judged to be normal, but typically patients show atrophy involving the anterior perisylvian and inferior opercular and insular portions of the dominant hemisphere (Gorno-Tempini et al., 2004; Peelle et al., 2008), again evident on coronal images. As the disease progresses there is involvement of the dorsolateral prefrontal cortex, temporal cortex, orbital and anterior cingulate regions, and parietal lobe (Grossman, 2010).

Structural Imaging Findings Associated With Genetic Mutations Neuroimaging studies have suggested that distinct patterns of brain atrophy are associated with the different genetic mutations. Mutations in the MAPT gene have been associated with symmetrical anterior temporal lobe atrophy, with involvement of the orbitofrontal cortices (Whitwell et al., 2009b; Rohrer et al., 2010b). One study found that when the mutation results in alterations in splicing then the atrophy is focused on the medial

FRONTOTEMPORAL DEMENTIA temporal lobe whereas when alterations in the structure of the protein occur then atrophy is focused on the lateral temporal lobe (Whitwell et al., 2009a). In GRN mutations atrophy is typically asymmetrical affecting the temporal, inferior frontal, and parietal lobes (Beck et al., 2008; Whitwell et al., 2009b; Rohrer et al., 2010b). The rate of whole brain atrophy may be more rapid in GRN mutations than MAPT mutations (Rohrer et al., 2010b; Whitwell et al., 2011b). C9orf72 imaging studies have been discussed earlier.

NEW ADVANCES IN IMAGING IN FTD While the atrophy patterns on MRI have been described, new techniques are likely to aid diagnosis and may offer the opportunity for earlier detection. These new techniques have also led to the concept of FTD as a disease of network dysfunction, rather than just a disease of a specific brain region.

DIFFUSION TENSOR IMAGING (DTI) DTI measures the diffusion of water across brain tissue and can be used to visualize and measure the function of white matter tracts. Several studies have examined DTI in the different clinical phenotypes in FTD (Zhang et al., 2009; Whitwell et al., 2010; Agosta et al., 2012). In bvFTD there is degeneration of frontal white matter tracts including the superior longitudinal fasciculus, anterior cingulum, and the genu of the corpus callosum. Involvement of the tracts that project to the temporal lobes have also been demonstrated, including the uncinate fasciculus and inferior longitudinal fasiculus. These changes are typically more severe anteriorly, but can involve the posterior portions of the tracts as the disease progresses. It has also been suggested that involvement of the anterior corpus callosum may be particularly useful in differentiating bvFTD from the other FTD syndromes (Agosta et al., 2012). One study of DTI in MND-FTD found a similar pattern of involvement of the frontal and temporal white matter tracts, but with greater corticospinal tract involvement, although to a lesser extent than that seen in those with pure MND (Lillo et al., 2012). In the PPA syndromes distinctive patterns of white matter degeneration have been shown. In left predominant semantic dementia there is degeneration in the uncinate fasciculus and inferior longitudinal fasiculus, with more severe abnormalities on the left-hand side (Agosta et al., 2010; Acosta-Cabronero et al., 2011; Schwindt et al., 2013). Involvement of the genu of the corpus callosum and arcuate fasiculus has also been demonstrated, with sparing of the posterior tracts of the brain (Whitwell and Josephs, 2012). In PPA-G abnormalities have been found in the dorsal language pathways (Rohrer and Rosen, 2013) including

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the left superior longitudinal fasiculus and arcuate fasiculus (Rohrer and Rosen, 2013). In patients with apraxia of speech, the premotor components of the superior longitudinal fasiculus appear to be affected (Josephs et al., 2012). Recently it has been suggested that DTI could be used to discriminate between τ and TDP-43 pathology with τ cases showing greater white matter damage on DTI (McMillan et al., 2013).

FUNCTIONAL MRI Resting-state functional MRI is a recently developedtechnique that allows the assessment of specific networks of brain function. This method examines the neuronal connectivity between different areas that appear to relate to specific structurally connected neuroanatomical networks, including the executive, memory, and visual networks (Whitwell and Josephs, 2012). A number of other networks that have been described including the default mode network (hippocampal, cingulo-temporal parietal network), a set of regions that decrease their activity during attention demanding tasks (Greicius et al., 2004), and the salience network (anterior cingulate cortex, frontoinsula, amygdala, and striatum), which is consistently activated in response to emotionally significant internal and external stimuli (Zhou et al., 2010). Studies in bvFTD (Zhou et al., 2010; Whitwell et al., 2011a; Farb et al., 2013; Filippi et al., 2013) have consistently found decreased activity in the salience network, with contrasting findings in the default mode network, including increased activity (Farb et al., 2013), partially increased activity (Whitwell et al., 2011a), and a trend toward decreased activity (Filippi et al., 2013). Abnormalities in functional connectivity may develop prior to atrophy (Whitwell et al., 2011a), suggesting that as the technique develops it may have an important role to play in the assessment of therapies of those at risk of FTD such as gene carriers.

PERFUSION TECHNIQUES Arterial spin labeling (ASL) MRI is a method used for assessing brain perfusion and assumes that brain perfusion and metabolism are coupled (Rohrer and Rosen, 2013); the method involves the coupling of arterial blood water to an endogenous diffusible tracer. Several studies using ASL have shown hypoperfusion in the bilateral frontal, anterior cingulate, and thalamus regions in bvFTD (Rohrer and Rosen, 2013).

PET AND SPECT IMAGING Both PET, using 18-F-flourodeoxyglucose (FDG), and SPECT, using 99mTc-hexamethylpropyleneamine, have been used to show hypometabolism in the frontal and

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temporal lobes in FTD and correlated to patterns of brain atrophy (Kipps et al., 2009). PET may improve the diagnostic accuracy to differentiate between AD and FTD (Foster et al., 2007). New PET imaging compounds include the Pittsburgh compound B and florbetapir that are radioactively labeled compounds that bind to amyloid plaques and can be used to differentiate FTD from AD. For example, PiB imaging is able to differentiate patients with pathologic AD presenting with aphasia and to validate the use of clinical criteria for PPA-L (Leyton et al., 2011). Following the success of amyloid PET imaging, researchers have turned their attention to finding suitable tracers for τ protein and a number of tracers have been developed (Villemagne et al., 2015). τ imaging has the potential to improve diagnostic accuracy in FTD through the identification of tauopathies during life, in contrast to the current situation whereby the underlying pathology can be identified postmortem only. This may allow more accurate case selection for clinical trials and subsequent pharmacologic therapies. τ PET imaging could also improve disease staging, as the τ burden is closely linked to cognitive impairment, and determine the role of τ deposition in the preclinical stages of neurodegeneration. Although the potential benefits of τ imaging for clinicians, researchers, and patients are clear there are issues to be resolved before the ideal ligand is identified and introduced into clinical practice.

Longitudinal imaging To date, neuroimaging studies in FTD have very largely been cross-sectional which have delineated the patterns of MRI change seen in the various FTD subtypes (Rohrer and Rosen, 2013) described earlier. Longitudinal neuroimaging studies have, however, immense potential as a means of determining disease progression, which may in turn be useful for monitoring response to treatment in pharmacologic drug trials. Given the rapid development of the neuroimaging field it seems likely that we will see an increase in these imaging techniques over the next few years. Recently, a detailed review of longitudinal imaging in neurodegeneration addressed the many methodological and recruitment issues associated with this type of study and suggested that a standardized design is needed to allow for meaningful comparisons and interpretation (Schuster et al., 2015). The longitudinal studies in FTD have focused largely on single modalities, comprising FDG-PET, SPECT, or MRI, with varying results found between the studies. MRI studies are by far the most common and are usually either a study of the gray or white matter although occasionally they incorporate both (Brambati et al., 2007; Lam et al., 2014). Even within the gray matter cortical regions some,

researchers chose to examine whole brain atrophy rates while others considered region of interest analyses, and others compared atrophy patterns in different patients at various stages of the disease (Avants et al., 2005; Diehl-Schmid et al., 2007; Seeley et al., 2008; Brambati et al., 2009; Krueger et al., 2010). Despite these differences, the majority of studies seem to suggest that brain changes in FTD initially affect and progress through the frontal and temporal lobes and the associated underlying white matter regions before progressing to more posterior areas and that it generally progresses faster than in AD (Frings et al., 2014). The pattern on FDGPET also seems to support this notion (Diehl-Schmid et al., 2007). Longitudinal analysis in FTD is also hampered by the relative rarity of the condition and hence the small group sizes, particularly when considering each FTD phenotype separately, which ultimately contract even further over a relatively short period of time when patients become too impaired for scanning. In an effort to combat this issue a mixed model statistical method is gaining popularity. This method allows cases with varying time-points and even only one time-point to be included. This technique has been applied to a cohort of patients with the rare syndrome of PPA-S, including a subgroup of the even rarer right-lateralized PPA-S, and found that these patients show a pattern of progression in both gray and white matter which is distinct depending on whether the presentation was initially right or left-lateralized. The study found that over time the left SD group showed progressive thinning in the right temporal pole, whereas right PPA-S had progressive thinning in the orbitofrontal cortex and anterior cingulate (Kumfor et al., 2016), which is in keeping with the prominent behavioral features often present in right-lateralized SD. Longitudinal neuroimaging techniques are also being applied to the genetic subgroups of FTD and have shown divergent trajectories (Mahoney et al., 2015; Whitwell et al., 2015). GRN carriers show the fastest rates of whole brain atrophy followed by sporadic FTD, C9orf72, and MAPT. As expected and in keeping with other nongenetic based imaging studies all of the genetic cases show greatest rates of atrophy in the frontal and temporal lobes. The C9orf72 expansion is also associated with faster rates of decline in the cerebellum, occipital cortex, and thalamus, although the sample size was small in one study (Mahoney et al., 2012b). For white matter, MAPT carriers show the greatest change within the left uncinate fasciculus, while C9orf72 carriers show fastest decline within the right paracallosal cingulum. Together these studies suggest that neuroimaging techniques may prove to be sensitive and objective biomarkers for disease progression and potentially for preclinical identification of brain changes.

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Neuroimaging beyond the frontal and temporal cortices More recently researchers are considering the contribution made by brain regions outside of the frontal and temporal cortices. The link between FTD, deranged metabolism, and abnormal eating behavior is becoming clearer and seems likely to be linked to a complex neural network centered on the hypothalamus (Ahmed et al., 2015, 2016). The cerebellum, previously considered to be concerned primarily with motor function, has been implicated in a range of cognitive dysfunctions. Atrophy of superior cerebellar regions, including the crus, has been linked to cognitive deficits in bvFTD, while atrophy of inferior cerebellar regions, including the vermis, are linked to motor deficits in MND (Tan et al., 2014). Notably, patients with FTD-MND have atrophy in both regions (Tan et al., 2014). Similarly, with the findings of preferential thalamic atrophy in C9orf72 carriers, the thalamus is now considered a potentially important structure in FTD. The thalamus is a key component in controlling the flow and nature of sensory perceptions within the cortex (Basso et al., 2005; Mitchell et al., 2014) and has important functions within the salience network, which is known to be disrupted in FTD.

Blood and CSF biomarkers CSF In the absence of specific CSF biomarkers for TDP-43, or to distinguish the different tauopathies, currently the most important clinical utility of CSF biomarkers in FTD is to distinguish underlying AD from other FTD pathologies. In particular, if CSF is appropriately handled and measured, reduction of Ab1–42 level would not be expected in cases with τ or TDP-43 proteinopathies. Several studies (Riemenschneider et al., 2002) have shown that CSF total-τ levels are lower in FTD than those seen in AD, but higher than that seen in controls (Riemenschneider et al., 2002), with total-τ levels correlating with neuropsychologic, neuroimaging, and prognosis in FTD patients (Borroni et al., 2011); however, in many cases with FTD, CSF total-τ levels can be normal. Phosphorylated-τ elevation is typically seen in AD rather than other neurodegenerative diseases, with one study of FTD finding that a reduced phospho-τ to total-τ ratio predicts TDP-43 pathology in FTD (Hu et al., 2013).

Fluid biomarkers TDP-43 Increased TDP-43 levels have been found in CSF in both FTD and MND cases (Steinacker et al., 2008).

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Kasai et al. (2009) found increased levels in MND particularly early in disease progression, suggesting that CSF TDP-43 may be an early marker of TDP-43 proteinopathies. Patients with C9orf72 or progranulin mutations, where TDP-43 pathology can reliably be predicted in vivo, have been shown to have increased plasma and CSF levels of phosphorylated TDP-43 compared to other FTD patients and normal controls; this same study found plasma levels of total TDP-43 to be decreased in mutation carriers, possibly due to alterations in the ratio of phosphorylated to total TDP-43 in favor of the former (Suarez-Calvet et al., 2013).

PROGRANULIN Serum progranulin levels show considerable promise as a biomarker of underlying progranulin mutations (Schofield et al., 2010). Null mutations have been associated with a fourfold reduction in plasma progranulin levels compared to controls (Ghidoni et al., 2008), with missense mutations resulting in a smaller reduction (Sleegers et al., 2009). Studies of large, mixed, FTD populations are required to determine the sensitivity and specificity of serum progranulin as a predictor of mutations and of the underlying pathology.

NEUROFILAMENT Two studies (Landqvist Waldo et al., 2013; Scherling et al., 2014) have found that elevated CSF NFL levels correlate with FTD disease severity (Scherling et al., 2014). The highest levels were in τ-negative cases and semantic dementia (Landqvist Waldo et al., 2013), where TDP-43 is the predominant pathology. Different levels, and, perhaps, forms of neurofilament may therefore find utility in differentiating the underlying pathology in cases of FTD, in distinguishing AD from non-AD pathology, and for tracking disease in patients with confirmed disease; however, as NFL is elevated in several other conditions—and notably vascular disease—its utility in isolated unselected cases is less clear.

BIOMARKERS OF NEUROINFLAMMATION As with AD, there is considerable interest in inflammation in FTD. Miller et al. (2013) showed increased serum TNF-a in two different conditions strongly associated with TDP-43 pathology, i.e., PPA-S and progranulin mutation carriers. A number of inflammatory biomarkers have been reported to be elevated in FTD. One study has suggested that IL-23 may be specific for FTD associated with τ, while IL-17 may be specific for FTD associated with TDP-43 pathology; this, however, requires further confirmation (Hales and Hu, 2013).

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MANAGEMENT Management of FTD largely focuses on symptomatic measures as, to date, no effective curative pharmacologic treatment exists. The day-to-day care of patients with FTD usually falls to their partners and in some cases their children. In FTD this is associated with its own distinct set of issues, given that patients and their carers are typically under 65 years of age, with many in their 50s. They are usually in full-time employment and have financial commitments, which would normally require this employment to continue. Furthermore, many community-based daycare facilities are developed with older adults with AD in mind and may not be suitable for patients with FTD. Yet, carers of patients with FTD show even greater levels of burden and stress than those caring for sufferers of AD (Mioshi et al., 2013). Early onset dementia programs are therefore essential to provide support, care, and information for patients with FTD and their families. There is clearly a need for nonpharmacologic management programs to target abnormal behaviors in FTD and to date a few have been published in the literature. More recently an occupational therapybased interventional program, TAPS, has shown promise in this area (O’Connor et al., 2015). Language-based programs have also shown promise for patients with semantic dementia and can help patients retain and relearn words commonly used in everyday life (Savage et al., 2013). With regard to pharmacologic treatments for FTD, a number of drugs targeted at symptomatic treatment of cognitive and behavioral features have been reported. Open label studies of anticholinesterase inhibitors have been negative and, in some instances, shown to exacerbate behavioral symptoms. Similarly, memantine was ineffective in a randomized placebo controlled trial (Boxer et al., 2013). Evidence for selective serotonin reuptake inhibitors and antipsychotic therapies is largely anecdotal. Despite this lack of evidence, they are generally considered helpful in the management of mood and behavioral features in individual patients. Disease modifying treatments in FTD have mainly focused on τ pathology. Recent attempts to inhibit τ phosphorylation using lithium and tideglusib have failed and while another study of leucomethylthionium showed promise the results have yet to be published (Medina, 2018). Other treatment methods currently being considered are targeted at reducing GRN levels using nimodipine and histone deacetylase inhibitors (HDACi). In all of these pathology targeted drug trials, CSF and blood biomarkers seem essential for accurate patient selection. Finally, the discovery of the C9orf72 expansion has led to the theory that antisense oligonucleotide therapy may be effective in the treatment of MND-FTD. These therapies are effective in other neurodegenerative

conditions with similar genetic profiles, including Huntington’s disease, and show activity against the toxic RNA effects seen in the C9orf72 expansion (Riboldi et al., 2014). Su and colleagues capitalized on the potential pathologic mechanism of non-ATG translation, which results in “C9RAN” proteins, to show that small molecules may be useful in the treatment of MND and FTD C9orf72 disease (Su et al., 2014). Pharmacologic therapies from MND are also relevant to FTD given the overlap between the conditions, although evidence for either symptomatic or disease altering interventions are also lacking in MND-FTD. To date the antiglutamate agent riluzole is the only approved therapy for treatment of MND, with results from two randomized control trials showing a modest impact on length of survival (6–8 months). Its efficacy in FTD-MND, however, has not been evaluated. Other compounds, including ceftriaxone and dexpramipexole, have been used in clinical trials in MND and showed encouraging results at stage II but unfortunately failed to show efficacy at stage III (Cudkowicz et al., 2013, 2014). It is possible that the therapeutic window for effective treatment may have been missed in these trials as included patients usually have well-established disease, which is in part due to diagnostic delay. It has been suggested that the clinical heterogeneity of MND is a confounding factor in the failure of these trials and perhaps better characterization of patients, based on genotype and phenotype, may prove a more reliable method of enrolment for future trials. Stem cell therapies are emerging as potential disease modulating therapies with Phase I trials demonstrating safety in the MND population (Mazzini et al., 2008, 2010). A variety of methodological approaches are suggested and remain to be validated in randomized controlled trials. A major drawback to this potential therapy is the need for invasive surgical methods. Turning next to immunologic therapies, results are currently awaited from a recent phase III anti-Nogo A study. Nogo A is one of three isoforms of the Nogo protein, which acts as a neurite outgrowth inhibitor and is encoded by the RTN4 gene. Nogo A is upregulated in MND and associated with poor recovery in spinal cord injuries whereas in animal models, antibodies to Nogo A have been shown to enhance axonal regeneration (Pernet and Schwab, 2012).

CONCLUSIONS AND FUTURE DIRECTIONS In summary, the last few decades have seen rapid advances in our understanding of FTD encompassing clinical, neuroimaging, genetic, and pathologic fields with hopefully even more exciting discoveries on the horizon. Better awareness of FTD, together with the

FRONTOTEMPORAL DEMENTIA development of diagnostic criteria, has facilitated earlier diagnosis to ensure that patients have timely access to care and support, although FTD is still poorly recognized in nonspecialist settings. The identification of the C9orf72 expansion has challenged the concept of MND and FTD as single disease entities by explaining the genetic link between the conditions and provides a platform to study the complex underlying biologic mechanisms at play in these conditions. Future developments are likely to lead to improved management and decision-making strategies. Global collaborative efforts are essential to better delineate the underlying molecular pathogenesis of these diseases, with a focus on translational research to identify neuroprotective agents.

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